PROVISIONAL APPLICATION COVER SHEET
`
`Commissioner For Patents
`PO. Box 1450
`Alexandria, VA 22313-1450
`
`This is a request for filino a PROVISIONAL APPLICATION under 37 CFR 1.53 c .
`PRD2901USPSP2
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`LAST NAME
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`|NVENTOR(s) l APPLICANT(s)
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`Vermeulen
`Wouters
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`An
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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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`Direct all correspondence to:
`IE Customer Number 000027777
`OR
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`I:I Firm of Individual Name:
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`I:I A check or money order is enclosed to cover the Provisional filing
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`The Commissioner is hereby authorized to charge filing fees and
`credit any overpayment to Deposit Account No. 10-
`0750/PRD2901USPSP2/HBW
`The invention was made by an agency of the United States Government or under a contract with an agency of the United States
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`I:I 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/
`
`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 5 2008
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`TELEPHONE (732) 524-2976
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`PROV S ONAT. ABET. CAT ON 12'
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`DOSING REGIMEN ASSOCIATED WITH LONG ACTING INJECTABLE
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`PALIPERIDONE ESTERS
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`PRD2901USPSP2
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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
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`long acting injectable 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
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`were introduced in the mid-1950s. These typical or first generation drugs are usually
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`effective in controlling the positive symptoms of schizophrenia, but are less effective in
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`moderating the negative symptoms or the cognitive impairment associated with the
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`disease. Atypical antipsychotics or second generation drugs, typified by risperidone and
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`olanzapine, were developed in the 1990s,
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`and are generally characterized by
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`effectiveness against both the positive and negative symptoms associated with
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`schizophrenia.
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`Paliperidone
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`palmitate
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`is
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`the
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`palmitate
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`ester
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`of
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`paliperidone
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`(9-hydroxy-risperidone), a monoaminergic antagonist that exhibits the characteristic
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`dopamine D2 and serotonin (5-hydroxytryptamine type 2A) antagonism of the
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`second—generation, atypical antipsychotic drugs. Paliperidone is the major active
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`metabolite of risperidone. Extcndcd rclcasc (ER) osmotic controlled release oral
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`delivery (OROS) paliperidone, as a tablet formulation, is marketed in the United States
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`(U.S.) for the treatment of schizophrenia and maintenance of effect.
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`Paliperidone palmitate is being developed as a long-acting, intramuscular (i.m.),
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`injectable aqueous nanosuspension for the treatment of schizophrenia and other
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`diseases that are normally treated with antipsychotic mediations. Because of extreme
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`low water solubility, paliperidone esters such as paliperidone palmitate dissolve slowly
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`PRD2901USPSP2
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`after an i.m. injection before being hydrolyzed to paliperidone and made available in
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`the systemic circulation.
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`Many patients with these mental
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`illnesses achieve symptom stability with
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`available oral antipsychotic medications; however, it is estimated that up to 75% have
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`difficulty adhering to a daily oral
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`treatment regimen,
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`i.e. compliance problems.
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`Problems with adherence often result in worsening of symptoms, suboptimal treatment
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`response, frequent relapses and re—hospitalizations, and an inability to benefit from
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`rehabilitative and psychosocial therapies.
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`Paliperidone palmitate injection has been developed to provide sustained plasma
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`concentrations of paliperidone when administered once monthly, which may greatly
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`enhance compliance with dosing. Paliperidone palmitate was formulated as an aqueous
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`nano suspension as is described in US Patents 6,577,545 and 6,555,544. However,
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`after the data was analyzed from the clinical trials of this formulation it was discovered
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`that the absorption of paliperidone from these injections was far more complex than
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`was originally anticipated. Additionally, attaining a potential therapeutic plasma level
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`of paliperidone in patients was discovered to be dependent on the site of injection until
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`steady state concentration is reached. Due to the challenging nature of ensuring an
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`optimum plasma concentration-time profile for treating patients with paliperidone it is
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`desirable to develop a dosing regimen that fulfills this goal in patients in need of
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`treatment.
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`BREIF DESCRIPTION OF THE FIGURES
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`Figure 1 shows the observed versus the population pharmacokinetics model
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`simulation for plasma paliperidone concentrations for paliperidone palmitate 150 mg
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`25
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`eq. in the deltoid on day 1, followed by 25 mg eq. in either the deltoid 0r gluteus on
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`days 8, 36, and 64.
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`Figure 2 shows the observed versus the population pharmacokinetics model
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`simulation for plasma paliperidone concentrations for paliperidone palmitate 150 mg
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`eq. in the deltoid on day 1, followed by 100 mg eq. in either the deltoid or gluteus on
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`days 8, 36, and 64.
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`PRD2901USPSP2
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`Figure 1 shows the observed versus the population pharmaeokineties model
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`simulation for plasma paliperidone concentrations for paliperidone palmitate 150 mg
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`eq. in the deltoid on day 1, followed by 150 mg eq. in either the deltoid or gluteus on
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`days 8, 36, and 64.
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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 of
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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. of paliperidone as a
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`paliperidone ester in a sustained release formulation on between about the 34111 and
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`about 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 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 of
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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. of paliperidone as a
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`paliperidone ester in a sustained release formulation approximately monthly from the
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`date of the second loading dose.
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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 of
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`PRD2901USPSP2
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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 between about the 34th day and the 38th day of
`
`treatment.
`
`In another embodiment of the present invention there is provided a dosing
`
`regimen for administering paliperidone palmitate to a psychiatric patient in need of
`
`treatment comprising administering intramuscularly in the deltoid of a patient in need
`
`of treatment a first loading dose of about 150 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 from about 100 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 about 25 mg-eq. to about 75 mg-eq. of paliperidone as
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`paliperidone palmitate in a sustained release formulation approximately monthly from
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`the date of the second loading dose.
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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 of about 150 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 from about 100 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 about 75 mg—eq. of paliperidone as paliperidone
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`palmitate in a sustained release formulation approximately monthly from the date of the
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`second loading dose.
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`PRD2901USPSP2
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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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`10
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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 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 lOOmg—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 approximately monthly from
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`the date of the second loading dose.
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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
`
`of treatment a first loading dose of about 75 mg—eq. of paliperidone as paliperidone
`
`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
`
`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.
`
`In one embodiment of the present invention there is provided a dosing regimen
`
`for administering paliperidone esters to a psychiatric patient in need of treatment
`
`comprising administering intramuscularly in thc dcltoid a first loading dose of about
`
`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
`
`regimen for administering paliperidone palmitate to a psychiatric patient in need of
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`treatment comprising administcring intramuscularly in thc dcltoid of a patient in nccd
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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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`palipcridonc 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
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`palmitate due to its dissolution rate-limited absorption exhibits flip-flop kinetics, where the
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`PRD2901USPSP2
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`apparent half-life is controlled by the absorption rate constant. Additionally the volume of
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`injected drug product also impacts the apparent rate constant. It was also discovered that
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`deltoid injections result in a faster rise in initial plasma concentration, facilitating a rapid
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`attainment of potential therapeutic concentrations. Consequently, to facilitate patients’
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`attaining a rapid therapeutic concentration of paliperidone it is preferred to provide the
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`initial loading dose of paliperidone palmitate in the deltoids. The loading dose should be
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`from about 100 mg-eq. to about 150 mg-eq. of paliperidone provided in the form of
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`paliperidone palmitate. After the first or more preferably after the second loading dose
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`injection patients will be approaching a steady state concentration of paliperidone in their
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`plasma and may be injected in either the deltoid or the gluteal muscle thereafter. However,
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`it 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 1 of treatment, followed by a second dose between days 6 to
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`10 of treatment, then a third dose between days 34 to 38 of treatment or monthly ::7 days
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`after the second dose. More preferably the patients will be administered a first dose on day
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`l, a second dose on day 8 and a third dose on or about day 36 of treatment or
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`approximately monthly ::3 days after the second dose. The first two doses will preferably
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`be injected in the deltoid muscle. Thereafter paliperidone palmitate will be administered
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`by injection approximately once a month (e.g. monthly ::7days or approximately once
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`every four weeks) thereafter. To assure that a potential therapeutic plasma level of
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`paliperidone is attained at least a first loading dose of 150 mg-eq of paliperidone as a
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`paliperidone palmitate ester should be administered on day one of treatment. Preferably
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`the first two doses will be loading dose of between from about 100 mg-eq. to about 150
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`mg—eq. of paliperidone as a paliperidone palmitate ester to assure that a potential
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`therapeutic plasma level of paliperidone is attained by the patient. The subsequent doses
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`thereafter will drop to a therapeutic maintenance dose of from about 25 mg-eq. to 150 mg-
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`eq. per month (i7 days). Preferably the maintenance dose will be from about 25mg eq. to
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`about 100 mg eq; more preferably the maintenance dose will be from about 25mg eq. to
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`about 75 mg eq; and most preferably the maintenance dose initially will be about 50 mg
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`eq., or more preferably the maintenance dose initially will be about 75 mg eq.which may
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`be administered intramuscularly into the deltoid or gluteal muscle, but more preferably
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`will be administered in the gluteal muscle. Those of ordinary skill in the art will
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`understand that the maintenance dose may be titrated up or down in view of the patients
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`condition (response to the medication and renal filnction).
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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 1 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. one a month :7 days or once
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`every four weeks) thereafter. For the purpose of this patent application renal function is
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`estimated by glomerular filtration rate (GFR) usually measured by the creatinine clearance
`
`(best calculated from a 24-hour urine collection). Creatine clearance may be estimated by
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`the Co ckcroft 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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`It is recommended that the second initiation dose of paliperidone palmitate be
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`given about one week (6-10 days) after the first dose. To avoid a missed dose, patients
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`may be given the second dose 2 days before or after the one-week timepoint. Similarly,
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`the third and subsequent injections after the initiation regimen are recommended to be
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`given monthly. To avoid a missed monthly dose, patients may be given the injection up
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`to 7 days before or after the monthly timepoint.
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`After initiation, the recommended injection cycle of paliperidone palmitate is
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`monthly. If less than 6 weeks have elapsed since the last injection, then the previously
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`stabilized dose should be administered as soon as possible, followed by injections at
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`monthly intervals.
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`If more than 6 weeks have elapsed since the last injection, reinitiation with the
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`same dose the patient was previously stabilized to should be resumed in the following
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`manner: 1) a deltoid injection as soon as practically possible, followed by 2) another
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`deltoid injection one week later, and 3) resumption of either deltoid or gluteal dosing at
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`monthly intervals.
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`If more than 6 months have elapsed since the last injection, it is recommended
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`to re-initiate dosing as described above.
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`Additionally, in this patient population needle length and BMI index are two
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`related variables that need to be considered to assure patients attain therapeutic
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`conccntration of palipcridonc in thc dcsircd timc framc. Paticnts with high BMI had lowcr
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`plasma concentration of paliperidone and a lessened treatment response. The lower initial
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`plasma concentration in high BMI patients was likely due to unintended partial or
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`complete injection into adipose tissue, instead of deep injection into muscle. However,
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`once steady—state plasma concentration are attained BMI no longer influenced plasma
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`concentrations or clinical efficacy. From these observations it was determined that for
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`patients weighing <90 kg (< 200 lb) a l-inch needle will be of adequate length to use in
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`injections to reach the muscle tissue for deltoid injections with preferably a 23 gauge
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`needle. However, for patients with high BMIs, 290 kg (2 200 lb) a 1.5-inch needle should
`
`be used for deltoid injections. For gluteal muscle injections a 1.5—inch needle should be
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`used. Preferably the 1.5—inch needle will be a 22—gauge needle.
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`Paliperidone esters are psychotic agents belonging to the chemical class of
`
`benzisoxazole derivatives, which contains a racemic mixture of (+)- and (-)-
`
`paliperidone, which are described in US Patent 5,254,556 (incorporated herein by
`
`reference). The chemical name for palipcridonc palmitate is (i)-3-[2-[4-(6-fluoro-l,2-
`
`benzisoxazol—3 —yl)— 1 —piperidinyl] ethyl] —6,7, 8 ,9—tetrahydro—2—methyl—4—oxo—4H—
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`pyrido[l ,2-a]pyrimidin-9-yl hexadecanoate. The structural formula is:
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`Mylan v. Janssen (IPR2020-00440) Ex. 1017 p. 010
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`PRD2901USPSP2
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`Paliperidone esters may be formulated with pharmaceutical excipients into injectable
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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). Injectable 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% ofthe 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 nanopartieles, 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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`1O
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`PRD2901USPSP2
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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, mcthylccllulosc,
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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 polyvinylpyr'rolidone;
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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 ICI 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, Ine.; 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 usefill
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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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`PRD2901USPSP2
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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 llO8-F availablc from Hodag, and SYNPERONICTM PE/F108
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`available from ICI 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 modifier 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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`Thc particlcs of this invcntion can bc prcparcd by a mcthod comprising thc
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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 bc contactcd with a surfacc modificr aftcr 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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`PRD2901USPSP2
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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 age