MX2007005885A - Injectable nanoparticulate olanzapine formulations - Google Patents

Abstract

Described are injectable formulations of nanoparticulate olanzapine that produce a prolonged duration of action upon administration, and methods of making and using such formulations. The injectable formulations comprise nanoparticulate olanzapine.

Description

OLANZAPJNA NANOPARTICULATED INJECTABLE FORMULATIONS FIELD OF THE INVENTION The present invention relates to novel delivery systems for psychotropic agents that ensure a better acceptance by the patient and therefore an improved therapeutic efficacy and a better overall mental health for the patient. More specifically, the present invention comprises injectable nanoparticulate olanzapine formulations having a long duration of action.

BACKGROUND OF THE INVENTION Background with respect to olanzapine Currently there are many drugs available for the treatment of central nervous system disorders. Among these drugs there is a category known as antipsychotics for the treatment of serious mental conditions such as schizophrenia and schizophreniform disease. The drugs available for such conditions are sometimes associated with unwanted side effects, and there is a need for even better products that control or eliminate the symptoms in a safe and more effective manner. Also, many patients do not respond or they respond partially to the treatment of present drug, and the estimates of said responses or partial responses can vary between 40% and 80% of those treated. Since the introduction of antipsychotics, it has been observed that patients are subject to drug-induced extrapyramidal symptoms, which include drug-induced Parkinsonism, acute dystonia reactions, akathisia, tardive dyskinesia and late dystonia. The Simpson-Angus scale, Barnes Acatisia classification scale, and abnormal involuntary movement scale (AIMS) are well-known scales for assessing extrapyramidal symptoms. Most of the drugs available for the treatment of schizophrenia are prone to produce these extra pyramidal side effects when used in dosages that have a beneficial effect on the symptoms of the disease. The severity of adverse cases and / or lack of efficacy in a considerable number of patients frequently results in poor acceptance or termination of treatment. Many of the drugs are associated with a sedative effect and may also have an undesirable influence on the affective symptoms of the disease, causing depression. In some cases prolonged use of the drug leads to irreversible conditions, such as tardive dyskinesia and late dystonia referred to above. This, together with the fact that many of the patients in need of such drugs do not have complete control of their mental faculties, sometimes it results in zero patient acceptance and diminished therapeutic effect. A dosage form of said drug having prolonged activity, and therefore requiring less frequent administration, is highly desirable. This is because such a dosage form can minimize complications caused by patients forgetting or stopping a dose. A widely used and popular antipsychotic drug useful in the treatment of central nervous system disorders is olanzapine; which is commercially available as Zyprexa® (Eli Lilly, Indianapolis, Ind). Zyprexa® is available in tablets administered orally and as formulations for intramuscular injection Olanzapine has the chemical name 2-methyl-4- (4-methyl-1-piperazinyl) -iOH-thieno [2,3-b] [1,5] benzodiazepine (C17H2oN S), with molecular weight of 312.439, and the following chemical structure: * ' Olanzapine is a yellow crystalline solid that is practically insoluble in water. The compound is described and claimed in the patent of E.U.A. No. 5,229,382 to Chakrabarti et al., Which is incorporated herein by reference. Olanzapine is a dopamine antagonist at the D-1 and D-2 receptors, and also has anti-muscarinic and anti-cholinergic properties, and is an antagonist for 5HT-2 receptor sites. The compound also has antagonist activity at alpha noradrenergic receptors. These properties indicate that the compound is a potential neuroleptic with relaxing, anxiolytic, or anti-emetic properties and is useful in the treatment of psychotic conditions such as schizophrenia, schizophreniform diseases, and acute mania. In lower doses the compound is indicated for use in the treatment of medium anxiety states. Olanzapine is a selective monoaminergic antagonist with high affinity that binds to the following serotonin receptors 5HT2A 2C (K ¡= 4 and 1 lnM, respectively), dopamine D 1- (K i = 11-31] 25 nM), histamine Hi ( K l = 7nM) and (alpha) i adrenergic receptors (K | = nM) GABAA, BZD, and adrenergic receptors (beta) (? | >; 10μ?). The mechanism of action of olanzapine, as with other drugs that have efficacy in schizophrenia is unknown. However, it has been proposed that this efficacy of the drug in schizophrenia is mediated through a combination of dopamine antagonism and serotonin type 2 (5HT2). The mechanism of action of olanzapine in the treatment of acute manic episodes associated with bipolar disorder 1 is unknown.

Antagonism at the different receptor of dopamine and 5HT2 with similar receptor affinities may explain part of the therapeutic and secondary effect of olanzapine. Antagonism of olanzapine from muscarinic Mi-5 receptors explains its anticholinergic effects. Olanzapine antagonism of Histamine histamine receptors may explain the somnolence observed with this drug. Olanzapine antagonism of adrenergic receptors (alpha) may explain the orthostatic hypotension observed with this drug.

B Background with respect to nanoparticulate drugs Bioavailability is the degree to which the drug is made available to the target tissue after administration. Many factors can affect the bioavailability including the dosage form and various properties, for example, dissolution rate of the drug. Scarce bioavailability is a significant problem encountered in the development of pharmaceutical compositions, particularly those containing an active ingredient that is sparingly soluble in water. Poorly water soluble drugs tend not to be safe for intravenous administration techniques, which are mainly used together with fully soluble pharmacological substances. It is known that the dissolution rate of a particulate drug can be increased by increasing the surface area, i.e. by decreasing the particle size. Consequently, methods for make finely divided drugs and efforts have been made to control the size and range of size of drug particles in pharmaceutical compositions. The patent of E.U.A. No.5, 145,684 for Liversidge et. al., which is incorporated herein by reference, discloses particles of a drug substance having a non-interlaced surface stabilizer absorbed on its surface and methods for its preparation. This patent does not show or suggest nanoparticulate compositions of olanzapine. Methods for making nanoparticulate compositions are described, for example, in the U.S.A. Nos. 5,518,187 and 5,862,999, both for "Method of Grinding Pharmaceutical Substances"; Patent of E.U.A. No. 5,718,388 for "Continuous Method of Grinding Pharmaceutical Substances" and U.S. Pat. No. 5,510,118 for "Process of Preparing Therapeutic Compositions Containing Nanoparticles". These patents do not describe methods for making nanoparticulate olanzapine. Nanoparticulate compositions are also described, for example, in the U.S.A. We 5,298,262 for "Use of Lonic Cloud Point Modifiers to Provent Partial Aggregation During Sterilization" 5,302,401 for "Method to Reduce Partial Size Growth During Lyophilization;" 5,336,507 for "Use of Charged Phospholipids to reduce Nanoparticle aggregation;" 5,340,564 for "Formulations Comprising Olin 10-G to Prevent Partiole Aggregation and Increase Stability;" 5,346,702 for "Use of Non-lonic Cloud Point Modifiers to Minimize Nanoparticulate Aggregation During Sterilization;" ,352,459 for "Use of Purified Surface Modifiers to Prevent Partial 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 "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 "Polyalkylene Block Copolymers as Surface Modifiers for Nanoparticles;" 5,569,448 for "Sulfated Non-ionic Block Copolymer 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 Gl Tract Using Nanoparticles Stabilized by High Molecular Weight, Linear Poly (Ethylene Oxide) 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 Stabilizer Dispersion; "5,622,938 for" Sugar 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 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 (HFV) 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 Partial Aggregation in Nanoparticle Compositions; "6,270,806 for" Use of PEG-Derivatized Lipids as Surface Stabilizers for Na noparticulate 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 Mili;" 6,432,381 for "Methods for Targeting Drug Delivery to the Upper and 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" Nanoparticulate Compositions Comprising Amorphous Cyclosporine; "6,742,734 for" System and Method for Milling Materials; "6,745,962 for" Small Scale Mili 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 reléase characteristics;" all of which are incorporated specifically for reference, In addition, the US patent application No. 20020012675 Al, published on January 31, 2002, for "Controlled Relay Nanoparticulate Compositions, "and WO 02/098565 for" System and Method for Milling Materials, "describe nanoparticulate active agent compositions, and are specifically incorporated for reference, none of which references describe nanoparticulate olanzapine compositions. , for example, in US Patent Nos. 4,783,484 to "Particulate Co mposition and Use Thereof as Antimicrobial Agent ", 4,826,689 for" Method for Making Uniformly Sized Particles from Water-lnsoluble Organic Compounds ", 4,997,454 for" Method for Making Uniformly-Sized Particles From lnsoluble Compounds "; 5,741, 522 for "Ultrasmall, Non-aggregated Porous Particles of Uniform Size for Entrapping Gas Bubbles Whitin 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 that overcome these and other problems associated with olanzapine formulations of the conventional art. The present invention satisfies these needs.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to nanoparticulate injectable olanzapine compositions. The compositions comprise olanzapine and at least one surface stabilizer, which is preferably absorbed or associated with the surface of the olanzapine particles. The nanoparticulate olanzapine particles have an effective average particle size of less than 5 microns. The surface stabilizer is present in an amount sufficient to maintain olanzapine in an effective average particle size that maintains the efficacy of the drug over a period of time, such as about a week or more than about a week. The size of nanoparticles of the olanzapine particles can be manipulated to provide the desirable blood profile and duration of action when administered either intramuscularly (I) or subcutaneously (SC). Long-acting antipsychotics are preferred, since the population of patients treated with these drugs may suffer from poor acceptance, resulting in a decreased therapeutic effect of the drug administered. Drugs that require multiple daily administration, or even daily administration, are not preferred by this patient population. A simpler dosage form, such as a dosage form once a week, can result in dramatically improved acceptance by the patient, and consequently an improved quality of life. Advantages and properties of the compositions of the invention are described herein. Another aspect of the invention relates 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, as well as any desired excipient. The invention also describes a method of making a nanoparticulate olanzapine composition. Said 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 may be in contact with olanzapine either before, preferably during, or after size reduction of olanzapine. The present invention also relates to methods of treatment using the nanoparticulate injectable olanzapine compositions of the invention for, for example, psychotropic therapy and treatment of disorders of the central nervous system. In one embodiment of the invention, intramuscular or subcutaneous injection of olanzapine is used. Administration of the drug in this manner allows the formation of an intramuscular or subcutaneous reservoir of olanzapine which slowly releases the drug into the patient's system for a longer period of time than if administered orally. The period of time over which the drug is released is preferably up to about a week, from about two weeks to about six weeks, and from about two weeks to about twelve weeks. Additional periods of time of effectiveness are described here. This allows for improved patient acceptance with improved therapeutic results. In addition, injectable formulations of olanzapine result in a significantly shorter response time compared to oral administration. Although the current conventional formulations of olanzapine can be formulated for injection (ie, Zyprexa®), such conventional injectable olanzapine formulations are difficult to prepare due to the low water solubility of the drug. In psychotropic therapy and in the treatment of central nervous system disorders, it is important to provide a dosage form of olanzapine that delivers the required therapeutic amount of the drug in vivo and produces the bioavailability of the drug in a rapid and consistent manner. The nanoparticulate olanzapine formulations of the present invention achieve those objectives by forming a deposit of drug, preferably after intramuscular injection. The reservoir slowly releases the drug into the bloodstream at nearly zero order kinetic parameters for approximately one (1) to approximately twelve (12) weeks through the control of the nanoparticle size of the drug. Different sizes of nanoparticles will dissolve in different proportions, and will therefore release the drug into the bloodstream of the reservoir at different release rates. Both the above general description and the following brief description of the drawings as well as the detailed description are exemplary and explanatory and are intended to provide an additional explanation of the claimed invention. Other objects, advantages and novel aspects will be readily apparent to those skilled in the art from the following detailed description of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS Figures 1A-1 D: show electronic micrographs of unground olanzapine. Figure 2: shows an electron micrograph of a ground nanoparticulate olanzapine formulation. Figures 3A-3D: show electron micrographs of a ground nanoparticulate olanzapine formulation.

Figure 4: graphically shows the plasma concentration (ng / mL) of olanzapine for a period of time of six hours after intramuscular administration to six male dogs of a nanoparticulate olanzapine formulation. Figure 5: graphically shows plasma concentration (ng / mL) of olanzapine for a period of time of six hours after intramuscular administration to six male dogs of a nanoparticulate olanzapine formulation.

DETAILED DESCRIPTION OF THE INVENTION The invention provides injectable nanoparticulate olanzapine formulations which can comprise high concentrations of drug at low injection volumes, with action durations that can be controlled to provide effective blood levels through manipulation of the particle size and thus dissolution during periods of about a week or more. In other embodiments of the invention, compositions of the invention provide effective drug levels of from about one week to about two weeks, from about a week to about three weeks, from about a week to about four weeks, from about a week to about five. weeks, from about a week to about six weeks, from about a week to about seven weeks, from about a week to about eight weeks, from about a week to about nine weeks, from about a week to about ten weeks, from about a week to about eleven weeks, 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. The composition of the invention is administered by injection, such as, for example, by intramuscular injection or subcutaneously to form a drug reservoir. The drug deposit results in effective drug levels of up to about a week or more. As shown in the patent of E.U.A. No. 5,145,684, not every combination of surface stabilizer and active agent will result in a stable nanoparticulate composition. Surprisingly it has been found that stable, injectable, nanoparticulate formulations of olanzapine can be made. Current formulations of olanzapine suffer from the following problems: (1) the poor solubility of the drug results in a relatively low bioavailability; (2) the dosage must be repeated several every day; and (3) a wide variety of side effects are associated with the current dosage forms of the drug. The present invention overcomes the problems encountered with olanzapine formulations of the prior art. Specifically, the nanoparticulate olanzapine formulations of the invention can offer the following advantages: (1) a decrease in the dosage frequency and / or prolonged therapeutic levels of the drug after dosing; (2) a faster onset of action; (3) smaller doses of olanzapine are required to obtain the same pharmacological effect; (4) increased bioavailability; (5) improved performance characteristics for intravenous, subcutaneous or intramuscular injection, such as for example a higher dose load and smaller liquid dose volumes; (6) Improved pharmacokinetic profiles, such as improved Cmax and AUC profiles; (7) Substantially similar or bioequivalent pharmacokinetic profiles of the nanoparticulate olanzapine compositions when administered in the diet against the fasting state; (8) bioadhesive olanzapine formulations, which can cover the desired site of application and can be retained for a period of time, thereby increasing the efficacy of the drug as well as eliminating or decreasing the dosage frequency; (9) high redispersibility of the nanoparticulate olanzapine particles present in the composition of the invention after administration; (10) liquid nanoparticulate low viscosity olanzapine dosage forms can be made; (11) the compositions of Nanoparticulate olanzapine can be used together 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 injectable formulation. However, the composition may also be formulated in a powder or solid for reconstitution before injectable administration, such as, for example, by lyophilization. The dosage form can be, for example, a controlled release dosage form, delayed release dosage form, extended release dosage form, pulsatile release dosage form, mixed immediate release form and controlled release form, or a combination of these. The present invention is described herein using various definitions, as shown below and throughout the application. As used herein, "approximately" will be understood by those skilled in the art and will vary to some degree in the context in which it is used. If there are uses of the term which are not clear to those skilled in the art given the context in which it is used, "approximately" will mean up to plus or minus 10% of the particular term.

"Conventional" or "non-nanoparticulate active agent" means an active people that is solubilized or which has an effective average particle size of more than about 5 microns. The nanoparticulate active agents as defined herein have an effective average particle size of less than about 5 microns. "Water-poorly soluble drugs" as used herein refers to those having a solubility of less than about 30 mg / ml, preferably less than about 20 mg / ml, preferably less than 10 mg / ml, or preferably less than about 1 mg / ml. mg / ml. As used herein with reference to stable drug particles, "stable" includes, but is not limited to, one or more of the following parameters: (1) olanzapine particles do not flocculate or agglomerate appreciably due to attractive forces between the particles, or an otherwise significant increase in particle size over time; (2) that the physical structure of the olanzapine particles is not altered over time, for example by conversion of an amorphous phase to a crystalline phase; (3) that the olanzapine particles are chemically stable; and / or (4) wherein the olanzapine has not been subjected to a heating step at or above the melting point of olanzapine in the preparation of nanoparticles of the invention. "Therapeutically effective amount" as used herein with respect to a drug dosage, means that the dosage provides the specific pharmacological response for which the drug is administered in a significant number of subjects in need of said treatment. It is emphasized that "therapeutically effective amount" administered to a particular subject in a particular instance will not always be effective in the treatment of diseases described herein, although such dosage is considered a "therapeutically effective amount" for those who have experience in The technique. It will further be understood that drug dosages are, in particular cases, considered as injectable dosages.

Increased pK Profiles The invention preferably also provides olanzapine compositions having a desirable pharmacokinetic profile when administered to mammalian subjects. The desirable pharmacokinetic profile of olanzapine compositions preferably includes, but is not limited to: (1) a Cmax for olanzapine, when tested in the plasma of a mammalian subject after administration, which preferably is greater than Cmax for a Non-nanoparticulate olanzapine formulation (eg, Zyprexa®), administered in the same dosage; and / or (2) an AUC for olanzapine, when tested in the plasma of a mammalian subject after administration, which is preferably greater than the AUC for a non-nanoparticulate olanzapine formulation (eg, Zyprexa®), administered in the same dosage. The desirable pharmacokinetic profile, as used herein, it is the pharmacokinetic profile measured after the initial injectable dose of olanzapine. Conventional olanzapine (eg, Zyprexa®) reaches peak plasma levels in 5-8 hours, and has a half-life of approximately 35 hours depending on the metabolism. A preferred injectable olanzapine composition of the invention exhibits in comparative pharmacokinetic tests with a non-nanoparticulate olanzapine formulation of (eg, Zyprexa®), administered in the same dosage, a Cmax that 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 less about 1000%, at least about 100%, 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 1800%, or at least approximately 1900% greater than the Cmax exhibited by the non-nanoparticulate olanzapine formulation. A preferred injectable olanzapine composition of the invention exhibits in comparative pharmacokinetic tests with a non-nanoparticulate olanzapine formulation (eg, Zyprexa®), administered in the same dosage, an AUC that is 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 650%, at 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%, at least about 1200%, greater than AUC exhibited by the non-nanoparticulate olanzapine formulation.

Compositions with Combination Pharmacokinetic Profile In still another embodiment of the invention, a first non-nanoparticulate olanzapine composition that provides a desired pharmacokinetic profile is co-administered, sequentially administered, or combined with at least some other olanzapine composition that generates a profile desired pharmacokinetic. More than two olanzapine compositions can be co-administered, administered sequentially, or combined. Although the first olanzapine composition has a nanoparticulate particle size, the one or more additional olanzapine compositions may be nanoparticulate, solubilized, or have a microparticle particle size. The second, third, fourth, etc., olanzapine compositions may differ from the first, and one from another, for example: (1) in the effective average particle sizes of olanzapine; or (2) in the dosage of olanzapine. Said combination composition can reduce the frequency of dose required. If the second olanzapine composition has a nanoparticulate particle size, preferably then the olanzapine particles of the second composition have at least one surface stabilizer associated with the surface of the drug particles. The one or more surface stabilizers may be the same as or different from the surface stabilizer (s) present in the first olanzapine composition. Preferably, when a co-administration of a "fast acting" formulation and a "longer duration" formulation is desired, the two formulations are combined in a single composition, for example a double release composition.

A. Olanzapine Compositions The invention provides compositions comprising nanoparticulate olanzapine particles and at least one surface stabilizer. The surface stabilizers are preferably adsorbed or associated with the surface of the olanzapine particles. The useful surface stabilizers here do not react chemically with the olanzapine particles or with each other. Preferably, the individual molecules of the surface stabilizer are essentially free of intermolecular entanglements. The compositions may comprise two or more surface stabilizers. The present invention also includes nanoparticulate olanzapine compositions together with one or more carriers, adjuvants or vehicles, physiologically acceptable, non-toxic, collectively referred to as carriers. The compositions can be formulated for parenteral injection (e.g., intravenous, intramuscular or subcutaneous injection). Olanzapine may be in a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase or a mixture of these. Illustrative but non-limiting compositions comprise, based on% p / p: Olanzapine 5-50% Surface stabilizer 0.1-50% Preservatives (optional) 0.05-0.25% pH adjusting agent from approximately 6 to approximately 7 Water for injection q.s 1. Surface stabilizers The choice of a surface stabilizer for olanzapine trivial and requires experimentation to make a desirable formulation. Combinations of more than one surface stabilizer can be used in the invention. Useful surface stabilizers that can be employed in the invention include, but are not limited to, organic pharmaceutical excipients and known inorganics. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants. Surface stabilizers include nonionic, ionic, anionic, cationic and zwitterionic surfactants. Preferred surface stabilizers include, but are not limited to, polysorbate, for example Tween 80, benzalkonium chloride, and their combinations Representative examples of useful surface stabilizers include but are not limited to hydroxypropyl cellulose of low solubility (HPC or HPC-SL); hydroxypropylmethylcellulose (HPMC); hydroxymethyl cellulose (HMC); ethylcellulose; povidone; pluronic; sodium deoxycholate; PEG-phospholipids; Tyloxapol and other approved tritons, polyvinylpyrrolidone, sodium lauryl sulfate, dioctyl sulfosuccinate, 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 (for example, macrogol ethers such as cetomacrogol 1000), derivatives castor oil polyoxyethylene, polyoxyethylene sorbitan fatty acid esters (e.g., commercially available Tweens® such as, for example, Tween 20® and Tween 80® (ICI Specialty Chemicals)); polyethylene glycols (for example, Carbowaxs 3550® and 934® (Union Carbide)), polyoxyethylene stearates, colloidal silicon dioxide, phosphates, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, phthalate, non-crystalline cellulose, silicate aluminum magnesium, triethanolamine, polyvinyl alcohol (PVA), polymer of 4- (1,1,3,3-tetramethylbutyl) -phenol with ethylene oxide and formaldehyde (also known as tyloxapol, superione and titron), poloxamers (for example, Pluronics F68® and F108®, which are block copolymers of ethylene oxide and propylene oxide); poloxamines (for example, Tetronic 908®, also known as Poloxamine 908®, which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide of ethylenediamine (BASF Wyandotte Corporation, Parsippany, N.J.)); Tetronic 1508® (T-1508) (BASF Wyandotte Corporation), Tritons X-200®, which is an alkylaryl polyether sulfonate (Rohm and Haas); Crodestas F-10®, which is a mixture of sucrose stearate and sucrose distearate (Croda Inc.); p-isononiifenoxipoli- (glycidol); also known as Olin-10G® or agent -G® surfactant (Olin Chemicals, Stamford Ct); Crodestas SL-40® (Croda, Inc.); and SA9OHCO which is C18H37CH2 (CON / CH3) -CH2 (CHOH) 4 (CH2OH) 2 (Eastman Kodak Co.); decanoyl-N-methylglucamide; n-decyl β-D-glucopyranoside; n-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-p-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexyl ß-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-p-D-glucopyranoside; octyl β-D-thioglucopyranoside; Phospholipid derivative-PEG, cholesterol derivative-PEG, derivative of coiesterol derivative-PEG, vitamin A derivative-PEG, vitamin E derivative-PEG, lysozyme, random copolymers of vinyl pyrrolidone and vinyl acetate, and the like.

Povidone Polymers In one embodiment of the invention, a povidone polymer is used as a surface stabilizer. Povidone polymers for injectable compositions preferably have a molecular weight of less than about 40,000 daltons. Povidone polymers, also known as polyvidone, povidone, PVP, and polyvinylpyrrolidone, are marketed under the tradenames Kollídon® (BASF Corp) and Plasdona® (ISP Technologiesjnc). They are polydisperse macromolecular molecules, with a chemical name of 1-ethenyl-2-pyrrolidinone polymers and 1-vinyl-2-pyrrolidinone polymers. Povidone polymers are commercially produced as a series of products that have molecular weights average ranging from approximately 10,000 to approximately 700,000 daltons. To be useful as a surface modifier for a drug compound to be administered to a mammal, the povidone polymer must have a molecular weight of less than about 40,000 daltons, as a molecular weight of more than 40,000 daltons, it may have difficulty in cleaning the body. Povidone polymers are prepared by, for example, Reppe 'process, which comprises: (1) obtaining 1,4-butanediol from acetylene and formaldehyde by the butenene Reppe synthesis; (2) Dehydrogenation of 1,4-butanediol on copper at 200 ° to form β-butyrolactone; and (3) the reaction of? -butyrolactone with ammonia to produce pyrrolidone. A subsequent treatment with acetylene provides the vinyl pyrrolidone monomer. The polymerization is carried out by heating in the presence of H2O and NH3. See The Merck Index, 10th Edition, pp. 7581 (Merck &Co., Rahway, NJ, 1983). The method of manufacturing the povidone polymers produces polymers that contain molecules of unequal chain length, and thus different molecular weights. The molecular weights of the molecules vary from about an average or average for each particular commercially available degree. Since it is difficult to directly determine the molecular weight of the polymer, the most widely used method for the classification of various molecular weight grades are the K-values, based on viscosity measurements. The K values of several Povidone polymer grades represent a function of molecular weight average, and are derived from viscosity measurements and calculated according to to the Fikentscher formula.

The average weight of the molecular weight, Mw, is determined through of methods that measure the weights of individual molecules, such as scattering of light. Table 1 provides molecular weight data for various commercially available povidone polymers, all of which are soluble.

CUADR0 1 * Because the molecular weight is greater than 40,000 daltons, this povidone polymer is not useful as a surface stabilizer for a pharmacological compound that will be administered parenterally (i.e., injected). ** Mv is the average molecular weight in viscosity, Mn is the number-average molecular weight, and MW is the weight-average molecular weight, MW and Mn are determined through light scattering and ultra-centrifugation, and Mv is determined through viscosity measurements.

Based on the data provided in table 1, polymers of povidone, commercially available, preferred for Injectable compositions, include, but are not limited to Plasdona C-15®, Kollidon 2 PF®, Kollidon 17 PF®, and Kollidon 25®.

Cationic Surface Stabilizers Depending on the desired method of administration, nanoparticulate olanzapine bioadhesive formulations can be prepared by selecting one or more cationic surface stabilizers that impart bioadhesive properties to the resulting composition. Subsequently, useful cationic surface stabilizers are described. Examples of useful cationic surface stabilizers include, but are not limited to, polymers, biopolymers, polysaccharides, cellulosic materials, alginates, phospholipids and non-polymeric compounds, such as zwitterionic stabilizers, poly-n-methylpyridinium, antriul pyridinium chloride, cationic phospholipids, chitosan, polylysine, polyvinylimidazole, polybrene, polymethylmethacrylate trimethylammonium bromide (PMMTMABr), hexyldesyltrimethylammonium bromide (HDMAB), polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N- [amino (polyethylene glycol) 2000] (sodium salt) (also known as DPPE-PEG (2000) -amine Na) (Avanti polar Lipids, Alabaster, Al), poly (2-methacryloxyethyl trimethylammonium bromide) (Polysciences, Inc. , Warrington, PA) (also known as S1001), poloxamines such as Tetronic 908®, also known as Poloxamine 908®, which is a tetrafunction block copolymer. of the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, N.J.), lysozyme, long chain polymers such as alginic acid, carrageenan (FMC Corp.), and POLYOX (Dow, Midland, MI). Other useful cationic stabilizers include, but are not limited to, cationic lipids, sulfonium, phosphonium and quaternary ammonium compounds, such as stearyltrimethylammonium chloride, benzyl-di (2-chloroethyl) ethylammonium bromide, trimethyl ammonium chloride or bromide of coconut, chloride or coconut methyl dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride or bromide, dimethyl C 2 -5-hydroxyethyl ammonium bromide, coconut dimethyl hydroxyethyl ammonium chloride or bromide, methyl sulfate myristyl trimethyl ammonium, lauryl dimethyl benzyl ammonium chloride or bromide, lauryl dimethyl (ethenoxy) ammonium chloride or bromide, N-alkyl (Ci2-i8) dimethylbenzyl ammonium chloride, N-alkyl (C14-18) chloride dimethylbenzyl ammonium, monohydrate N-tetradecyldimethylbenzyl ammonium chloride, dimethyl didecyl ammonium chloride, N-alkyl and dimethyl (Ci2-i4) 1-naphthylmethyl ammonium chloride, trimethylammonium halide, alkyl trimethylammonium salts and dialkyl dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkylamidoalkyldialkylammonium salt and / or etholysed trialkyl ammonium salt, dialkylbenzene dialkylammonium chloride, N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl ammonium chloride, monohydrate chloride, N- alkyl (Ci2-i4) dimethyl 1-naphthylmethyl ammonium and dodecyldimethylbenzyl ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C 2 bromides, C 5i C17 trimethyl ammonium, dodecylbenzyl chloride triethyl ammonium, poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chlorides, alkyldimethylammonium halides, tricholyl methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride (ALIQUAT 336 ™), POLYQUAT 10 ™, tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters (such as fatty acid choline esters), benzalkonium chloride, stearalkonium chloride compounds (such as stearyltrimonium chloride and Di-stearyldimonium chloride), cetyl pyridinium bromide or chloride, quaternized polyoxyethylalkylaminide halide salts, MIRAPOL ™ and ALKAQUAT ™ (Alkaril Chemical Company), alkyl pyridinium salts, amines such as alkylamines, dialkylamines, alkanolamines, polyethylenepolyamines, α, β-dialkylaminoalkyl acrylates, and vinyl pyridine, amine salts, such as lauryl amine acetate, stearyl amine acetate, alkylpyridinium salt, and alkylimidazolium salt, and amine oxides; salts of azolium measurement; protonated quaternary acrylamides; methylated quaternary polymers, such as diallyl dimethyl ammonium polychloride] and poly-[N-methyl vinyl pyridinium duro]; and cationic guar. Such exemplary cationic surface stabilizers and other useful cationic surface stabilizers are described in J. Cross and E. Singer, Cationic Surfactants: Analytical and Biological! Evaluation (Marcel Dekker, 1994); P. and D. Rubingh (editor), Cationic Surfactants: Physical Chemistry (Marcel Dekker, 1991); and J. Richmond, Cationic Surfactants: Organic Chemistry, (Marcel Dekker, 1990).

The non-polymeric cationic surface stabilizers are any non-polymeric compound, such as benzalkonium chloride, a carbonium compound, a phosphonium compound, an oxonium compound, a halonium compound, a cationic organometallic compound, a quaternary phosphorous compound, a pyridinium compound, a compound anilinio, an ammonium compound, a hydroxylammonium compound, a primary ammonium compound, a secondary ammonium compound, a tertiary ammonium compound, and quaternary ammonium compounds of the formula NR- | R2R3R4 (+). For compounds of the formula NR-, R2R3R4 (+): (i) none of R- | -R are CH3; (iii) three of R1-R4 are CH3; (iv) all of RrR4 are CH3; (v) two of R R4 are CH3, one of R R is C6H5CH2, and one of RrR4 is an alkyl chain of seven carbon atoms or less; (vi) two of R R 4 are CH 3, one of R R 4 is C 6 H 5 CH 2, and one of R 4 is an alkyl chain of nineteen carbon atoms or more; (vii) two of R R4 are CH3, and one of R R is the group C6H5 (CH2) n, where n > 1; (viii) two of R R4 are CH3, one of Ri-R is C6H5CH2, and one of R R comprises at least one heteroatom; (X) two of R R4 are CH3, one of R1-R4 is C6H5CH2) and one of Ri-R4 comprises at least one halogen; (x) two of R R4 are CH3, one of R R4 is C6H5CH2, and one of R-i-R4 comprises at least one cyclic fragment; (xi) two of R R4 are CH3 and one of R R4 is a phenyl ring; or (xii) two of R-pR4 are CH3 and two of R-i-R4 are purely aliphatic fragments. Such compounds include, but are not limited to, behenalconium chloride, benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride, lauralconium chloride, cetalconium chloride, cetrimonium bromide, cetrimonium chloride, cetylamine hydrofluoride, chloralylmethanamine chloride (quaternary 15), distearyldimonium chloride (Quaternium-5), dodecyl dimethyl ethylbenzyl ammonium chloride (Quaternium 14), Quaternium 22, Quaternium 26, Quaternium hectorite 18, dimethylaminoethylchloride hydrochloride, cysteine hydrochloride, diethanolammonium phosphate POE (10) olethyl ether , diethanolammonium phosphate POE) (3) oleyl ether, tallow alkoxide, dimethyl dioctadecylammonium bentonite, stearalkonium chloride, domifenium bromide, denatonium benzoate, miristalkonium chloride, lauryrimonium chloride, ethylene diamine dihydrochloride, guanidine hydrochloride, pyridoxine HC , Iophetamine hydrochloride, meglumine hydrochloride, methylbenzethonium chloride, myrtrimonium bromide, oleyltrimonium loride, polyquaternium-1, procaine hydrochloride, cocobetaine, stearalkonium bentonite, stearalkoniohectonite, stearyl trihydroxyethyl propylene diamine dihydrofluoride, tallow trimonium chloride, and hexadecyltrimethyl ammonium bromide.

Most of these surface stabilizers are known pharmaceutical excipients and are described in detail in Handbook of Pharmaceutical Excipient, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain (The Pharmaceutical Press, 2000), specifically incorporated for reference. Surface stabilizers are commercially available and / or can be prepared by techniques known in the art. While applicants do not wish to bind by theoretical mechanisms, it is believed that the stabilizers hinder the flocculation and / or agglomeration of olanzapine particles by functioning as a mechanical or spatial barrier between the particles, minimizing the closed interparticle method, necessary for agglomeration and flocculation. 2. Excipients Exemplary preservatives include methylparaben (approximately 0.18% based on% w / w), propylparaben (approximately 0.02% based on% w / w), phenol (approximately 0.5% based on% w / w) and benzyl alcohol (up to 2% v / v). An exemplary pH adjusting agent is sodium hydroxide, and an exemplary liquid carrier is sterile water for injection. Other useful preservatives, pH adjusting agents, and liquid carriers are well known in the art. 3. - Nanoparticulate particle size of olanzapine. As used herein, the particle size is determined on the basis of the average weight particle size as measured by conventional particle size measurement techniques well known to those skilled in the art. Such techniques include, for example, fractionation of sedimentation field flux, photon correlation spectroscopy, light scattering, and disk centrifugation. The compositions of the invention comprise olanzapine nanoparticles having an effective average particle size of at least about 5 microns. In other embodiments of the invention, the olanzapine particles have a size of less than about 4900 nm, less than about 4800 nm, less than about 4700 nm, less than about 4600 nm, less than about 4500 nm, less than about 4400 nm , less than about 4300 nm, less than about 4200 nm, less than about 4100 nm, less than about 4 microns, less than about 3900 nm, less than about 3800 nm, less than about 3700 nm, less than about 3600 nm, less about 3500 nm, less than about 3400 nm, less than about 3300 nm, less than about 3200 nm, less than about 3100 nm, less than about 3 microns, less than about 2900 nm, less than about 2800 nm, less than about 2700 nm, less than about 2600 nm, less than about 2500 nm, less than about 2400 nm, less than about 2300 nm, less than about 2200, less than about 2100 nm, less than about 2000 nm, less than about 900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 500 nm, less than about 1400 nm, less than about 1300, less than about 200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less of about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 140 nm, less than about 130 nm, less than about 120 nm, less than about 110 nm, less than about 10 0 nm, less than about 90 nm, less than about 80 nm, less than about 70 nm, less than about 60 nm, or less than about 50 nm, when measured by the techniques described above. By "an effective average particle size of less than about 5 microns" means that at least 50% of the nanoparticulate olanzapine particles have a weight average particle size of less than about 5 microns, when measured by the techniques described above. In other embodiments of the invention, at least about 70%, at least about 90%, at least about 95%, or at least about 99% of the nanoparticulate olanzapine particles have a particle size of less than average effective, by weight, that is, less than about 5 microns, less than about 4900 nm, less than less than about 4800 nm, less than about 4700 nm, etc. (as listed in the previous paragraph). If the nanoparticulate olanzapine composition is combined with an olanzapine active agent composition or without microparticulate olanzapine, then said composition is solubilized or has an effective average particle size of more than about 5 microns. By "an effective average particle size of more than about 5 microns" means that at least 50% of the particles of active agent of olanzepine or without microparticulate olanzapine have a particle size of more than about 5 microns, by weight when measured by the techniques described above. In other embodiments of the invention, at least about 70%, at least about 90%, at least about 95% or at least about 99%, by weight, of the active agent particles of olanzapine or without microparticulate olanzapine they have a particle size of more than about 3 microns.

In the present invention, the value for D50 of a nanoparticulate olanzapine composition is the particle size below which 50% of the olanzapine particles fall, by weight. Similarly, D90 and D99 are the particle sizes below which 90% and 99%, respectively, of the olanzapine particles fall, by weight. 4. Concentration of nanoparticulate surface stabilizers and olanzapine The relative amounts of olanzapine and one or more surface stabilizers can vary widely. The optimum amount of the individual components may depend, for example, on the hydrophilic lipophilic balance (HLB), melting point, and the surface tension of the aqueous solutions of the stabilizer, etc. The concentration of olanzapine can vary from about 99.5% to about 0.001%, from about 95% to about 0.1%, from about 90% to about 0.5%, or from about 5.0% to about 50%, by weight, based on the total combined dry weight of olanzapine and at least one surface stabilizer, not including other excipients. The concentration of at least one surface stabilizer can vary from about 0.5% to about 99.999%, from about 5.0% to about 99.9%, from about 10% to about 99.5%, or about 0.1 to about 50% by weight, based on the total combined dry weight of olanzapine and at least one surface stabilizer, not including other excipients.

. Additional active agents The invention includes the nanoparticulated olanzapine compositions of the invention formulated or co-administered with one or more active agents without olanzapine. Methods for using said combination compositions are also included by the invention. The active agents without olanzapine may be present in a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, or a mixture thereof. The compounds to be administered in combination with a nanoparticulate olanzapine composition of the invention can be formulated separately from the nanoparticulate composition of olanzapine or co-formulated with the nanoparticulate composition of olanzapine. When a nanoparticulate olanzapine composition is co-formulated with a second active agent, the second active agent may be formulated in any suitable manner, such as immediate release, rapid onset, sustained release, or dual release form. Such active agents without olanzapine can be, for example, a therapeutic agent. A therapeutic agent can be a pharmaceutical agent, which includes a biological agent. The active agent can be selected from a variety of known classes of drugs, including, for example, amino acids, proteins, peptides, nucleotides, anti-obesity drugs, central nervous system stimulants, carotenoids, corticosteroids, elastase inhibitors, anti-fungals, oncological therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, such as inhibitors of NSAIDs and COX-2, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, anti-thyroid agents , antiviral agents, anxiolytics, sedatives (hypnotics and neuroleptics), astringents, alpha-adrenergic receptor blocking agents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, corticosteroids, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics (antiparkinsonian agents), hemostats, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and bisphosphonates, prostaglandins, radiopharmaceuticals, sex hormones (including spheroids), anti-allergic agents, stimulants and anorexics, sympathomimetics, thyroid agents, vasodilators, and xanthines. Examples of secondary active agents particularly useful in the compositions of the invention include, but are not limited to, antidepressants. Examples of classes of useful antidepressants include, without limited to selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants, and monoamine oxidase inhibitors (MAOI). Examples of antidepressants include, but are not limited to, citalopram (Celexa®), escitalopram HB (Lexapro®), fluoxetine hydrochloride (Prozac®), paroxetine (Paxil®), fluvoxamine (Luvox®), sertraline (Zoloft®), venlafaxine ( Effexor®), amitriptyline (Elavil®), desipramine, nortriptyline, duloxetine (Cymbalta®), mirtazepine (Remeron®), phenelzine (Nardil®), tranylcypromine (Parnate®), nefazodone (Serzona®); trazodone, and bupropion (Wellbutrin®). A particularly useful antidepressant is fluoxetine (Prozac®).

B. Methods of Making Injectable Olanzapine Formulations In another aspect of the invention, a method is provided for the preparation of injectable nanoparticulate olanzapine formulations of the invention. The method comprises one of the following methods: friction, precipitation, evaporation, or combinations thereof. Exemplary methods of making nanoparticulate compositions are described in the U.S.A. No. 5,145,684. The methods of making nanoparticulate compositions are also described in the patent of E.U.A. No. 5,518,187 for "Method of Grinding Pharmaceutical Substances", patent of E.U.A. No. 5,718,388 for "Continuous Method of Grinding Pharmaceutical Substances"; patent of E.U.A. No. 5,862,999 for "Method of Grinding Pharmaceutical Substances", patent of E.U.A. No. 5,665,331 for "Co- Microprecipitation of nanoparticulate Pharmaceutical Agents with Crystal Growth Modifiers "; U.S. Patent No. 5,662,883 for" Co-Microprecipitation of Nanoparticulate pharmaceutical Agents with Crystal Growth Modifiers; "U.S. Patent No. 5,560,932 for" Microprecipitation of nanoparticulate pharmaceutical Agents "; No. 5,543,133 for "" Process of preparing X-Ray Contrast Compositions Containing Nanoparticles ", US patent No. 5,534,270 for "Method of Preparing Stable Drug nanoparticles"; patent of E.U.A. No. 5,510,118 for "Process of Preparing Therapeutic Compositions Containing nanoparticles"; and U.S. Patent No. 5,470,583 to "Method of preparing nanoparticles Compositions Containing charged Phospholipids to Reduce Aggregation"; all of which are incorporated specifically for reference. After grinding, homogenization, precipitation, etc., the resulting nanoparticulate olazepine composition can be used as a liquid dosage formulation for injectable administration. In one embodiment of the invention, the olanzapine particles are reduced to an effective average particle size of less than about 600 nm. Preferably, the effective average particle size of nanoparticulate olanzapine is less than about 450 nm, more preferably less than 300 nm, still more preferably less than about 250 nm, and more preferably less than about 100 nm. The pH of the liquid dispersion medium is preferably kept within the range of about 3.0 to about 8.0, or about 5.0 to about 7.5, more preferably, at a pH of about 7.4, during the size reduction process. Preferably, the dispersion medium used for the size reduction process is aqueous. However, any medium in which olanzapine is poorly soluble and dispersible can be used as a dispersion medium. Non-aqueous examples of the dispersion medium include, but are not limited to, aqueous saline solutions, safflower oil and solvents such as ethanol, t-butanol, hexane, and glycol. Effective methods of providing mechanical strength for the reduction of olanzapine particle size include ball milling, media grinding, and homogenization, for example, with a Microfluidizer® (Microfluidics Corp). Ball milling is a low-energy milling process that uses grinding media, drug, stabilizer, and liquid. The materials are placed in a grinding vessel that is rotated at an optimum speed such as the medium cascades and reduces the particle size of the drug by impaction. The media used must have a high density since the energy for particle reduction is provided by the gravity and mass of the friction wear media. Media milling is a high-energy milling process. The drug, stabilizer, and liquid are placed in a container and recirculated in a chamber containing means and a rotating shaft / propeller. The axis of rotation agitates the media that subject the drug to impaction and shearing forces, thereby reducing the size of the drug particle.

Homogenization is a technique that does not use grinding media. Drug, stabilizer, and liquid (or drug and liquid with stabilizer added after reduction of particle size) constitute a process stream propelled within a process zone, which in the Microfluidizer® is called the interaction chamber. The product to be treated is introduced into the pump, and then forced to exit. The safety valve of the Microfluidizer® purges air out of the pump. Once the pump is filled with the product, the safety valve closes and the product is pressed through the interaction chamber. The geometry of the interaction chamber produces intense forces of cut, impact, and cavitation that are responsible for the reduction of particle size. Specifically, within the interaction chamber, the pressurized product separates into two streams and accelerates at extremely high speeds. The jets formed then go towards each other and collide in the interaction zone. The resulting product has a uniform and very fine particle size or small droplet size. The microfluidizer® also provides a heat exchanger to allow product cooling. The patent of E.U.A. No. 5,510,118, which is incorporated specifically for reference, refers to a process using Microfluidizer® that results in nanoparticulate particles. Olanzapine can be added to a liquid medium in which it is essentially insoluble to form a premix. The concentration of olanzapine in the liquid medium can vary from about 5 to about 60%, and preferably is from about 15 to about 50% (w / v), and more preferably from about 20 to about 40%. The surface stabilizer may be present in the premix, may be during particle size reduction, or may be added to the drug dispersion after the reduction in particle size. The concentration of the surface stabilizer can vary from about 0.1 to about 50%, and preferably is from about 0.5 to about 20%, and more particularly from about 1 to about 10% by weight. The premix can be used directly by subjecting it to mechanical means to reduce the average particle size of olanzapine in the dispersion to the desired size, preferably less than about 5 microns. It is preferred that the premix be used directly when a ball mill is used for frictional wear. Alternatively, olanzapine and the surface stabilizer can be dispersed in the liquid media using suitable agitation, for example, a Cowles-type mixer, until a homogeneous dispersion is observed where there are no longer large agglomerates visible to the eye. It is preferred that the premix be subjected to said pre-grinding dispersion step when a grinding of recirculating media for frictional wear is used. The mechanical means applied to reduce the particle size of olanzapine conveniently can take the form of a dispersion mill. Suitable dispersion mills include a ball mill, a grinder, a vibratory mill, and media mills such as sand mill and a pearl mill. A medium mill is preferred due to the relatively shorter grinding time required to provide the desired reduction in particle size. For media grinding, the apparent viscosity of the premix is preferably from about 100 to about 1000 centipoise, and for ball milling the apparent viscosity of the premix preferably is from about 1 to about 100 centipoise. Such scales tend to produce an optimal balance between efficient particle size reduction and media erosion but are not limited in any way. The wear time by friction can vary widely and depends primarily on the particular mechanical means and the selected processing conditions. For ball mills, processing times of up to five days or longer may be required. Alternatively, processing times of less than 1 day (residence times of one minute to several hours) are possible with the use of a high shear media mill. The olanzapine particles must be reduced in size at a temperature at which olanzapine is not significantly degraded. Processing temperatures of less than about 30 ° to less than about 40 ° C are ordinarily preferred. If desired, the processing equipment can be cooled with cooling equipment conventional. Temperature control, for example, by screwing or immersing the grinding chamber with a cooling liquid, is contemplated. Generally, the method of the invention is conveniently carried out under ambient temperature conditions and processing pressures that are safe and effective for the milling process. The ambient processing pressures are typical of the ball mills, grinders, and vibratory mills.

Rectification Means The rectification means may comprise particles that are preferably substantially spherical in shape, for example, beads, consisting essentially of polymeric resin or glass or zirconium silicate or other suitable compositions. Alternatively, the rectification means may comprise a core having a coating of a polymer resin bonded thereto. In general, suitable polymer resins are chemically and physically inert, substantially free of metals, solvent, and monomers and of sufficient hardness and friability to allow them to not burr or crush during grinding. Suitable polymeric resins include entangled polystyrenes, such as polystyrene entangled with divinylbenzene, styrene copolymers; polycarbonates; polyacetals, such as Delrin® (E.l. du Pont de Neumours and Co.); vinyl chloride polymers and copolymers; polyurethanes, polyamides; poly (tetrafiuoroethylenes), for example, Teflon® (E.I. du Pont de Nemours and Co.) and other fluoropolymers; high density polyethylenes; polypropylenes; ethers and cellulose esters such as cellulose acetate; poiihydroxymethacrylate; polyhydroxyethyl acrylate; and silicone-containing polymers such as polysiloxanes and the like. The polymer can be biodegradable. Exemplary biodegradable polymers include poly (lactides), poly (glycolide) copolymers of lactides and glycolide, polyanhydrides, poly (hydroxyethyl methacrylate), poly (imino carbonates), poly (N-acylhydroxyproline) esters, poly (N-palmitoyl hydroxyproline) esters , ethylene-vinyl acetate copolymers; poly (orthoesters), poly (caprolactones) and poly (phosphazenes). For biodegradable polymers, contamination of the media by themselves can advantageously be metabolized in vivo into biologically acceptable products that can be eliminated from the body. The rectification means preferably range in size from about 0.01 to about 3 mm. For fine grinding, the grinding media preferably is from about 0.02 to about 2 mm, and more preferably from about 0.03 to about 1 mm in size. The polymeric resin can have a density of about 0.8 to about 3.0 g / cm3. In one embodiment of the invention, the olanzapine particles are made continuously. Said method comprises the continuous introduction of olanzapine into a grinding chamber, putting in contact the olanzapine with the rectification means while in the chamber the particle size of olanzapine is reduced, and the nanoparticulate olanzapine from the milling chamber is continuously removed. The rectification media can be separated from the ground nanoparticulate olanzapine using conventional separation techniques, in a secondary process such as by simple filtration, sieving through a mesh screen or sieve, and the like. Other separation techniques such as centrifugation can also be employed. Alternatively, a screen can be used during the milling process to remove the grinding media after the completion of the reduction in particle size.

Sterile Product Manufacturing The development of injectable compositions requires the production of a sterile product. The manufacturing process of the present invention is similar to manufacturing processes typically known for sterile suspensions. A flowchart of the typical sterile suspension manufacturing process is as follows: Conditioning of the media i Formation of the composite i Reduction of the particle size i filled with the bottle i Lyophilization and / or terminal sterilization As indicated by the optional steps in parentheses, part of the processing is dependent on the method of particle size reduction and / or sterilization method. For example, the conditioning of the media is not required for a milling method that does not use media. If terminal sterilization is not feasible due to chemical and / or physical instability, aseptic processing can be used.

C. Treatment method Still another aspect of the present invention provides a method of treating a mammal, including a human, of central nervous system disorders including, but not limited to, psychiatric treatment. Said treatment comprises the administration to the injectable nanoparticulate olanzapine formulation subject of the invention. As used herein, the term "subject" is used to refer to an animal, preferably a mammal, which includes a human or non-human. The terms patient and subject can be used interchangeably. Examples of disorders that can be treated with olanzapine include, but are not limited to, schizophrenia and related psychosis, bipolar mania and / or bipolar disorder, stroke, obsessive / compulsive disorders, generalized anxiety disorder, post-traumatic distress syndrome , extreme shyness, diabetic nerve pain, cigarette abstinence, and depression. Particularly advantageous aspects of the present invention are that the pharmaceutical formulation of the invention exhibits a prolonged duration of action that can be controlled in the administration, and produces minimal pain or does not produce pain or irritation in the administration. For example, the compositions of the invention can provide effective drug levels of up to about a week, from about two to six weeks, or from about two to about twelve weeks. In addition, the injectable formulation of the invention can provide a high concentration of olanzapine in a small volume that will be injected. A general protocol for its administration comprises an intramuscular or subcutaneous bolus injection of olanzapine. Conventional olanzapine (Zyprexa®) has a single start dose of 10 mg. The usual maximum dose should be 20 mg. For the treatment of psychosis, such as schizophrenia, the dosage for adults it is 5-10 mg / day initially, with a target dose of 10 mg / day within several days. Olanzapine shows mesolimbic sensitivity, conditional block avoidance at lower doses than those inducing catalepsy, substitutes for clozapine in a drug discrimination trial, produces a modest increase in prolactin, produces few extra pyramidal side effects, and reduces positive and negative symptoms of schizophrenia as effectively as clozapine. However, despite this "atypical" profile, olanzapine has a weaker alpha-2 block than clozapine or risperidone. It has a relatively high affinity for 5HT-2 muscarinic receptors, and D1, D2 and D4. The trials suggest a good response in schizophrenia with few extra pyramidal side effects (EPSE). Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable carriers, diluents, solvents or aqueous and non-aqueous vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol and the like), their suitable mixtures, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of agents surfactants. The nanoparticulate compositions may also contain adjuvants such as preservatives, wetting, emulsification and dispersion. The prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be carried about by the use of agents that retard absorption, such as aluminum monostearate and gelatin. One of ordinary skill will appreciate that the effective amounts of olanzapine can be determined empirically and can be used in pure form or, where such forms exist, in a pharmaceutically acceptable salt, ester, or prodrug. The effective dosage levels of olanzapine in the nanoparticulate compositions of the invention can be varied to obtain an amount of olanzapine that is effective to obtain a desired therapeutic response for a particular composition and method of administration. The selected dosage level therefore depends on the desired therapeutic effect, the route of administration, the potency of olanzapine administered, the desired duration of treatment, and other factors. Dosage unit compositions may contain such amounts of their submultiples as may be used to constitute the daily dose. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors: the type and degree of cellular or physiological response that will be obtained; activity of the specific agent or composition used; the specific agents or composition used; age, body weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the agent; the duration of treatment, drugs used in combination or coincident with the specific agent; and similar factors well known in the medical arts. The following examples are provided to illustrate the present invention. It should be understood, however, that the essence and scope of the invention should not be limited to the specific conditions or details described in these examples but should be limited only by the scope of the claims that follow. All references identified herein, including the patents of E.U.A. they are expressly incorporated by this means for reference.

EXAMPLE 1 The purpose of this example is to illustrate the procedure for the identification of a suitable nanoparticulate formulation of olanzapine. The study can be conducted by grading eleven surface stabilizers to identify the most appropriate stabilizer for parenteral administration of olanzapine. Dispersions can be formulated in 40% solids at 2.4% surface stabilizer.

TABLE 2 Plasmodium C15® (polyvinylpyrrolidone) surface stabilizer Kollidon 17PF® (a polyvinylpyrrolidone polymer) Povidone K30® (a polymer of polyvinylpyrrolidone) Tyloxapol Pluronic F68® (a high molecular weight polyoxyalkylene ether) Pluronic F108® (a high-polyoxyalkylene ether) molecular weight) Tween 80® (a polyoxyethylene sorbitan fatty acid ester Dioctylsulfuccinate (CAS No. 577-11-7; sodium aka docusate) B20-5000® (a triblock copolymer surface modifier) B20-5000-sulfonated (a triblock copolymer surface modifier) Lecithin (CAS No. 8002-43-5) Povidone K30® and Pluronic F108® Said combinations can produce stable dispersions of nanoparticulate size differentiation that will have durations of action differentiation when administered. Preclinical and clinical studies will identify the optimal formulation and size associated with the duration Preferred desired prolonged action.

EXAMPLE 2 The purpose of this example is to prepare a formulation nanoparticle of olanzapine. The particle size of olanzapine drug crystals is first measured before incorporation into a nanoparticulate formulation. The particle size, as measured using a Horiba LA 910 particle size analyzer (Horiba Instruments, Irvine, CA), is a midpoint of 137.08 microns and a D90 of less than 335.59 microns. See Figures 1A-1 D. An aqueous dispersion of 10% olanzapine (Camida LLC, Newark, NJ), combined with 1% Tween 80, 0.1% benzalkonium chloride, and 20% dextrose, is ground in a Nanomill® 0.01 (Elan Drug Delivery), together with 500 micras of Poly ill® rectification medium (Dow Chemical) (50-89% media loading). The mixture is milled at a rate of 1009-5500 rpm, at a temperature of 5-10 ° C, for approximately 30 minutes. After grinding, the particle size of ground olanzapine particles is measured, in deionized distilled water, using an Horiba LA 910 particle size analyzer. The medium sized olanzapine particle size is 347 nm, with a size medium of 606 nm, a D90 of 1.28 microns, and a D83 of less than 1 miera. See figure 2.

EXAMPLE 3 The purpose of this example is to prepare a formulation nanoparticle of olanzapine. A 30% aqueous dispersion of olanzapine (Camida LLC, Newark, NJ), combined with 2.5% Tween 80, is ground in a Nanomill® 0.01 (Elan Drug Delivery), along with 500 micras of PolyMill® rectification media (Dow Chemical) (50-89% media loading). The mixture is milled at a rate of 1009-5500 rpm, at a temperature of 5-10 ° C, for approximately 30 minutes. After grinding, the particle size of the ground olanzapine particles is measured, in deionized distilled water, using an Horiba LA 910 particle size analyzer. The medium sized olanzapine particle size is 990 nm, with an average size of 1.136 nm, a D90 of 2.07 microns, and a D50 of less than 1 miera. See Figures 3A-3D.

EXAMPLE 4 The purpose of this example is to determine the in vivo characteristics of the nanoparticulate formulation of olanzapine prepared in Example 2. An in vivo study, using male malted dogs, is conducted to determine the therapeutic levels of olanzapine present in vivo over a period of time. after intramuscular (IM) administration of the nanoparticulate olanzapine formulation prepared in example 2. Six dogs are given a single intramuscular dose of 10 mg / kg (approximately 100 mg / animal), which is approximately 10x of the daily dose in humans. Blood samples are taken at t = 0, 0.5, 1, 2, 4, 8, 24 and 49 hours after administration, and 4, 7, 14 and 28 days after administration. The concentration of plasma (ng / ml) for a period of 168 hrs is shown in figure 4. As shown in figure 4, therapeutic levels of olanzapine from 5 to 22 ng / ml are presented in vivo for a period of time. 168 hrs. Figure 5 further demonstrates that for all dosed animals, the therapeutic levels of olanzapine, from 5 to 22 ng / ml, were present in vivo for a period of 168 hrs. In addition to demonstrating that the injectable olanzapine formulations of the invention produce medial and detectable levels of drug in plasma for more than seven days after administration, this example further demonstrates: (1) that the olanzapine formulation prepared as in the example 2 is injectable with a 23 gauge needle, and (2) that the olanzapine formulation prepared as in example 2 is well tolerated by mammals. It will be apparent to those skilled in the art that various modifications and variations can be made in the methods and compositions of the present invention without deviating from the essence and scope of the invention. Thus, it is intended that the present invention cover the modifications and variations of this invention as long as they are within the scope of the appended claims and their equivalents.

Claims (31)

NOVELTY OF THE INVENTION CLAIMS

1. - An injectable nanoparticulate olanzapine composition comprising: (a) olanzapine nanoparticles having an effective average particle size resulting in a therapeutic efficacy of about one week or more; (b) at least one surface stabilizer; and (c) a pharmaceutically acceptable carrier.

2. The composition according to claim 1, further characterized in that the composition is administered through intramuscular or subcutaneous injection to thereby form a deposit.

3. The composition according to claim 2, further characterized in that the reservoir releases the olanzapine at therapeutic levels for a period of time from about two to about six weeks.

4. The composition according to claim 1, further characterized in that the reservoir releases the olanzapine at therapeutic levels for a period of time from about two to about twelve weeks.

5. - The composition according to claim 1, characterized in that the deposit releases olanzapine in levels Therapeutics for a period of time selected from the group consisting of one week to about two weeks, from about a week to about three weeks, from about a week to about four weeks, from about a week to about five weeks, of about a week at about six weeks, from about a week to about seven weeks, from about a week to about eight weeks, from about a week to about nine weeks, from about a week to about ten weeks, from about a week to about eleven weeks, from about a week to about twelve weeks, and any combination thereof.

6. - The composition according to claim 1, further characterized in that olanzapine is selected from the group consisting of the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, and mixtures of this.

7. - The composition according to claim 1, further characterized in that the effective average particle size of the olanzapine particles of less than about 5 microns.

8. The composition according to claim 7, further characterized in that the effective average particle size of the olanzapine particles is selected from the group consisting of less than about 4900 nm, less than about 4800 nm, less than about 4700 nm, less than about 4600 nm, less than about 4500 nm, less than about 4400 nm, less than about 4300 nm, less than about 4200 nm, less than about 4100 nm, less than about 4 microns, less than about 3900 nm, less than about 3800 nm, less than about 3700 nm, less than about 3600 nm, less than about 3500 nm, less than about 3400 nm, less than about 3300 nm, less than about 3200 nm, less than about 3100 nm, less than about 3 microns, less than about 2900 nm, less than about 2800 nm, less than about 2700 nm, less than about 2600 nm, less than about 2500 nm, less than about 2400 nm, less than about 2300 nm, less than about 2200, less than about 2100 nm, less than about 2000 nm, less than about 1900 nm, less than about 800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000, less of about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about about 200 nm, less than about 150 nm, less than about 140 nm, less than about 130 nm, less than about 120 nm, less than about 10 nm, less than about 100 nm, less than about 90 nm, less than about 80 nm, less than about 70 nm, less than about 60 nm, and less than about 50 nm. 9. - The composition according to claim 1, further characterized in that: (a) the olanzapine is in an amount selected from the group consisting of the group consisting of from about 99.5% to about 0.001%, from about 95% to about 0.1 %, from about 90% to about 0.5%, and from about 5.0% to about 50%, by weight, based on the total combined weight of olanzapine and at least one surface stabilizer, not including other excipients; and (b) the at least one surface stabilizer is present in an amount selected from the group consisting of from about 0.5% to about 99.999% by weight, from about 5.0% to about 99.

9% by weight, from about 10% to about 99.5. %, and from about 0.1 to about 50% by weight, based on the total combined dry weight of olanzapine and at least one surface stabilizer, not including other excipients.

10. The composition according to claim 1, further characterized in that the surface stabilizer is selected from the group consisting of a nonionic surface stabilizer, an ionic surface stabilizer, an anionic surface stabilizer, a cationic surface stabilizer, and a zwitterionic surface stabilizer.

11. The composition according to claim 1, further characterized in that at least one surface stabilizer is selected from the group consisting of cetyl pyridinium chloride, gelatin, casein, phosphatides, dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, bromide of dodecyl trimethyl ammonium, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecyl sulfate, calcium carboxymethylcellulose, hydroxypropyl celluloses, hypromellose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, noncrystalline cellulose, aluminum magnesium silicate, triethanolamine, polyvinyl alcohol , polyvinylpyrrolidine, polymer of 4- (1,1,1,3-tetramethylbutyl) -phenol with ethylene oxide and formaldehyde, poloxamers; poloxamines, a charged phospholipid, dioctyl sulfosuccinate, dialkyl esters of sodium sulfosuccinic acid, sodium laurel sulfate, alkylaryl polyether sulfonates, mixtures of sucrose stearate and sucrose distearate, p-isononylphenoxypoly- (glycidol); decanoyl-N-methylglucamide; n-decyl β-D-glucopyranoside; n-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-N-methyl glucamide; n-heptyl-p-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexyl ß-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl ^ -D-glucopyranoside; octyl β-D-thioglucopyranoside; lysozyme, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, random copolymers of vinyl acetate and vinylpyrrolidone, cationic polymers, cationic biopolymers, cationic polysaccharides, cationic cellulosics, cationic alginates, cationic non-polymeric compounds, cationic phospholipids, cationic lipids, polymethylmethacrylate trimethylammonium bromide, sulfonium compounds, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, hexadecyltrimethylammonium bromide, phosphonium compounds, quaternary ammonium compounds, benzyl-di (2-chloroethyl) ethylammonium bromide, coconut trimethyl ammonium chloride, coconut trimethyl ammonium bromide, coconut methyl dihydroxyethyl ammonium chloride, coconut methyl dihydroxyethyl ammonium bromide , decyl trimethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium bromide chloride, C12-15 dimethyl chloride hydroxyethyl ammonium chloride, dimethyl Ci2-i5-hydroxyethyl ammonium bromide, dimethyl hydroxyethyl chloride coconut ammonium, coconut dimethyl hydroxyethyl ammonium bromide, myristyl trimethyl ammonium methyl sulfate, lauryl dimethyl benzyl ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl (ethenoxy) 4 ammonium chloride, lauryl dimethyl (ethenoxy) bromide 4 ammonium, N-alkyl (C 2 - i 8) dimethylbenzyl ammonium chloride, N-alkyl (C 14-18) dimethylbenzyl chloride ammonium, N-tetradecyldimethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and dimethyl (C12-i4) -1-naphthylmethyl ammonium chloride, trimethylammonium halide, alkyl trimethylammonium salts, dialkyl-dimethylammonium salts, chloride of lauryl trimethyl ammonium, ethoxylated alkylamidoalkyldialkylammonium salt, an etholylated trialkyl ammonium salt, dialkylbenzene dialkylammonium chloride, N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl ammonium chloride, monohydrate chloride, N-alkyl (Ci2-i4) dimethyl-naphthylmethyl chloride ammonium, dodecyldimethylbenzyl ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C2 trimethyl ammonium bromides, C- | 5 trimethyl ammonium bromides, bromides of C17 trimethyl ammonium, dodecylbenzyl triethyl ammonium chloride, poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chlorides, alkali halides uildimethylammonium, tricetyl methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride, POLYQUAT 10 ™, tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters, benzalkonium chloride, stearalkonium, cetyl pyridinium bromide, cetyl pyridinium chloride, quaternized polyoxyethylalkylamines halide salts, MIRAPOL ™ and ALKAQUAT ™, alkyl pyridinium salts, amines, amine salts, amine oxides; imidazole salts; protonated quaternary acrylamides; methylated quaternary polymers, and cationic guar.

12. - The composition according to claim 1, further characterized in that it comprises a surface stabilizer selected from the group consisting of a polysorbate, benzalkonium chloride, dextrose, and combinations thereof.

13. The composition according to claim 1, further characterized in that it comprises at least one additional olanzapine composition having an effective average particle size that is different from the effective average particle size of the olanzapine composition of claim 1

14. The composition according to claim 1, further characterized in that it additionally comprises one or more active agents without olanzapine.

15. The composition according to claim 14, further characterized in that at least one agent without olanzapine is an antidepressant.

16. The composition according to claim 15, further characterized in that the antidepressant is fluoxetine.

17. The composition according to claim 1, further characterized in that the composition is injectable with a 23 gauge needle.

18. The composition according to claim 1, further characterized in that it is well tolerated by a mammal.

19. - A method of making a composition of Injectable nanoparticulate olanzapine which produces an intramuscular reservoir in the administration comprising: contacting olanzapine particles or their salt with at least one surface stabilizer for a time and under conditions sufficient to provide an olanzapine composition having an average particle size effective that results in a therapeutic efficacy of approximately a week or more.

20. The method according to claim 19, further characterized in that the contact comprises rectification, wet rectification, homogenization, or combinations thereof.

21. The method according to claim 19, further characterized in that the effective average particle size of the olanzapine particles is less than about 5 microns.

22. The composition according to claim 21, further characterized in that the effective average particle size of olanzapine particles is selected from the group consisting of less than about 4900 nm, less than about 4800 nm, less than about 4700 nm, less than about 4600 nm, less than about 4500 nm, less than about 4400 nm, less than about 4300 nm, less than about 4200 nm, less than about 4 00 nm, less than about 4 microns, less than about 3900 nm, less than about 3800 nm, less than about 3700 nm, less than about 3600 nm, less than about 3500 nm, less than about 3400 nm, less than about 3300 nm, less than about 3200 nm, less than about 3100 nm, less than about 3 microns, less than about 2900 nm, less than about 2800 nm, less than about 2700 nm, less than about 2600 nm, less than about 2500 nm, less than about 2400 nm, less than about 2300 nm, less than about 2200, less than about 2100 nm, less than about 2000 nm, less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less of about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm , less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 140 nm, less than about 130 nm, less than about 120 nm, less than about 110 nm, less than about about 100 nm, less than about 90 nm, less than about 80 nm, less than about 70 nm, less than about 60 nm, and less than about 50 nm.

23.- A method for the treatment of a subject of disorders of the central nervous system comprising administering to the subject an effective amount of an injectable composition comprising: (a) olanzapine nanoparticles having an effective average particle size resulting in a therapeutic efficacy of about one week or more; (b) at least one surface stabilizer; (c) at least one pharmaceutically acceptable carrier.

24. The method according to claim 23, further characterized in that the effective average particle size of the olanzapine particles is less than about 5 microns.

25. The method according to claim 24, further characterized in that the effective average particle size of the olanzapine particles is selected from the group consisting of less than about 4900 nm, less than about 4800 nm, less than about 4700 nm , less than about 4600 nm, less than about 4500 nm, less than about 4400 nm, less than about 4300 nm, less than about 4200 nm, less than about 4100 nm, less than about 4 microns, less than about 3900 nm, less of about 3800 nm, less than about 3700 nm, less than about 3600 nm, less than about 3500 nm, less than about 3400 nm, less than about 3300 nm, less than about 3200 nm, less than about 3100 nm, less than about 3 microns, less than about 2900 nm, less than about 2800 nm, less than about 2700 nm, less than about 2600 nm, less than about 2500 nm, less than about 2400 nm, less than about 2300 nm, less than about 2200, less than about 2100 nm, less than about 2000 nm, less than about 1900 nm , less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm , less than about 200 nm, less than about 150 nm, less than about 140 nm, less than about 130 nm, less than about 120 nm, less than about 110 nm, less than about 100 nm, less than about 90 nm, less than about 80 nm, less than about 70 nm, less of about 60 nm, and less than about 50 nm.

26. The method according to claim 23, further characterized in that the reservoir releases the olanzapine at therapeutic levels for a period of time from about two weeks to about six weeks.

27. The method according to claim 23, further characterized in that the reservoir releases the olanzapine at therapeutic levels for a period of time from about two weeks to about twelve weeks.

28. The method according to claim 23, further characterized in that the reservoir releases the olanzapine at therapeutic levels for a period of time selected from the group consisting of one week to about two weeks, from about one week to about three weeks, from about a week to about four weeks, from about a week to about five weeks, from about a week to about six weeks, from about a week to about seven weeks, from about a week to about eight weeks, of about a week to about about nine weeks, from about a week to about ten weeks, from about a week to about eleven weeks, from about a week to about twelve weeks, and combinations thereof.

29. The method according to claim 23, further characterized in that the AUC of olanzapine, when analyzed in the plasma of a mammalian subject after the injectable administration, is greater than the AUC of a non-nanoparticulate olanzapine formulation, administered in the same dosage.

30. - The method according to claim 29, further characterized in that the AUC is selected from the group consisting of 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 650%, at 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 less about 1150%, or at least about 1200% greater than AUC exhibited by the non-nanoparticulate olanzapine formulation, administered in the same dosage.

31. The method according to claim 23, further characterized in that the method is used to treat an indication selected from the group consisting of schizophrenia and related psychosis, bipolar mania, bipolar disorder, stroke, disorders obsessive / compulsive, generalized anxiety disorder, post-traumatic distress syndrome, extreme shyness, diabetic nerve pain, cigarette abstinence, and depression.