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`Olanzapine is a yellow crystalline solid which is practically insoluble in
`
`water. The compound is disclosed and claimed in US. 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 antimuscan'nic, anti—cholinergic properties, and is an antagonist for
`
`5HT-2 receptor sites. The compound also has antagonist activity at
`
`noradrenergic alpha-receptors. These properties indicate that the compound is a
`
`10
`
`potential neuroleptic with relaxant, anxiolytic, or anti-emetic properties, and is
`
`useful in treating psychotic conditions such as schizophrenia, schizophreniforrn
`
`diseases, and acute mania. At lower doses the compound is indicated for use in
`
`the treatment of mild anxiety states.
`
`Olanzapine is a selective monoaminergic antagonist with high affinity
`
`15
`
`binding to the following receptors serotonin SHT 2mg (K 1: 4 and 11nM,
`
`respectively), dopamine D 1-4 (K 1:11-31 1 25 11M), histamine H 1(K I =7nM), and
`
`adrenergic (alpha) 1 receptors (K 1: nM) GABA A, BZD, and (beta) adrenergic
`
`receptors (K 1 > 10 uM).
`
`‘
`
`The mechanism of action of olanzapine, as with other drugs having
`
`20
`
`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 of action of
`
`olanzapine in the treatment of acute manic episodes associated with Bipolar 1
`
`Disorder is unknown.
`
`Antagonism at receptor other than dopamine and SHT zwith similar
`
`receptor affinities may explain some of 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 histamine H 1 receptors may
`
`explain somnolence observed with this drug. Olanzapine’s antagonism of
`
`30
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`adrenergic (alpha) receptors may explain orthostatic hypotensiou observed with
`
`this drug.
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`B.
`
`Background Regarding Nanoparticula’te 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, e.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
`
`10
`
`in conjunction with firlly soluble drug substances.
`
`It is known that the rate of dissolution of a particulate drug can increase
`
`with increasing surface area, i.e., 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
`
`15
`
`compositions. US. 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 for the
`
`preparation thereof. This patent does not teach or suggest nanop articulate
`
`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. 5,708,388, for
`
`“Continuous Method of Grinding Pharmaceutical Substances;” and US. 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 US.
`
`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 Lyophiiizationf’ 5,336,507 for "Use of Charged
`
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`Phospholipids to Reduce Nanoparticle Aggregation,” 5,340,564 for
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`“Formulations Comprising Olin lO-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
`
`10
`
`15
`
`Nanoparticles,” 5,429,824 for “Use of Tyloxapol as a Nanoparticulate
`
`Stabilizer,” 5,470,583 for “Method of Prep aring Nanoparticle Compositions
`
`Containing Charged Phospholipids to Reduce Aggregation,” 5,518,738 for
`
`“Nanoparticulate NSAID Formulations,” 5,552,160 for “Surface Modified
`
`NSAID Nanoparticles,” 5,560,931 for “Formulations of Compounds as
`
`Nanoparticulate Dispersions in Digestible Oils or Fatty Acids,” 5,565,188 for
`
`“Polyallcylene Block Copolymers as Surface Modifiers for Nanoparticles,”
`
`5,569,448 for “Sulfated Non-ionic Block Copolyrner Surfactant as Stabilizer
`
`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)
`
`2O
`
`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 Copolyniers 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 Stabilizers;” 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;”
`
`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
`
`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
`
`Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate,” 6,582,285 for
`
`“Apparatus for sanitary wet milling;” 6,656,504 for “Nanop articulate
`
`Compositions Comprising Amorphous Cyclosporine;” 6,742,734 for “System and
`
`Method for Milling Materialsf’ 6,745,962 for “Small Scale Mill and Method
`
`Thereof;” 6,811,767 for “Liquid droplet aerosols of nanoparticulate drugs;” and
`
`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, US. Patent Application No. 20020012675 A1, published
`
`on January 31, 2002, for “Controlled Release Nanoparticulatc Compositions,”
`
`tJ'l
`
`10
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`15
`
`20
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`25
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`and WO 0224398565 for “System and Method for Milling Materials,” describe
`
`nanoparticulate active agent compositions, and are specifically incorporated by
`
`reference. None of these references describe nanoparticulate compositions of
`
`olanzapine.
`
`Amorphous small particle compositions are described, for example, in
`
`US. 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
`
`‘Ultrasmall, 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
`
`describe nanoparticulate olanzapine.
`
`There is a need in the art for nanoparticulate olanzapine formulations
`which overcome these and other problems associated with prior conventional
`
`15
`
`olanzapine formulations. The present invention satisfies these needs.
`
`20
`
`The present invention relates to inj ectable nanoparticulate olanzapine
`
`SUMMARY OF THE INVENTION
`
`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
`
`25
`
`particle size that maintains the 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 ([M) or
`
`subcutaneous (S C) 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 for this 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 canier,
`
`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 and at
`
`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
`
`inj ectable nanoparticulate olanzapine compositions of 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 administration 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 drug is
`
`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.
`'fhis allows for improved patient
`
`compliance with enhanced therapeutic outcomes. Moreover, inj ectable
`
`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
`
`inj ectable 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 in vivo 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 release rates.
`
`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
`
`25
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`the art from the following detailed description of the invention.
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`BRIEF DESCRIPTION OF THE FIGURE
`
`Figure 1:
`
`Shows an electron micrograph of unmilled olanzapine.
`
`Figure 2:
`
`Shows an electron micrograph of a milled nanoparticulate
`
`olanzapine formulation.
`
`Figure 3:
`
`Shows an 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 over a. six hour time period following intramuscular administration to
`
`six male dogs of a nanoparticulate olanzapine formulation.
`
`Detailed Description ofInvention
`
`The invention provides inj ectable 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 of particle size and hence dissolution for periods of about one week
`or greater.
`-
`
`In other embodiments of the invention, compositions of the invention
`
`20
`
`provide efficacious levels of drug from about one week to about two 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, from 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 US. 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, inj ectable, nanoparticulate olanzapine
`
`fomiulations 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
`
`bioavailability; (2) dosing must be repeated several times each day; and (3) a
`
`Wide variety of side effects are associated with the current dosage forms of the
`
`drug.
`
`The present invention overcomes problems encountered with the prior art
`
`olanzapine formulations. Specifically, the nanoparticulate olanzapine
`
`formulations of the invention may offer the following advantages: (1) a decrease
`in the frequency of dosing and!or prolonged therapeutic levels of drug following
`
`10
`
`15
`
`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
`
`2O
`
`intramuscular injection, such as higher dose loading and smaller liquid dose
`
`volumes; (6) improved pharmacokinetic profiles, such as improved me and
`
`AUC profiles; (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 be retained 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 compositions of the invention following administration;
`
`11
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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
`
`other active agents; (12) the nanoparticulate olanzapine compositions can be
`
`sterile filtered; (13) the nanoparticulate olanzapine compositions are suitable for
`
`parenteral administration; and (14) the nanoparticulate olanzapine compositions
`
`do not require organic solvents or pH extremes.
`
`A preferred dosage form of the invention is a liquid inj ectable
`
`formulation. However, the composition may also be formulated in a powder or
`
`solid for reconstitution prior to inj ectable 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.
`
`As used herein, “about” will be understood by persons of ordinary skill in
`
`the art and will vary to some extent on the context in which it is used. Ifthere are
`
`uses of the term which are not clear to persons of ordinary skill in the art given
`
`the context in which it is used, “abou ” will mean up to plus or minus 10% of the
`
`particular term.
`
`“Conventional” or “non-nanoparticulate active agent” shall mean an
`
`active agent which is solubilized or which has an effective average particle size
`
`of greater than about 5 microns. Nanoparticulate active agents as defmed 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.
`
`12
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`As used herein with reference to stable drug particles, ‘stable’ includes,
`
`but is not limited to, one or more of the following parameters: (1) that the
`
`olanzapine particles do not appreciably flocculate 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 altered
`
`over time, such as by conversion from an amorphous phase to 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 dosages are, in particular instances, measured as
`
`inj ectable dosages.
`
`20
`
`Enhanced 9K Profiles
`
`The invention also preferably provides olanzapine compositions having a
`
`desirable phannacokinetic profile when administered to mammalian subjects.
`
`The desirable pharrnacokinetic profile of the olanzapine compositions preferably
`
`includes, but is not limited to:
`
`(1) a Cmax for olanzapine, when assayed in the
`
`25
`
`plasma of a mammalian subject following administration, that is preferably
`
`greater than the CW for a non-nanoparticulate olanzapine formulation (e.g.,
`
`Zyprexa®), administered at the same dosage; andr’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 olauzapine
`
`formulation (e.g., Zyprexa®), administered at the same dosage. The desirable
`
`pharmacokinetic profile, as used herein, is the pharmacokinetic pro file measured
`
`after the initial inj ectable dose of olanzapine.
`
`Conventional olanzapine (rag, Zyprexa®), reaches peak plasma levels in
`
`5-8 hours, and has a half-life of about 35 hours, depending on metabolism.
`
`A preferred inj ectable olanzapine composition of the invention exhibits in
`
`comparative pharmacokinetic testing with a non-nanoparticulate olanzapine
`
`formulation of (rag, Zyprexa®), administered at the same dosage, a Cmax which is
`
`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
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`1800%, or at least about 1900% greater than the Cmax exhibited by the non-
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`15
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`nanopartieulate olanzapine formulation.
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`A preferred inj ectable olanzapine composition of the invention exhibits in
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`comparative pharmacokinetic testing with a non-nanopaiticulate olanzapine
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`formulation (e.g., Zyprexa®), administered at the same dosage, an AUC which is
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`at least about 25%, at least about 50%, at least about 75%, at least about 100%, at
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`least about 125%, at least about 150%, at least about 175%, at least about 200%,
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`at least about 225%, at least about 250%, at least about 275%, at least about
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`300%, at least about 350%, at least about 400%, at least about 450%, at least
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`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%,
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`at least about 900%, at least about 950%, at least about 1000%, at least about
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`1050%, at least about 1100%, at least about 1150%, or at least about 1200%
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`greater than the AUC exhibited by the non-nanoparticulate olanzapine
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`formulation.
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`Combination Pharmacokinetic Profile Compositions
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`In yet another embodiment of the invention, a first nanoparticulate
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`olanzapine composition providing a desired pharmacokinetic profile is co-
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`adn1inistered, sequentially administered, or combined with at least one other
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`olanzapine composition that generates a desired different pharmacokinetic
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`profile. More than two olanzapine compositions can be co-administered,
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`sequentially administered, or combined. While the first olanzapine composition
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`has a nanoparticulate particle size, the additional one or more olanzapine
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`compositions can be nanoparticulate, solubilized, or have a microparticulate
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`particle size.
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`The second, third, fourth, era, olanzapine compositions can differ from
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`the first, and from each other, for example: (1) in the effective average particle
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`sizes of olanzapine; or ('2) in the dosage of olanzapine. Such a combination
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`composition can reduce the dose frequency required.
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`If the second olanzapine composition has a nanoparticulate particle size,
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`then preferably the olanzapine particles of the second composition have at least
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`one surface stabilizer associated with the surface of the drug particles. The one
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`or more surface stabilizers can be the same as or different from the surface
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`stabilizer(s) present in the first olanzapine composition.
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`Preferably where co-administration of a ”fast—acting” formulation and a
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`"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.
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`Olanazpine Compositions
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`The invention provides compositions comprising nanoparticulate
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`olanzapine particles and at least one surface stabilizer. The surface stabilizers are
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`preferably adsorbed to or associated with the surface of the olanzapine particles.
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`Surface stabilizers useful herein do not chemically react with the olanzapine
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`particles or itself. Preferably, individual molecules of the surface stabilizer are
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`essentially free of intermolecular cross-linkages. The compositions can comprise
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`two or more surface stabilizers.
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`The present invention also includes nanoparticulate olanzapine
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`compositions together with one or more non—toxic physiologically acceptable
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`carriers, adjuvants, or vehicles, collectively referred to as carriers. The
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`compositions can be formulated for parenteral injection (cg, intravenous,
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`intramuscular, or subcutaneous).
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`Olanzapine can be in a crystalline phase, an amorphous phase, a semi-
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`crystalline phase, a semi-amorphous phase, or a mixtures thereof.
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`Illustrative but not limiting compositions comprise, based 011 % wlw:
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`Olanzapine
`Surface stabilizer
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`preservatives (Optional)
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`pH adjusting agent
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`water for injection
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`1.
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`Surface Stabilizers
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`5 — 50%
`0.1 — 50%
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`0.05 - 0.25%
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`pH about 6 to about 7
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`q.s.
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`The choice of a surface stabilizer for olanzapine is non-trivial and
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`required experimentation to realize a desirable formulation. Combinations of
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`more than one surface stabilizer can be used in the invention. Useful surface
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`stabilizers which can be employed in the invention include, but are not limited to,
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`known organic and inorganic pharmaceutical excipients. Such excipients include
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`various polymers, low molecular weight oligomers, natural products, and
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`surfactants. Surface stabilizers include nonionic, ionic, anionic, cationic, and
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`zwitterionic surfactants.
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`Preferred surface stabilizers include, but are not limited to, a polysorbate,
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`such as Tween 80, benzalkoniurn chloride, and combinations thereof.
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`Representative examples of useful surface stabilizers include but are not
`
`limited to Low viscosity hydroxypropyl cellulose (HPC or HPC-SL);
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`hydroxypropyl methyl cellulose (HPMC); hydroxyinethyl cellulose (HMC);
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`ethycellulose; povidone; Pluronics; soditun deoxycholate; PEG-Phospholipids;
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`Tyloxapol and other approved tritons, polyvinylpyrrolidone, sodium lauryl
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`sulfate, dioctylsulfosuccinate, gelatin, casein, lecithin (phosphatides), dextran,
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`gtun acacia, cholesterol, tragac anth, stearic acid, benzalkonium chloride, calcium
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`stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying
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`wax, sorbitan esters, polyoxyethylene alkyl others (e.g., macrogol others such as
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`cctomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene
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`15
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`sorbitan fatty acid esters (e.g., the commercially available Tweens
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`® such as e.g.,
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`Tween 20® and Tween 80® (ICI Speciality Chemicals»; polyethylene glycols
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`(3.53., Carbowaxs 355 0® and 934® (Union Carbide)), polyoxyethylene stearates,
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`colloidal silicon dioxide, phosphates, carboxymethylcellulose calcium,
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`carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose,
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`20
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`hydroxypropyhnethylcellulose phthalate, noncrystalline cellulose, magnesium
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`aluminium silicate, triethanolamine, polyvinyl alcohol (PVA), 4—(1,1,3,3~
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`tetramethylbutyl)~phenol polymer with ethylene oxide and formaldehyde (also
`
`known as tyloxapol, superione, and triton), poloxarners (3.32, Pluronics F68® and
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`F108®, which are block copolymers of ethylene oxide and propylene oxide);
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`poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, which is a
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`tetrafimctional block copolymer derived from sequential addition of propylene
`
`oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation,
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`Parsippariy, 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);
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`Crodestas F-110®, which is a. mixture of sucrose stearate and sucrose distearate
`
`(Croda Inc);p-isonony1phenoxypoly—(glycidol), also known as Olin-IOG® or
`
`Surfactant 10—G® (Olin Chemicals, Stamford, CT); Crodestas SL—40® (Croda,
`
`Inc.); and SA9OHCO, which is C13H37CH2(CON(CH3)-
`
`CH2(CHOH)4(CH20H)2 (Eastman Kodak Co.); decanoyl-N—methylglucarnide;
`
`n—decyl B-D-glucopyranoside; nudecyl B-D-maltopyranoside; n—dodecyl [3-D—
`
`glucopyranoside; n-dodecyl B-D-maltoside; heptanoyl-N—methylglucamide; n~
`
`heptyl-B-D-glucopyranoside; n-heptyl B-D-thioglucoside; n-hexyl [3-D-
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`10
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`glucopyranoside; nonanoyl-N—methylglucamide; 11-noyl B-D-glucopyranoside;
`
`octanoyl-N-methylglucamide; 11-0ctyl-B-D—glucopyranoside; octyl [3-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
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`15
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`and vinyl acetate, and the like.
`
`Povidone Polymers
`
`In one embodiment of the invention, a povidone polymer is utilized as a
`
`surface stabilizer. Povidone polymers for injectable compositions preferably
`
`have a molecular weight of less than about 40,000 daltons. Povidone polymers,
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`20
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`also known as polyvidon(e), povidonum, PVP, and po