Dosing regimen associated with sustained release paliperidone injectable formulations

Abstract

To provide a method for treating a psychotic patient in need of treatment with a long-acting injectable paliperidone palmitate formulation.SOLUTION: 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, comprising administering a second dose of the paliperidone palmitate sustained release injectable suspension to the deltoid or gluteal muscle of the patient up to two weeks before or three weeks after a time point that is six months after administration of the first dose, wherein there are no intervening doses of paliperidone palmitate between the first dose and the second dose.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application is a continuation of U.S. Provisional Patent Application No. 63 / 119,388, filed November 30, 2020. No. 6,239,999, filed on Oct. 1, 2003, the disclosure of which is incorporated herein by reference.

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

[0003] BACKGROUND OF THE INVENTION Antipsychotic medications are used to treat schizophrenia, schizoaffective disorder, and schizophreniform disorders. Antipsychotic drugs were first introduced in the mid-1950s. These classic or first generation drugs are usually effective in controlling the positive symptoms of schizophrenia. but are less effective in alleviating negative symptoms or cognitive impairment associated with the disease Atypical or second-generation antipsychotics, typified by risperidone and olanzapine Developed in the 1990s, the drug is used to treat the positive and negative symptoms commonly associated with schizophrenia. It is characterized by its effectiveness against both.

[0004] Paliperidone palmitate is a second-generation atypical antipsychotic with a characteristic dopamine D Monoaminergic receptor agonists with 2 and serotonin (5-hydroxytryptamine type 2A) antagonistic properties Paliperidone (9-hydroxy-risperidone) palmitate ester, a vasopressin antagonist Paliperidone (9-OH risperidone) is the major active metabolite of risperidone. Extended release (ER) osmotic controlled release oral delivery Paliperidone (orthotropic oral delivery, OROS) is available as a tablet for the treatment of schizophrenia. It is sold in the United States for the treatment and maintenance of symptoms.

[0005] Paliperidone palmitate is used to treat schizophrenia and other related conditions that are typically treated with antipsychotics. Long-acting, intramuscularly (IM) injectable aqueous naphthalene for the treatment of chronic diseases It has been developed as a suspension. Due to its very low water solubility, Which paliperidone esters are hydrolyzed to paliperidone before becoming available in the systemic circulation? It dissolves slowly after intramuscular injection.

[0006] Many patients with psychiatric disorders achieve symptom stability with available oral antipsychotic medications. However, up to 75% have difficulty complying with a daily oral treatment regimen; Adherence problems are often associated with worsening symptoms, suboptimal treatment, and Response, frequent relapses and rehospitalizations, and benefit from rehabilitation and psychosocial therapy Paliperidone palmitate injection once a month provides sustained relief of paliperidone. It has been developed to provide plasma concentrations that may greatly enhance dosing compliance. Paliperidone palmitate formulated as an aqueous nanosuspension is disclosed in U.S. Pat. Nos. 77,843 and 6,555,544, each of which is incorporated by reference. In addition, paliperidone palmitate for treating a patient is also included. The administration regimen is described in U.S. Patent Nos. 9,439,906 and 10,143,693. No. 6,239,999, 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 drug that is used by adults in many countries. Paliperidone palmitate once-monthly is approved for the treatment of schizophrenia in Japan. The efficacy and tolerability profile have been demonstrated in clinical trials totaling over 3,800 patients. Patients who initially responded to paliperidone palmitate for acute exacerbations of symptoms should be given monthly Patients who continued treatment with paliperidone palmitate were randomized to placebo. The risk of recurrence was approximately four times lower than in patients with steroid use. It provides a long dosing interval, with the injection administered once every three months. This sustained dosing interval is longer than previously thought. However, there is expected to be less opportunity for non-adherence than with the long-acting injectable formulations available today. Subtherapeutic plasma concentrations and their associated negative consequences in patients with schizophrenia and consequently reduce the risk of recurrence.

[0008] Paliperidone is available in three formulations: an oral sustained-release formulation (INVEGA®); ) extended-release [ER] tablets, INVEGA® prolonged-release [ER] tablets, and two long-acting injectables. , LAI) formulation (paliperidone palmitate 1-month injection [INVEGA SUSTEN NA® or XEPLION®)], and paliperidone palmitate 3 Monthly injection [INVEGA TRINZA® or TREVICTA® )]) are currently available. In order to further improve the efficacy of paliperidone palmitate, the drug was administered once every six months (paliperidone palmitate 6 months). Another paliperidone palmitate product intended for monthly injection has been developed.

[0009] Patients who do not take their medication regularly suffer many consequences, most notably relapse of schizophrenia. For oral antipsychotics, an interval of just one day between doses may reduce the risk of rehospitalization. This typically results in worsening psychiatric comorbidities, loss of employment, and interruption of education. The biological consequences are neurotransmitters, especially in the frontal lobes. Relapse of functional schizophrenia is associated with a loss of synaptic plasticity. This is associated with pruning at the level of the ventricle junction. Overall, this is accompanied by an enlargement of the ventricles. These changes can be measured radiologically by widespread shrinkage of the gray matter of the brain. can be seen on CT / MRI scans of the brain. Each subsequent relapse leads to further damage to the brain. Progressive changes are typically observed. Currently, there is no known cure for schizophrenia. The only proven way to treat the disease is with antipsychotic medication along with social and behavioral interventions. The strongest predictor of relapse in schizophrenia is antipsychotic adherence. be.

[0010] Paliperidone palmitate products intended to be given once every 6 months should be given in doses of exactly 6 This presents a challenge for patients remembering to come in for treatment at the month point. This is compounded by the fact that the length of a month varies between 28 and 31 days. It is intended to be given by a medical professional and not self-administered, so patients should not go to the clinic Allowing patients to have the flexibility to schedule their visit and receive their injections is an important consideration. Most other antipsychotic regimens (oral and LAI) typically: It is given over a monthly cycle and patients receive either prescription refills or injections. The 6-month dosing interval poses unique challenges to ensure compliance. Present the topic.

[0011] Patients may also miss doses of medication, resulting in missed doses of their regularly scheduled medication. The dosing regimen should be restarted for patients who have missed doses.

[0012] Moreover, weight gain is a very common phenomenon in the treatment of patients requiring antipsychotic medication. Patients with schizophrenia or schizoaffective disorder or any other psychotic disorder During long-term treatment with antipsychotics in adults, obesity and other cardiovascular risk factors increase, It has a significant negative impact on long-term morbidity and even mortality in patients with severe mental disorders. Researchers also noted the risk of treatment side effects, such as weight gain, especially in young patients in the early stages of the disease. They face stigma and a reduced quality of life due to their weight gain. This will allow those patients to maintain their social lives, reduce stigma and improve quality of life. Either weight loss or stabilization of current weight can help reduce risk. For patients requiring long-term symptom protection treated with periperidone or paliperidone, It would be beneficial.

[0013] (Summary of the Invention) In one embodiment, the present disclosure provides a first formulation of a paliperidone palmitate extended release injectable suspension. Patients who require paliperidone palmitate and have been receiving a 1. A method for administering paliperidone phosphate, the method comprising administering the first dose to a patient six months after the first dose. Paliperidone palmitate sustained-release injectable suspension was administered up to 2 weeks before or 3 weeks after the time point. and administering a second dose of the suspension to the patient's deltoid or gluteal muscles, wherein the first and second doses are wherein there is no intervening dose of paliperidone palmitate between the doses.

[0014] In other embodiments, the present disclosure provides a method for treating a patient who misses their regularly scheduled medication dose. The resumption dosing regimen is based on the time elapsed since the patient's last dose. For example, the present disclosure provides a first paliperidone palmitate sustained-release injectable suspension (first The first dose of paliperidone palmitate (a suspension of paliperidone palmitate) was administered. 1. A method for administering paliperidone palmitate to a patient, the method comprising: More than 6 months and 3 weeks after administration of the first dose of the first suspension, but more than 8 months after administration of the first dose of the first suspension At a time less than one month later, a second paliperidone palmitate extended-release injectable suspension (second administering a loading dose of a second suspension to the patient's deltoid muscle; At approximately 1 month (± 7 days) after administration of the first suspension, a maintenance dose of the first suspension is administered to the patient in the deltoid or and administering the compound to the gluteal muscle.

[0015] Other reinstatement regimens include the first paliperidone palmitate extended-release injectable suspension (first The first dose of paliperidone palmitate (a suspension of paliperidone palmitate) was administered. The method includes administering paliperidone palmitate to a patient having a first A second dose of palmitic acid pariperi was administered 8 to 11 months after the first dose of the suspension. Paliperidone Palmitate 156 mg Sustained-Release Injectable Suspension (Secondary Suspension) administering a first re-loading dose of the second suspension to the deltoid muscle of the patient; Approximately 8 days (± 4 days) after the dose was administered, a second suspension containing 156 mg of palmitic acid palmitate was administered. administering a second loading dose of riperidone to the patient's deltoid muscle and administering a second loading dose of the second suspension. Approximately 1 month (±7 days) after administration of the loading dose of the first suspension, approximately 1 month (±7 days) after administration of the maintenance dose of the first suspension 0.92 mg to approximately 1560 mg of paliperidone palmitate is administered into the patient's deltoid or gluteal muscles. It involves doing something.

[0016] Other reinstatement regimens include the first paliperidone palmitate extended-release injectable suspension (first The first dose of paliperidone palmitate (a suspension of paliperidone palmitate) was administered. The method comprises administering paliperidone palmitate to a patient having: (1) More than 11 months after administration of the first dose of the first suspension, Paliperidone palmitate 234 mg of extended-release injectable suspension (second suspension) (2) administering a first resumption loading dose of the second suspension to the patient's deltoid muscle; and Approximately 8 days (± 4 days) after the loading dose, a second suspension of 156 mg palmitate (3) administering a second loading dose of paliperidone acid to the patient's deltoid muscle; and Approximately 1 month (±7 days) after administration of the loading dose, 39 mg to approximately 234 mg of the second suspension was administered. The first restart maintenance dose of 1 mg of paliperidone palmitate is administered to the patient in the deltoid or gluteal muscle. and (4) approximately 1 month (± 7 days) after administration of the first resumption maintenance dose of the second suspension. Then, a second suspension of about 39 mg to about 234 mg of paliperidone palmitate is administered. (5) administering a second suspension to the patient's deltoid or gluteal muscles; and Approximately 1 month (±7 days) after administration of the maintenance dose, approximately 39 mg to approximately 234 mg of the second suspension A third restart maintenance dose of 1 mg of paliperidone palmitate is administered to the patient in the deltoid or gluteal muscle. and (6) approximately 1 month (± 7 days) after administration of the third resumption maintenance dose of the second suspension. After that, a maintenance dose of about 1092 mg to about 1560 mg of palmitic acid paraffinate from the first suspension is administered. and administering riboflavin to the patient's deltoid or gluteal muscles. Additional restart maintenance doses are administered in the first may be administered before a maintenance dose of the suspension (e.g., a fourth restart maintenance dose, a fifth restart maintenance dose, In certain embodiments, the resumption maintenance dose of paliperidone palmitate is about 156 to approximately 234 mg.

[0017] The present disclosure also provides pulsed pulse therapy at either one-month intervals (PP1M) or three-month intervals (PP3M). To stabilize or improve the weight of patients who have been treated with paliperidone mitate extended-release injectable suspension 1. A method of reducing PP1M or PP3M comprising administering a final dose of PP1M or PP3M, and then Paliperidone palmitate sustained-release injectable suspension with a 6-month dosing interval (PP6M) and administering an initial dose of the solution. [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 in this invention is best understood in connection with the accompanying examples, which form a part of this disclosure. The present invention will be more readily understood by reference to the following detailed description, which is to be construed as a The present invention relates to the specific formulations, methods, or methods described and / or illustrated herein. The parameters are not limited to the above, and the terminology used herein is given by way of example only. are for the purpose of describing specific embodiments only and are not intended to limit the claimed invention. It should be understood that this is not intended to

[0020] When values ​​are expressed as approximations by use of the descriptors "about" or "substantially," It will be understood that each specific value forms another embodiment. The use of "substantially" will vary depending on the desired properties sought to be obtained by the disclosed subject matter. Indicates approximations that may vary, based on their function and the specific context in which they are used. should be interpreted.

[0021] Certain features of the invention are described herein for clarity in the context of separate embodiments. It will be appreciated that certain features may also be provided in combination in a single embodiment. That is, unless expressly incompatible or excluded, each individual embodiment: Any other combinations are considered compatible and such combinations are considered separate embodiments. Conversely, it is contemplated that the present invention, which is described for brevity in the context of a single embodiment, The different features may be provided separately or in any subcombination.

[0022] Where present, all ranges are inclusive and combinable. For example, "1 to When listing a range of "1 to 5", the listed ranges are "1 to 4", "1 to 3", "1 to 2", "1 to 5 ... ranges such as "~2 and 4~5" and "1~3 and 5" should be interpreted as including ranges in an optional manner. In addition, if a list of alternatives is explicitly provided, such list also For example, if a range of "1 to 5" is stated, the embodiment may include embodiments in which any of the ranges may be excluded. If so, such statement shall not be construed as a circumstance in which any of 1, 2, 3, 4, or 5 is excluded. Therefore, the description "1 to 5" can be interpreted as "1 and 3 to 5, but , 2 is not included" or simply "2 is not included".

[0023] As used herein, "PP1M" refers to palmitoyl palmitate in an amount suitable for administration between doses of approximately one month. Paliperidone palmitate extended release injectable suspension with paliperidone palmitate or other This refers to a type of formulation. Commercially available examples include INVEGA SUSTENNA® or XEPLION®. See also Patent No. 9,439,906.

[0024] As used herein, "PP3M" refers to palmitoyltransferase in an amount suitable for an administration interval of approximately 3 months. Paliperidone palmitate extended release injectable suspension with paliperidone palmitate or other Commercially available examples include INVEGA TRINZA® and TREVICTA® is a registered trademark of U.S. Pat. No. 6,429,493, which is incorporated herein by reference. See also Patent No. 10,143,693.

[0025] As used herein, "PP6M" refers to palmitoyltransferase in an amount suitable for an administration interval of approximately 6 months. Paliperidone palmitate extended release injectable suspension with paliperidone palmitate or other This refers to a type of formulation.

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

[0027] PP6M is typically a PP1M (e.g., INVEGA SUSTENNA 156 mg or about 23 mg for several months, in certain embodiments for at least 4 months. Administered to patients who have been adequately treated with a PP1M dose of 4 mg paliperidone palmitate It is further recommended that the last two doses of PP1M be at the same dosage strength as before the initiation of PP6M. Alternatively, PP6M may be replaced by PP3M (e.g., INVEGA TRINZA (registered trademark)). Patients who have been adequately treated with at least one 3-month cycle of A PP3M dose of about 546 mg or about 819 mg of paliperidone palmitate is administered.

[0028] PP6M typically contains about 1000 mg to about 1600 mg of paliperide palmitate. It is available in a range of doses to provide sustained therapeutic concentrations of paliperidone over a 6-month dosing interval. Preferably, PP6M provides about 1092 mg or about 1560 mg palmitate. Paliperidone is provided in a dosage strength of 100mg / mL. The formulation is hydrolyzed to the active moiety, paliperidone. These resulted in dose strengths of approximately 700 mg equivalent or approximately 1000 mg equivalent of paliperidone, respectively. do.

[0029] PP6M is preferably in a 700 mg equivalent (3.5 mL) or 1000 mg equivalent (5 mL) 0 mL) paliperidone (1092 mg or 1560 mg of paliperidone palmitate, respectively) as peridon) (plunger stopper, plunger rod, and tip cap (bromo butyl rubber), a backstop, and a needle, preferably thin-walled 20 gauge (G), 1 1 / 2 Pre-filled syringes (with 1 / 4" safety needle) with either cyclic olefin copolymers).

[0030] PP6M is intended for intramuscular use. It is not recommended to administer it by any other route. Care should be taken to prevent inadvertent intravascular injection. The dose is preferably administered as a single For example, split injections may alter the release profile. If necessary, the injection is preferably administered slowly deep into the patient's muscles, particularly the deltoid or gluteal muscles. Preferably, PP6M is administered into the gluteal muscle, taking into account the volume of injection.

[0031] Intramuscular injection Typically, regardless of patient weight, PP6M is used in thin-walled syringes, e.g., 20 gauge. The drug is administered intramuscularly into the deltoid or gluteal muscles using a gauge, 1 1 / 2 inch needle. To the extent that it is administered into the deltoid muscle, paliperidone palmitate typically penetrates the center of the deltoid muscle. , preferably alternating between the two deltoid muscles per injection (i.e., opposite (The deltoid muscle will be used at the next scheduled administration interval.) For PP6M, the gluteal intramuscular injection will be For example, PP6M can be administered to the upper outer quadrant of the gluteal muscle. Injections should be alternated between two gluteal muscles per injection (i.e., contralateral It is also preferred that the gluteal muscle be used at the next scheduled administration interval.

[0032] Incomplete administration PP6M is typically a highly concentrated product. As a result, important considerations are Ensure complete suspension / resuspension of the product before administration. To achieve uniform dispersion of the suspension, the syringe is shaken and / or mechanically agitated. For example, the syringe should preferably be held with the syringe tip cap facing up for at least 15 seconds. A short rest period is allowed, and then the syringe is shaken again for a further 15 seconds. It may be, and preferably is, shaken again to ensure resuspension and to prevent the needle from slipping during injection. To avoid clogging, injections should preferably be performed immediately or within 5 minutes of the final shaking. cormorant.

[0033] Due to the slow release characteristics of PP6M, this product provides an immediate transition to oral LAI antipsychotic therapy. PP6M is not intended for use in patients transitioning to It is used in patients who are already adequately treated with either PP1M or PP3M at the start. The determination of appropriate treatment is typically made by the prescribing clinician. Typically, PP6M administration is followed by: A) PP1M for at least 4 months; After one month of adequate treatment (e.g., INVEGA SUSTENNA®) or B) a PP3M (e.g., INVEGA TRINZA®) dose is appropriate PP6M was started 3 months after the established treatment. PP6M was started 1 month after the last PP1M injection. (±7 days) or 3 months (±14 days) after the last PP3M injection.

[0034] After the first PP6M injection, PP6M should be administered every 6 months. In such cases, paliperidone palmitate may be administered at a dose of 1 mg / kg based on individual patient tolerability and / or efficacy. The dose can be adjusted every 6 months in increments within the range of 0.92mg to 1560mg. Typically, the dosage is about 1092 mg or about 1560 mg of palmitic acid pariperidin. Due to the long-acting nature of PP6M, patient response to the adjusted dose may vary. It may not appear for several months.

[0035] Administration period As described herein, non-adherence can be a symptom of mental illness, particularly when a person is not consulting a medical practitioner or caregiver. A major issue in the treatment of patients with schizophrenia is that they often abruptly discontinue their medication without any treatment. Lack of adherence has been identified as the strongest predictor of relapse, which , typically resulting in worsening psychiatric comorbidities, loss of employment, interruption of education, and impaired family relationships. For oral antipsychotics, just a one-day gap in dosing doubles the risk of rehospitalization. Long-acting injectable (LAI) antipsychotics address this issue and may increase non-adherence. It was developed to ensure timely intervention for chronic patients to prevent relapse and hospitalization.

[0036] However, a commonly encountered difficulty in clinical practice is that subjects are often on LAI antipsychotics. The only downside is that you will need to return to the clinic on a specific date after receiving your previous maintenance injection. Having a window in which a drug can be administered gives prescribers, patients, and caregivers greater flexibility. This window is often prescribed by a medical professional and / or or set by a regulatory body.

[0037] Previously, for PP1M, the target injection date (the planned injection date based on the administration interval) was ±1 A dosing window of 12 weeks was established. For PP3M, this window was set at the target injection date. The range was extended to ±2 weeks, up to 2 weeks before the target injection date of PP6M and up to It has been found that a dosing window of up to three weeks can be used, providing further dosing flexibility. was done.

[0038] Dosing recommendations have historically targeted paliperidone plasma concentrations above a threshold of 7.5 ng / mL. This threshold is determined by the activity of 60% of central dopamine type 2 (D2) receptors. Although receptor occupancy is associated with the rate of receptor occupancy, a range of 60% to 80% is considered satisfactory. It is believed to be necessary for the antipsychotic response. As reflected in the Examples section (see Example 7). To assess the median time to recurrence and the median paliperidone concentration, a simulation was performed. The relationship between the median plasma paliperidone concentration and the point at which the median value was less than 7.5 ng / mL was evaluated. The time point at which the median value decreased to 7.5 ng / mL and the median time to recurrence, i.e., the time Half of the subjects experienced a relapse, while the other half either relapsed later or did not relapse during the study. A clear delay lasting weeks to months was observed between the time of treatment and the time of treatment. The response was longer than expected based on the 7.5 ng / mL threshold, and the risk of relapse was It appears that the protection window can be further sustained in the positive direction.

[0039] In one embodiment, the maximum target injection date of PP6M (i.e., the planned 6-month time point) A dosing window of up to two weeks before and up to three weeks after is used. has received a first dose of paliperidone palmitate extended-release injectable suspension, Paliperidone palmitate is administered to patients who require it. 2. A method for administering a first dose of steroids to a subject, comprising administering a first dose of steroids to a subject up to two weeks before or three weeks after the time point six months after administration of the first dose. A second dose of paliperidone palmitate extended-release injectable suspension was administered to the patient within 1 week. and administering the dose to the deltoid or gluteal muscles, preferably the gluteal muscles, between the first and second doses. The first and second doses are administered without an intervening dose of paliperidone palmitate. The doses are those in the sequence of the described method, but not necessarily the exact first dose administered to the patient. It should be appreciated that this does not refer to the first (initial) or second dose.

[0040] Unless otherwise indicated, as used herein, "month" refers to a month in the Gregorian calendar. The length can be as short as 28 days (e.g., February) or as long as 31 days (e.g., October). It may vary to 29, 30, or 31 days. The six-month time point reflects six consecutive calendar months. As set forth herein, the specific testing reflected in the examples, including simulations, It was based on 30 days used for a month. A "week" refers to seven days.

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

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

[0043] Typically, the plasma concentration of paliperidone in the patient is about 5 to about 5% upon administration of the second dose. 0 ng / mL, or about 10 to about 40 ng / mL when the first dose is administered. When the dose of paliperidone palmitate in patients is 1092 mg, The plasma concentration of riboflavin 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. ng / mL. 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 upon administration of the second dose. or about 20 to about 30 ng / mL. In this context, "the time of the second dose" refers to the time of the first dose. This refers to the concentration level immediately before the dose of 2, typically C トラフ Represents a value.

[0044] In other embodiments, the plasma concentration of paliperidone in the patient is about 10 to 20% after administration of the second dose. about 150 ng / mL, 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, In some cases, the plasma concentration of paliperidone in the patient is about 10 to about 10 after administration of the second dose. The first dose is 156 mg / mL, or a peak of about 25 ng / mL, or about 50 to about 90 ng / mL. 0 mg of paliperidone palmitate, the paliperidone plasma concentration in the patient After administration of the second dose, about 35 to about 145 ng / mL, or about 70 to about 110 ng / mL Reach a peak.

[0045] In certain embodiments, the PP3M and PP6M may have the same formulation. In terms of morphology, the pharmacokinetic properties of PP6M are similar to those of PP3M. Considering the larger amount of drug and longer administration frequency, higher peaks and lower troughs are expected. As shown in Example 6, absolute drug plasma concentrations are It was lower for PP3M at the target interval than for PP6M at the target interval. Given that M established a ±2-week dosing window around the target injection date, Positively widening the dosing window for formulations that result in lower drug plasma concentrations at intervals However, as reflected herein, the therapeutic effect was not suggested to be due to the pharmacokinetics of The effect is longer than predicted based on pharmacokinetic data, and therefore the dosing window is positive. It has been found that this allows the device to be more oriented.

[0046] Missing dose Patients receiving LAI antipsychotics return to their healthcare provider periodically to receive injections of the drug. The timing of their administration is typically carefully prescribed. As will be seen, for any given antipsychotic, the optimal dosing cycle may be determined without regard to any adverse effects. The recommended dosage window (±) is within which these drugs can be tolerated without side effects or loss of efficacy. In the present disclosure, after the initial dose of PP6M, PP6M is administered every six months. Skipping doses of PP6M should be avoided, but the prescribed dosing window should be maintained. Injections given within the 24-hour period will not be considered missed doses. Based on patient tolerance and / or efficacy, 1092 mg to 1560 mg of palmitic acid palmitate Dose adjustments between riperidone dose levels may occur every 6 months.

[0047] However, despite this, it is possible that schizophrenic patients may become non-compliant at some point during their illness. Therefore, based on population pharmacokinetic simulations, Guidelines are provided for skipping a dose of PP6M beyond the dosing window.

[0048] The present disclosure provides a method for preventing a patient from undergoing treatment with PP6M if the patient becomes fully or partially non-compliant. Administration of PP6M initially inhibits PP1M / PP3 This depends on the patient being stabilized on M, so this may require the patient to start anew. In addition, the therapeutic effect will be greater than the expected effect based on pharmacokinetic data. It was found that the effect was longer than that of PP6M, so patients who received at least one PP6M injection , and are expected to remain relapse-free for a longer period. This is true even in the setting of non-adherence. Provides a positive effect of PP6M on preventing relapse.

[0049] The present disclosure relates to patients who miss their regularly scheduled medication doses, i.e., Provide a restart dosing regimen for patients who are outside of the dosing window, and the regimen In some embodiments, the missed dose depends on the time elapsed since the last dose. It may range from 6 months and 3 weeks after injection, but not exceeding 7-9 months, for example, not exceeding 8 months.

[0050] For example, as long as the administration window is up to two weeks before and up to three weeks after the target injection date, The present disclosure relates to a first paliperidone palmitate sustained-release injectable suspension (first suspension). Patients who have received the first dose of paliperidone palmitate and require administration of paliperidone palmitate should be given the first dose of paliperidone palmitate. A method for administering paliperidone lumitate, comprising administering a first dose of a first suspension. more than 6 months and 3 weeks after administration but less than 7 to 9 months after administration of the first dose of the first suspension; For example, at less than 8 months, a second paliperidone palmitate sustained-release injectable suspension may be administered. administering a resumption loading dose of the second suspension to the patient's deltoid muscle; and Approximately 1 month (±7 days) after administration of the loading dose, patients were administered a maintenance dose of the first suspension. and administering to the deltoid or gluteal muscles of a second The loading dose of the suspension and the maintenance dose of the first suspension were determined based on the first dose as shown in Table 1 below. and the administration of the first suspension is preferably based on the patient's Administration in the gluteal muscle.

[0051] [Table 1]

[0052] To the extent that a different dosing window is prescribed, the same restart dosing regimen as above may be implemented. However, it can be adjusted based on the outer delivery window parameters. Resuscitation of the second suspension was performed up to 1 week before and up to 2 weeks after the target injection date. The dose is administered more than 6 months and 2 weeks after administration of the first dose of the first suspension, but The first dose is administered at a time point that is less than 7 to 9 months, for example, less than 8 months, after administration of the first dose.

[0053] Other restart regimens include reinjecting the missed dose 7 to 9 months and 10 to 14 months after the last injection. For example, the present disclosure provides a first paliperidone palmitate sustained-release injectable suspension ( The first dose of paliperidone palmitate (first suspension) has been administered. administering paliperidone palmitate to a patient having a first suspension of the first suspension. 7 to 9 months after administration of the dose, including, for example, 8 months up to 10 to 14 months, for example, up to 1 month At the one-month inclusion time point, a second paliperidone palmitate sustained-release injectable suspension (second A first loading dose of 156 mg of paliperidone palmitate (suspension) was administered to the patient's deltoid muscle. and approximately 8 days (± 4 days) after administration of the first loading dose of the second suspension. ) received a second loading dose of 156 mg of paliperidone palmitate in a second suspension. and administering the second loading dose of the second suspension to the deltoid muscle of the patient approximately 1 month after administration of the second loading dose of the second suspension. After 1 month (±7 days), a maintenance dose of about 1092 mg to about 1560 mg palmitoylureas of the first suspension is administered. and administering paliperidone phosphate to the patient's deltoid or gluteal muscle. The first dose of the first suspension is about 1092 mg of paliperidone palmitate, and the second dose of the first suspension is about 1092 mg of paliperidone palmitate. The maintenance dose of suspension 1 is approximately 1092 mg of paliperidone palmitate. In the form, 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 first administration of the suspension is to the patient's gluteal muscles.

[0054] Other restart regimens are based on doses skipped >10–14 months after the last injection. For example, The present disclosure provides a first paliperidone palmitate sustained-release injectable suspension (first suspension). In patients requiring administration of paliperidone palmitate who have received a first dose of (1) administering a first dose of a first suspension; If a second paliperidone palmitate dose is administered more than 10 to 14 months after administration, e.g., more than 11 months after administration, Paliperidone palmitate 234 mg sustained-release injectable suspension (second suspension) (2) administering a first loading dose of a second suspension to the deltoid muscle of the patient; Approximately 8 days (± 4 days) after the loading dose, a second suspension of 156 mg palmitic acid (3) administering a second resumption loading dose of paliperidone to the patient's deltoid muscle; and Approximately 1 month (±7 days) after administration of the loading dose, 39 mg of the second suspension was administered to approximately 234 mg of The patient receives a first restart maintenance dose of 100 mg of paliperidone palmitate in the deltoid or gluteal muscles. and (4) approximately 1 month (± 7 days) after administration of the first restart maintenance dose of the second suspension. and a second suspension of about 39 mg to about 234 mg of paliperidone palmitate. (5) administering a maintenance dose to the patient's deltoid or gluteal muscles; and (6) administering a second maintenance dose of the second suspension. Approximately 1 month (±7 days) after administration of the first dose, approximately 39 mg to approximately 234 mg of the second suspension were administered. A third restart maintenance dose of 100 mg of paliperidone palmitate is administered to the patient in the deltoid or gluteal muscles. and (6) approximately 1 month (± 7 days) after administration of the third restart maintenance dose of the second suspension. The first suspension contains a maintenance dose of about 1092 mg to about 1560 mg of palmitic acid pariperidin. and administering the first suspension to the patient's deltoid or gluteal muscles. In one embodiment, the first dose of the first suspension is administered to the gluteal muscle. Paliperidone lumitate, and the maintenance dose of the first suspension is approximately 1092 mg of paliperidone lumitate. In another embodiment, the first dose of the first suspension is about 1560 mg of paliperidone phosphate. mg of paliperidone palmitate, and the maintenance dose of the first suspension is approximately 1560 mg In another embodiment, the second and third suspensions are paliperidone palmitate. The open maintenance dose is the same. An additional reopen maintenance dose is administered 1 hour before the first suspension maintenance dose. May be administered at monthly (±7 day) intervals (e.g., 4th restart maintenance dose, 5th restart maintenance dose, In certain embodiments, the resumption maintenance dose of paliperidone palmitate is about 15 6 to about 234 mg. For any of the restart regimens, the maintenance dose of the first suspension After administration, the first suspension is typically administered at six-month intervals as described herein. will be done.

[0055] In a particular embodiment, the first suspension is PP6M and the second suspension is PP1M. Exemplary restart regimens based on PP1M and PP6M are further disclosed in Example 8. The goal of the restart regimen is to prevent overshoot due to the applied restart regimen. achieve rapid return to paliperidone plasma concentrations similar to those prior to the skipped dose without The method includes administering the doses of the skipped dosing regimen described herein between the listed doses. For example, an intervention dose of paliperidone palmitate between the first dose and the resumption loading dose is contemplated. It should be recognized that this is not an illustration.

[0056] Another aspect of the present disclosure is the prevention of weight gain in a patient population where most treatments cause weight gain. Observation of longer-acting paliperidone palmitate treatment for stabilization or reduction In particular, patients who have been adequately treated with PP1M or PP3M should be treated with PP6M. Transitioning to palliative care while maintaining good pharmacological efficacy and preventing relapse is that lidocaine-induced weight gain can be reduced, stopped, or potentially partially reversed was found.

[0057] As a result, the present disclosure provides a method for treating overweight patients who have been treated with risperidone or paliperidone. and require long-term symptom protection and therefore antipsychotic treatment, but allow continued weight gain. Filling an unmet medical need for patients who cannot tolerate weight gain during long-term treatment Addition increases risk factors for higher morbidity and mortality (e.g., from cardiovascular disease). In addition, weight gain can affect the patient's mobility and functionality, resulting in lifestyle changes. The PP6M formulations and regimens disclosed herein may significantly reduce the quality of other paliperidone or paliperidone palmitate formulations (e.g., PP1M or PP3 weight-neutral or weight-loss treatment for patients while providing the same efficacy compared to This makes treatment possible.

[0058] In one embodiment, the present disclosure provides a method for administering PP1M or PP3M at one-month intervals. Weight of patients who have been treated with paliperidone palmitate sustained-release injectable suspension in either 1. A method for stabilizing or reducing PP1M or PP3M, comprising administering a final dose of PP1M or PP3M. and then paliperidone palmitate extended-release with a 6-month dosing interval (PP6M). and administering an initial dose of the injectable suspension. The patient has been receiving PP for at least 4 months, at least 5 months, or at least 6 months. In another embodiment, the patient is treated with at least one dose at 3-month intervals. have been treated with PP3M for at least two 3-month intervals or at least three 3-month intervals There are.

[0059] In embodiments where the patient is being treated with PP1M, the initial dose of PP6M is It is administered approximately 1 month (± 7 days) after the final dose. If the final dose is about 156 mg paliperidone palmitate, the initial dose of PP6M is: In another embodiment, the final dose of PP1M is about 1092 mg paliperidone palmitate. , approximately 234 mg paliperidone palmitate, the initial dose of PP6M is approximately 156 0mg paliperidone palmitate.

[0060] In embodiments where the patient is being treated with PP3M, the initial dose of PP6M is It is administered approximately 3 months (± 14 days) after the final dose. If the final dose is approximately 546 mg paliperidone palmitate, the initial dose of PP6M is In another embodiment, the final dose of PP3M is about 1092 mg paliperidone palmitate. is approximately 819 mg paliperidone palmitate, the initial dose of PP6M is approximately 15 60mg paliperidone palmitate.

[0061] After the initial dose of PP6M, PP6M is administered at 6-month intervals as described herein. will be done.

[0062] Further analysis of the data showed that overweight patients (body mass index of about 25 and less than about 30) The study showed particular benefit in older adults (aged 18 to 25 years) and younger patients (aged 18 to 25 years).

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

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

[0065] Typically, weight stabilization occurs from the time of transition to PP6M (at the time of the first dose of PP6M). It refers to a BMI change of about -1 to about +1, or about -0.5 to about +0.5. The BMI change is approximately 0. Regarding weight loss, negative weight loss from the time of transition to PP6M The change can be seen as weight loss. Such stabilization or weight loss is due to the PP6M This could occur within approximately 12 months of the transition to

[0066] In another embodiment, the patient's weight is adjusted to 100 mg / kg / day or 100 mg / kg / day at the time of the final dose of PP1M or PP3M. Evaluate or assess at the time of first administration, at a later time point after transition to PP6M, or a combination thereof. is determined.

[0067] Paliperidone palmitate preparations Paliperidone esters contain a racemic mixture of (+)- and (-)-paliperidone. They are antipsychotic drugs that belong to the chemical class of benzisoxazole derivatives, and are No. 5,254,556, which is 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]pyrimidine-9 The structural formula is:

[0068] [ka]

[0069] Paliperidone esters are disclosed in U.S. Patent Nos. 5,254,556 and 6,077,844. 3, both of which are incorporated herein by reference, The injectable formulation may be formulated in an aqueous carrier. It is possible.

[0070] Described in U.S. Pat. No. 9,439,906, which is incorporated herein by reference. Thus, the one-month aqueous formulation contains nanoparticles with an average size of less than about 2,000 nm to about 100 nm. For example, the nanoparticles are a suspension of nanoparticles having a size of about 1600 nm to about 400 nm. or has an average particle size (d50) of about 1400 nm to about 900 nm. d10 is less than about 300 nm to about 600 nm, or less than about 4,400 nm. nm. As used herein, d10: particles having a diameter smaller than this value d50: the proportion of particles with a diameter smaller than this value is 50%. d90: The percentage of particles with a diameter smaller than this value is 90%. can be achieved by techniques known in the art such as sedimentation field flow fractionation, photon correlation spectroscopy, or disk centrifugation. This is the case when measured by the prior art.

[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 a diameter of about 5 μm to about 15 μm, about 3 μm to about 10 μm. The average particle size (d50) is about 50 μm, about 1 μm, or about 5 μm to about 9 μm. 0 μm to about 30 μm, or about 10 μm to about 20 μm. μm, or about 1 μm to about 5 μm.

[0072] In certain embodiments, the 6-month (PP6M) formulation has a particle size of less than about 30 μm to about 1 μm, or about In other embodiments, the particles have an average particle size of about 3 μm to about 25 μm. μm, about 5 μm to about 15 μm, about 3 μm to about 10 μm, or about 5 μm to about 9 μm The diameter (d50) is 60 μm, or about 50 μm, or about 10 μm to about 30 μm. , or about 10 μm to about 20 μm. d10 is about 1 μm to about 15 μm, or 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. Pat. No. 6,555, which is incorporated herein by reference. In some embodiments, the formulation may contain microparticles, surfactants, an agent, a suspending agent, and any agent selected from the group consisting of a preservative, a buffering agent, and a tonicity agent; One or more additional ingredients may be included.

[0074] A useful surface modifier for paliperidone palmitate formulations is one that physically adheres to the surface of the active agent. Suitable surface modifiers are preferred, but are not chemically bonded thereto. Alternatively, the excipients may be selected from known organic and inorganic pharmaceutical excipients. Preferred surface modifiers include polymers, low molecular weight oligomers, natural products, and surfactants. Representative examples of excipients include gelatin, Casein, lecithin (phosphatide), gum arabic, cholesterol, tragacanth, Stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate Late, Cetostearyl Alcohol, Cetomacrogol Emulsifying Wax, Sorbitan Ester, Polyoxyethylene alkyl ethers (e.g., macrogol such as cetomacrogol 1000) Gol ether), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan Fatty acid esters (e.g., commercially available TWEENS™), polyethylene glycol, ... Trioxyethylene stearate, colloidal silicon dioxide, phosphate, dodecyl sulfate Sodium, carboxymethylcellulose calcium, carboxymethylcellulose sodium sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose cellulose, hydroxypropyl methylcellulose phthalate, amorphous cellulose, aluminum silicate Magnesium phosphate, triethanolamine, polyvinyl alcohol hol, PVA), poloxamer, tyloxapol, and polyvinylpyrrolidone (polyvinyl Most of these excipients are manufactured by American Pharmaceuticals. Pharmaceutical Association and The Pharmaceutical Co-published by the Artificial Society of Great Britain, the Handbook of Pharmaceutical Excipients s, the Pharmaceutical Press, 1986. Surface modifying agents are commercially available and / or can be prepared by techniques known in the art. Two or more surface modifying agents may be used in combination.

[0075] Particularly preferred surface modifiers include polyvinylpyrrolidone, tyloxapol, and poloxamer. mers (e.g., ethylene oxide and propylene oxide bridging copolymers available from BASF) PLURONIC™ F68, F108, and F127, which are block copolymers; Poloxamines (e.g., ethyleneoxy groups to ethylenediamine, available from BASF) It is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and propylene oxide. TETRONIC™ 908 (T908), dextran, lecithin, Aeros ol OT™ (AOT) (available from Cytec Industries) dioctyl ester of sodium succinate), DUPONOL™ P (Du sodium lauryl sulfate available from Pont), TRITON™ X-2 00 (Alkylaryl polyether sulfonate available from Rohm and Haas) nate), TWEEN™ 20, 40, 60, and 80 (ICI Speci Polyoxyethylene sorbitan fatty acid esters available from ality Chemicals SPAN™ 20, 40, 60, and 80 (a sorbitan ester of fatty acids) ARLACEL™ 20, 40, 60, and 80 (Hercules s, Inc.), CARBOWAX ( Trademarks) 3550 and 934 (polyethylene glycols available from Union Carbide) recalled), CRODESTA™ F110 (available from Croda Inc. (a mixture of sucrose stearate and sucrose distearate), CRO DESTA™ SL-40 (available from Croda, Inc.), hexyl Decyltrimethylammonium chloride (hexyldecyl trimethyl ammonium chloride, C TAC), bovine serum albumin and SA90HCO(C 18 H 17 CH2(CON(CH 3) CH2(CHOH)4CH2OH)2) has been found to be particularly useful. Suitable surface modifiers include tyloxapol and poloxamer, preferably Pluronic (trademark) F108 and Pluronic (trademark) F68.

[0076] Pluronic™ F108 corresponds to Poloxamer 338 and is a compound of x, y, and z. The average values ​​of HO[CHCHO] are 128, 54, and 128, respectively. x [CH(CH3)CH2O] y [CH2CH2O] z Polyoxyethylene generally conforming to H Other commercially available products of Poloxamer 338 include: The name is Hodag NONIONIC™ 1108-F, available from Hodag; and SYNPERONIC™ PE / F1 available from ICI Americas It's 08.

[0077] The optimal relative amounts of paliperidone palmitate and surface modifier depend on various parameters. The optimum amount of surface modifier will depend, for example, on the particular surface modifier selected, the amount of surface modifier that is present in the micelles, and the amount of surface modifier that is present in the micelles. The formation of the surface modifier may depend on the critical micelle concentration of the surface modifier, the surface area of ​​the antipsychotic drug, etc. The specific surface modifier preferably has a surface area of ​​1 square meter of paliperidone palmitate. Paliperidone palmitate (9-palmitate) is present in an amount of about 0.1 to about 1 mg per tablet. In the case of hydroxyrisperidone, PLURONIC (trade name) was used as a surface modifier. It is preferred to use standard F108, with a relative amount (w / w) of both components of about 6:1. It is suitable.

[0078] The particles of the present invention can be prepared by a process comprising dispersing paliperidone palmitate in a liquid dispersion medium and powdering the paliperidone palmitate. mechanical means to reduce the particle size of the antipsychotic drug to an effective average particle size in the presence of a grinding medium; The particles may be prepared by a method comprising the steps of: applying a surface modifying agent to the particles; Alternatively, the particles can be contacted with a surface modifier after abrasion. Cut.

[0079] A general procedure for preparing the particles described herein is to: (a) prepare a polysaccharide containing palmitate; (b) adding paliperidone palmitate to a liquid medium to obtain a premixed paliperidone. and (c) reducing the particle size to an effective average particle size in the presence of grinding media. and subjecting the premix to mechanical means.

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

[0081] Paliperidone palmitate is then added to the essentially insoluble paliperidone palmitate solution to form the premix. The concentration of paliperidone palmitate in the liquid medium (per weight) The amount (by weight) of the surface modifier selected can vary widely and depends on other factors. The preferred concentration of paliperidone palmitate in the composition is about 0.1 to about 60%. The range is preferably about 0.5 to about 30%, and more preferably about 7% (w / v). For PP1M, approximately 100 mg equivalent of paliperidone per mL, or 1 m It is currently preferred to use a concentration of about 156 mg of paliperidone palmitate per liter. For PP3M, approximately 200 mg equivalent of paliperidone per mL, or It is preferred to use a concentration of about 312 mg of paliperidone palmitate. For paliperidone, approximately 200 mg equivalent per mL, or approximately 312 mg equivalent per mL It is preferred to use a concentration of paliperidone palmitate in mg.

[0082] A more preferred procedure is to pre-treat the granules prior to subjecting them to mechanical means to reduce the effective average particle size. Addition of surface modifier to the mix. Concentration of surface modifier (weight percentage) The amount of the hydroxybenzoate may range from about 0.1% to about 90%, preferably from about 0.5% to about 80%, more preferably from about 0.5% to about 80%. More preferably, it is about 7% (w / v).

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

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

[0085] The grinding media for the particle size reduction step is preferably less than about 3 mm, more preferably about The hard media may be selected from spherical or granular morphologies with an average size of less than 1 mm. Such a medium desirably allows for shorter processing times to provide the particles of the present invention. This reduces the wear on the grinding equipment. The choice is not believed to be important. However, magnesia, zirconium silicate, and Approximately 95% ZrO stabilized with glass grinding media is an acceptable particle size for the preparation of pharmaceutical compositions. Further, polymer beads, stainless steel, titania, alumina, and yttria are also provided. Other media such as about 95% ZrO stabilized with zinc are useful. Approximately 2.5g / cm 3 and stabilized with magnesia and polymer beads. Contains approximately 95% ZrO.

[0086] Wear 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 used for small particles. may be needed.

[0087] The particles typically reduce in size at temperatures that do not significantly degrade the antipsychotic drug. Processing temperatures of less than about 40°C are generally preferred. If necessary, the processing equipment may be equipped with conventional cooling equipment. The method is conventionally performed under ambient temperature conditions and is safe and effective for the grinding process. The process is carried out at pressure.

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

[0089] Aqueous compositions according to the invention advantageously contain suspending agents and buffers, and optionally preservatives and and an isotonicity agent. may function as more than one agent at the same time, for example acting as a preservative and a buffer; It can act as a buffer and an isotonic agent.

[0090] Suitable suspending agents (also called physical stabilizers) for use in aqueous suspensions according to the invention cellulose derivatives, such as methylcellulose and carboxymethylcellulose Sodium and hydroxypropyl methylcellulose, polyvinylpyrrolidone, algin Acid, chitosan, dextran, gelatin, polyethylene glycol, polyoxyethylene and polyoxy-propylene ether. Preferably, carboxymethyl cellulose Sodium is used at a concentration of about 0.5 to about 2%, most preferably about 1% (w / v). can be.

[0091] Preferred surfactants selected from those described for use in aqueous suspensions according to the invention. Suitable wetting agents include polyoxyethylene derivatives of sorbitan esters, such as polysorbates. Polysorbate 20 and Polysorbate 80, lecithin, polyoxyethylene, and polyoxypropyl ethylene ether, sodium deoxycholate. Preferably, polysorbate 20 , about 0.5 to about 3%, more preferably about 0.5 to about 2%, most preferably about 1.1% Used at a concentration of (w / v).

[0092] Suitable buffering agents are salts of weak acids, with sufficient pH to make the dispersion basic from about pH 6.0. Preferably, the pH is in the range of about 6.0 to about 9.0, or about 6. The pH is in the range of about 0 to about 8.0, or about 6.5 to about 7.5. For example, the pH is in 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 in the range of about 8.0 to about 8.5, or about 8.5 to about 9.0. sodium phosphate monohydrate (anhydrous) (typically about 0.9% (w / v)) and sodium dihydrogen phosphate monohydrate The use of a mixture of the buffer (typically about 0.6% (w / v)) is particularly preferred. , making the dispersion isotonic and, in addition, reducing the tendency of the ester suspended therein to aggregate.

[0093] Preservatives include benzoic acid, benzyl alcohol, butylated hydroxyanisole, butylated Hydroxytoluene, chlorobutol, gallates, hydroxybenzoates, EDTA , phenol, chlorocresol, metacresol, benzethonium chloride, millichloride Consisting of still-gamma-picolinium chloride, phenylacetate nitrate, and thimerosal In particular, it is an antimicrobial agent and an antioxidant that can be selected from the group consisting of: (w / v), preferably benzyl alcohol, which may be used at a concentration of up to about 1.5% (w / v). It's a call.

[0094] Isotonic agents include, for example, sodium chloride, dextrose, mannitol, sorbitol, The suspension is conveniently about 0% to about 10% (w / v) isotonic Mannitol may be used at a concentration of about 0% to about 7%, but more preferably, Presumably because the ions help prevent aggregation of the suspended esters, about 1% to about 3% ( The suspension is preferably provided with one or more electrolytes, particularly about 1.5% to about 2% (w / v). Used to make the solution isotonic. In particular, the electrolytes in the buffer act as isotonic agents. .

[0095] A particularly desirable property of an injectable formulation relates to the ease with which it can be administered. In particular, Such injections should be possible in the shortest possible time and with the thinnest possible needle. This must be easily drawn into a syringe (e.g., from a vial) and must be thin enough to This is achieved with the aqueous suspension of the present invention by maintaining a specific viscosity that allows it to be injected through a needle. For example, the PP1M viscosity may be less than about 75 mPa·s, or less than about 60 mPa·s at room temperature. s less than 23G, 1 inch needle or 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 used. For PP6M, a 20G, 1 1 / 2 inch needle is typically used. Used typically.

[0096] Ideally, the aqueous suspensions described in this invention are tolerable so as to keep injection volumes to a minimum. Contains as much paliperidone palmitate as possible and as little other ingredients as possible .

[0097] In particular, for PP3M or PP6M, the composition comprises: (a) about 200 to about 500 mg / mL of paliperidone palmitate, (b) about 2 to about 25 mg / mL of a wetting agent, and (c) about 2 (d) one or more buffering agents at about 0.5 to about 50 mg / mL; and (e) one or more buffering agents at about 25 to about 150 mg / mL. mL of suspending agent; (e) optionally up to about 2% (w / v) of a preservative; and (f) 10 mL of suspending agent; and water in an amount up to 0%. The P3M or PP6M composition has a pH of about 6.0 to about 8.0, preferably about 6.5 to about 7. It has a pH of 5.

[0098] In other embodiments, for PP3M or PP6M, the composition comprises: (a) about 250 to about 4 00 mg / mL of paliperidone palmitate, and (b) about 5 to about 20 mg / mL of a wetting agent. and (c) one or more buffering agents at about 5 to about 25 mg / mL; and (d) one or more buffering agents at about 50 to about 1 (e) optionally, up to about 2% (w / v) of a preservative; (f) water, and quantities made up to 100%.

[0099] In another embodiment, for PP3M or PP6M, the composition comprises: (a) about 280 to about 3 50 mg / mL of paliperidone palmitate, and (b) about 8 to about 12 mg / mL of a wetting agent. and (c) one or more buffering agents at about 5 to about 15 mg / mL; and (d) one or more buffering agents at about 65 to about 8 mg / mL. (e) optionally, up to about 2% (w / v) of a preservative; f) water, qs. to 100%, and

[0100] In certain embodiments, the active ingredient in PP3M or PP6M is paliperide palmitate. In certain embodiments, the inactive hydroxybenzoates in PP3M or PP6M are The active ingredients are polysorbate 20 (approximately 10 mg / mL), polyethylene glycol 4000 (approximately 75 mg / mL), citric acid monohydrate (approximately 7.5 mg / mL), sodium dihydrogen phosphate sodium monohydrate (approximately 6 mg / mL), sodium hydroxide (approximately 5.4 mg / mL), and injection The exemplified PP3M is disclosed in Example 2. The exemplified PP6M is , as disclosed in Example 3.

[0101] In particular, the composition for PP1M comprises, by weight based on the total volume of the composition, (a) about 1% to 5% 0% (w / v) paliperidone palmitate and (b) approximately 0.1% to 5% (w / v) humectant. (c) one or more buffers; and (d) about 0.1% to about 5% (w / v) of a suspension. (e) optionally, up to about 2% (w / v) of a preservative; and (f) up to 100%. and an appropriate amount of water until the composition becomes The composition has a pH of about 6.0 to about 8.0, preferably about 6.5 to about 7.5.

[0102] Composition PP1M preferably contains, by weight based on the total volume of the composition, (a) about 2% to 40% % (w / v) of paliperidone palmitate and (b) about 0.25% to 3% (w / v) of a moisturizer. (c) one or more buffers; and (d) about 0.25% to about 3% (w / v) of (e) optionally, up to about 2% (w / v) of a preservative; and (f) 100% and a quantity of water until the composition is substantially the same as or contains or is essentially consistent with the composition.

[0103] The composition for PP1M more preferably comprises, by weight based on the total volume of the composition: (a) (b) about 3% to 20% (w / v) paliperidone palmitate and (c) about 0.5% to 2% (w (v / v) of a humectant, (c) one or more buffering agents, and (d) about 0.5% to about 2% (w (e) optionally up to about 2% (w / v) of a preservative; and (f) 1 and water in an amount up to 00%.

[0104] Specifically for PP1M, the composition comprises: (a) about 50 to about 250 mg / mL palmitic acid; (b) about 2 to about 25 mg / mL of a wetting agent; and (c) about 2.5 to about 50 mg / mL of a wetting agent. g / mL of one or more buffering agents; and (d) about 5 to about 75 mg / mL of a suspending agent. (e) optionally, up to about 2% (w / v) of a preservative; and (f) appropriate amounts up to 100%. and an amount of water.

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

[0106] In another embodiment, for PP1M, the composition comprises: (a) about 140 to about 180 mg / m L of paliperidone palmitate, (b) about 8 to about 16 mg / mL of a wetting agent, and (c) about (d) about 20 to about 40 mg / mL of one or more buffering agents; (e) optionally up to about 2% (w / v) of a preservative; and (f) 100% and an amount of water in an amount sufficient to provide a solution of 100% by weight of the soluble solids.

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

[0108] Preferably, aqueous suspensions are prepared under sterile conditions and preservatives are not used. Suitable methods for preparing paliperidone lumitate are described in US Pat. No. 6,423,139, which are incorporated herein by reference. This is described in International Publication No. 2006 / 114384.

[0109] A preferred aqueous formulation is a soluble sorbent of polysorbate 20, polyethylene glycol 4000, citric acid, Acid Monohydrate, Disodium Hydrogen Phosphate Anhydrous, Sodium Dihydrogen Phosphate Monohydrate, Hydroxide It contains the following inactive ingredients: sodium, and water for injection.

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

[0111] When administered at 6-month intervals, paliperidone palmitate doses are (mg equivalents), approximately 1092 and 1560 mg of paliperidone palmitate These correspond to approximately 700 and 1000 mg equivalents of paliperidone, respectively. , administering to the patient about 700 mg equivalent to about 1000 mg equivalent of paliperidone or about 1092 mg to about 1092 mg equivalent of paliperidone. Preferably, about 1560 mg of paliperidone palmitate is administered.

[0112] When administered every 3 months, paliperidone palmitate is administered in mg equivalent doses of paliperidone. (mg equivalent), and contains approximately 273, 410, 546, and 819 mg of palmitic acid palmitate. Riperidone is approximately 175, 263, 350, and 525 mg equivalent of paliperidone, respectively. For a 3-month treatment, patients receive approximately 175 mg equivalent to approximately 525 mg equivalent of Paris. Paliperidone or approximately 273 mg to approximately 819 mg of paliperidone palmitate may be administered. preferable.

[0113] When administered at monthly intervals, paliperidone palmitate is administered at mg equivalent doses of paliperidone. (mg equivalent), approximately 39, 78, 117, 156, and 234 mg of palmitic acid Paliperidone acid is administered in doses of approximately 25, 50, 75, 100, and 150 mg equivalents of paliperidone, respectively. For one month of administration, patients receive approximately 25 mg equivalent to approximately 150 mg equivalent. Paliperidone or about 39 mg to about 234 mg of paliperidone palmitate, or about 100 mg equivalent to approximately 150 mg equivalent of paliperidone or approximately 156 mg to approximately 234 mg of palmitate Paliperidone palmitate, e.g., about 156 mg of paliperidone palmitate or about 234 mg of Paliperidone palmitate is preferably administered.

[0114] As used herein, the term "antipsychotic" or "antipsychotic medication" means a Any drug used to reduce or improve psychotic symptoms in patients with psychotic disorders It means drug therapy.

[0115] As used herein, the term "psychiatric patient" refers to a person who is undergoing treatment or experimentation for a "psychiatric disorder." The term "mental illness" refers to a person who is affected by a mental disorder, and is defined by the American Psychiatric Association (APA). Association (APA) Diagnostic and Statistical Manual of Mental Disorders, 5th Edition Those skilled in the art will understand that the terms "DSM-5" and "DSM-6" refer to those provided in the DSM-5 (Dist. Risperidone esters (e.g., paliperidone palmitate) are the only known derivatives of risperidone. It is understood that the drug may be administered to psychiatric patients for use in treating mental disorders. These psychiatric disorders include: Schizophrenia; bipolar disorder; or other medical conditions manifested by psychosis, aggressive behavior, anxiety, or depression As described in DSM-5, schizophrenia refers to conditions characterized by schizophrenia, schizoaffective disorder, and schizophreniform disorders Bipolar disorder is a condition characterized by bipolar disorder, including bipolar disorder I and bipolar disorder II. The DSM is a compilation of the American Psychiatric Association's Task Force on Nomenclature and Statistics. History and Statistics of the American Psychiatric Association It provides a clear explanation for the diagnostic classification. Pathological mental conditions that may be associated with the trait include the following disorders characterized in the DSM: but not limited to: Diagnostic and Statistical Manual of Mental Disorders,Revised,5th E See, e.g., (2013). Those skilled in the art will appreciate alternative nomenclatures for pathological mental conditions. There are nosology, nosology, and classification systems that have contributed to scientific advances in medicine. Examples of pathological mental conditions that can be treated include mild intellectual disability. Harm, moderate intellectual disability, severe intellectual disability, very profound intellectual disability, unspecified intellectual disability severity, autism personality disorder, Rett disorder, childhood disintegrative disorder, Asperger's disorder, and pervasive developmental disorder not otherwise specified , Attention-Deficit / Hyperactivity Disorder (ADH) Combined Type, Attention-Deficit / Hyperactivity Disorder (ADH) Predominantly Inattentive Type, Attention-Deficit / Hyperactivity Disorder (ADH) Disorders: Predominantly impulsive, Attention-Deficit / Hyperactivity Disorder (NOS), Conduct Disorder (Childhood-Onset and Adolescent type, oppositional defiant disorder, unspecified disruptive behavior disorder, isolated aggressive type, conduct disorder, undifferentiated type, Tourette's syndrome, chronic motor or vocal tic disorder, transient tic disorder, tic disorder N OS, alcohol-induced delirium, alcohol-withdrawal delirium, alcohol-induced persistent cognition Alcohol-induced psychotic disorder with delusions, Alcohol-induced psychotic disorder with hallucinations harm, amphetamine or similar sympathomimetic drug intoxication, amphetamine or Sympathomimetic drugs with similar effects include amphetamines or similarly acting drugs, which are associated with delirium and delusions. Sympathomimetic psychosis with hallucinations, amphetamine or similarly acting psychotic drugs Symptom-modifying psychosis, cannabis-induced psychotic disorder with delusions, cannabis-induced with hallucinations Psychotic disorders, cocaine intoxication, cocaine-induced delirium, cocaine-induced psychosis with delusions Sexual disorders, cocaine-induced psychotic disorder with hallucinations, hallucinogen intoxication, hallucinogen Toxic delirium, hallucinogen-induced psychotic disorder with delusions, hallucinogen with delusions Hallucinogen-induced psychotic disorder, hallucinogen-induced mood disorder, hallucinogen-induced anxiety disorder , unspecified hallucinogen-related disorder, inhalation poisoning, inhalation toxic delirium, inhalation-induced persistent Dementia, inhalation-induced psychotic disorder with delusions, inhalation-induced psychosis with hallucinations, inhalation-induced Mood disorders, inhalant-induced anxiety disorder, inhalant-related disorder not otherwise specified, opioid-induced delirium, delirium Opioid-induced psychotic disorder with delirium, opioid-induced delirium, opioid-induced delirium with hallucinations Opioid-induced psychotic disorder, opioid-induced mood disorder, phencyclidine , PCP) or similarly acting arylcyclohexylamine poisoning, phencyclidine PCP or similar arylcyclohexylamine toxicities: delirium, delusions Phencyclidine (PCP) or similarly acting arylcyclohexylamine Phencyclidine (PCP)-induced psychotic disorder, hallucinations, or similar effects Arylcyclohexylamine-induced psychotic disorder, phencyclidine (PCP) or It acts similarly to arylcyclohexylamine mood disorders, such as phencyclidine (PCP). or similarly acting arylcyclohexylamine-induced anxiety disorder, unspecified phenotype Disorders associated with PCP or similarly acting arylcyclohexylamines , sedative, hypnotic, or anxiolytic addiction, sedative, hypnotic, or anxiolytic addiction Delirium, sedative, hypnotic, or anxiolytic withdrawal Delirium, sedative, hypnotic, or anxiolytic withdrawal Drug-induced persistent dementia, sedative-, hypnotic-, or anxiolytic-induced psychotic disorder with delusions Harm, hallucinogenic sedatives, hypnotics, or anxiolytic-induced psychotic disorder, sedatives, hypnotics or anxiolytic-induced mood disorder, sedative, hypnotic, or anxiolytic-induced anxiety disorder , other (or unknown) drug intoxication, other (or unknown) drug-induced delirium, other (or unknown) drugs Drug-induced persistent dementia, other (or unknown) drug-induced psychosis with delusions, other with hallucinations (or unknown) drug-induced psychotic disorder, other (or unknown) drug-induced mood disorder, other (or unknown) Drug-induced anxiety disorder (unspecified or unknown), other (or unknown) drug disorder, obsessive-compulsive disorder, psychotic disorder Post-traumatic stress disorder, generalized anxiety disorder, unspecified anxiety disorder, body dysmorphic disorder, hypochondriasis ( or hypochondriasis), somatization disorder, unspecified somatoform disorder, unspecified somatoform disorder Harm, Intermittent Explosive Disorder, Kleptomania, Pathological Gambling, Pyromania, Trichotillomania, and Impulse Control Disorder (NOS), Schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared mentality Disorder, psychotic disorder due to general medical condition with delusions, psychotic disorder due to general medical condition with hallucinations , Unspecified psychotic disorder, Major depression, Single episode, Severe, No psychotic features, Major depression, Recurrent Bipolar disorder, severe, without psychotic features, mixed, severe, without psychotic features, bipolar disorder Bipolar disorder, mixed, severe, with psychotic features, bipolar disorder, manic, severe, without psychotic features, bipolar Bipolar disorder, manic, severe, with psychotic features; Bipolar disorder, depressive, severe, with psychotic features Bipolar disorder, depression, severe, with psychotic features, bipolar II disorder, unspecified bipolar disorder Harm, personality disorder, paranoia, personality disorder, schizophrenia, personality disorder, schizophrenic, personality disorder These include, but are not limited to, borderline, antisocial, and personality disorders.

[0116] As used herein, the term "therapeutically effective amount" refers to a dose of a compound or compound that is effective for the disease or disorder being treated. the effects in humans sought by researchers, physicians, or other clinicians, including the alleviation of symptoms of harm; "Inactive ingredient" refers to the amount of an active compound or pharmaceutical agent that elicits the desired biological or pharmaceutical response.

[0117] Those skilled in the art of treating diseases will appreciate that the effective amount to be administered for the treatment of the diseases listed above is well known. As an example, the use of paliperidone for the treatment of psychiatric disorders can be determined. An effective amount of don is about 0.01 mg / kg to about 2 mg / kg of body weight per day. For twice-yearly dosing, patients receive approximately 700 mg equivalent to approximately 1000 mg equivalent of paliperidone or It is preferred to administer about 1092 mg to about 1560 mg of paliperidone palmitate. The amount of paliperidone palmitate is determined after the palmitic acid moiety is removed from the ester. Provided in an amount sufficient to provide an equivalent dose of paliperidone (e.g., 1560 mg (equivalent to 1000 mg of paliperidone). Six months of treatment provides patients with approximately 700 mg of Amount equivalent to about 1000 mg of paliperidone or about 1092 mg to about 1560 mg of palmitate It is preferred to administer paliperidone phosphate.

[0118] The following examples are provided to illustrate some of the concepts described within this disclosure. Although the present invention is considered to describe specific embodiments, it is to be understood that the more general embodiments described herein may be used interchangeably. The following non-limiting examples further illustrate the invention and should not be construed as limiting the scope of the invention. Provided for illustration purposes. Unless otherwise specified, PP1M, PP References to Example 1 (PP1M), Example 2 (PP3M), and Example 3 (PP6M) are to Example 1 (PP1M), Example 2 (PP3M), and Example 3 (PP6M). Refers to the formulation described in Example 3 (PP6M).

[0119] Example 1: One-month sustained release formulation (PP1M) Table 2 below shows examples of paliperidone equivalent to 100 mg / mL suitable for intramuscular (IM) injection. Contains a representative 1-month sustained release formulation (PP1M).

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

[0121] PP1M is filled into syringes with different volumes of the bulk suspension equivalent to 100 mg / mL. Pre-filled tablets with dosage strengths ranging from 25 mg equivalents to 150 mg equivalents are obtained by The syringes can be supplied in prefilled syringes. Table 3 lists syringe sizes and nominal fill volumes. Different dosage strengths including:

[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 shows an example of paliperidone equivalent to 200 mg / mL suitable for intramuscular (IM) injection. Contains a representative 3-month sustained release formulation (PP3M).

[0126] [Table 5]

[0127] PP3M is filled into syringes with different volumes of a 200 mg / mL equivalent bulk suspension. Prescription drugs with dosage strengths ranging from 175 mg equivalents to 525 mg equivalents are obtained by It can be provided in a filled syringe. Table 6 lists syringe sizes and nominal fill volumes. Different dosage strengths are shown, including:

[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 shows the equivalent of 200 mg / mL of palmitic acid suitable for intramuscular (IM) injection. Exemplary formulations include 6-month sustained release formulations of peridon (PP6M).

[0132] [Table 8]

[0133] PP6M is filled into syringes with different volumes of a 200 mg / mL equivalent bulk suspension. The dosage strength ranges from 700 mg equivalent to 1000 mg equivalent. It can be provided in pre-filled syringes. Table 9 lists syringe sizes and nominal fills. Different dosage strengths including the product are shown.

[0134] [Table 9]

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

[0136] [Table 10]

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

[0138] Prior to the maintenance phase, some subjects were on oral antipsychotics, injectable risperidone, or previous If a study on PP1M was initiated but not yet stabilized, Patients participated in a transition phase involving 1 to 5 injections. The combination of the transition and maintenance phases was as follows: It is called the period.

[0139] Randomization: 702 subjects were treated with either PP3M (n=224) or PP6M (n=478). Patients were randomized in a 1:2 ratio to one of the treatment groups. Randomization was based on the study center and maintenance dose level (intermediate). The data were stratified by (high or low).

[0140] Primary analysis population for efficacy: Received at least one dose of double-blind study medication Double-blind intent-to-treat (DBT) was defined as all randomized subjects. , DB ITT) analysis set.

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

[0142] Additional analysis population for efficacy: patients who received at least one dose of double-blind study drug and Major protocol violations, i.e., violation of intended study population, treatment assignment error, or The study had no major protocol deviations that could affect efficacy, such as the use of excluded drugs. The per-protocol analysis set was defined as all randomized subjects who completed the study.

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

[0144] Planned sample size: The sample size for the double-blind portion of the study was determined based on the primary endpoint 549 randomized subjects based on a decision to provide at least 80% power for The sample size was determined based on the predicted survival rate (remaining recurrence-free at 12 months) in the PP3M group. The percentage of subjects with ≥ 1 should be 85% and the one-sided significance level should be 2.5%. Taking these assumptions into account, a 1:2 ratio (PP3M:PP6M) was used. Of the 549 randomized subjects, the percentage of subjects remaining relapse-free at 12 months was A 10% non-inferiority margin is required to confirm that PP6M is not worse than PP3M in 80% of cases. It was necessary to demonstrate power.

[0145] Main purpose The primary efficacy objective consisted of a single dose of PP6M (700 or 1000 mg equivalent). The injection cycle consisted of the corresponding dose of PP1M (100 or 150 mg equivalent) or PP3 In subjects with schizophrenia previously stabilized with M (350 or 525 mg equivalent) For the prevention of recurrence of PP3M (350 or 525 mg equivalent), two consecutive injections of PP3M were administered. The goal is to demonstrate that it is more effective than

[0146] Subject and Treatment Information The study enrolled 841 subjects across 20 countries and 126 centers. The 702 subjects were divided into two groups in a 1:2 ratio (224 in PP3M and 478 in PP6M). 702 subjects in the DB ITT population were randomized to one of the following treatment groups: Of these, 23 subjects were excluded from the per-protocol population and included in the per-protocol analysis set. The number of subjects included in the PP3M and PP6M treatment groups was 217 and 462, respectively. In the DB ITT analysis population, 521 (74.2%) of the subjects were Caucasian. Of these, 480 (68.4%) were male. The mean (SD) age was 40.8 (11. 53) years old, with an age range of 18 to 69 years old.

[0147] Of the 702 randomized subjects, 571 (81.3%) subjects experienced a recurrent event or After completing the 12-month double-blind phase, 47 (6.7%) subjects were found to have a recurrent event. The double-blind period was completed by 54 patients (7.7%). It was a case of "object-induced detachment" by the elephant.

[0148] Effectiveness The primary efficacy endpoint was based on 12-month cumulative Kaplan-Meier estimates of survival. Based on the data, the percentage of subjects who were relapse-free at the end of the 12-month double-blind period was used. 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 1 (4.9%) subjects in the PP6M group Thirty-six (7.5%) subjects experienced a recurrent event during the 12-month double-blind phase. Estimated difference between treatment groups (PP6M-PP3M) in the percentage of subjects who remained (95%CI) is -2.9% (-6.8%, 1.1%). Lower limit of the 95% confidence interval is greater than the pre-specified non-inferiority margin of -10%, and therefore PP6M is , and can be declared non-inferior to PP3M (Figure 2).

[0150] In the per-protocol analysis population, 10 (4.6%) subjects in the PP3M group and PP6 Thirty-five subjects (7.6%) in Group M experienced a recurrent event during the double-blind phase. B Similar to the results obtained for the ITT population, the non- relationship between PP6M and PP3M Further confirmation of recessiveness (Figure 3).

[0151] By including data collected during the follow-up period on subjects who withdrew from the double-blind period Supplementary analyses were performed for the primary efficacy analysis. The results are consistent with the primary efficacy analysis. .

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

[0153] safety Overall, 297 / 478 (62.1%) subjects in the PP6M group and 10 / 478 (62.1%) subjects in the PP3M group 131 / 224 patients (58.5%) experienced at least one TEAE during the double-blind phase The most common (≥5%) TEAE during the double-blind period was weight gain (8%) in the PP6M group. 0.4%), injection site pain (7.7%), headache (6.7%), and upper respiratory tract infection (5.0%). In the PP3M group, weight gain (7.6%), nasopharyngitis (5.8%), and headache (5.4%) were observed. there were.

[0154] One patient and one patient were randomly assigned to the open-label (combined transition and maintenance) and double-blind phases, respectively. Three patients died. Of the three deaths during the double-blind phase, one (0.2%) occurred in the PP6M group. and 2 (0.9%) were in the PP3M group.

[0155] 39 subjects (24 [5.0%] in PP6M and 15 [6.7%] in PP3M). However, he experienced a serious TEAE during the double-blind phase.

[0156] During the double-blind phase, the study drug was evaluated for adverse events with the following incidence rates across treatment groups: Permanently discontinued: 16 (3.3%) subjects in the PP6M group and 16 (3.3%) subjects in the PP3M group Six (2.7%) subjects in

[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] PP1M (after at least 4 months of treatment) or PP3M (after at least one 3-month injection) Patients who are adequately treated with either PP6M or PP6C and do not require dose adjustment should be switched to PP6M. PP6M is the next period after PP1M (±7 days) or PP3M (±14 days). The dose of PP6M should be started instead of the scheduled dose. Therefore, the dose should be based on the previous corresponding dose of PP3M or PP1M. When transitioning to PP6M, the final two doses of PP1M should be repeated to establish a consistent maintenance dose. The amount is recommended to be the same dosage strength as before starting PP6M.

[0161] During pretreatment with PP1M or PP3M, paliperidone plasma concentrations transition to PP6M. Ensure that the system is at or near steady state before

[0162] Model-based simulations were performed from PP1M (at least 4 months after treatment) to PP Subjects who transition directly to 6M will be those who transition from PP3M (after at least one 3-month injection cycle) to P demonstrated similar paliperidone exposure levels when compared with subjects transitioning to P6M As a result, subjects may first transition to PP3M before starting PP6M administration. It is possible to move directly from PP1M to PP6M without

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

[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 recurrence were included in the screening period (up to 28 days), Paliperidone palmitate 1-month (PP1M) or Pal Paliperidone palmitate 3-month (PP3M) A maintenance phase including one injection cycle of 1 or 3 months duration, depending on the The double-blind period consisted of paliperidone palmitate and paliperidone palmitate. 6-month (paliperidone palmitate 6 month, PP6M) (study drug and alternating placebo) The study was designed to include one injection cycle of PP3M (active control) or four injection cycles of PP3M (active control). To determine the time course of paliperidone plasma concentrations, the open-label phase of the study (PP1M and P Multiple pharmacokinetic blood samples were collected during the P3M and double-blind phases (PP3M and PP6M). The purpose of the PK evaluation was to assess the plasma concentration of paliperidone and the time course of PK parameters (maximum The objective of this study was to characterize the effects of steroids on the steroid activity (e.g., the maximum and minimum plasma concentrations and their associated timing). Therefore, the three PK samples were taken at the expected paliperidon peak approximately 1 month after PP6M administration. Six PK samples were scheduled weekly near the end of the 6-month dosing interval. When scheduled weekly.

[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 ,teeth , 8 days, with a median t of 7 days after administration of the 150 mg equivalent dose max It was equivalent to 3 After administration of 50 or 525 mg equivalent doses, (PP3M) median t max is equivalent to 28 days Based on visual inspection, C トラフ , C max , and AUC 3M PP1M and There appeared to be a dose-proportional increase for both PP3M. Dose-normalized mean C トラフ , C max , and AUC 3M was comparable for PP1M and PP3M. Trough ratios were 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 similar for PP3M and PP6M on day 1 ( At later time points, patients receiving PP6M had a mean blood glucose level of 24.6 ng / mL and 25.0 ng / mL, respectively. Subjects received PP3M (22.2 ng / mL on day 183 and 24 ng / mL on day 365). Approximately 25-28% lower trough concentrations (16.7ng / mL on day 183) compared with 0.1ng / mL. The mean mean mean blood cholesterol levels were 17.3 ng / mL at day 365 and 17.3 ng / mL at day 365. or 525 mg equivalent of PP3M or 700 or 1000 mg equivalent of PP6M After administration of max was comparable for all treatments, i.e., approximately 28 days Similarly, the 350 or 525 mg equivalent dose of PP in the second 6 months of the double-blind phase After administration of 3 mg or 700 or 1000 mg equivalents of PP6M, the median t max However, etc., ranging from 29 to 32 days. Based on visual inspection, C トラフ , C max , and and AUC 6M After each of the first and second doses in the double-blind phase, PP6M( There appeared to be a dose-proportional increase for the 700 or 1000 mg equivalent doses. PK exposure parameters (C トラフ , C max , and AUC 6M )teeth , the first and third doses of PP3M (350 or 525 mg equivalent) in the double-blind period After the dose, it appears to be proportional to the dose. Dose-normalized mean C max compared to PP3M The mean dose-normalized total PPAR. Peridone exposure (AUC 6M ) were comparable in the double-blind period after administration of PP3M and PP6M. The results are summarized in Table 12 below and in Figure 4.

[0167] The median peak-to-trough ratio after PP3M administration in the maintenance and double-blind phases was The results were comparable, with the mean values ​​being 1.85-1.92 and 1.02 in the maintenance and double-blind periods, respectively. The range of the PP6M dose was 6 months. The median peak-to-trough ratios ranged from 2.71 to 3.41.

[0168] Median peak-to-trough ratios following PP6M administration during the double-blind phase were comparable across doses , and only slightly higher after the first dose compared with the second dose (range 2.71–3.20). was very high (range 3.32-3.41).

[0169] Dosage administered for some groups, maintenance product, injection site during maintenance, gender, and year After stratification by age and creatinine clearance category, C max , AUC 6M to The ranges overlap due to the high intersubject variability for the PP3M and PP6M subgroups. Therefore, no clinically significant differences were observed.

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

[0171] [Table 12] a n=92(C トラフ (AUC 3M and AUC 6M About hand) 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 hand) 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 Continuation or shortening of the dosing interval for effect Allowance for administration windows of 2 weeks before and 3 weeks after regularly scheduled 6-month maintenance injections The properties were evaluated as follows: Using a medium-strength dose of PP6M (700 mg equivalent), the dosing interval is maintained at a lower C ト ラフ As shown in Table 13, the worst case scenario resulting in 1, 2, and 3 for scheduled 6-month injections after reaching PP6M steady state in g equivalents For injections delayed by weeks, the median C トラフ ng / mL to 15. 3 (-3.2%), 14.9 (-5.6%), and 14.4 (-8.9%) ng / mL It decreased. The highest dose strength of PP6M (1000 mg equivalent) was used to shorten the dosing interval most significantly. C max The worst-case scenario was simulated, as shown in Table 13, reproduced below. Scheduled 6-month injections after reaching PP6M steady state at 1000 mg equiv. For injections given 1 week and 2 weeks prior to max is 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 simulation was performed to determine the optimal dose for each study before the double-blind phase, as shown in Figure 5. Final steady-state dose (oral paliperidone ER 12 mg, PP1M 150 mg equivalent, PP3M 5 The median time to relapse and The relationship between the time point at which the median paliperidone concentration decreased to 7.5 ng / mL was evaluated. The time when the median plasma paliperidone concentration decreased to 7.5 ng / mL and the time to relapse Median, i.e., half of the subjects experienced a relapse, while the other half of the subjects later relapsed or a clear delay lasting weeks to months was observed between the time of relapse and the time of no relapse during the study. Therefore, the treatment effect was greater than that predicted based on the 7.5 ng / mL threshold. has also been extended, and the relapse protection window appears to be more sustained in a positive direction.

[0175] Regarding Figure 5, the simulations were performed using 1) 12 mg oral paliperidone ER; 2) 15 mg oral paliperidone ER; 0 mg equivalents of PP1M, 3) 525 mg equivalents of PP3M, and 4) 1000 mg equivalents of P Steady-state dosing of P6M was performed using high dose levels for each formulation as a representative scenario. The median time to relapse was 1.2 months. Based on the final Kaplan-Meier estimates, the following studies: oral paliperidone ER (R07 6477SCH301), PP1M (R092670PSY3001), and PP3M ( Calculated from the placebo group (R092670PSY3012).

[0176] Therefore, up to 2 weeks and 3 weeks before the target 6-month date for maintenance treatment with PP6M A later dosing window is possible, allowing for rescheduling without loss of efficacy or worsening side effects. This provides flexibility in serving and enhances treatment adherence.

[0177] Example 8: Skipped doses Based on population pharmacokinetic simulations, the dose of PP6M was increased beyond the administration window. Guidelines for skipping are provided. More than 6 months and 3 weeks after the last injection of PP6M If less than 8 months have elapsed, the following restart regimen may be used:

[0178] [Table 14]

[0179] If 8 to 11 months have passed since the last PP6M injection, use the following restart regimen: It is possible.

[0180] [Table 15]

[0181] If more than 11 months have passed since the last injection of PP6M, Patients should then resume treatment with PP1M as directed. After adequate treatment with 1M, PP6M can be resumed. Establish a consistent maintenance dose. To achieve this, the last two doses of PP1M should be at the same dose intensity as before resuming PP6M. It is recommended that

[0182] The timing of restarting the regimen after skipping a dose and continuing the PP6M maintenance regimen will depend on the final P These recommendations depend on the time interval from P6M administration, as shown in Figures 6 to 8. To address the scenario of a skipped dose in patients stabilized on PP6M treatment Based on simulations performed in the past. The criteria were the over- dose Rapid return to paliperidone plasma concentrations similar to those before the skipped dose without causing a drop in blood pressure It was to achieve recovery.

[0183] With respect to Figure 6, the central solid line represents the median paliperidone concentration, and the lower and upper dotted lines The shaded area between represents the 90% prediction band. Monthly treatment (initial dose, followed by maintenance dose), followed by PP6M administration. Delay in the final PP6M dose At the indicated high dose level, resumption was performed with a single dose of 150 mg equivalent of PP1M in the deltoid muscle. The lightly dotted area indicates the change from the trough concentration to the peak concentration before the PP6M administration interval was changed. The range of degrees (defined by the 90% prediction band) is shown.

[0184] With respect to Figure 7, the central solid line represents the median paliperidone concentration, and the lower and upper dotted lines The shaded area between represents the 90% prediction band. Monthly treatment (initial dose, followed by maintenance dose), followed by PP6M administration. Delay in the final PP6M dose The resumption of PP1M was shown in two doses of 100 mg equivalent to the deltoid muscle. The dark stippled area indicates the range from trough concentration to peak concentration before the PP6M administration interval was changed ( 90% predicted band).

[0185] With respect to Figure 8, the central solid line represents the median paliperidone concentration, and the lower and upper dotted lines The shaded area between represents the 90% prediction band. Monthly treatment (initial dose, followed by maintenance dose), followed by PP6M administration. Delay in the final PP6M dose The lightly stippled area indicates the PP6 The range from the trough concentration to the peak concentration before the M administration interval was changed (by the 90% prediction band) (defined as follows).

[0186] These guidelines require that patients undergo PP if they become fully or partially non-compliant. Treatment with 6M can be restarted, thereby reducing the need to start new treatments This provides a mechanism for

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

[0188] Further analysis of the data showed that overweight patients (BMI between 25 and <30) were significantly more likely to be obese than those in the age group 18-22. 5 patients (Figure 11), as well as those in the 6th group, would benefit from switching to PP6M (Figure 10). While showing a beneficial effect on weight, the study also included intention-to-treat and part-time Time to relapse at the end of the 12-month period in both protocol analysis sets demonstrated non-inferior efficacy of PP6M compared with PP3M for the primary endpoint of The safety profile observed for PP6M is comparable to previous safety profiles of PP1M and PP3M formulations. Consistent with previous studies, no new safety signals emerged.

[0189] Most of the weight gain was reported at the double-blind baseline (Day 1) of the study, so weight It was shown that an increase occurred during the open-label stabilization period. There was no increase in mean weight gain, suggesting that the less frequent injections had a stabilizing effect on mean weight gain. Therefore, patients who are gaining weight should switch to PP6M to improve their It can help stabilize weight or support weight loss.

[0190] Changes in weight, waist circumference, and BMI from baseline (DB) to the double-blind endpoint The baseline weight gain was numerically higher in the PP3M group compared to the PP6M group. The mean (SD) increase from baseline (MA) to double-blind endpoint was PP6M and PP For the 3M group, the results were 0.10 (4.959) kg and 0.96 (5.103) kg, respectively. there were.

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

[0192] Regarding Figure 10, the mean (SD) change from baseline (DB) BMI was normal (< 25) For subjects with a baseline BMI of 0.28 (3.4 04) kg, and in the PP3M group, 1.42 (4.456) kg and overweight (BMI2 For subjects with a mean age of 5 to <30, the PP6M group showed a mean age of -0.53 (4.386) kg and P 1.15 kg (4.814 kg) in the P3M group, and subjects with obesity (BMI ≥ 30) Regarding the PP6M group, the weight loss was 0.71 (6.448) kg and the weight loss was 0. The weight was 30 (5.955) kg.

[0193] Regarding Figure 11, the mean (SD) change by age was The mean values ​​were -0.65 (4.955) kg in the PP6M group and 4.33 kg in the PP3M group. (7.112) kg in the 25-50 year old group, and 0.29 (4 0.878) kg in the PP3M group and 0.91 (4.600) kg in the 51-65 age group For the subjects, the PP6M group had a weight of -0.31 (5.247) kg and the PP3M group had a weight of -0.31 (5.247) kg. For subjects over 65 years of age, the PP6M group showed a mean mean of -1.20 (4.763) kg. The mean values ​​were 1.76 (4.738) kg and 5.47 (5.707) kg, respectively.

Claims

1. Paliperidone palmitate sustained-release injectable suspension Paliperidone palmitate is administered to patients who require it. wherein the first dose is administered up to two weeks prior to or six months after administration of the first dose. A second dose of the paliperidone palmitate sustained-release injectable suspension is administered up to three weeks later. administering the first dose and the second dose to the patient's deltoid or gluteal muscles; A method wherein there is no intervening dose of paliperidone palmitate.

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

3. wherein the patient has a steady-state plasma concentration of paliperidone upon administration of the first dose.

3. The method according to claim 1 or 2.

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

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

6. The first dose is about 1092 mg of paliperidone palmitate or about 1560 mg of paliperidone palmitate. The method of any one of claims 1 to 5, comprising paliperidone palmitate.

7. the second dose is about 1092 mg of paliperidone palmitate or about 1560 mg of paliperidone palmitate The method of any one of claims 1 to 6, comprising paliperidone palmitate.

8. the first dose and the second dose each contain about 1092 mg of paliperide palmitate; The method of any one of claims 1 to 7, comprising:

9. the first dose and the second dose each containing about 1560 mg of paliperide palmitate; The method of any one of claims 1 to 7, comprising:

10. a plasma concentration of paliperidone in said patient is between about 5 and about 50 nM upon administration of said second dose; The method according to any one of claims 1 to 9, wherein the concentration is in g / mL.

11. If the first dose contains 1092 mg of paliperidone palmitate, the paliperidone plasma concentration in the patient is about 5 to about 30 ng / mL upon administration of the second dose. The method of claim 10, wherein

12. If 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. The method of claim 10, wherein

13. the paliperidone plasma concentration is from about 10 to about 150 ng / mL after administration of the second dose The method according to any one of claims 1 to 12, wherein the peak

14. If the first dose is 1092 mg of paliperidone palmitate, the patient the paliperidone plasma concentration in the blood is about 10 to about 125 ng / mL after administration of the second dose.

14. The method of claim 13, wherein a peak of mL is reached.

15. If the first dose is 1560 mg of paliperidone palmitate, the patient the paliperidone plasma concentration in the patient is about 35 to about 145 ng / mL after administration of the second dose.

14. The method of claim 13, wherein a peak of mL is reached.

16. The paliperidone palmitate extended release injectable suspension comprises: about 280 mg / mL to about 350 mg / mL of said 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; and an appropriate amount of water to make up to 100%. Law.

17. 17. The method of claim 16, wherein the suspension has a pH of about 6.0 to about 8.

0.

18. The one or more buffering agents may be selected from the group consisting of citric acid monohydrate, sodium phosphate monohydrate, and the like.

18. The method of claim 16 or 17, wherein the phosphate buffer solution contains sodium hydroxide, disodium hydrogen phosphate anhydrous, or sodium hydroxide. The method described below.

19. The paliperidone palmitate extended release injectable suspension comprises: about 312 mg / mL paliperidone palmitate; about 10 mg / mL of polysorbate 20; and about 75 mg / mL polyethylene glycol 4000. method.

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