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`10
`
`15
`
`Olanzapine is a yellow crystalline solid whichis practically insoluble in
`water. The compoundis disclosed and claimed in U.S. Patent No. 5,229,382 to
`Chakrabarti et al., which is incorporated herein by reference.
`Olanzapine is an antagonist of dopamine at D-1 and D-2 receptors, and in
`addition has antimuscarinic, anti-cholinergic properties, and is an antagonist for
`5HT-2 receptor sites. The compoundalso has antagonist activity at
`noradrenergic alpha-receptors. These properties indicate that the compoundis a
`potential neuroleptic with relaxant, anxiolytic, or anti-emetic properties, and is
`useful in treating psychotic conditions such as schizophrenia, schizophreniform
`diseases, and acute mania. At lower doses the compoundis indicated for use in
`the treatment of mild anxiety states.
`Olanzapine is a selective monoaminergic antagonist with high affinity
`binding to the following receptors serotonin SHT 2ac (K 1-4 and 11nM,
`respectively), dopamine D 1-4 (K ;=11-31 25 nM), histamine H ;(& 1 =7nM), and
`adrenergic (alpha) , receptors (K ;= nM) GABA aBZD,and(beta) adrenergic
`receptors (K ;> 10 pM).
`The mechanism of action of olanzapine, as with other drugs having
`efficacy in schizophrenia is unknown. However, it has been proposed that this
`drug’s efficacy in schrizophrenia is mediated through a combination of dopamine
`and serotonin type 2 (SHT 2) antagonism. The mechanism ofaction of
`olanzapine in the treatment of acute manic episodes associated with Bipolar 1
`Disorder is unknown.
`Antagonism at receptor other than dopamine and 5HT2with similar
`receptor affinities may explain someof the other therapeutic and side effect of
`olanzapine. Olanzapine’s antagonism of muscorinic M 1.5 receptors explains its
`anticholinergic effects. Olanzapine’s antagonism of histamme H 1 receptors may
`explain somnolence observed with this drug. Olanzapine’s antagonism of
`adrenergic (alpha) receptors may explain orthostatic hypotension observed with
`this drug.
`
`20
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`30
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`B.
`
`Background Regarding Nanoparticulate Drugs
`
`Bioavailability is the degree to which a drug becomes available to the
`target tissue after administration. Many factors can affect bioavailability
`including the dosage form and various properties, ¢.g., dissolution rate of the
`drug. Poor bioavailability is a significant problem encountered in the
`development of pharmaceutical compositions, particularly those containing an
`active ingredient that is poorly soluble in water. Poorly water soluble drugs tend
`to be unsafe for intravenous administration techniques, which are used primarily
`in conjunction with fully soluble drug substances.
`It is known that the rate of dissolution of a particulate drug can increase
`
`with increasing surface area, i.¢., decreasing particle size. Consequently,
`
`methods of making finely divided drugs have been studied and efforts have been
`
`made to control the size and size range of drug particles in pharmaceutical
`
`10
`
`15
`
`compositions. U.S. Patent No. 5,145,684 to Liversidge et. al., which is herein
`
`incorporated by reference, discloses particles of a drug substance having a non-
`
`crosslinked surface stabilizer absorbed on the surface thereof and methods forthe
`
`preparation thereof. This patent does not teach or suggest nanoparticulate
`
`compositions of olanzapine.
`
`20
`
`Methods of making nanoparticulate compositions are described, for
`
`example, in U.S. Patent Nos. 5,518,187 and 5,862,999, both for “Method of
`
`Grinding Pharmaceutical Substances;” U.S. Patent No. 5,718,388, for
`
`“Continuous Method of Grinding Pharmaceutical Substances;” and U.S. Patent
`
`No. 5,510,118 for “Process of Preparing Therapeutic Compositions Containing
`
`25
`
`Nanoparticles.” These patents do not describe methods of making
`
`nanoparticulate olanzapine.
`
`Nanoparticulate compositions are also described, for example, in U.S.
`
`Patent Nos. 5,298,262 for “Use of Ionic Cloud Point Modifiers to Prevent Particle
`
`Aggregation During Sterilization;” 5,302,401 for “Method to Reduce Particle
`
`30
`
`Size Growth During Lyophilization;” 5,336,507 for “Use of Charged
`
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`Phospholipids to Reduce Nanoparticle Aggregation;” 5,340,564 for
`
`“Formulations Comprising Olin 10-G to Prevent Particle Aggregation and
`
`increase Stability;” 5,346,702 for “Use of Non-Ionic Cloud Point Modifiers to
`
`Minimize Nanoparticulate Aggregation During Sterilization;” 5,352,459 for “Use
`
`of Purified Surface Modifiers to Prevent Particle Aggregation During
`
`Sterilization;5,399,363 and 5,494,683, both for “Surface Modified Anticancer
`
`Nanoparticles;” 5,429,824 for “Use of Tyloxapol as a Nanoparticulate
`
`Stabilizer;” 5,470,583 for “Method of Preparing Nanoparticle Compositions
`
`Containing Charged Phospholipids to Reduce Aggregation;” 5,518,738 for
`
`10
`
`“Nanoparticulate NSAID Formulations;” 5,552,160 for “Surface Modified
`
`NSAID Nanoparticles;’’ 5,560,931 for “Formulations of Compoundsas
`
`Nanoparticulate Dispersions in Digestible Oils or Fatty Acids;” 5,565,188 for
`
`“Polyalkylene Block Copolymers as Surface Modifiers for Nanoparticles;”
`
`5,569,448 for “Sulfated Non-ionic Block Copolymer Surfactant as Stabilizer
`
`15
`
`Coatings for Nanoparticle Compositions;” 5,571,536 for “Formulations of
`
`Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids;”
`
`5,573,783 for “Redispersible Nanoparticulate Film Matrices With Protective
`
`Overcoats;” 5,580,579 for “Site-specific Adhesion Within the GI Tract Using
`
`Nanoparticles Stabilized by High Molecular Weight, Linear Poly(ethylene Oxide)
`
`20
`
`Polymers;” 5,585,108 for “Formulations of Oral Gastrointestinal Therapeutic
`
`Agents in Combination with Pharmaceutically Acceptable Clays;” 5,587,143 for
`
`“Butylene Oxide-Ethylene Oxide Block Copolymers Surfactants as Stabilizer
`
`Coatings for Nanoparticulate Compositions;” 5,591,456 for “Milled Naproxen
`
`with Hydroxypropyl Cellulose as Dispersion Stabilizer;” 5,622,938 for “Sugar
`
`25
`
`Based Surfactant for Nanocrystals;” 5,718,919 for “Nanoparticles Containing the
`
`R(-)Enantiomer of Ibuprofen;” 5,747,001 for “Aerosols Containing
`
`Beclomethasone Nanoparticle Dispersions;” 5,834,025 for “Reduction of
`
`Intravenously Administered Nanoparticulate Formulation Induced Adverse
`
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`Physiological Reactions;” 6,045,829 “Nanocrystalline Formulations of Human
`
`Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface
`
`Stabilizers;” 6,068,858 for “Methods of Making Nanocrystalline Formulations of
`
`Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic
`
`Surface Stabiltzers;” 6,153,225 for “Injectable Formulations of Nanoparticulate
`
`Naproxen;” 6,165,506 for “New Solid Dose Form of Nanoparticulate Naproxen;”
`
`6,221,400 for “Methods of Treating Mammals Using Nanocrystalline
`
`Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors;”
`
`6,264,922 for “Nebulized Aerosols Containing Nanoparticle Dispersions;”
`
`10
`
`6,267,989 for “Methods for Preventing Crystal Growth and Particle Aggregation
`
`in Nanoparticle Compositions;” 6,270,806 for “Use of PEG-Derivatized Lipids as
`Surface Stabilizers for Nanoparticulate Compositions;” 6,316,029 for “Rapidly
`
`Disintegrating Solid Oral Dosage Form,” 6,375,986 for “Solid Dose
`
`Nanoparticulate Compositions Comprising a Synergistic Combination of a
`
`is
`
`Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate,” 6,428,814 for
`
`“Bioadhesive nanoparticulate compositions having cationic surface stabilizers;”
`
`6,431,478 for “Small Scale Mill;” 6,432,381 for “Methods for Targeting Drug
`
`Delivery to the Upper and/or Lower Gastrointestinal Tract,” 6,592,903 for
`
`“Nanoparticulate Dispersions Comprising a Synergistic Combination of a
`
`20
`
`Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate,” 6,582,285 for
`
`“Apparatus for sanitary wet millmg;” 6,656,504 for “Nanoparticulate
`
`Compositions Comprising Amorphous Cyclosporine;” 6,742,734 for “System and
`
`Method for Milling Materials;” 6,745,962 for “Small Scale Mill and Method
`
`Thereof;” 6,811,767 for “Liquid droplet aerosols of nanoparticulate drugs;” and
`
`25
`
`6,908,626 for “Compositions having a combination of immediate release and
`
`controlled release characteristics;”all of which are specifically incorporated by
`
`reference. In addition, U.S. Patent Application No. 20020012675 A1, published
`
`on January 31, 2002, for “Controlled Release Nanoparticulate Compositions,”
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`and WO 02/098565 for “System and Method for Milling Materials,” describe
`
`nanoparticulate active agent compositions, and are specifically incorporated by
`reference. None ofthese references describe nanoparticulate compositions of
`
`olanzapine.
`
`Amorphous small particle compositions are described, for example, in
`
`U.S. Patent Nos. 4,783,484 for “Particulate Composition and Use Thereof as
`
`Antimicrobial Agent;” 4,826,689 for “Method for Making Uniformly Sized
`
`Particles from Water-Insoluble Organic Compounds;” 4,997,454 for “Method for
`
`Making Uniformly-Sized Particles From Insoluble Compounds,” 5,741,522 for
`
`10
`
`“Ulirasmall, Non-aggregated Porous Particles of Uniform Size for Entrapping
`
`Gas Bubbles Within and Methods;” and 5,776,496, for “Ultrasmall Porous
`
`Particles for Enhancing Ultrasound Back Scatter.” These references do not
`
`1S
`
`20
`
`25
`
`describe nanoparticulate olanzapine.
`
`There is a need in the art for nanoparticulate olanzapine formulations
`which overcome these and other problems associated. with prior conventional
`olanzapine formulations. The present inventionsatisfies these needs.
`
`SUMMARYOF THE INVENTION
`The presentinvention relates to injectable nanoparticulate olanzapine
`compositions. The compositions comprise olanzapine and at least one surface
`stabilizer, which is preferably adsorbed on or associated with the surface of the
`olanzapine particles. The nanoparticulate olanzapine particles have an effective
`average particle size of less than about 5 microns. The surface stabilizer is
`present in an amount sufficient to maintain the olazapine at an effective average
`particle size that maintainsthe efficacy of the drug over a period of time, such as
`about one week or greater than about one week. The nanoparticle size of the
`
`olanzapine particles can be manipulated to give the desirable blood profile and
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`duration of action when administered by either intramuscular (IM) or
`
`subcutaneous (SC) routes.
`
`Long acting anti-psychotics are preferred, as the patient population treated.
`
`with such drugs can suffer from poor patient compliance, resulting in diminished
`
`therapeutic effect for the administered drug. Drugs requiring multiple daily
`
`administration, or even daily administration, are not preferred forthis patient
`
`population. A simpler dosage form, such as a once-weekly dosage form, can
`
`result in dramatically improved patient compliance, and consequently improved
`
`quality of life. Advantages and properties of the compositions of the invention
`
`10
`
`are described herein.
`
`Another aspect of the invention is directed to pharmaceutical
`
`compositions comprising a nanoparticulate olanzapine composition of the
`
`invention. The pharmaceutical compositions preferably comprise olanzapine,at
`
`least one surface stabilizer, and at least one pharmaceutically acceptable carrier,
`
`15
`
`as well as any desired excipients.
`
`The invention further discloses a method of making a nanoparticulate
`
`olanzapine composition, Such a method comprises contacting olanzapine andat
`
`least one surface stabilizer for a time and under conditions sufficient to provide a
`
`nanoparticulate olanzapine composition. The one or more surface stabilizers can
`
`20
`
`be contacted with olanzapine either before, preferably during,or after size
`
`reduction of the olanzapine.
`
`The present invention is also directed to methods of treatment using the
`
`injectable nanoparticulate olanzapine compositionsof the invention for, for
`
`example, psychotropic therapy and the treatment of central nervous system
`
`25
`
`disorders. In one embodiment of the invention, intramuscular or subcutaneous
`
`injection of olanzapine is utilized, The adminisiration of the drug in this manner
`
`allows for the formation of an intramuscular or subcutaneous depot of olanzapine
`
`which slowly releases the drug into the patient’s system over a longer period of
`
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`time than if administered orally. The period of time over which the drugis
`
`released is preferably up to about one week, from about two weeks to about six
`
`weeks, and from about two weeks to about twelve weeks. Additional time
`periods of efficacy are described herein. This allows for improved patient
`compliance with enhanced therapeutic outcomes. Moreover, injectable
`
`formulations of olanzapine result in a significantly shorter response time as
`
`compared to oral administration. While current conventional formulations of
`
`olanzapine can be formulated for injection (i.e., Zyprexa®), such conventional
`
`injectable olanzapine formulations are difficult to prepare due to the low water
`
`10
`
`solubility of the drug.
`
`In psychotropic therapy and the treatment of central nervous system
`
`disorders,it is important to provide an olanzapine dosage form that delivers the
`
`required therapeutic amount of the drug za vive and renders the drug bioavailable
`
`in a rapid and consistent manner. The nanoparticulate olanzapine formulations of
`
`15
`
`the present invention achieve those goals through the formation of a drug depot,
`
`preferably following intramuscular injection. The depot slowly releases the drug
`
`into the bloodstream at almost zero order kinetics for about one (1) to about
`
`twelve (12) weeks through control of the nanoparticle size of the drug. Different
`
`nanoparticle sizes will dissolve at different rates, and will therefore release the
`
`20
`
`drug to the bloodstream from the depot at different releaserates.
`
`Both the foregoing general description and the following brief description
`
`of the drawings and detailed description are exemplary and explanatory and are
`
`intended to provide further explanation of the invention as claimed. Other
`objects, advantages, and novel features will be readily apparent to those skilled in
`the art from the following detailed description of the invention.
`
`20
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`BRIEF DESCRIPTION OF THE FIGURE
`
`Figure 1:
`
`Figure 2:
`
`Shows an electron micrograph of unmilled olanzapine.
`
`Shows an electron micrograph of a milled nanoparticulate
`
`olanzapine formulation.
`
`Figure 3:
`
`Showsan electron micrograph of a milled nanoparticulate
`
`olanzapine formulation.
`
`Figure 4:
`
`Graphically shows the plasma concentration (ng/mL) of
`
`olanazpine over a six hour time period following intramuscular administration to
`
`six male dogs of a nanoparticulate olanzapine formulation.
`
`10
`
`Figure 5:
`
`Graphically shows the plasma concentration (ng/mL) of
`
`olanazpine overasix hour time period following intramuscular administration to
`
`six male dogs of a nanoparticulate olanzapine formulation.
`
`Detailed Description of Invention
`
`The invention provides injectable nanoparticulate olanzapine formulations
`
`15
`
`that can comprise high drug concentrations in low injection volumes, with
`
`durations of action that can be controlled to give efficacious blood levels through
`
`manipulation ofparticle size and hence dissolution for periods of about one week
`or greater.
`.
`In other embodiments ofthe invention, compositions of the invention
`
`20
`
`provide efficacious levels of drug from about one week to about iwo weeks, from
`about one week to about three weeks, from about one week to about four weeks,
`
`from about one week to about five weeks, from about one week to about six
`
`weeks, from about one week to about seven weeks, from about one week to about
`
`eight weeks, ftom about one week to about nine weeks, from about one week to
`
`25
`
`about ten weeks, from about one week to about eleven weeks, from about one
`
`week to about twelve weeks, and any combination thereof, such as from about
`
`two weeks to about six weeks, from about three weeks to about four weeks, from
`
`about three weeks to about seven weeks,etc.
`
`10
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`The composition of the invention is administered via injection, such as by
`
`intramuscular or subcutaneously, to form a drug depot. The drug depot results in
`
`efficacious levels of drug up to about one week or greater.
`
`As taught in U.S. Patent No. 5,145,684, not every combination of surface
`
`stabilizer and active agent will result in a stable nanoparticulate composition. It
`
`was surprisingly discovered that stable, injectable, nanoparticulate olanzapine
`
`formulations can be made.
`
`The current formulations of olanzapine suffer from the following
`
`problems: (1) the poor solubility of the drug results in a relatively low
`
`10
`
`bioavailability; (2) dosing must be repeated several times each day; and (3) a
`
`wide variety of side effects are associated with the current dosage formsofthe
`
`drug.
`
`The present invention overcomes problems encountered with the priorart
`
`olanzapine formulations. Specifically, the nanoparticulate olanzapine
`
`15
`
`formulations of the invention mayoffer the following advantages: (1) a decrease
`in the frequency of dosing and/or prolonged therapeutic levels of dug following
`dosing; (2) faster onset of action; (3) smaller doses of olanzapine required to
`
`obtain the same pharmacological effect, (4) increased bioavailability; (5)
`
`improved performance characteristics for intravenous, subcutaneous, or
`
`20
`
`intramuscular injection, such as higher dose loading and smallerliquid dose
`
`volumes; (6) improved pharmacokinetic profiles, such as improved Cha, and
`
`AUCprofiles; (7) substantially similar or bioequivalent pharmacokinetic profiles
`
`of the nanoparticulate olanzapine compositions when administered in the fed
`
`versus the fasted state; (8) bioadhesive olanzapine formulations, which can coat
`
`25
`
`the desired site of application and beretained for a period of time, thereby
`
`increasing the efficacy of the drug as well as eliminating or decreasing the
`
`frequency of dosing; (9) high redispersibility of the nanoparticulate olanzapine
`
`particles present in the compositionsof the invention following administration;
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`(10) low viscosity liquid nanoparticulate olanzapine dosage forms can be made;
`(11) the nanoparticulate olanzapine compositions can be used in conjunction with
`
`otheractive agents; (12) the nanoparticulate olanzapine compositions can be
`
`sterile filtered; (13) the nanoparticulate olanzapine compositions are suitable fox
`
`parenteral administration; and (14) the nanoparticulate olanzapine compositions
`
`do not require organic solvents or pH extremes.
`
`A preferred dosage form of the inventionis a liquid injectable
`
`formulation. However, the composition may also be formulated in a powder or
`
`solid for reconstitution prior to injectable administration, such as by
`
`10
`
`lyophilization. The dosage form can be, for example, controlled release dosage
`
`form, delayed release dosage form, extended release dosage form, pulsatile
`
`release dosage form, mixed immediate release and controlled release dosage
`
`form, or a combination thereof.
`
`The present invention is described herein using several definitions,as set
`
`15
`
`forth below and throughout the application.
`
`Asused herein, “about” will be understood by persons of ordinary skill in
`
`the art and will vary to some extent on the context in whichit is used. If there are
`
`uses of the term which are not clear to persons of ordinary skill in the art given
`
`the context in whichit is used, “about” will mean up to plus or minus 10% of the
`
`particular term.
`
`“Conventional”or “non-nanoparticulate active agent” shall mean an
`
`active agent whichis solubilized or which has an effective average particle size
`
`of greater than about 5 microns. Nanoparticulate active agents as defined herein
`have an. effective average particle size of less than about 5 microns,
`
`25
`
`“Poorly water soluble drugs” as used herein means those having a
`
`solubility of less than about 30 mg/ml, preferably less than about 20 mg/ml,
`
`preferably less than about 10 mg/ml,or preferably less than about 1 mg/ml.
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`Asused herein with reference to stable drug particles, ‘stable’ includes,
`
`but is not limited to, one or moreof the following parameters: (1) that the
`
`olanzapine particles do not appreciably floccuiate or agglomerate due to
`
`interparticle attractive forces, or otherwise significantly increase in particle size
`
`overtime; (2) that the physical structure of the olanzapine particles is not aliered
`
`over time, such as by conversion from an amorphousphaseto crystalline phase;
`
`(3) that the olanzapine particles are chemically stable; and/or (4) where the
`
`olanzapine has not been subject to a heating step at or above the melting point of
`
`the olanzapine in the preparation of the nanoparticles of the invention.
`
`10
`
`‘Therapeutically effective amount’ as used herein with respect to a drug
`
`dosage, shall mean that dosage that provides the specific pharmacological
`
`response for which the drug is administered in a significant number of subjects in
`
`need of such treatment. It is emphasized that ‘therapeutically effective amount,’
`
`administered to a particular subject in'a particular instance will not always be
`
`15
`
`effective in treating the diseases described herein, even though such dosage is
`
`deemed a ‘therapeutically effective amount’ by those skilled in the art. It is to be
`
`further understood that drug dosagesare, in particular instances, measured as
`
`injectable dosages.
`
`20
`
`Enhanced pk. Profiles
`
`The invention also preferably provides olanzapine compositions having a
`
`desirable pharmacokinetic profile when administered to mammalian subjects.
`
`The desirable pharmacokinetic profile of the olanzapme compositions preferably
`
`includes, but is not limited to: (1}a Cinax for olanzapine, when assayed in the
`
`20
`
`plasma of a mammalian subject foliowing administration, that is preferably
`
`greater than the C,.x for a non-nanoparticulate olanzapine formulation (e.g.,
`
`Zyprexa®), administered at the same dosage; and/or (2) an AUC for olanzapine,
`
`when assayed in the plasma of a mammalian subject following administration,
`
`13
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`that is preferably greater than the AUC for a non-nanoparticulate olanzapine
`
`formulation (e.g., Zyprexa®), administered at the same dosage. The desirable
`
`pharmacokinetic profile, as used herein, is the pharmacokinetic profile measured
`
`after the initial injectable dose of olanzapine.
`
`Conventional olanzapine (e.g., Zyprexa®), reaches peak plasmalevels in
`
`5-8 hours, and has a half-life of about 35 hours, depending on metabolism.
`
`A preferred injectable olanzapine composition of the invention exhibits in
`
`comparative pharmacokinetic testing with a non-nanoparticulate olanzapine
`formulation of(e.g., Zyprexa’), administered at the same dosage, a Cra, which is
`
`10
`
`at least about 50%, at least about 100%,at least about 200%, at least about 300%,
`
`at least about 400%,at least about 500%, at least about 600%, at least about
`
`700%, at least about 800%,at least about 900%,at least about 1000%,at least
`
`about 1100%,at least about 1200%,at least about 1300%,at least about 1400%,
`
`at least about 1500%,at least about 1600%,at least about 1700%,at least about
`
`13
`
`1800%, or at least about 1900% greater than the Cymax exhibited by the non-
`
`nanoparticulate olanzapine formulation.
`
`A preferred injectable olanzapine composition of the invention exhibits in
`
`comparative pharmacokinetic testing with a non-nanoparticulate olanzapine
`
`formulation (¢.g., Zyprexa®), administered at the same dosage, an AUC whichis
`
`at least about 25%,at least about 50%,at least about 75%,at least about 100%,at
`
`least about 125%, at least about 150%, at least about 175%, at least about 200%,
`
`at least about 225%,at least about 250%,at least about 275%, at least about
`300%, at least about 350%,at least about 400%, at least about 450%,at least
`about 500%, at least about 550%,at least about 600%,at least about 750%,at
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`least about 700%, at least about 750%, at least about 800%,at least about 850%,
`
`at least about 900%,at least about 950%,at least about 1000%, at least about
`
`1050%, at least about 1100%, at least about 1150%,or at least about 1200%
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`AQUESTIVE EXHIBIT 1004=page 1762
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`AQUESTIVE EXHIBIT 1004 page 1762
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`greater than the AUC exhibited by the non-nanoparticulate olanzapine
`
`formulation.
`
`Combination Pharmacokinetic Profile Compositions
`
`In yet another embodimentof the invention, a first nanoparticulate
`
`olanzapine composition providing a desired pharmacokinetic profile is co-
`
`administered, sequentially administered, or combined with at least one other
`
`olanzapine composition that generates a desired different pharmacokinetic
`
`profile. More than two olanzapine compositions can be co-administered,
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`10
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`sequentially administered, or combined. While the first olanzapine composition
`
`has a nanoparticulate particle size, the additional one or more olanzapine
`
`compositions can be nanoparticulate, solubilized, or have a microparticulate
`
`particle size.
`
`The second,third, fourth, efe., olanzapine compositions can differ from
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`the first, and from each other, for example: (1) in the effective average particle
`
`sizes of olanzapine; or (2) in the dosage of olanzapine. Such a combination
`
`composition can reduce the dose frequency required.
`
`If the second olanzapine composition has a nanoparticulate particle size,
`
`then preferably the olanzapine particles of the second composition have atleast
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`20
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`one surtace stabilizer associated with the surface of the drug particles. The one
`
`or more surface stabilizers can be the sameas or different from the surface
`
`stabilizer(s) present in the first olanzapine composition.
`
`Preferably where co-administration of a "fast-acting" formulation and a
`
`"longer-lasting" formulation is desired, the two formulations are combined within
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`a single composition, for example a dual-release composition.
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`A.
`
`Olanazpine Compositions
`
`The invention provides compositions comprising nanoparticulate
`
`olanzapine particles and at least one surface stabilizer. The surface stabilizers are
`
`preferably adsorbed to or associated with the surface of the olanzapineparticles,
`
`Surface stabilizers useful herein do not chemically react with the olanzapine
`
`particles or itself. Preferably, individual molecules of the surface stabilizer are
`
`essentially free of intermolecular cross-linkages. The compositions can comprise
`
`two or more surface stabilizers.
`
`The present invention also includes nanoparticulate olanzapine
`
`10
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`compositions together with one or more non-toxic physiologically acceptable
`
`carriers, adjuvants, or vehicles, collectively referred to as carriers. The
`
`compositions can be formulated for parenteral injection (e.g., intravenous,
`
`intramuscular, or subcutaneous).
`
`Olanzapine can be in a crystalline phase, an amorphous phase, a semi-
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`15
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`crystalline phase, a semi-amorphous phase, or a mixtures thereof.
`
`Illustrative but not limiting compositions comprise, based on % w/w:
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`20
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`Olanzapine
`Surface stabilizer
`
`preservatives (Optional)
`pH adjusting agent
`water for injection
`
`1.
`
`Surface Stabilizers
`
`5—50%
`0.1 — 50%
`
`0.05 - 0.25%
`pH about6 to about 7
`q.s.
`
`The choice of a surface stabilizer for olanzapine is non-trivial and
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`20
`
`required experimentation to realize a desirable formulation. Combinations of
`
`more than one surface stabilizer can be used in the invention. Useful surface
`
`stabilizers which can be employed in the invention include, but are not limitedto,
`
`known organic and inorganic pharmaceutical excipients. Such excipients include
`
`various polymers, low molecular weight oligomers, natural products, and
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`surfactants. Surface stabilizers include nonionic, ionic, anionic, cationic, and
`
`zwitterionic surfactants.
`
`Preferred surface stabilizers include, but are not limited to, a polysorbate,
`
`such as Tween 80, benzalkonium chloride, and combinations thereof.
`
`Representative examples of useful surface stabilizers include but are not
`
`limited to Low viscosity hydroxypropyl cellulose (HPC or HPC-SL);
`
`hydroxypropyl methyl cellulose (HPMC); hydroxymethy] cellulose (HMC);
`
`ethycellulose; povidone; Pluronics; sodium deoxycholate; PEG-Phospholipids;
`
`Tyloxapol and other approved tritons, polyvinylpyrrolidone, sodium lauryl
`
`10
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`sulfate, dioctylsulfosuccinate, gelatin, casein, lecithin (phosphatides), dextran,
`
`gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium
`
`stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying
`
`wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as
`
`13
`
`cetomacrogol 1000), polyoxyethylene castor o1] derivatives, polyoxyethylene
`sorbitan fatty acid esters (e.g., the commercially available Tweens” suchas ¢.g.,
`Tween 20° and Tween 80° (ICI Speciality Chemicals)); polyethylene glycols
`(e.g., Carbowaxs 3550" and 934® (Union Carbide)), polyoxyethylenestearates,
`
`colloidal silicon dioxide, phosphates, carboxymethylcellulose calcium,
`
`carboxymethylcellulose sodtum, methylcellulose, hydroxyethylcellulose,
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`20
`
`hydroxypropyimethylcellulose phthalate, noncrystalline cellulose, magnesium
`
`aluminium silicate, triethanolamine, polyvinyl aleohol (PVA), 4-(1,1,3,3-
`
`tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also
`known as tyloxapol, superione, and triton), poloxamers (e¢.g., Pluronics F68® and
`F108°, which are block copolymers of ethylene oxide and propylene oxide);
`poloxamines(e.g., Tetronic 908°, also known as Poloxamine 908°, which is a
`
`25
`
`tetrafunctional block copolymer derived from sequential addition of propylene
`
`oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation,
`Parsippany, N.J.)); Tetronic 1508° (T-1508) (BASF Wyandotte Corporation),
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`Tritons X-200°, which is an alkyl aryl polyether sulfonate (Rohm and Haas);
`Crodesias F-1 10°, which is a mixture of sucrose stearate and sucrose distearate
`(Croda Inc.); p-isononylphenoxypoly-(glycidol), also known as Olin-lOG® or
`Surfactant 10-G® (Olin Chemicals, Stamford, CT); Crodestas SL-40® (Croda,
`Inc.); and SA9OHCO, which is C1 gH37CH2(CON(CH3)-
`
`CH2(CHOH)4(CH20H)2 (Eastman Kodak Co.); decanoyl-N-methylglucamide;
`
`n-decyl B-D-glucopyranoside; n-decyl B-D-maltopyranoside; n-dodecyl B-D-
`
`glucopyranoside; n-dodecyl B-D-maltoside; heptanoyl-N-methylglucamide; n-
`
`heptyl-B-D-glucopyranoside; n-heptyl B-D-thiogiucoside; n-hexyl B-D-
`
`10
`
`glucopyranoside; nonanoyl-N-methylglucamide; n-noyl 6-D-glucopyranoside;
`
`octanoyl-N-methylglucamide; n-octyl-B-D-glucopyranoside; octyl B-D-
`
`thioglucopyranoside; PEG-derivatized phospholipid, PEG- derivatized
`
`cholesterol, PEG- derivatized cholesterol derivative, PEG- derivatized vitamin A,
`
`PEG- derivatized vitamin E, lysozyme, random copolymers of vinyl pyrrolidone
`
`15
`
`and vinyl acetate, and the like.
`
`Povidone Polymers
`
`In one embodimentof the invention, a povidone polymeris utilized as a
`
`surface stabilizer. Povidone polymers for injectable compositions preferably
`
`have a molecular weight of less than about 40,000 daltons. Povidone polymers,
`
`20
`
`also known as polyvidon(e), povidonum, PVP, and polyvinylpyrrolidone, are sold
`underthe trade names Kollidon® (BASF Corp.) and Plasdone® (ISP
`
`Technologies, Inc.). They are polydisperse macromolecular molecules, with a
`
`chemical name of 1-ethenyl-2-pyrrolidinone polym