PROVISIONAL APPLICATION COVER SHEET
`
`Commissioner For Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`This is a request for filing a PROVISIONAL APPLICATION under 37 CFR 1.53 (c).
`DOCKET
`PRD2901USPSPPRD
`NUMBER
`2901USPSP2
`
`INVENTOR(s) / APPLICANT(s)
`
`LAST NAME
`
`FIRST NAME
`
`MIDDLE
`INITIAL
`
`RESIDENCE
`(CITY AND EITHER STATE OR FOREIGN COUNTRY)
`
`Vermeulen
`Wouters
`
`An
`Alfons
`
`TURNHOUTSEWEG 30 BEERSE BE
`TURNHOUTSEWEG 30 BEERSE BE
`
`TITLE OF THE INVENTION (280 characters max)
`DOSING REGIMEN ASSOCIATED WITH LONG ACTING INJECTABLE
`PALIPERIDONE ESTERS
`
`CORRESPONDENCE ADDRESS
`
`Direct all correspondence to:
`Direct all correspondence to:
` Customer Number 000027777
`OR
`
`□ Firm of Individual Name:
`ENCLOSED APPLICATION PARTS (check all that apply)
`□ Application Data Sheet
`Number of
`Pages
`Number of
`□ CD(s), Number
`Claims
`□ Other (specify)
`
` Specification
`
` Claims
`□ Drawing(s)
`
`Number of
`Sheets
`
`4360
`
`34
`
`3
`
`-
`
`____
`___
`
`I
`
`METHOD OF PAYMENT (check one)
`□ A check or money order is enclosed to cover the Provisional
`
`Provisional Filing
`
`$
`
`Fee Amount ($)
`
`0
`
`200210.0
`
`filing fees.
` 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
`Government.
` No
`
`□ Yes, the name of the U.S. Government agency and the Government contract number are:
`
`Respectfully submitted,
`
`SIGNATURE:
`
`/Hal Brent Woodrow/
`
`REGISTRATION NO. 32,501
`
`TYPED or PRINTED NAME
`
`Hal B. Woodrow
`
`DATE: December 19, 20075, 2008
`
`TELEPHONE
`
`(732) 524-2976
`PROVISIONAL APPLICATION FILING ONLY
`
`142335459v1
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`PRD2901USPSPPRD2901USPSP2
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`DOSING REGIMEN ASSOCIATED WITH LONG ACTING INJECTABLE
`PALIPERIDONE ESTERS
`
`FIELD OF THE INVENTION
`
`This invention relates to a method of treating patients in need of treatment with long
`acting injectable paliperidone palmitate formulations.
`
`BACKGROUND OF THE INVENTION
`
`Antipsychotic medications are the mainstay in the treatment of schizophrenia,
`schizoaffective disorder, and schizophreniform disorders. Conventional antipsychotics were
`introduced in the mid-1950s. These typical or first generation drugs are usually effective in
`controlling the positive symptoms of schizophrenia, but are less effective in moderating the
`negative symptoms or the cognitive impairment associated with the disease. Atypical
`antipsychotics or second generation drugs, typified by risperidone and olanzapine, were
`developed in the 1990s, and are generally characterized by effectiveness against both the positive
`and negative symptoms associated with schizophrenia.
`Paliperidone palmitate is the palmitate ester of paliperidone (9-hydroxy-risperidone), a
`monoaminergic antagonist that exhibits the characteristic dopamine D2 and serotonin (5-
`hydroxytryptamine type 2A) antagonism of the second-generation, atypical antipsychotic drugs.
`Paliperidone is the major active metabolite of risperidone. Extended release (ER) osmotic
`controlled release oral delivery (OROS) paliperidone, as a tablet formulation, is marketed in the
`United States (U.S.) for the treatment of schizophrenia and maintenance of effect.
`Paliperidone palmitate is being developed as a long-acting, intramuscular (i.m.),
`injectable aqueous nanosuspension for the treatment of schizophrenia and other diseases that are
`normally treated with antipsychotic mediations. Because of extreme low water solubility,
`paliperidone esters such as paliperidone palmitate dissolve slowly after an i.m. injection before
`being hydrolyzed to paliperidone and made available in the systemic circulation.
`Many patients with these mental illnesses achieve symptom stability with available oral
`antipsychotic medications; however, it is estimated that up to 75% have difficulty adhering to a
`daily oral treatment regimen, i.e. compliance problems. Problems with adherence often result in
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`worsening of symptoms, suboptimal treatment response, frequent relapses and re-
`hospitalizations, and an inability to benefit from rehabilitative and psychosocial therapies.
`Paliperidone palmitate injection has been developed to provide sustained plasma
`concentrations of paliperidone when administered once monthly, which may greatly enhance
`compliance with dosing. Paliperidone Palmitate was formulated as an aqueous nano suspension
`as is described in US Patents 6,577,545 and 6,555,544. However, after the data was analyzed
`from the clinical trials of this formulation it was discovered that the absorption of paliperidone
`from these injections was far more complex than was originally anticipated. Additionally,
`attaining a potential therapeutic plasma level of paliperidone in patients was discovered to be
`dependent on the site of injection until steady state concentration is reached. Due to the
`challenging nature of ensuring an optimum plasma concentration-time profile for treating
`patients with paliperidone it is desirable to develop a dosing regimen that fulfills this goal in
`patients in need of treatment.
`BRIEF DESCRIPTION OF THE FIGURES
`
`Figure 1 shows the observed versus the population pharmacokinetics model simulation
`for plasma paliperidone concentrations for paliperidone palmitate 150 mg eq. in the deltoid on
`day 1, followed by 25 mg eq. in either the deltoid or gluteus on days 8, 36, and 64.
`Figure 2 shows the observed versus the population pharmacokinetics model simulation
`for plasma paliperidone concentrations for paliperidone palmitate 150 mg eq. in the deltoid on
`day 1, followed by 100 mg eq. in either the deltoid or gluteus on days 8, 36, and 64.
`Figure 1 shows the observed versus the population pharmacokinetics model simulation
`for plasma paliperidone concentrations for paliperidone palmitate 150 mg eq. in the deltoid on
`day 1, followed by 150 mg eq. in either the deltoid or gluteus on days 8, 36, and 64.
`
`SUMMARY OF THE INVENTION
`
`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 the deltoid a first loading dose from about 100 mg-eq. to about
`150 mg-eq. of paliperidone as a paliperidone palmitate formulated in a sustained release
`formulation on the first day of treatment; administering intramuscularly a second loading dose
`from about 100 mg to about 150 mg-eq of paliperidone as a paliperidone palmitate formulated in
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`a sustained release formulation between about the 6th to 10th day of treatment; and
`administering intramuscularly in the gluteal a maintenance dose of about 25 to about 150 mg-eq.
`of paliperidone as a paliperidone ester in a sustained release formulation on between about the
`34th and about 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 the deltoid a first loading dose from about 100 mg-eq. to about
`150 mg-eq. of paliperidone as a paliperidone palmitate formulated in a sustained release
`formulation on the first day of treatment; administering intramuscularly a second loading dose
`from about 100 mg to about 150 mg-eq of paliperidone as a paliperidone palmitate formulated in
`a sustained release formulation between about the 6th to 10th day of treatment; and
`administering intramuscularly in the gluteal a maintenance dose of about 25 to about 150 mg-eq.
`of paliperidone as a paliperidone ester in a sustained release formulation approximately monthly
`from the date of the second loading dose.
`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
`from about 100 mg-eq. to about 150 mg-eq of paliperidone as paliperidone palmitate formulated
`in a sustained release formulation on the first day of treatment; administering intramuscularly in
`the deltoid muscle of the patient in need of treatment a second loading dose from about 100 mg-
`eq. to about 150 mg-eq. of paliperidone as paliperidone palmitate formulated in a sustained
`release formulation on the eighth day of treatment; and administering intramuscularly in the
`deltoid or gluteal muscle of the patient in need of treatment a maintenance dose of about 25 mg-
`eq. to about 75 mg-eq. of paliperidone as paliperidone palmitate in a 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 palmitate formulated in a sustained release
`formulation on the first day of treatment; administering intramuscularly in the deltoid muscle of
`the patient in need of treatment a second loading dose from about 100 mg-eq. of paliperidone as
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`paliperidone palmitate formulated in a sustained release formulation on the eighth day of
`treatment; and administering intramuscularly in the deltoid or gluteal muscle of the patient in
`need of treatment a maintenance dose of about 25 mg-eq. to about 75 mg-eq. of paliperidone as
`paliperidone palmitate in a sustained release formulation approximately monthly from the date of
`the second loading dose.
`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 palmitate formulated in a sustained release
`formulation on the first day of treatment; administering intramuscularly in the deltoid muscle of
`the patient in need of treatment a second loading dose from about 100 mg-eq. of paliperidone as
`paliperidone palmitate formulated in a sustained release formulation on the eighth day of
`treatment; and administering intramuscularly in the deltoid or gluteal muscle of the patient in
`need of treatment a maintenance dose of about 75 mg-eq. of paliperidone as paliperidone
`palmitate in a sustained release formulation approximately monthly from the date of the second
`loading dose.
`In yet another embodiment of the present invention there is provided a dosing regimen
`for administering paliperidone esters to a renally impaired psychiatric patient in need of
`treatment comprising administering intramuscularly in the deltoid a first loading dose of about
`75mg-eq of paliperidone as a paliperidone palmitate formulated in a sustained release
`formulation on the first day of treatment; administering intramuscularly a second loading dose of
`about 75 mg-eq of paliperidone as a paliperidone palmitate formulated in a sustained release
`formulation between about the 6th to 10th day of treatment; and administering intramuscularly in
`the gluteal a maintenance dose of about 25 mg-eq. to about 75 mg-eq of paliperidone as a
`paliperidone palmitate in a sustained release formulation on between about the 34th and about
`the 38th day of treatment.
`In yet another embodiment of the present invention there is provided a dosing regimen
`for administering paliperidone esters to a renally impaired psychiatric patient in need of
`treatment comprising administering intramuscularly in the deltoid a first loading dose of about
`100mg-eq of paliperidone as a paliperidone palmitate formulated in a sustained release
`formulation on the first day of treatment; administering intramuscularly a second loading dose of
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`about 75 mg-eq of paliperidone as a paliperidone palmitate formulated in a sustained release
`formulation between about the 6th to 10th day of treatment; and administering intramuscularly in
`the gluteal a maintenance dose of about 25 mg-eq. to about 75 mg-eq of paliperidone as a
`paliperidone palmitate in a sustained release formulation approximately monthly from the date of
`the second loading dose.
`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 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; administering intramuscularly in the deltoid muscle of
`the patient in need of treatment a second loading dose of about 75 mg-eq of paliperidone as
`paliperidone palmitate formulated in a sustained release formulation on the eighth day of
`treatment; and 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
`paliperidone as paliperidone palmitate in a sustained release formulation on about the 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 the deltoid a first loading dose of about 150 mg-eq. of
`paliperidone as a paliperidone palmitate formulated in a sustained release formulation on the first
`day of treatment; thereafter administering intramuscularly a second maintenance dose of from
`about 25 mg-eq. to about 100 mg-eq of paliperidone as a paliperidone palmitate formulated in a
`sustained release formulation between about the 6th to 10th day of treatment; and administering
`intramuscularly in the gluteal a maintenance dose of about 25 to about 100 mg-eq. of
`paliperidone as a paliperidone palmitate in a sustained release formulation on between about the
`34th and about the 38th day of treatment.
`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 treatment comprising
`administering intramuscularly in the deltoid of a patient in need of treatment a first loading dose
`from about 150 mg-eq. of paliperidone as a paliperidone palmitate ester in a sustained release
`formulation on the first day of treatment; thereafter administering intramuscularly in the deltoid
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`muscle of the patient in need of treatment a maintenance dose from about 25 mg-eq. to about
`100 mg-eq. of paliperidone as paliperidone palmitate formulated in a sustained release
`formulation on the eighth day of treatment; and administering intramuscularly in the deltoid or
`gluteal muscle of the patient in need of treatment a maintenance dose of about 25 mg-eq. to
`about 100 mg-eq. of paliperidone as paliperidone palmitate in a sustained release formulation on
`about the 34th day and the 38th day of treatment.
`
`This and other objects and advantages of the present invention may be appreciated from a
`review of the present applications.
`
`DETAILED DESCRIPTION
`
`We have discovered after extensive analysis of the clinical data that paliperidone
`palmitate due to its dissolution rate-limited absorption exhibits flip-flop kinetics, where the
`apparent half-life is controlled by the absorption rate constant. Additionally the volume of
`injected drug product also impacts the apparent rate constant. It was also discovered that deltoid
`injections result in a faster rise in initial plasma concentration, facilitating a rapid attainment of
`potential therapeutic concentrations. Consequently, to facilitate patients’ attaining a rapid
`therapeutic concentration of paliperidone it is preferred to provide the initial loading dose of
`paliperidone palmitate in the deltoids. The loading dose should be from about 100 mg-eq. to
`about 150 mg-eq. of paliperidone provided in the form of paliperidone palmitate. After the first
`or more preferably after the second loading dose injection patients will be approaching a steady
`state concentration of paliperidone in their plasma and may be injected in either the deltoid or the
`gluteal muscle thereafter. However, it is preferred that the patients receive further injections in
`the gluteal muscle.
`In view of these discoveries the recommended dosing regimen for patients to attain a
`therapeutic plasma level of paliperidone is for patients to receive the first dose of paliperidone
`palmitate on day 1 of treatment, followed by a second dose between days 6 to 10 of treatment,
`then a third dose between days 34 to 38 of treatment. or monthly ±7 days after the second dose.
`More preferably the patients will be administered a first dose on day 1, a second dose on day
`8 and a third dose on or about day 36 of treatment. or approximately monthly +3 days after the
`second dose. The first two doses will preferably be injected in the deltoid muscle. Thereafter
`paliperidone palmitate will be administered by injection approximately once a month (e.g.
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`PRD2901USPSPPRD2901USPSP2
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`monthly ±7 days or approximately once every four weeks) thereafter. To assure that a potential
`therapeutic plasma level of paliperidone is attained at least a first loading dose of 150 mg-eq of
`paliperidone as a paliperidone palmitate ester should be administered on day one of treatment.
`Preferably the first two doses will be loading dose of between from about 100 mg-eq. to about
`150 mg-eq. of paliperidone as a paliperidone palmitate ester to assure that a potential therapeutic
`plasma level of paliperidone is attained by the patient. The subsequent doses thereafter will drop
`to a therapeutic maintenance dose of from about 25 mg-eq. to 150 mg-eq. per month. (+7 days).
`Preferably the maintenance dose will be from about 25mg eq. to about 100 mg eq; more
`preferably the maintenance dose will be from about 25mg eq. to about 75 mg eq; and most
`preferably the maintenance dose initially will be about 50 mgeq., or more preferably the
`maintenance dose initially will be about 75 mg-eq.which may be administered intramuscularly
`into the deltoid or gluteal muscle, but more preferably will be administered in the gluteal muscle.
`Those of ordinary skill in the art will understand that the maintenance dose may be titrated up or
`down in view of the patients condition (response to the medication and renal function).
`Since paliperidone is mainly eliminated through the kidneys, patients with renal
`impairment will have a higher total exposure to paliperidone after i.m. injections of paliperidone
`palmitate. For patients with renal impairment it would be desirable to adjust the loading doses to
`account for the increased exposure levels of patients with renal impairment. For patients with
`mild renal impairment the loading doses should be reduced to 75 mg-eq. for the first two loading
`doses. The maintenance doses should range from about 25 mg-eq. to about 75 mg-eq. and more
`preferably with range from about 25 mg-eq. to about 50 mg-eq. The doses would be
`administered on day 1 of treatment, followed by a second dose between days 6 to 10 of
`treatment, then a third dose between days 34 to 38 of treatment. More preferably the patients
`will be administered a first dose on day 1, a second dose on day 8 and a third dose on day 36 of
`treatment. The first two doses will preferably be injected in the deltoid muscle. Thereafter
`paliperidone palmitate will be administered by injection approximately once a month (e.g. one a
`month ±7 days or once every four weeks) thereafter. For the purpose of this patent application
`renal function is 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 the 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 31-41.
`Patients with mild renal impairment have a creatinine clearance of 50 to <80 mL/minute.
`It is recommended that the second initiation dose of paliperidone palmitate be given
`about one week (6-10 days) after the first dose. To avoid a missed dose, patients may be given
`the second dose 2 days before or after the one-week timepoint. Similarly, the third and
`subsequent injections after the initiation regimen are recommended to be given monthly. To
`avoid a missed monthly dose, patients may be given the injection up to 7 days before or after the
`monthly timepoint.
`After initiation, the recommended injection cycle of paliperidone palmitate is monthly. If
`less than 6 weeks have elapsed since the last injection, then the previously stabilized dose should
`be administered as soon as possible, followed by injections at monthly intervals.
`If more than 6 weeks have elapsed since the last injection, reinitiation with the same dose
`the patient was previously stabilized to should be resumed in the following manner: 1) a deltoid
`injection as soon as practically possible, followed by 2) another deltoid injection one week later,
`and 3) resumption of either deltoid or gluteal dosing at monthly intervals.
`If more than 6 months have elapsed since the last injection, it is recommended to
`re-initiate dosing as described above.
`Additionally, in this patient population needle length and BMI index are two related
`variables that need to be considered to assure patients attain therapeutic concentration of
`paliperidone in the desired time frame. Patients with high BMI had lower plasma concentration
`of paliperidone and a lessened treatment response. The lower initial plasma concentration in
`high BMI patients was likely due to unintended partial or complete injection into adipose tissue,
`instead of deep injection into muscle. However, once steady-state plasma concentration are
`attained BMI no longer influenced plasma concentrations or clinical efficacy. From these
`observations it was determined that for patients weighing <90 kg (< 200 lb) a 1-inch needle will
`be of adequate length to use in injections to reach the muscle tissue for deltoid injections. with
`preferably a 23 gauge needle. However, for patients with high BMIs, >90 kg (> 200 lb) a 1.5-
`inch needle should be used for deltoid injections. For gluteal muscle injections a 1.5-inch needle
`should be used. Preferably the 1.5-inch needle will be a 22-gauge needle.
`Paliperidone esters are psychotic agents belonging to the chemical class of benzisoxazole
`derivatives, which contains a racemic mixture of (+)- and (-)-paliperidone, which are described
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`in US Patent 5,254,556 (incorporated herein by reference). The chemical name for paliperidone
`palmitate is (±)-3-[2-4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethyl]-6,7,8,9-tetrahydro-
`2-methyl-4-oxo-4H-pyrido [1,2-a]pyrimidin-9-yl hexadecanoate. The structural formula is:
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`Paliperidone esters may be formulated with pharmaceutical excipients into injectable dosage
`forms as described in US Patent 5,254,556 and US Patent 6,077,843 (incorporated herein by
`reference). Injectable formulations may be formulated in aqueous carriers.
`Currently it is preferred to administer paliperidone palmitate in a once monthly aqueous
`depot. Suitable aqueous depot formulations are described in US Patent 6,077,843 (incorporated
`herein by reference). The aqueous formulation would preferably be a nano particle suspension
`of wherein the nano particles would be of an averages size of less than 2000 nm to about 100 nm.
`Preferably the nano particles would have an average particle size (d50) of from about 1600 nm to
`400 nm and most preferably about 1400 nm to 900 nm. Preferably the d90 will be less than
`about 5000 nm and more preferably less than about 4400 nm. As used herein, an effective
`average particle size (d50) of less than 2,000 nm means that at least 50% of the particles have a
`diameter of less than 2,000 nm when measured by art-known conventional techniques, such as
`sedimentation field flow fractionation, photon correlation spectroscopy or disk centrifugation.
`With reference to the effective average particle size, it is preferred that at least 90%, e.g.
`5,000 nm. Most preferably, 90% of the particles have a size of less than 4,400 nm.
`Suitable aqueous nano particle depot formulations are described in US Patent 6,555,544
`(incorporated herein by reference). In one embodiment of the present invention the formulation
`would comprise nanoparticles, a surfactant, a suspending agent, and optionally one or more
`additional ingredients selected from the group consisting of preservatives, buffers and an
`isotonizing agents.
`Useful surface modifiers are believed to include those that physically adhere to the surface of the
`active agent but do not chemically bond thereto.
`Suitable surface modifiers can preferably be selected from known organic and inorganic
`pharmaceutical excipients. Such excipients include various polymers, low molecular weight
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`oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and
`anionic surfactants. Representative examples of excipients include gelatin, casein, lecithin
`(phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium
`stearate, glyceryl monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan
`esters, polyoxyethylene alkyl ethers, e.g., macrogol ethers such as cetomacrogol 1000,
`polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, e.g., the
`commercially available TWEENSTM, polyethylene glycols, polyoxyethylene stearates, colloidal
`silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium,
`carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose,
`hydroxypropylcellulose, hydroxypropylmethylcellulose phtalate, noncrystalline cellulose,
`magnesium aluminate silicate, triethanolamine, polyvinyl alcohol (PVA), poloxamers, tyloxapol
`and polyvinylpyrrolidone (PVP). Most of these excipients are described in detail in the
`Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical
`Association and The Pharmaceutical Society of Great Britain, the Pharmaceutical Press, 1986.
`The surface modifiers are commercially available and/or can be prepared by techniques known
`in the art. Two or more surface modifiers can be used in combination.
`Particularly preferred surface modifiers include polyvinylpyrrolidone; tyloxapol;
`poloxamers, such as PLURONICTM. F68, F108 and F127 which are block copolymers of
`ethylene oxide and propylene oxide available from BASF; poloxamines, such as TETRONICTM
`908 (T908) which is a tetrafunctional block copolymer derived from sequential addition of
`ethylene oxide and propylene oxide to ethylenediamine available from BASF; dextran; lecithin;
`Aerosol OTTM (AOT) which is a dioctyl ester of sodium sulfosuccinic acid available from Cytec
`Industries; DUPONOLTM P which is a sodium lauryl sulfate available from DuPont; TRITONTM
`X-200 which is an alkyl aryl polyether sulfonate available from Rohm and Haas; TWEENTM. 20,
`40, 60 and 80 which are polyoxyethylene sorbitan fatty acid esters available from ICI Speciality
`Chemicals; SPANTM 20, 40, 60 and 80 which are sorbitan esters of fatty acids; ARLACELTM 20,
`40, 60 and 80 which are sorbitan esters of fatty acids available from Hercules, Inc.;
`CARBOWAXTM 3550 and 934 which are polyethylene glycols available from Union Carbide;
`CRODESTATM F110 which is a mixture of sucrose stearate and sucrose distearate available from
`Croda Inc.; CRODESTATM SL-40 which is available from Croda, Inc.; hexyldecyl trimethyl
`ammonium chloride (CTAC); bovine serum albumin and SA9OHCO which is C18 H17 CH2
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`5
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`10
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`15
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`20
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`25
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`30
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`10
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`Mylan v. Janssen (IPR2020-00440) Ex. 1012 p. 011
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`PRD2901USPSPPRD2901USPSP2
`
`(CON(CH3)CH2 (CHOH)4 CH2 OH)2. The surface modifiers which have been found to be
`particularly useful include tyloxapol and a poloxamer, preferably, Pluronic.TM. F108 and
`Pluronic.TM. F68.
`Pluronic.TM. F108 corresponds to poloxamer 338 and is the polyoxyethylene,
`polyoxypropylene block copolymer that conforms generally to the formula HO[CH2 CH2 O]x
`[CH(CH3)CH2 O]y [CH2 CH2 O]z H in which the average values of x, y and z are respectively
`128, 54 and 128. Other commercial names of poloxamer 338 are Hodag NONIONICTM 1108-F
`available from Hodag, and SYNPERONICTM PE/F108 available from ICI Americas.
`The optimal relative amount of paliperidone palmitate and the surface modifier depends
`on various parameters. The optimal amount of the surface modifier can depend, for example,
`upon the particular surface modifier selected, the critical micelle concentration of the surface
`modifier if it forms micelles, the surface area of the antipsychotic agent, etc. The specific
`surface modifier preferably is present in an amount of 0.1 to 1 mg per square meter surface area
`of the paliperidone palmitate. It is preferred in the case of paliperidone palmitate (9-
`hydroxyrisperidone palmitate) to use PLURONICTM F108 as a surface modifier, a relative
`amount (w/w) of both ingredients of approximately 6:1 is preferred.
`The particles of this invention can be prepared by a method comprising the steps of
`dispersing paliperidone palmitate in a liquid dispersion medium and applying mechanical means
`in the presence of grinding media to reduce the particle size of the antipsychotic agent to an
`effective average particle size of less than 2,000 nm. The particles can be reduced in size in the
`presence of a surface modifier. Alternatively, the particles can be contacted with a surface
`modifier after attrition.
`A general procedure for preparing the particles of this invention includes (a) obtaining
`paliperidone palmitate in micronized form; (b) adding the micronized paliperidone palmitate to a
`liquid medium to form a premix; and (c) subjecting the premix to mechanical means in the
`presence of a grinding medium to reduce the effective average particle size.
`The paliperidone palmitate in micronized form may be prepared using techniques known
`in the art. It is preferred that the particle size of the micronized paliperidone palmitate be less
`than about 100 µm as determined by sieve analysis. If the particle size of the micronized
`paliperidone palmitate is greater than about 100 µm, then it is preferred that the particles of
`paliperidone palmitate be reduced in size to less than 100 µm.
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`5
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`10
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`15
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`20
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`25
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`30
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`11
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`Mylan v. Janssen (IPR2020-00440) Ex. 1012 p. 012
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`

`

`PRD2901USPSPPRD2901USPSP2
`
`The micronized paliperidone palmitate can then be added to a liquid medium in which it
`is essentially insoluble to form a premix. The concentration of paliperidone palmitate in the
`liquid medium (weight by weight percentage) can vary widely and depends on the selected
`antipsychotic agent, the selected surface modifier and other factors. Suitable concentrations of
`paliperidone palmitate in compositions vary between 0.1 to 60%, preferably is from 0.5 to 30%,
`and more preferably, is approximately 7% (w/v). It is currently preferred to use a concentration
`of about 100mg eq of paliperidone per ml or about 156 mg of paliperid