Method of treatment with risperidone via an implantable subcutaneous device

Abstract

Methods for treating with risperidone are described. In an embodiment, the method comprises implanting into a subject a device that release risperidone for a treatment period. Risperidone is administered to the subject at a zero-order rate or a pseudo-zero order rate of release from the device for a release period that is at least about half of the treatment period to provide a steady state plasma concentration of risperidone for the release period.

Description

METHOD OF TREATMENT WITH RISPERIDONE VIA AN IMPLANTABLE SUBCUTANEOUS DEVICECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 597,664, filed November 9, 2023, incorporated herein by reference in its entirety.STATEMENT REGARDING GOVERNMENT INTEREST

[0002] This invention was made with Government support under contract R44MH094036 awarded by the National Institute of Mental Health of the National Institutes of Health. The Government has certain rights in the invention.TECHNICAL FIELD

[0003] The subject matter described herein relates to methods of treatment with risperidone using a device that is implanted subcutaneously to release the drug at a zeroorder rate or a pseudo-zero order rate of release to provide a steady state plasma concentration of risperidone and 9-hydroxy risperidone that is equal to or less than the minimum plasma concentration of risperidone and 9-hydroxy risperidone achieved by an oral dose of the drug. In embodiments, the pharmacodynamic response provided by the steady state plasma concentration achieved from the implanted device is substantially the same as or better than that provided by an oral dose of the drug.BACKGROUND

[0004] Risperidone is an antipsychotic whose primary therapeutic activity is postulated to be mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) antagonism. Risperidone is currently marketed as immediate-release tablets, orally disintegrating tablets, an oral solution, and as a long-acting intramuscular injection. The drug is approved for acute and maintenance therapy of schizophrenia and, as monotherapy or adjunct! vely, in the acute treatment of bipolar disorder I. It is also approved for the management of irritability in pediatric and adolescent patients with autistic disorder. Disruptions of antipsychotic therapy are associated with greater symptoms and increased likelihood of relapse. An implantable device for delivery of risperidone for maintenance therapy for treatment of these and other disorders is desired.

[0005] The foregoing examples of the related art and limitations related therewith are intended to be illustrative and not exclusive. Other limitations of the related art will become apparent to those of skill in the art upon a reading of the specification and a study of the drawings.BRIEF SUMMARY

[0006] The following aspects and embodiments thereof described and illustrated below are meant to be exemplary and illustrative, not limiting in scope.

[0007] In one aspect, a method of treatment with risperidone is provided. The method comprises implanting subcutaneously to a subject in need a device comprising risperidone; and administering risperidone from the device for a treatment period, wherein risperidone is administered at a zero-order rate or a pseudo-zero order rate of release from the device for a release period that is at least about half of the treatment period to provide a steady state plasma concentration of risperidone and 9-hydroxy risperidone for the release period that is equal to or less than the minimum plasma concentration of risperidone and 9- hydroxy risperidone achieved by an oral dose of risperidone of between 1-6 mg / day.

[0008] In an embodiment, the steady state plasma concentration of risperidone and 9- hydroxy risperidone for the release period that is equal to or less than the minimum plasma concentration of risperidone and 9-hydroxy risperidone achieved by an oral dose of risperidone of 1 mg / day, 2 mg / day, 3mg / day, 4 mg / day55 mg / daysor 6 mg / day.

[0009] In one embodiment, the subject in need is a subject with a disorder selected from the group consisting of schizophrenia, depression, obsessive-compulsive disorder, post- traumatic stress disorder, a personality disorder, bipolar disorder, paranoia, Tourette’s syndrome, autism and agitation in dementia.

[0010] In one embodiment, the subject in need is a subject with schizophrenia, and wherein the subject was previously treated with risperidone.

[0011] In one embodiment, the subject was previously treated with risperidone administered orally at a dose of between 2 mg - 4 mg. For example, the subject was previously treated with risperidone administered orally at a dose of 1 mg / day, 2 mg / day, 3mg / day, 4 mg / dayi5 mg / day5or 6 mg / day. In an embodiment, the subject was previously treated with risperidone for at least about 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 16 weeks or 20 weeks.

[0012] In an embodiment, the subject while being previously treated with risperidone was stable as measured using Positive and Negative Syndrome Scale (PANSS) and / or Clinical Global Impression - Improvement (CGI-I). In an embodiment, symptoms due to schizophrenia were stabilized in the subject by treatment with orally administered risperidone, as measured by PANSS and / or CGI-I.

[0013] In one embodiment, the symptoms due to schizophrenia were stabilized with orally administered risperidone for between about 1-10 weeks, 1-8 weeks, 2-10 weeks or 2-8weeks, or for at least about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks. In one embodiment, the symptoms were stabilized by 2 mg of risperidone once daily. In other embodiments, the symptoms were stabilized by 1 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg or 8 mg once daily, for a period 2 weeks- 12 weeks, 2 weeks- 10 weeks, 2 weeks-8 weeks.

[0014] In one embodiment, implanting comprises implanting a single device comprising risperidone. In one embodiment, implanting comprises implanting comprises implanting two devices or two or more devices comprising risperidone. In one embodiment, the device stabilizes symptoms due to schizophrenia. In one embodiment, the stabilizes symptoms due to schizophrenia and wherein the device has an average daily output of risperidone of less than about 1200 mg, 1100 mg, 1000 mg, 900 mg, 800 mg, 750 mg, 700 mg, 600 mg, 500 mg, 450 mg, or 400 mg.

[0015] In one embodiment, implanting comprises implanting a device comprising a salt of risperidone.

[0016] In one embodiment, implanting comprises implanting a device comprising between about 100-1500 mg, 100-1300 mg, 100-1200 mg, 100-1000 mg, 100-750 mg, 200-1500 mg, 200-1300 mg, 200-1200 mg, 200-1000 mg, 200-750 mg, 300-1500 mg, 300-1300 mg, 300-1200 mg, 300-1000 mg, or 300-750 mg.

[0017] In one embodiment, administering provides a pharmacodynamic response substantially the same as or better than that provided by the oral dose of risperidone as measured by PANSS and / or CGI-1 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks or 8 weeks after treatment with oral risperidone.

[0018] In one aspect, a method of treatment with risperidone is provided. The method comprises implanting subcutaneously to a subject in need a device comprising risperidone; and administering risperidone from the device for a treatment period, wherein risperidone is administered at a zero-order rate or a pseudo-zero order rate of release from the device for a release period that is at least about half of the treatment period to provide a steady state plasma concentration of risperidone for the release period. In an embodiment, administering achieves a pharmacodynamic response substantially the same as or better than that provided by an oral dose of risperidone of between 1-6 mg / day as measured by PANSS and / or CGI-I 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks or 8 weeks after treatment.

[0019] In one embodiment, release of risperidone from the device for the release period provides a daily risperidone dose of between about 1-2 mg and the pharmacodynamicresponse is better than that provided by an oral dose of risperidone that is greater than 2 mg.

[0020] In one embodiment, release of risperidone from the device for the release period provides an average daily risperidone dose of between about 2-4 mg and the pharmacodynamic response is better than that provided by an oral dose of risperidone that is greater than the average daily risperidone dose administered by the device.

[0021] In one embodiment, administering provides a steady state plasma concentration of risperidone and 9-hydroxy risperidone for the release period that is equal to or greater than the minimum plasma concentration of risperidone and 9-hydroxy risperidone achieved by an oral dose of risperidone of between 1-6 mg / day.

[0022] In one embodiment, release of risperidone from the device for the release period provides an average daily risperidone dose, and wherein said administering provides a steady state plasma concentration of risperidone and 9-hydroxy risperidone for the release period that is equal to or greater than the minimum plasma concentration of risperidone and 9-hydroxy risperidone achieved by an oral dose of risperidone that is the same as or greater than the average daily risperidone dose.

[0023] In another aspect, a method of treatment with risperidone is provided. The method comprises implanting, in a patient previously treated with an antipsychotic, a device comprising an amount of risperidone sufficient for a treatment period; and administering risperidone from the device for the treatment period, wherein risperidone is released at a constant rate from the device for a release period, wherein the release period is at least about half of the treatment period, where a steady state plasma concentration of risperidone and 9-hydroxy risperidone is released from the device for the release period that is equal to or less than the minimum plasma concentration of risperidone and 9-hydroxy risperidone achieved by an oral dose of risperidone of between 1-6 mg / day.

[0024] In one embodiment, the patient previously treated with an antipsychotic was previously treated with an antipsychotic administered orally or as a subcutaneous depot or long-acting injection.

[0025] In one embodiment, the a patient previously treated with an antipsychotic was previously treated with an antipsychotic administered as a subcutaneous depot comprised of a biodegradable polymeric microspheres comprising the antipsychotic

[0026] In one embodiment, the biodegradable polymeric microspheres are poly(d,l-lactide- co-glycolide) microspheres comprising risperidone (e.g., RISPERDAL CONSTA).

[0027] In one embodiment, the antipsychotic is selected from the group consisting of haloperidol, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone.

[0028] In one embodiment, symptoms of a psychotic disorder were stabilized in the patient during previous treatment with an antipsychotic.

[0029] In one embodiment, the symptoms of a psychotic disorder were stabilized as measured using PANSS and / or CGI-I.

[0030] In one embodiment, the PANSS score is below about 85, 80, 75, 70, 65, or 60.

[0031] In one embodiment, the release period is at least about 3 months, about 4 months, about 6 months, about 9 months or about 12 months.

[0032] In one embodiment, administering provides a pharmacodynamic response, as measured by a psychiatric rating scale, that is essentially equal to or better than the pharmacodynamic response in patients treated with the oral dose of risperidone.

[0033] In one embodiment, the method further comprises administering an oral dose of risperidone for 1 , 2 or 3 days. In one embodiment, the oral dose is administered before and after the implanting. In one embodiment, the oral dose is administered at least once daily for 3 days, where a first dose is administered within 24 hours of the implanting and a second dose and a third dose are administered 24 hours after the implanting.

[0034] In addition to the exemplary aspects and embodiments described above, further aspects and embodiments will become apparent by reference to the drawings and by study of the following descriptions. Additional embodiments of the present methods will be apparent from the following description, drawings, and claims. As can be appreciated from the foregoing and following description, each and every feature described herein, and each and every combination of two or more of such features, is included within the scope of the present disclosure provided that the features included in such a combination are not mutually inconsistent. In addition, any feature or combination of features may be specifically excluded from any embodiment of the present disclosure. Additional aspects and advantages of the present disclosure are set forth in the following description and claims, particularly when considered in conjunction with the accompanying examples and drawings.BRIEF DESCRIPTION OF THE DRAWINGS

[0035] FIG. 1 is a graph of plasma concentration of risperidone and 9-OH risperidone, in ng / mL, in subjects treated with risperidone from a subcutaneous implant for 6 months (n=14) or 12 months (n=12); an oral dose of risperidone was given on the first several daysof the study (see Example 1), and thereafter no oral risperidone was provided. Error bars indicate + / - 1 SD.

[0036] FIG. 2 is a bar graph showing the mean PANSS score during the oral phase and the implant phase of a study on the subjects in the study of FIG. 1.

[0037] FIG. 3 is a bar graph showing the CGI-I scores during the implant phase of the study of the subjects of FIG. 1. Error bars indicate + / - 1 SD.DETAILED DESCRIPTIONI. Definitions

[0038] Various aspects now will be described more fully hereinafter. Such aspects may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey its scope to those skilled in the art.

[0039] Where a range of values is provided, it is intended that each intervening value between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure. For example, if a range of 1 pm to 8 pm is stated, it is intended that 2 pm, 3 pm, 4 pm, 5 pm, 6 pm, and 7 pm are also explicitly disclosed, as well as the range of values greater than or equal to 1 pm and the range of values less than or equal to 8 pm.

[0040] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "polymer" includes a single polymer as well as two or more of the same or different polymers, reference to an "excipient" includes a single excipient as well as two or more of the same or different excipients, and the like.

[0041] The term “about”, particularly in reference to a given quantity, is meant to encompass deviations of plus or minus five percent.

[0042] The compositions of the present disclosure can comprise, consist essentially of, or consist of, the components disclosed.

[0043] All percentages, parts and ratios are based upon the total weight of the topical compositions and all measurements made are at about 25 °C., unless otherwise specified.

[0044] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, salts, compositions, dosage forms, etc., which are— within the scope of sound medical judgment-suitable for use in contact with the tissues of human beings and / or othermammals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. In some aspects, "pharmaceutically acceptable" means approved by a regulatory agency of the federal or a state government, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals (e.g., animals), and more particularly, in humans.

[0045] By reserving the right to proviso out or exclude any individual members of any such group, including any sub-ranges or combinations of sub-ranges within the group, that can be claimed according to a range or in any similar manner, less than the full measure of this disclosure can be claimed for any reason. Further, by reserving the right to proviso out or exclude any individual substituents, analogs, compounds, ligands, structures, or groups thereof, or any members of a claimed group, less than the full measure of this disclosure can be claimed for any reason.

[0046] Throughout this disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure.

[0047] For convenience, certain terms employed in the specification, examples and claims are collected here. Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs.II. Methods of Treatment

[0048] Methods of treatment with risperidone are provided. In an embodiment, the method comprises implanting subcutaneously to a subject in need a device comprising risperidone; and administering risperidone from the device for a treatment period, wherein risperidone is administered at a zero-order rate or a pseudo- zero order rate of release from the device for a release period that is at least about half of the treatment period to provide a steady state plasma concentration of risperidone and 9-hydroxy risperidone for the release period that is equal to or less than the minimum plasma concentration of risperidone and 9- hydroxy risperidone achieved by an oral dose of risperidone of between 1-6 mg / day. In another embodiment, the method comprises implanting subcutaneously to a subject in need a device comprising risperidone; and administering risperidone from the device for a treatment period, wherein risperidone is administered at a zero-order rate or a pseudo-zeroorder rate of release from the device for a release period that is at least about half of the treatment period to provide a steady state plasma concentration of risperidone for the release period. In an embodiment, administering achieves a pharmacodynamic response substantially the same as or better than that provided by an oral dose of risperidone of between 1-6 mg / day as measured by PANSS and / or CGI-1 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks or 8 weeks after treatment.

[0049] In an embodiment, the device is a configured for subcutaneous implantation into a subject. The device generally comprises a housing member that defines an internal reservoir. The housing has one or more outlets for release of drug contained within the drug reservoir. In an embodiment, the housing has a first end and / or a second end. In embodiments, one or both of the first end or the second end has a porous screen or membrane or a non-porous membrane across which drug (and other excipients in the drug reservoir) can diffuse. Exemplary devices and drug compositions for risperidone are described in US2019 / 0224322 and US2022 / 0280494, each of which is incorporated by reference herein in its entirety. In an embodiment, the device is dimensioned such that it comprises an amount of drug for release in a therapeutically effective amount for a period of at least about 6 months, 9 months, or 12 months.

[0050] A study was conducted to evaluate the safety, tolerability, and pharmacokinetics (PK) of treatment with risperidone administered from a subcutaneously implanted device in patients previously treated with orally administered risperidone. In the study, subjects with schizophrenia, stable on a 2-3 mg dose of oral risperidone for at least about 2 weeks were randomized for treatment with risperidone administered from a subcutaneously implanted device for a six month or a twelve month period. Two devices were implanted in the abdomen of each subject. During the study, primary endpoints included subject safety and local tolerance and secondary endpoints included active moiety - risperidone plus 9- OH-risperidone PK and symptoms as measured by PANSS and CGI-I scores. Results are shown in FIGS. 1, 2 and 3.

[0051] As seen in FIG. 1, the PK profile in both groups followed near zero-order kinetics until the end of study. The average steady-state active moiety plasma concentration ranged between 7-13 ng / mL The observed burst in the first days was due to a 3 mg oral supplement used for the first 3 days after implant placement; during the remainder of the treatment period, risperidone from only the implant was provided without oral supplements.

[0052] As seen in FIG. 2 and FIG. 3, average PANSS scores were from 50-60 and CGI-I scores from 3-4, and both were comparable between the oral and the implant phases of the study. Average PANSS and CGI-I scores were similar between the oral and implant treatment phases, demonstrating that risperidone provided from the implantable device provided a comparable therapeutic benefit to oral risperidone. Plasma concentrations of risperidone and 9-OH-risperidone were substantially constant for 6-12 months.

[0053] Accordingly, a method for treating a subject in need of treatment with risperidone is provided. In an embodiment, a subcutaneously implantable device having a non- erodible housing with a first end and a second end is provided. The housing defines a reservoir that comprises a formulation of risperidone salt and a 2-fold or 3-fold or 4-fold or 5-fold molar excess of an organic acid, which, in an embodiment, is the salt counterion of the risperidone salt. For example, in an embodiment, the risperidone salt is risperidone aminobenzoate and the organic acid in molar excess relative to the molar amount of risperidone is para-aminobenzoic acid. In another embodiment, the risperidone salt is risperidone vanillate and the organic acid in molar excess relative to the molar amount of risperidone is vanillic acid. In another embodiment, the risperidone salt is risperidone fumerate and the organic acid in molar excess relative to the molar amount of risperidone is fumaric acid. Other risperidone salts and organic acids are set forth in WO2018 / 057968, incorporated by reference herein. In an embodiment, the risperidone formulation is in the form of a tablet or tablets (e.g. more than one table) that is / are placed in the reservoir of the drug delivery device. After subcutaneous implantation of the device, or in some embodiments, before subcutaneous implantation, an aqueous fluid contacts the tablet(s) to form a mixture comprised of dissolved and undissolved (e.g., solid state) risperidone formulation. The dissolved fraction of the mixture comprises water, dissolved risperidone and salt counterion; the undissolved fraction of the mixture comprises the risperidone salt, organic acid in dry form (e.g., tablets or particulates).

[0054] It will also be appreciated that treatment of a patient previously treated with an antipsychotic is provided. The method comprises implanting in the previously treated patient a device comprising an amount of risperidone sufficient for a treatment period; and administering risperidone from the device for the treatment period, wherein risperidone is released at a constant rate from the device for a release period, wherein the release period is at least about half of the treatment period, where a steady state plasma concentration of risperidone and 9-hydroxy risperidone is released from the device for the release periodthat is equal to or less than the minimum plasma concentration of risperidone and 9- hydroxy risperidone achieved by an oral dose of risperidone of between 1-6 mg / day.III. Examples

[0055] The following examples are illustrative in nature and are in no way intended to be limiting.EXAMPLE 1MAINTENANCE TREATMENT OF SCHIZOPHRENIA

[0056] The study was an open-label, parallel group design that assessed the safety, tolerability, and PK profile of two versions of an implantable device comprising risperidone. Two groups of 12-15 schizophrenia patients who were currently on oral risperidone therapy (2-3 mg / day), or who were stable on an antipsychotic other than oral risperidone (2-3 mg / day) but completed the conversion phase were planned to receive two of the device implants, either the 6-month version (Group 1) or the 12-month version (Group 2).

[0057] 28 subjects were enrolled (14 subjects / group; 6-months and 12-months) of whom 23 completed the study (12 in Group 1 and 11 in Group 2). Two subjects were lost to follow up and one requested that the implant be removed prior to the end of the dosing period. One nonrelated SAE (pulmonary embolism) was reported. The placement and removal procedures were well tolerated. Treatment-related AEs were generally mild, and included implant site pain / soreness / tenderness, drowsiness, ecchymosis, increased appetite, insomnia, and headache.

[0058] Two versions of an implantable device were provided - a version designed to operate for 6 months, and a version designed to operate for 1 year. Both device versions were drug-device combination products consisting of a symmetrical cylindrical titanium reservoir (5 mm in diameter and either 44 mm in length for the 6-month version or 50 mm in length for the 12 month version) with an internal drug compartment and diffusion ports at either end. The drug reservoir of the devices was filled with a dry, compressed mixture of risperidone aminobenzoate plus a two-fold stochiometric excess of para- aminobenzoic acid (PABA). The fill weight of the drug reservoir was 650 mg for the 6-month version or 780 mg for the 12-month device version. To aid in tableting the formulation, PVP40 and stearic acid were added. Standard polyvinylidene difluoride (PVDF) membranes were positioned at each end of the reservoir. The device was sealed in a vial under vacuum and activated by the end-user by introduction of sterile saline into the vial (similarly toreconstitution of a lyophilized product). The formulation components and projected daily exposure are shown Table 1-1.Table 1-1 Drug Substance Components, Component Amounts per Device, and Projected Daily Exposure after ImplantationPABA = para-aminobenzoic acid; PVP40 = polyvinylpyrrolidone 401Mass loaded into individual units assuming a fill weight of 650 mg (6 month version) or 780 mg (12 month version).2Normalized to dose elution rate of 1.0 mg / day projected for active.

[0059] The device implant is a combination drug-device product designed to continuously elute the equivalent of a daily 1-2 mg oral dose of risperidone following subcutaneous (SC) implantation.

[0060] STUDY PLAN: Eligible patients were assigned to one of two groups following completion of the conversion phase, if applicable (described below), and supervised oral risperidone dosing (3 mg for 4 days). Both groups were switched to 2 implantable devices on Day 1, and safety and PK were assessed in parallel for 6 months (Group 1) or 12 months (Group 2). The study also evaluated the PK profile in subjects with the implanted device as compared to the marketed oral form of risperidone.

[0061] Patients that received an antipsychotic other than oral risperidone (2-3 mg / day) were required to enter a conversion phase. During the weekly visits in the conversion phase, patients were to be cross-titrated, at the clinician’ s discretion, from other antipsychotic(s) to oral risperidone therapy over a minimum of 2 weeks. The objective of the oral conversion phase was for all patients to achieve an oral risperidone dose of 3 mg by Day- 14.

[0062] The study was conducted in the following sequential periods for both groups (patients either entered the conversion phase or the unsupervised oral risperidone [3 mg / day] period) following screening:a) Conversion phase [patients receiving an antipsychotic other than oral risperidone(2-3 mg) only]: cross-titration, at the discretion of the Principal Investigator (PI), from other antipsychotic(s) to oral risperidone therapy over a minimum of 2 weeks to achieve an oral risperidone dose of 3 mg / day by Day -14. b) Unsupervised oral risperidone (3 mg / day). c) Supervised oral risperidone (3 mg / day). d) Device implant treatment with oral supplement. e) Device implant treatment.

[0063] On Day-7, or as early as Day-10 at the clinician’s discretion, through Day-5, patients who were currently on oral risperidone therapy (2-3 mg / day) self-administered 3 mg / day oral risperidone. Patients were dispensed a sufficient quantity of oral risperidone to last until the next scheduled study visit (±3 days). Compliance with oral study medication was monitored by tablet counts. Starting on Day -4, patients self-administered 3 mg / day oral risperidone in the clinical facility under the supervision. Each oral dose of risperidone was administered with a full cup (approximately 24 mL) of non-carbonated, room temperature water. Tablets had to be swallowed whole and not chewed, divided, dissolved, or crushed.

[0064] Oral risperidone (3 mg / day) was taken daily for six days on Days-4 to 2. The penultimate dose of oral risperidone was administered immediately prior to device implantation, and the final dose of oral risperidone was administered 24 hours after device implantation.

[0065] The device remained implanted for either 183 (±7) days (Group 1) or 364 (±7) days (Group 2). Upon completion of the implant treatment period, the device was removed by a qualified medical professional.

[0066] Blood was collected for the determination of plasma concentrations of risperidone, 9-OH risperidone, and active moiety (risperidone + 9-OH risperidone) were determined on the last day of oral risperidone treatment, throughout the duration of the device implant treatment, and following removal of the device implants. Pharmacokinetic (PK) endpoints included the evaluation of plasma concentrations of risperidone, 9-OH risperidone, and active moiety (risperidone + 9-OH risperidone). PK parameters calculated for the oral risperidone treatment period and for the DLP-114 implant treatment period included maximum concentration (Cmax), minimum concentration (Cmin), time to maximum concentration (Tmax), time to minimum concentration (Tmin), average concentration (Cave) and area under the plasma concentration vs. time curve (AUC).

[0067] At each collection, 3 mL of blood were collected into a collection tube containing dipotassium ethylenediaminetetraacetic acid (K2EDTA) as the anticoagulant. The tube was inverted gently 8 to 10 times and immediately placed on crushed ice. Within 30 minutes of blood collection, the blood sample was centrifuged at 1000-2000 x g for 10 minutes, preferably at approximately 4°C (although not required). If feasible, the sample was centrifuged at 2000 x g for 15 minutes to deplete platelets in the plasma. Immediately following centrifugation, approximately 0.35 mL aliquots of the plasma (upper liquid) layer were transferred into each of three 2 mL externally threaded cryovials. The samples were to be maintained at approximately 4°C or on crushed ice while handling. If there was insufficient plasma for all three cryovials, it was ensured that the primary aliquot contained approximately 0.35 mL plasma. The aliquots were labeled “primary (xl) and back-up (x2). Samples were frozen within 25 minutes of centrifugation in an upright position to keep the plasma in the bottom of the tube. Samples were stored in a freezer set at or below -20°C (-80°C preferred) until shipment to the bio-analytical laboratory.

[0068] PK findings are shown in FIG. 1. Patients generally appeared to be clinically stable or exhibit slight improvement during device implant treatment. CGI-I scores for most patients indicated no change or minimal symptom improvement throughout the treatment period, with occasional scores reflecting greater improvement (FIG. 3). PANSS scores are shown in FIG. 2.

[0069] C-SSRS was administered at Screening and each patient visit (at least biweekly). CGLI was administered at least monthly and PANSS approximately every 3 months. PANSS was administered more frequently if the CGLI worsened.

[0070] Columbia-Suicide Severity Rating Scale (C-SSRS): The C-SSRS is a suicidal ideation rating scale. The scale identifies behaviors and thoughts that are associated with an increased risk of suicidal actions in the future. The C-SSRS Baseline / Screening version was conducted at Screening, and the Since Last Visit version was used for all subsequent visit.

[0071] Positive and Negative Syndrome Scale (PANSS): The PANSS measures positive and negative syndromes associated with schizophrenia. The scale consists of 33 items, 30 of which contribute to the PANSS Total Score (i.e., the sum of the seven P, or positive, items with the seven N, or negative, items and the 16 G, or general pathology, items). The PANSS Total Score ranges from 30 to 210, with higher scores indicating greater pathology. Individual PANSS items are scored from 1 to 7, as follows:1 = Absent2 = Minimal3 = Mild4 = Moderate5 = Moderate / Severe6 = Severe7 = Extreme

[0072] The PANSS was administered at Screening, baseline, and at additional time points. For study eligibility, the PANSS Total Score at screening had to be less than or equal to 80 and the following five individual items had to be less than or equal to 4: conceptual disorganization, suspiciousness, hallucinatory behavior, unusual thought content, and hostility. Additionally, there could not be a >20% change in the PANSS Total Score from Screening to baseline. Finally, if the PANSS Total Score worsened by >30% compared to baseline at subsequent study visits (confirmed at an additional visit 1 to 7 days later), the patient could have been exhibiting signs of relapse and may have met stopping criteria.

[0073] Clinical Global Impression - Severity (CGI-S) and Clinical Global Impression - Improvement (CGI- 1): CGI-S was rated based upon the severity of schizophrenia symptoms at Screening and Day - 1 during the oral risperidone period, immediately prior to the device implant treatment period with oral supplement. Severity of illness was assessed based on the following ratings:0 = Not assessed1 = Normal, not at all symptomatic2 = Minimally symptomatic3 = Mildly symptomatic4 = Moderately symptomatic5 = Markedly symptomatic6 = Severely symptomatic7 = Among the most extremely symptomatic patients

[0074] Drug response for symptoms of schizophrenia will be evaluated by CGI-I. CGI-I scores range from 1 to 7:0 = Not assessed (missing)1 = Very much improved2 = Much improved3 = Minimally improved4 = No change5 = Minimally worse6 = Much worse7 = Very much worse

[0075] EPS symptoms were monitored by the Barnes Akasthisia Rating Scale (BARS), Simpson-Angus Scale (SAS), and Abnormal Involuntary Movements Scale (AIMS) at the beginning and at the end of the study, and assessments could be performed more frequently based on symptoms at the clinician’s discretion.

[0076] The BARS is a rating scale administered by physicians to assess the severity of drug-induced akathisia. This scale includes objective and subjective items such as the level of restlessness and global clinical assessment of akathisia. The objective and subjective items are rated on a 4-point scale from 0 to 3 and are summed yielding a total score ranging from 0 to 9. The global clinical assessment of akathisia uses a 5-point scale ranging from 0 to 4.

[0077] The AIMS is a clinician-administered scale used to detect tardive dyskinesia (TD) and to follow the severity of a person’s TD over time. This 12-item anchored scale is clinician administered and scored.Items 1 through 10 are rated on a 5-point anchored scale:0 = None1 = Minimal, may be extreme normal2 = Mild3 = Moderate4 = SevereItems 1 through 4 assess orofacial movements. Items 5 through 7 assess extremity and truncal dyskinesia. Items 8 through 10 assess global severity as judged by the examiner and the person’s awareness of the movements and the distress associated with them.Items 11 and 12 are yes-no questions concerning problems with teeth and / or dentures, because such problems can lead to a mistaken diagnosis of dyskinesia. A positive AIMS examination is a score of 2 in multiple movements or a score of 3 or 4 in a single movement.

[0078] The SAS is a clinician-administered 10-item rating scale assessing the presence of drug-related extrapyramidal signs. The 10 performance tasks are rated on a scale of 0 to 4 (normal to severe, as relevant to the task assessed). The SAS score is the sum of the 10 performance tasks, ranging from 0 to 40.EXAMPLE 2METHODS OF RISPERIDONE TREATMENT FROM DEVICES COMPRISING RISPERIDONE FORMULATIONS

[0079] Drug delivery devices comprising different formulations of risperidone were prepared and tested. Three formulations were tested. The formulations included (1) risperidone hexanoate salt mixed with poly(lactic-co-glycolic acid) (PLGA) copolymer; and risperidone free base mixed with (2) a two-fold or (3) a three-fold molar excess of para- aminobenzoic acid (PABA). The devices filled with the risperidone formulations comprised a porous partition on each end of the device. The devices were implanted in animal subjects (rats or rabbits) for an implant period of 119 days or 183 days. Release of risperidone from the devices was evaluated by plasma concentration over time, clinical observations, and post-explant tissue necropsy and histopathology.

[0080] The PK data showed that devices with the risperidone PABA formulations had an initial burst release of risperidone followed by a steady state release by week 2 at about three times below the maximum concentration (Cinax). The plasma concentration remained steady (e.g., flat) for the remainder of the implant period.

[0081] While a number of exemplary aspects and embodiments have been discussed above, those of skill in the art will recognize certain modifications, permutations, additions and sub-combinations thereof. It is therefore intended that the following appended claims and claims hereafter introduced are interpreted to include all such modifications, permutations, additions and sub-combinations as are within their true spirit and scope.

Claims

IT IS CLAIMED:

1. A method of treatment with risperidone, comprising: implanting subcutaneously to a subject in need a device comprising risperidone; and administering risperidone from the device for a treatment period, wherein risperidone is administered at a zero-order rate or a pseudo- zero order rate of release from the device for a release period that is at least about half of the treatment period to provide a steady state plasma concentration of risperidone and 9-hydroxy risperidone for the release period that is equal to or less than the minimum plasma concentration of risperidone and 9- hydroxy risperidone achieved by an oral dose of risperidone of between 1-6 mg / day.

2. The method of claim 1, wherein the subject in need is a subject with a disorder selected from the group consisting of schizophrenia, depression, obsessive-compulsive disorder, post-traumatic stress disorder, a personality disorder, bipolar disorder, paranoia, Tourette’s syndrome, autism and agitation in dementia.

3. The method of claim 1 or claim 2, wherein the subject in need is a subject with schizophrenia, and wherein the subject was previously treated with risperidone.

4. The method of claim 3, wherein the subject was previously treated with risperidone administered orally at a dose of between 2 mg - 4 mg.

5. The method of claim 4, wherein symptoms due to schizophrenia were stabilized in the subject by treatment with orally administered risperidone, as measured using Positive and Negative Syndrome Scale (PANSS) and / or Clinical Global Impression - Improvement (CGI-I).

6. The method of claim 5, wherein the symptoms were stabilized with orally administered risperidone for at least about 2 weeks.

7. The method of claim 5, wherein the symptoms were stabilized by 2 mg of risperidone once daily.

8. The method of claim 6, wherein said implanting comprises implanting a single device comprising risperidone.

9. The method of claim 5, wherein the symptoms were stabilized by 2 mg, 3 mg, or 4mg of risperidone once daily.

10. The method of claim 8, wherein said implanting comprises implanting comprises implanting two devices comprising risperidone.

11. The method of any one of claims 1-5, wherein said implanting comprises implanting two devices comprising risperidone.

12. The method of any one of claims 1-11, wherein said implanting comprises implanting a device comprising a salt of risperidone.

13. The method of any one of claims 1-12, wherein said implanting comprises implanting a device comprising between about 100-1500 mg, 100-1300 mg, or 360-435 mg risperidone.

14. The method of any one of claims 1-13, whereby said administering provides a pharmacodynamic response substantially the same as or better than that provided by the oral dose of risperidone as measured by Positive and Negative Syndrome Scale (PANSS) and / or Clinical Global Impression - Improvement (CGI-I) 1 week, 2 weeks, 3weeks, 4 weeks or 6 weeks after treatment with oral risperidone.

15. A method of treatment with risperidone, comprising: implanting subcutaneously to a subject in need a device comprising risperidone; and administering risperidone from the device for a treatment period, wherein risperidone is administered at a zero-order rate or a pseudo- zero order rate of release from the device for a release period that is at least about half of the treatment period to provide a steady state plasma concentration of risperidone for the release period, whereby said administering achieves a pharmacodynamic response substantially the same as or better than that provided by an oral dose of risperidone of between 1-6 mg / day as measured by Positive and Negative Syndrome Scale (PANSS) and / or Clinical Global Impression - Improvement (CGI-I) 1 week, 2 weeks, 3weeks, 4 weeks or 6 weeks after treatment with oral risperidone.

16. The method of claim 15, wherein release of risperidone from the device for the release period provides a daily risperidone dose of between about 1-2 mg and the pharmacodynamic response is better than that provided by an oral dose of risperidone thatis greater than 2 mg.

17. The method of claim 15, wherein release of risperidone from the device for the release period provides an average daily risperidone dose of between about 2-4 mg and the pharmacodynamic response is better than that provided by an oral dose of risperidone that is greater than the average daily risperidone dose administered by the device.

18. The method of any one of claims 15-17, wherein said administering provides a steady state plasma concentration of risperidone and 9-hydroxy risperidone for the release period that is equal to or greater than the minimum plasma concentration of risperidone and 9-hydroxy risperidone achieved by an oral dose of risperidone of between 1-6 mg / day.

19. The method of any one of claims 15-17, wherein release of risperidone from the device for the release period provides an average daily risperidone dose, and wherein said administering provides a steady state plasma concentration of risperidone and 9-hydroxy risperidone for the release period that is equal to or greater than the minimum plasma concentration of risperidone and 9-hydroxy risperidone achieved by an oral dose of risperidone that is the same as or greater than the average daily risperidone dose.

20. A treatment method, comprising: implanting, in a patient previously treated with an antipsychotic, a device comprising an amount of risperidone sufficient for a treatment period; and administering risperidone from the device for the treatment period, wherein risperidone is released at a constant rate from the device for a release period, wherein the release period is at least about half of the treatment period, where a steady state plasma concentration of risperidone and 9-hydroxy risperidone is released from the device for the release period that is equal to or less than the minimum plasma concentration of risperidone and 9-hydroxy risperidone achieved by an oral dose of risperidone of between 1-6 mg / day.

21. The method of claim 20, wherein the patient previously treated with an antipsychotic was previously treated with an antipsychotic administered orally or as a subcutaneous depot or long-acting injection.

22. The method of claim 20 or claim 21, wherein the a patient previously treated with an antipsychotic was previously treated with an antipsychotic administered as a subcutaneous depot comprised of a biodegradable polymeric microspheres comprising theantipsychotic23. The method of claim 22, wherein the biodegradable polymeric microspheres are poly(dj-lactide-co-glycolide) microspheres comprising risperidone (e.g., RISPERDAL CONSTA)24. The method of any one of claims 20-23, wherein the antipsychotic is selected from the group consisting of haloperidol, olanzapine, paliperidone, queti apine, risperidone, and ziprasidone.

25. The method of any one of claims 20-24, wherein symptoms of a psychotic disorder were stabilized in the patient during previous treatment with an antipsychotic.

26. The method of claim 25, wherein the symptoms of a psychotic disorder were stabilized as measured using Positive and Negative Syndrome Scale (PANSS) and / or Clinical Global Impression - Improvement (CGLI).

27. The method of claim 26, wherein the PANSS score is below about 85, 80, 75, 70, 65, or 60.

28. The method of any preceding claim, wherein the release period is at least about 3 months, about 4 months, about 6 months, about 9 months or about 12 months.

29. The method of any preceding claim, whereby said administering provides a pharmacodynamic response, as measured by a psychiatric rating scale, that is essentially equal to or better than the pharmacodynamic response in patients treated with the oral dose of risperidone.

30. The method of any preceding claim, further comprising administering an oral dose of risperidone for 1 , 2 or 3 days.

31. The method of claim 30, wherein the oral dose is administered before and after the implanting.

32. The method of claim 30, wherein the oral dose is administered at least once daily for 3 days, where a first dose is administered within 24 hours of the implanting and a second dose and a third dose are administered 24 hours after the implanting.

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