`
`Commissioner For Patents
`PO. Box 1450
`Alexandria, VA 22313-1450
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`This is a reouest for film. a PROVISIONAL APPLICATION under 37 CFR 1.53 c .
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`PRD2901USPSP
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`LAST NAME
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`FIRST NAME
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`MIDDLE
`INITIAL
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`RESIDENCE
`CITY AND EITHER STATE OR FOREIGN COUNTRY
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`INVENTOR(s) / APPLICANT(s)
`
`Vermeulen
`Wouters
`
`An
`AI'IOI'IS
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`TURNHOUTSEWEG 30 BEERSE BE
`TURNHOUTSEWEG 30 BEERSE BE
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`TITLE OF THE INVENTION (280 characters max)
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`DOSING REGIMEN ASSOCIATED WITH LONG ACTING INJECTABLE
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`PALIPERIDONE ESTERS
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`CORRESPONDENCE ADDRESS
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`
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`Direct all correspondence to:
`IXI CustomerNumber 000027777
`OR
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`I:I Firm of Individual Name:
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`ENCLOSED APPLICATION PARTS (check all that apply)
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`E Specification
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`E
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`[I
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`Number of
`Pages
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`Number of
`Claims
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`El
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`METHOD OF PAYMENT (check one)
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`D A check or money order is enclosed to cover the Provisional filing
`fees-
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`PIOViSiona' Filing
`Fee Amount ($)
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`IXI The Commissioner is hereby authorized to charge filing fees and
`credit any overpayment to Deposit Account No. 10-0750
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`The invention was made by an agency of the United States Government or under a contract with an agency of the United States
`Government.
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`IZNo
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`El Yes, the name of the US. Government agency and the Government contract number are:
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`Respectfully submitted,
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`SIGNATURE:
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`/Ha| Brent Woodrow/
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`REGISTRATION NO. 32 501
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`TYPED or PRINTED NAME
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`Hal B. Woodrow
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`DATE: December 19 2007
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`TELEPHONE (732) 524-2976
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`PROVISIONAL APPLICA TION FILING ONLY
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`PRD2901USPSP
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`DOSING REGIMEN ASSOCIATED WITH LONG ACTING INJECTABLE
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`PALIPERIDONE ESTERS
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`FIELD OF THE INVENTION
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`This invention relates to a method of treating patients in need of treatment with long
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`acting inj ectable paliperidone palmitate formulations.
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`BACKGROUND OF THE INVENTION
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`Antipsychotic medications are the mainstay in the treatment of schizophrenia,
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`schizoaffective disorder, and schizophreniform disorders. Conventional antipsychotics were
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`introduced in the mid-1950s. These typical or first generation drugs are usually effective in
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`controlling the positive symptoms of schizophrenia, but are less effective in moderating the
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`negative symptoms or
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`the cognitive impairment associated with the disease. Atypical
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`antipsychotics or second generation drugs,
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`typified by risperidone and olanzapine, were
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`developed in the 1990s, and are generally characterized by effectiveness against both the
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`positive and negative symptoms associated with schizophrenia.
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`Paliperidone palmitate is the palmitate ester of paliperidone (9-hydroxy-risperidone), a
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`monoaminergic antagonist
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`that exhibits
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`the characteristic dopamine D2 and serotonin
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`(5-hydroxytryptamine type 2A) antagonism of the second-generation, atypical antipsychotic
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`drugs. Paliperidone is the major active metabolite of risperidone. Extended release (ER)
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`osmotic controlled release oral delivery (OROS) paliperidone, as a tablet formulation,
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`is
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`marketed in the United States (U.S.) for the treatment of schizophrenia and maintenance of
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`effect.
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`Paliperidone palmitate is being developed as a long-acting,
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`intramuscular (i.m.),
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`injectable aqueous nanosuspension for the treatment of schizophrenia and other diseases that
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`are normally treated with antipsychotic mediations. Because of extreme low water solubility,
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`paliperidone esters such as paliperidone palmitate dissolve slowly after an i.m. injection before
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`being hydrolyzed to paliperidone and made available in the systemic circulation.
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`Many patients with these mental illnesses achieve symptom stability with available oral
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`antipsychotic medications; however, it is estimated that up to 75% have difficulty adhering to a
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`daily oral treatment regimen, i.e. compliance problems. Problems with adherence often result
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`in worsening of symptoms,
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`suboptimal
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`treatment
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`response,
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`frequent
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`relapses and re-
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`hospitalizations, and an inability to benefit from rehabilitative and psychosocial therapies.
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`Paliperidone palmitate injection has been developed to provide sustained plasma concentrations
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`of paliperidone when administered once monthly, which may greatly enhance compliance with
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`dosing. Paliperidone palmitate was formulated as an aqueous nano suspension as is described
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`in US Patents 6,577,545 and 6,555,544. However, after the data was analyzed from the clinical
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`trials of this formulation it was discovered that the absorption of paliperidone from these
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`injections was far more complex than was originally anticipated. Additionally, attaining a
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`potential therapeutic plasma level of paliperidone in patients was discovered to be dependent on
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`the site of injection until steady state concentration is reached. Due to the challenging nature of
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`ensuring an optimum plasma concentration-time profile for treating patients with paliperidone
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`it is desirable to develop a dosing regimen that fulfills this goal in patients in need of treatment.
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`SUMMARY OF THE INVENTION
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`In one embodiment of the present invention there is provided a dosing regimen
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`for administering paliperidone esters to a psychiatric patient in need of treatment
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`comprising administering intramuscularly in the deltoid a first loading dose from about
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`100 mg—eq. to about 150 mg—eq. of paliperidone as a paliperidone palmitate formulated
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`in a sustained release formulation on the first day of treatment; administering
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`intramuscularly a second loading dose from about 100 mg to about 150 mg—eq 0f
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`paliperidone as a paliperidone palmitate formulated in a sustained release formulation
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`between about the 6th to 10th day of treatment; and administering intramuscularly in
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`the gluteal a maintenance dose of about 25 to about 150 mg—eq. 0f paliperidone as a
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`paliperidone ester in a sustained release formulation on between about the 34th and
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`about the 38th day of treatment.
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`In another embodiment of the present invention there is provided a dosing
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`regimen for administering paliperidone palmitate to a psychiatric patient in need of
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`treatment comprising administering intramuscularly in the deltoid of a patient in need
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`of treatment a first loading dose from about 100 mg—eq. to about 150 mg—eq 0f
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`paliperidone as paliperidone palmitate formulated in a sustained release formulation on
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`the first day of treatment; administering intramuscularly in the deltoid muscle of the
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`patient in need of treatment a second loading dose from about 100 mg—eq. to about 150
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`mg-eq. of paliperidone as paliperidone palmitate formulated in a sustained release
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`formulation on the eighth day of treatment; and administering intramuscularly in the
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`deltoid or gluteal muscle of the patient in need of treatment a maintenance dose of
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`about 25 mg—eq. to about 75 mg—eq. of paliperidone as paliperidone palmitate in a
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`sustained release formulation on about the 34th day and the 38th day of treatment.
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`In yet another embodiment of the present invention there is provided a dosing
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`regimen for administering paliperidone esters to a renally impaired psychiatric patient
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`in need of treatment comprising administering intramuscularly in the deltoid a first
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`loading dose of about 75mg—eq of paliperidone as a paliperidone palmitate formulated
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`in a sustained release formulation on the first day of treatment; administering
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`intramuscularly a second loading dose of about 75 mg—eq of paliperidone as a
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`paliperidone palmitate formulated in a sustained release formulation between about the
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`6th to 10th day of treatment; and administering intramuscularly in the gluteal a
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`maintenance dose of about 25 mg—eq. to about 75 mg—eq of paliperidone as a
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`paliperidone palmitate in a sustained release formulation on between about the 34th and
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`about the 38th day of treatment.
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`In a further embodiment of the present invention there is provided a dosing
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`regimen for administering paliperidone palmitate to a psychiatric patient in need of
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`treatment comprising administering intramuscularly in the deltoid of a patient in need
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`of treatment a first loading dose of about 75 mg—eq. of paliperidone as paliperidone
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`palmitate formulated in a sustained release formulation on the first day of treatment;
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`administering intramuscularly in the deltoid muscle of the patient in need of treatment a
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`second loading dose of about 75 mg—eq of paliperidone as paliperidone palmitate
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`formulated in a sustained release formulation on the eighth day of treatment; and
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`administering intramuscularly in the deltoid or gluteal muscle of the patient in need of
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`treatment a maintenance dose of from about 25 mg—eq. to about 50 mg—eq. of
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`paliperidone as paliperidone palmitate in a sustained release formulation on about the
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`34th day and the 38th day of treatment.
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`In one embodiment of the present invention there is provided a dosing regimen
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`for administering paliperidone esters to a psychiatric patient in need of treatment
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`comprising administering intramuscularly in the deltoid a first loading dose of about
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`150 mg-eq. of paliperidone as a paliperidone palmitate formulated in a sustained
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`release formulation on the first day of treatment; thereafter administering
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`intramuscularly a second maintenance dose of from about 25 mg—eq. to about 100 mg—
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`eq of paliperidone as a paliperidone palmitate formulated in a sustained release
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`formulation between about the 6th to 10th day of treatment; and administering
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`intramuscularly in the gluteal a maintenance dose of about 25 to about 100 mg—eq. of
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`paliperidone as a paliperidone palmitate in a sustained release formulation on between
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`about the 34th and about the 38th day of treatment.
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`In a further embodiment of the present invention there is provided a dosing
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`regimen for administering paliperidone palmitate to a psychiatric patient in need of
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`treatment comprising administering intramuscularly in the deltoid of a patient in need
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`of treatment a first loading dose from about 150 mg-eq. of paliperidone as a
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`paliperidone palmitate ester in a sustained release formulation on the first day of
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`treatment; thereafter administering intramuscularly in the deltoid muscle of the patient
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`in need of treatment a maintenance dose from about 25 mg—eq. to about 100 mg—eq. of
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`paliperidone as paliperidone palmitate formulated in a sustained release formulation on
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`the eighth day of treatment; and administering intramuscularly in the deltoid or gluteal
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`muscle of the patient in need of treatment a maintenance dose of about 25 mg—eq. to
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`about 100 mg-eq. of paliperidone as paliperidone palmitate in a sustained release
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`formulation on about the 34th day and the 38th day of treatment.
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`This and other objects and advantages of the present invention may be
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`appreciated from a review of the present applications.
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`DETAILED DESCRIPTION
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`We have discovered after extensive analysis of the clinical data that paliperidone palmitate
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`due to its dissolution rate-limited absorption exhibits flip-flop kinetics, where the apparent half-life
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`is controlled by the absorption rate constant. Additionally the volume of injected drug product also
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`impacts the apparent rate constant. It was also discovered that deltoid injections result in a faster
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`rise in initial plasma concentration, facilitating a rapid attainment of potential therapeutic
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`concentrations. Consequently, to facilitate patients’ attaining a rapid therapeutic concentration of
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`paliperidone it is preferred to provide the initial loading dose of paliperidone palmitate in the
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`deltoids. The loading dose should be fiom about 100 mg-eq. to about 150 mg-eq. of paliperidone
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`provided in the form of paliperidone palmitate. After the first or more preferably after the second
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`loading dose injection patients will be approaching a steady state concentration of paliperidone in
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`their plasma and may be injected in either the deltoid or the gluteal muscle thereafter. However, it
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`is preferred that the patients receive further injections in the gluteal muscle.
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`In view of these discoveries the recommended dosing regimen for patients to attain
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`a therapeutic plasma level of paliperidone is for patients to receive the first dose of
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`paliperidone palmitate on day l of treatment, followed by a second dose between days 6
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`to 10 of treatment, then a third dose between days 34 to 38 of treatment. More preferably
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`the patients will be administered a first dose on day l, a second dose on day 8 and a third
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`dose on day 36 of treatment. The first two doses will preferably be injected in the deltoid
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`muscle. Thereafter paliperidone palmitate will be administered by injection approximately
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`once a month (e. g. once every four weeks) thereafter. To assure that a potential
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`therapeutic plasma level of paliperidone is attained at least a first loading dose of 150 mg-
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`eq of paliperidone as a paliperidone palmitate ester should be administered on day one of
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`treatment. Preferably the first two doses will be loading dose of between from about 100
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`mg—eq. to about 150 mg—eq. of paliperidone as a paliperidone palmitate ester to assure that
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`a potential therapeutic plasma level of paliperidone is attained by the patient. The
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`subsequent doses thereafter will drop to a therapeutic maintenance dose of from about 25
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`mg—eq. to 150 mg-eq. per month. Preferably the maintenance dose will be from about
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`25mg eq. to about 100 mg eq; more preferably the maintenance dose will be from about
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`25mg eq. to about 75 mg eq; and most preferably the maintenance dose initially will be
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`about 50 mg eq., which may be administered intramuscularly into the deltoid or gluteal
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`muscle, but more preferably will be administered in the gluteal muscle. Those of ordinary
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`skill in the art will understand that the maintenance dose may be titrated up or down in
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`view of the patients condition (response to the medication and renal function).
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`Since paliperidone is mainly eliminated through the kidneys, patients with renal
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`impairment will have a higher total exposure to paliperidone after i.m. injections of
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`paliperidone palmitate. For patients with renal impairment it would desirable to adjust the
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`loading doses to account for the increased exposure levels of patients with renal
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`impairment. For patients with mild renal impairment the loading doses should be reduced
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`to 75 mg—eq. for the first two loading doses. The maintenance doses should range from
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`about 25 mg—eq. to about 75 mg—eq. and more preferably with range from about 25 mg—eq.
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`to about 50 mg—eq. The doses would be administered on day l of treatment, followed by a
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`second dose between days 6 to 10 of treatment, then a third dose between days 34 to 38 of
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`treatment. More preferably the patients will be administered a first dose on day l, a
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`second dose on day 8 and a third dose on day 36 of treatment. The first two doses will
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`preferably be injected in the deltoid muscle. Thereafter paliperidone palmitate will be
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`administered by injection approximately once a month (e. g. once every four weeks)
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`thereafter. For the purpose of this patent application renal function is estimated by
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`glomerular filtration rate (GFR) usually measured by the creatinine clearance (best
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`calculated from a 24-hour urine collection). Creatine clearance may be estimated by the
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`Cockcroft and Gault method based on serum creatinine concentration, as described in
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`Prediction of creatinine clearance from serum creatinine. Nephron 1976; vol 16. pages 31—
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`41. Patients with mild renal impairment have a creatinine clearance of 50 to <80
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`mL/minute.
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`Additionally, in this patient population needle length and BMI index are two related
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`variables that need to be considered to assure patients attain therapeutic concentration of
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`paliperidone in the desired time frame. Patients with high BMI had lower plasma concentration of
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`paliperidone and a lessened treatment response. The lower initial plasma concentration in high
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`BMI patients was likely due to unintended partial or complete injection into adipose tissue, instead
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`of deep injection into muscle. However, once steady-state plasma concentration are attained BMI
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`no longer influenced plasma concentrations or clinical efficacy. From these observations it was
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`determined that for patients weighing <90 kg (< 200 lb) a l-inch needle will be of adequate length
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`to use in injections to reach the muscle tissue for deltoid injections. However, for patients with
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`high BMIs, 290 kg (2 200 lb) a 1.5-inch needle should be used for deltoid injections. For gluteal
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`muscle injections a 1.5-inch needle should be used. Preferably the 1.5-inch needle will be a 22-
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`gauge needle.
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`Paliperidone esters are psychotic agents belonging to the chemical class of
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`benzisoxazole derivatives, which contains a racemic mixture of (+)- and (-)-
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`paliperidone, which are described in US Patent 5,254,556 (incorporated herein by
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`reference). The chemical name for paliperidone palmitate is (i)-3-[2-[4-(6-fiuoro-1,2-
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`benzisoxazol-3 -yl)- 1 -piperidinyl] ethyl] -6,7, 8,9-tetrahydro-2-methyl-4-oxo-4H—
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`pyrido[1,2—a]pyrimidin-9—yl hexadecanoate. The structural formula is:
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`N
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`\O
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`b»!/ |
`\VECAN
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`O O
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`N
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`O
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`(i)
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`F
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`Paliperidone esters may be formulated with pharmaceutical excipients into inj ectable
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`dosage forms as described in US Patent 5,254,556 and US Patent 6,077,843
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`(incorporated herein by reference). Inj ectable formulations may be formulated in
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`aqueous carriers.
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`Currently it is preferred to administer paliperidone palmitate in a once monthly
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`aqueous depot. Suitable aqueous depot formulations are described in US Patent
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`6,077,843 (incorporated herein by reference). The aqueous formulation would
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`preferably be a nano particle suspension of wherein the nano particles would be of an
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`averages size of less than 2000 nm to about 100 nm. Preferably the nano particles
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`would have an average particle size (d50) of from about 1600 nm to 400 nm and most
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`preferably about 1400 nm to 900 nm. Preferably the d90 will be less than about 5000
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`nm and more preferably less than about 4400 nm. As used herein, an effective average
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`particle size (d50) of less than 2,000 nm means that at least 50% of the particles have a
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`diameter of less than 2,000 nm when measured by art-known conventional techniques,
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`such as sedimentation field flow fractionation, photon correlation spectroscopy or disk
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`centrifugation. With reference to the effective average particle size, it is preferred that
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`at least 90%, e. g. 5,000 nm. Most preferably, 90% of the particles have a size of less
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`than 4,400 nm.
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`Suitable aqueous nano particle depot formulations are described in US Patent
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`6,555,544 (incorporated herein by reference). In one embodiment of the present
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`invention the formulation would comprise nanoparticles, a surfactant, a suspending
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`agent, and optionally one or more additional ingredients selected from the group
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`consisting of preservatives, buffers and an isotonizing agents.
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`Useful surface modifiers are believed to include those that physically adhere to the
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`surface of the active agent but do not chemically bond thereto.
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`Suitable surface modifiers can preferably be selected from known organic and
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`inorganic pharmaceutical excipients. Such excipients include various polymers, low
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`molecular weight oligomers, natural products and surfactants. Preferred surface
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`modifiers include nonionic and anionic surfactants. Representative examples of
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`excipients include gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol,
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`tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl
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`monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters,
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`polyoxyethylene alkyl ethers, e. g., macrogol ethers such as cetomacrogol 1000,
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`polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, e. g.,
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`the commercially available TWEENSTM, polyethylene glycols, polyoxyethylene
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`stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate,
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`carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose,
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`hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose
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`phtalate, noncrystalline cellulose, magnesium aluminate silicate, triethanolamine,
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`polyvinyl alcohol (PVA), poloxamers, tyloxapol and polyvinylpyrrolidone (PVP). Most
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`of these excipients are described in detail in the Handbook of Pharmaceutical
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`Excipients, published jointly by the American Pharmaceutical Association and The
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`Pharmaceutical Society of Great Britain, the Pharmaceutical Press, 1986. The surface
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`modifiers are commercially available and/or can be prepared by techniques known in
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`the art. Two or more surface modifiers can be used in combination.
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`Particularly preferred surface modifiers include polyvinylpyrrolidone;
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`tyloxapol; poloxamers, such as PLURONICTM. F68, F108 and F127 which are block
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`copolymers of ethylene oxide and propylene oxide available from BASF; poloxamines,
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`such as TETRONICTM 908 (T908) which is a tetrafunctional block copolymer derived
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`from sequential addition of ethylene oxide and propylene oxide to ethylenediamine
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`available from BASF; dextran; lecithin; Aerosol OTTM (AOT) which is a dioctyl ester
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`of sodium sulfosuccinic acid available from Cytec Industries; DUPONOLTM P which is
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`a sodium lauryl sulfate available from DuPont; TRITONTM X-200 which is an alkyl
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`aryl polyether sulfonate available from Rohm and Haas; TWEENTM. 20, 40, 60 and 80
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`which are polyoxyethylene sorbitan fatty acid esters available from 1C1 Speciality
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`Chemicals; SPANTM 20, 40, 60 and 80 which are sorbitan esters of fatty acids;
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`ARLACELTM 20, 40, 60 and 80 which are sorbitan esters of fatty acids available from
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`Hercules, Inc.; CARBOWAXTM 3550 and 934 which are polyethylene glycols
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`available from Union Carbide; CRODESTATM F110 which is a mixture of sucrose
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`stearate and sucrose distearate available from Croda Inc.; CRODESTATM SL-40 which
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`is available from Croda, Inc.; hexyldecyl trimethyl ammonium chloride (CTAC);
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`bovine serum albumin and SA90HCO which is C18 H17 CH2 (CON(CH3)CH2 (CHOH)4
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`CH2 OH)2. The surface modifiers which have been found to be particularly useful
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`include tyloxapol and a poloxamer, preferably, Pluronic.TM. F108 and Pluronic.TM.
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`F68.
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`Pluronic.TM. F108 corresponds to poloxamer 338 and is the polyoxyethylene,
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`polyoxypropylene block copolymer that conforms generally to the formula HO[CH2
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`CH2 O]X [CH(CH3)CH2 O]y [CH2 CH2 O]Z H in which the average values of x, y and z
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`are respectively 128, 54 and 128. Other commercial names of poloxamer 338 are
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`Hodag NONIONICTM 1108—F available from Hodag, and SYNPERONICTM PE/F108
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`available from 1C1 Americas.
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`The optimal relative amount of paliperidone palmitate and the surface modifier
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`depends on various parameters. The optimal amount of the surface modif1er can
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`depend, for example, upon the particular surface modifier selected, the critical micelle
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`concentration of the surface modifier if it forms micelles, the surface area of the
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`antipsychotic agent, etc. The specific surface modifier preferably is present in an
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`amount of 0.1 to 1 mg per square meter surface area of the paliperidone palmitate. It is
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`preferred in the case of paliperidone palmitate (9-hydroxyrisperidone palmitate) to use
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`PLURONICTM F108 as a surface modifier, a relative amount (w/w) of both ingredients
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`of approximately 6:1 is preferred.
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`The particles of this invention can be prepared by a method comprising the
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`steps of dispersing paliperidone palmitate in a liquid dispersion medium and applying
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`mechanical means in the presence of grinding media to reduce the particle size of the
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`antipsychotic agent to an effective average particle size of less than 2,000 nm. The
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`particles can be reduced in size in the presence of a surface modifier. Alternatively, the
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`particles can be contacted with a surface modifier after attrition.
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`A general procedure for preparing the particles of this invention includes (a)
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`obtaining paliperidone palmitate in micronized form; (b) adding the micronized
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`paliperidone palmitate to a liquid medium to form a premix; and (c) subjecting the
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`premix to mechanical means in the presence of a grinding medium to reduce the
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`effective average particle size.
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`The paliperidone palmitate in micronized form may be prepared using
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`techniques known in the art. It is preferred that the particle size of the micronized
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`paliperidone palmitate be less than about 100 um as determined by sieve analysis. If the
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`particle size of the micronized paliperidone palmitate is greater than about 100 um,
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`then it is preferred that the particles of paliperidone palmitate be reduced in size to less
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`than 100 um.
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`The micronized paliperidone palmitate can then be added to a liquid medium in
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`which it is essentially insoluble to form a premix. The concentration of paliperidone
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`palmitate in the liquid medium (weight by weight percentage) can vary widely and
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`depends on the selected antipsychotic agent, the selected surface modifier and other
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`factors. Suitable concentrations of paliperidone palmitate in compositions vary between
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`0.1 to 60%, preferably is from 0.5 to 30%, and more preferably, is approximately 7%
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`(w/v). It is currently preferred to use a concentration of about 100mg eq of
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`paliperidone per ml or about 156 mg of paliperidone palmitate per ml.
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`A more preferred procedure involves the addition of a surface modifier to the
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`premix prior to its subjection to mechanical means to reduce the effective average
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`particle size. The concentration of the surface modifier (weight by weight percentage)
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`can vary from 0.1% to 90%, preferably from 0.5% to 80%, and more preferably is
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`approximately 7% (w/v).
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`The premix can be used directly by subjecting it to mechanical means to reduce
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`the effective average particle size in the dispersion to less than 2,000 nm. It is preferred
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`that the premix be used directly when a ball mill is used for attrition. Alternatively, the
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`antipsychotic agent and, optionally, the surface modifier, can be dispersed in the liquid
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`medium using suitable agitation such as, for example, a roller mill or a Cowles type
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`mixer, until a homogeneous dispersion is achieved.
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`The mechanical means applied to reduce the effective average particle size of
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`the antipsychotic conveniently can take the form of a dispersion mill. Suitable
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`dispersion mills include a ball mill, an attritor mill, a vibratory mill, a planetary mill,
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`media mills--such as a sand mill and a bead mill. A media mill is preferred due to the
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`relatively shorter milling time required to provide the desired reduction in particle size.
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`For media milling, the apparent viscosity of the premix preferably is anywhere between
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`0.1 and 1 Pa°s. For ball milling, the apparent viscosity of the premix preferably is
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`anywhere between 1 and 100 mPa°s.
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`The grinding media for the particle size reduction step can be selected from
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`rigid media preferably spherical or particulate in form having an average size less than
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`3 mm and, more preferably, less than 1 mm. Such media desirably can provide the
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`particles of the invention with shorter processing times and impart less wear to the
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`milling equipment. The selection of the material for the grinding media is believed not
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`to be critical. However, 95% ZrO stabilized with magnesia, zirconium silicate, and
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`glass grinding media provide particles having levels of contamination which are
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`acceptable for the preparation of pharmaceutical compositions. Further, other media,
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`such as polymeric beads, stainless steel, titania, alumina and 95% ZrO stabilized with
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`yttrium, are useful. Preferred grinding media have a density greater than 2.5 g/cm.sup.3
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`and include 95% ZrO stabilized with magnesia and polymeric beads.
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`The attrition time can vary widely and depends primarily upon the particular
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`mechanical means and processing conditions selected. For rolling mills, processing
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`times of up to two days or longer may be required.
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`The particles must be reduced in size at a temperature which does not
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`significantly degrade the antipsychotic agent. Processing temperatures of less than
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`30°C to 40°C are ordinarily preferred. If desired, the processing equipment may be
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`cooled with conventional cooling equipment. The method is conveniently carried out
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`under conditions of ambient temperature and at processing pressures which are safe and
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`effective for the milling process.
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`The surface modifier, if it was not present in the premix, must be added to the
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`dispersion after attrition in an amount as described for the premix above. Thereafter,
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`the dispersion can be mixed by, for example, shaking vigorously. Optionally, the
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`dispersion can be subjected to a sonication step using, for example, a ultrasonic power
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`supply.
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`Aqueous compositions according to the present invention conveniently further
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`comprise a suspending agent and a buffer, and optionally one or more of a preservative
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`and an isotonizing agent. Particular ingredients may function as two or more of these
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`agents simultaneously, e. g. behave like a preservative and a buffer, or behave like a
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`buffer and an isotonizing agent.
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`Suitable suspending agents for use in the aqueous suspensions according to the
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`present invention are cellulose derivatives, e.g. methyl cellulose, sodium
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`carboxymethyl cellulose and hydroxypropyl methyl cellulose, polyvinylpyrrolidone,
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`alginates, chitosan, dextrans, gelatin, polyethylene glycols, polyoxyethylene- and
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`polyoxy—propylene ethers. Preferably sodium carboxymethyl cellulose is used in a
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`concentration of 0.5 to 2%, most preferably 1% (w/v). Suitable wetting agents for use
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`in the aqueous suspensions according to the present invention are polyoxyethylene
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`derivatives of sorbitan esters, e. g. polysorbate 20 and polysorbate 80, lecithin,
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`polyoxyethylene- and polyoxypropylene ethers, sodium deoxycholate. Preferably
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`polysorbate 20 is used in a concentration of 0.5 to 3%, more preferably 0.5 to 2%, most
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`preferably 1.1% (w/v).
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`Suitable buffering agents are salt of weak acids and should be used in amount
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`sufficient to render the dispersion neutral to very slightly basic (up to pH 8.5),
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`preferably in the pH range of 7 to 7.5. Particularly preferred is the use of a mixture of
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`disodium hydrogen phosphate (anhydrous) (typically about 0.9% (w/v)) and sodium
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`dihydrogen phosphate monohydrate (typically about 0.6% (w/v)). This buffer also
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`renders the dispersion isotonic and, in addition, less prone to flocculation of the ester
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`suspended therein.
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`Preservatives are antimicrobials and anti-oxidants which can be selected from
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`the group consisting of benzoic acid, benzyl alcohol, butylated hydroxyanisole,
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`butylated hydroxytoluene, chlorbutol, a gallate, a hydroxybenzoate, EDTA, phenol,
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`chlorocresol, metacresol, benzethonium chloride, myristyl—gamma—piccolinium
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`chloride, phenylmercuric acetate and thimerosal. In particular, it is benzyl alcohol
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`which can be used in a concentration up to 2% (w/v), preferably up to 1.5% (w/v).
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`Isotonizing agents are, for example, sodium chloride, dextrose, mannitol,
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`sorbitol, lactose, sodium sulfate. The suspensions conveniently comprise from 0 to 10%
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`(w/v) isotonizing agent. Manni