US 2013 0331402A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0331402 A1 Lewyn-Briscoe et al. (43) Pub. Date: Dec. 12, 2013 (54) DOSING REGIMENASSOCATED WITH (60) Provisional application No. 61/256,696, filed on Oct. LONG-ACTING INUECTABLE 30, 2009. PALIPERDONE ESTERS (71) Applicant: Janssen Pharmaceutica NV, Beerse Publication Classification (BE) (51) Int. Cl. (72) Inventors: Peter H. Lewyn-Briscoe, Newtown, PA A 6LX3/59 (2006.01) (US); Christina Gassmann-Mayer, A619/00 (2006.01) Pennington, NJ (US); Srihari Gopal, (52) U.S. Cl. Belle Mead, NJ (US); David W. Hough, CPC ............. A6IK3I/519 (2013.01); A61 K9/0019 Wallingford, PA (US); Bart M. M. (2013.01) Remmerie, Gent (BE); Mahesh N. USPC ..................................................... S14/259.41 Samtani, Flemington, NJ (US) (73) Assignee: Janssen Pharmaceutica NV, Beerse (57) ABSTRACT (BE) Appl. No.: The present application provides a method for treating (21) 13/903,638 patients in need of psychiatric treatment, wherein said patient (22) Filed: May 28, 2013 misses a stabilized dose of a monthly maintenance regimen of paliperidone palmitate. The present application also provides Related U.S. Application Data a method for treating psychiatric patients in need of a Switch (62) Division of application No. 12/916,910, filed on Nov. ing treatment to paliperidone palmitate in a Sustained release 1, 2010, now abandoned. formulation. Patent Application Publication Dec. 12, 2013 Sheet 1 of 6 US 2013/0331402 A1 First-Orier Process Zero-Order Process Patent Application Publication Dec. 12, 2013 Sheet 2 of 6 US 2013/0331402 A1 25mg eq 50E. e e to 50mged issed dose of Wik 4, Patient feturns or k 5 issed dose of k & Patient eins of k 6 3 A 2 2024 issed dose on Wiki. Patient feturns on Wk 2 62 24 . 2 is 224 Time (week) Patent Application Publication Dec. 12, 2013 Sheet 3 of 6 US 2013/0331402 A1 (uffu) doeiuaguo genSeoid? Patent Application Publication Dec. 12, 2013 Sheet 4 of 6 US 2013/0331402 A1 {}{}}. (uffu) use. 83 iOC Patent Application Publication Dec. 12, 2013 Sheet 5 of 6 US 2013/0331402 A1 FIG. 5 Daily Extended Release Paliperidone invega 6 mg) 6-ing invegaswitched to 15G/4GGingeq. Pali-Palmitate ki---- N ikkilikilikiki ikikilikikilikkilikiki. Daily Extended Release Paliperidone (invega 6mo) TT 6-ing invega Switched over to 150 mg eq, Pai-Palmitate O .7 1 8 5 22 29 Time (day) Patent Application Publication Dec. 12, 2013 Sheet 6 of 6 US 2013/0331402 A1 F.G. 6 - 100 s E. 3. t g 1 S 9.O1 4 Doses of 50 ge i . < 0.01 - 100 s s SE 3 g 1 s O1 :::::::::100mge g aipeidone Paisitate 's < 0.01 Time (wk) US 2013/0331402 A1 Dec. 12, 2013 DOSING REGIMENASSOCATED WITH palmitate for treating patients is disclosed in US Patent Appli LONG-ACTING INUECTABLE cation Publication No. 20090163519. PALPERDONE ESTERS 0007 Paliperidone palmitate is an atypical antipsychotic drug administered by injection. Paliperidone palmitate may CROSS REFERENCE TO RELATED be administered at flexible injection sites including gluteal or APPLICATIONS deltoid muscle. Previous oil-based antipsychotic agents are 0001. This application is a divisional of U.S. patent appli indicated for gluteal muscle injection and may be associated cation Ser. No. 12/916,910, filed Nov. 1, 2010, pending, with pain on injection, which may cause undesired effects of which claims the benefit of U.S. Provisional Application needle phobia and perceived injection pain. This may reduce 61/256,696, filed on Oct. 30, 2009, the entire disclosures of patients’ acceptance towards these medications and result in which are hereby incorporated in their entirety. a negative influence on the clinical management of these patients. The administration of paliperidone palmitate at flex FIELD OF THE INVENTION ible injection sites may improve patients’ acceptance and compliance to psychotic treatment. 0002 This invention relates to a method for treating 0008. In addition, paliperidone palmitate provides ben patients in need of Switching treatment from other antipsy efits of Sustained dose release in plasma without significant chotic drug to long-acting injectable paliperidone palmitate concentration variation, regular monitor, reduced side effects formulations. and increased treatment efficacy. The administration of pali BACKGROUND OF THE INVENTION peridone palmitate may improve effectiveness of psychotic treatment. 0003 Antipsychotic medications are the mainstay in the 0009. Therefore, there may be an increasing demand to treatment of Schizophrenia, Schizoaffective disorder, and switch treatment of patients in need thereof from oral or Schizophreniform disorders. Conventional antipsychotics injectable antipsychotic drugs to paliperidone palmitate. Fur were introduced in the mid-1950s. These typical or first gen ther, there is a need to reinitiate a dosing regimen for patients eration drugs are usually effective in controlling the positive who misses their maintenance or stabilized dose. Thus, the symptoms of Schizophrenia, but are less effective in moder objective of the present application is to provide a dosing ating the negative symptoms or the cognitive impairment regimen of paliperidone palmitate for patients in need of a associated with the disease. Atypical antipsychotics or sec treatment Switching from other antipsychotic agents to pali ond generation drugs, typified by risperidone and Olanzapine, peridone palmitate. Another objective of the present applica were developed in the 1990s, and are generally characterized tion is to provide a dosing regimen of paliperidone palmitate by effectiveness against both the positive and negative symp for patients who have missed the monthly maintenance or toms associated with Schizophrenia. stabilized dosing regimen of paliperidone palmitate. 0004 Paliperidone palmitate is the palmitate ester of pali peridone (9-hydroxy-risperidone), a monoaminergic antago SUMMARY OF THE INVENTION nist that exhibits the characteristic dopamine D and seroto nin (5-hydroxytryptamine type 2A) antagonism of the second 0010. In one embodiment of the present application a dos generation, atypical antipsychotic drugs. Paliperidone is the ing regimen is provided for administering paliperidone major active metabolite of risperidone. Extended release palmitate to a patient in need of psychiatric treatment, (ER) osmotic controlled release oral delivery (OROS) pali wherein said patient misses a stabilized monthly maintenance peridone, as a tablet formulation, is marketed in the United dose for more than about 4 weeks and less than about 6 weeks, States (U.S.) for the treatment of schizophrenia and mainte comprising administering intramuscularly in the deltoid a nance of effect. first reinitiation loading dose of paliperidone as a paliperi 0005 Paliperidone palmitate is being developed as a long done palmitate formulated in a Sustained release formulation acting, intramuscular (i.m.), injectable aqueous nanosuspen on the first day of treatment; and administering intramuscu sion for the treatment of schizophrenia and other related larly in the gluteal a reinitiation maintenance dose of paliperi diseases that are normally treated with antipsychotic medica done as a paliperidone esterina Sustained release formulation tions. Because of extreme low water solubility, paliperidone on the 23" day to about the 37' day or between about 30+7 esters such as paliperidone palmitate dissolve slowly after an day after said first day of treatment. i.m. injection before being hydrolyzed to paliperidone and 0011. In another embodiment of the present application a made available in the systemic circulation. dosing regimen is provided for administering paliperidone 0006. Many patients with the mental illnesses achieve esters to a patient in need of psychiatric treatment, wherein symptom stability with available oral antipsychotic medica said patient misses a stabilized monthly maintenance dose for tions; however, it is estimated that up to 75% have difficulty more than about 6 weeks, comprising administering intra adhering to a daily oral treatment regimen, i.e. compliance muscularly in the deltoid a first reinitiation loading dose of problems. Problems with adherence often result in worsening paliperidone as a paliperidone palmitate formulated in a Sus of symptoms, Suboptimal treatment response, frequent tained release formulation on the first day of treatment; relapses and re-hospitalizations, and an inability to benefit administering intramuscularly in the deltoid a second reini from rehabilitative and psychosocial therapies. Paliperidone tiation loading dose of paliperidone as a paliperidone palmi palmitate injection has been developed to provide Sustained tate formulated in a sustained release formulation 1 week plasma concentrations of paliperidone when administered later (on the eighth day of treatment); and administering once monthly, which may greatly enhance compliance with intramuscularly in the gluteal a reinitiation maintenance dose dosing. Paliperidone palmitate formulated as an aqueous of paliperidone as a paliperidone ester in a Sustained release nanosuspension is described in U.S. Pat. Nos. 6,577.545 and formulation on about the 23" day to about the 37' day or 6,555,544. In addition, a dosing regimen of paliperidone between about 30+7 days after said first day of treatment. US 2013/0331402 A1 Dec. 12, 2013 0012. According to the present application, the first reini 0022 FIG. 5. Switching treatment from oral paliperidone tiation dose and the second reinitiation dose may be the same ER to paliperidone palmitate.