EP1874267A1 - Injizierbare depot-formulierungen und verfahren für die verzögerte freisetzung von schwerlöslichen arzneimitteln mit nanoteilchen - Google Patents

Injizierbare depot-formulierungen und verfahren für die verzögerte freisetzung von schwerlöslichen arzneimitteln mit nanoteilchen

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Publication number
EP1874267A1
EP1874267A1 EP06727541A EP06727541A EP1874267A1 EP 1874267 A1 EP1874267 A1 EP 1874267A1 EP 06727541 A EP06727541 A EP 06727541A EP 06727541 A EP06727541 A EP 06727541A EP 1874267 A1 EP1874267 A1 EP 1874267A1
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EP
European Patent Office
Prior art keywords
formulation
compound
weight
particle size
another embodiment
Prior art date
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Application number
EP06727541A
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English (en)
French (fr)
Inventor
Jaymin Chandrakant Shah
Parag Suresh Shah
Dawn Renee Wagner
Peter Wisniecki
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Pfizer Products Inc
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Pfizer Products Inc
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Publication of EP1874267A1 publication Critical patent/EP1874267A1/de
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention comprises a pharmaceutical formulation comprising: a compound of low water solubility, having a maximum average particle size; a carrier; and at least two surface stabilizers.
  • the present invention also comprises methods of treatment with such a formulation and processes for making such a formulation.
  • Targeted delivery of drugs to the colon has become popular in recent years because the delivery of drugs labile to acid and enzymes in a region that is less hostile metabolically results in enhanced absorption of certain drugs. Drugs with poor solubility may not dissolve in the colon where there is not as much fluid as in the upper portion of the Gl tract.
  • the current technologies are mainly focused on delayed release, that is, no release until the dosage form reaches the colon.
  • the time-delay approach relies on drug release following a predetermined lag time and would therefore be less dependable.
  • Nanotechnology presents an opportunity to increase the bioavailability of drug particles.
  • a decrease in particle size results in increased surface area, which may result in faster dissolution, normally by a small order of magnitude. In some cases, this may be enough to result in increased bioavailability.
  • faster dissolution may not be sufficient to overcome exposure to acid and enzymes in the gut. Additionally, as in the case with oral insulin, this exposure may require higher dosing of the drug, resulting in unnecessary and potentially undesirable subject exposure to breakdown products as well as create significant waste.
  • a depot formulation is specially formulated to provide slow absorption of the drug from the site of administration, often keeping therapeutic levels of the drug in the patient's system for days or weeks at a time.
  • a depot formulation may provide convenience for a patient in need of chronic medication. By delivering drug without exposure to the Gl tract, the potential issue of drug degradation is avoided.
  • a depot formulation may provide better compliance due to the infrequent dosing regimen and convenience. Additional characteristics of a depot formulation that will enhance patient compliance are good local tolerance at the injection site and ease of administration. Good local tolerance means minimal irritation and inflammation at the site of injection; ease of administration refers to the size of needle and length of time required to administer a dose of a particular drug formulation.
  • U.S. Patent No. 6,232, 304 (granted May 15, 2001) describes a ziprasidone salt solubilized with cyclodextrins for an immediate release intramuscular injection formulation.
  • U.S. Patent No. 6,150, 366 (granted November 21, 2000) describes a pharmaceutical composition describing crystalline ziprasidone and a carrier.
  • U.S. Patent No. 6, 267, 989 (granted July 31 , 2001 ) describes a water-insoluble crystalline drug to which a surface modifier is adsorbed in an amount sufficient to maintain a defined particle size.
  • U.S. Patent No. 5,145, 684 (granted September 8, 1992) describes low solubility crystalline drug substances to which a surface modifier is adsorbed in an amount sufficient to maintain a defined particle size.
  • U.S. Patent No. 5, 510, 118 (granted April 23, 1996) describes a homogenization process to obtain sub-micron drug substances without milling media.
  • U.S. Patent No. 5, 707, 634 (granted January 13, 1998) describes a method precipitating a crystalline solid from liquid.
  • U.S. Patent No. 5, 314, 685 (granted May 24, 1994) describes techniques for solubilizing hydrophobic compounds with low water solubility.
  • U.S. Patent No. 4, 992, 271 (granted February 12, 1991 ) describes techniques for solubilizing hydrophobic compounds with low water solubility.
  • WO 00/18374 (filed October 1 , 1999) describes a controlled release nanoparticle composition.
  • WO 00/09096 (filed August 12, 1999) describes an injectable nanoparticle formulation of naproxen.
  • Certain potential pharmaceuticals are hydrophobic and typically have low aqueous solubility and hence low oral bioavailability. It is believed that the invention provides an acceptable depot formulation of low water solubility drug nanoparticles, which is efficacious and has an acceptable injection volume. In addition to enhancing patient compliance, a nanoparticle depot formulation of a low solubility drug may reduce overall exposure to the drug compared to oral capsules while providing sufficient exposure to ensure efficacy.
  • the present invention comprises a pharmaceutical formulation suitable for use as a depot formulation for administration via intramuscular or subcutaneous injection.
  • the formulation comprises (1 ) a low solubility drug or pharmaceutically acceptable salt thereof; (2) a pharmaceutically acceptable carrier; and (3) at least two surface stabilizers.
  • the formulations of the invention may, for example, comprise from two to ten surface stabilizers, preferably two to five surface stabilizers.
  • the formulation consists of two surface stabilizers.
  • the formulation consists of three surface stabilizers.
  • the formulation consists of two surface stabilizers and a bulking agent.
  • the present invention comprises processes for preparing such a formulation.
  • the present invention comprises the use of such a composition as a medicament in the treatment of a wide range of disorders. In yet another embodiment, the present invention comprises methods of treating these disorders.
  • the term "compound” refers to a form of a therapeutic or diagnostic agent which is a component of an injectable depot formulation.
  • the compound may be a pharmaceutical, including, without limitation, biologies such as proteins, peptides and nucleic acids or a diagnostic, including, without limitation, contrast agents.
  • the compound is crystalline.
  • the compound is amorphous.
  • the compound is a mixture of crystalline and amorphous forms.
  • the compound has low water solubility.
  • the logP of the compound is at least about 3 or greater.
  • the compound has a high melting point.
  • a high melting compound is one with a melting point greater than about 130 degrees Celsius.
  • a compound having "low water solubility" refers to any compound having a solubility in water, measured at 37°C, not greater than about 10 mg/ml. In another embodiment, the measured solubility is not greater than about 1 mg/ml. In another embodiment, the measured solubility is not greater than about 0.1 mg/ml.
  • a synonymous term is "low aqueous solubility.” Solubility in water for many drugs can be readily determined from standard pharmaceutical reference books, for example The Merck Index, 13th ed., 2001 (published by Merck & Co., Inc., Rahway, NJ); the United States Pharmacopoeia, 24th ed. (USP 24), 2000; The Extra Pharmacopoeia, 29th ed., 1989 (published by Pharmaceutical Press, London); and the Physicians Desk Reference (PDR), 2005 ed. (published by Medical Economics Co., Montvale, NJ).
  • individual compounds of low solubility as defined herein include those drugs categorized as “slightly soluble”, “very slightly soluble”, “practically insoluble” and “insoluble” in USP 24, pp. 2254-2298; and those drugs categorized as requiring 100 ml or more of water to dissolve 1 g of the drug, as listed in USP 24, pp. 2299-2304.
  • Exemplary compounds include, without limitation; compounds from the following classes: abortifacients, ACE inhibitors, ⁇ - and ⁇ -adrenergic agonists, ⁇ - and ⁇ -adrenergic blockers, adrenocortical suppressants, adrenocorticotropic hormones, alcohol deterrents, aldose reductase inhibitors, aldosterone antagonists, anabolics, analgesics (including narcotic and non-narcotic analgesics), androgens, angiotensin Il receptor antagonists, anorexics, antacids, anthelminthics, antiacne agents, antiallergics, antialopecia agents, antiamebics, antiandrogens, antianginal agents, antiarrhythmics, antiarteriosclerotics, antiarthritic/antirheumatic agents, antiasthmatics, antibacterials, antibacterial adjuncts, anticholinergics, anticoagul
  • Suitable compounds include, without limitation, acetohexamide, acetylsalicylic acid, alclofenac, allopurinol, atropine, benzthiazide, carprofen, celecoxib, chlordiazepoxide, chlorpromazine, clonidine, codeine, codeine phosphate, codeine sulfate, deracoxib, diacerein, diclofenac, diltiazem, estradiol, etodolac, etoposide, etoricoxib, fenbufen, fendofenac, fenprofen, fentiazac, flurbiprofen, griseofulvin, haloperidol, ibuprofen, indomethacin, indoprofen, ketoprofen, lorazepam, medroxyprogesterone acetate, megestrol, methoxsalen, methyl
  • Further exemplary compounds include, without limitation, Acenocoumarol, Acetyldigitoxih, Anethole, Anileridine, Benzocaine, Benzonatate, Betamethasone, Betamethasone Acetate, Betamethasone Valerate, Bisacodyl, Bromodiphenhydramine, Butamben, Chlorambucil, Chloramphenicol, Chlordiazepoxide, Chlorobutanol, Chlorocresol, Chlorpromazine, Clindamycin Palmitate, Clioquinol, Cortisone Acetate, Cyclizine Hydrochloride, Cyproheptadine Hydrochloride, Demeclocycline, Diazepam, Dibucaine, Digitoxin, Dihydroergotamine Mesylate, Dimethisterone, Disulfiram, Docusate Calcium, Docusate Sodium, Dihydrogesterone, Enalaprilat, Ergotamine Tartrate, Erythromycin, Erythromycin Estolate
  • surface stabilizer refers to a molecule that: (1 ) is adsorbed on the surface of a compound; (2) otherwise physically adheres to the surface of a compound; or (3) remains in solution with a compound, acting to maintain the effective particle size of the compound.
  • a surface stabilizer does not chemically react (i.e. form a covalent bond) with the drug substance (compound).
  • a surface stabilizer also does not necessarily form covalent crosslinkages with itself or other surface stabilizers in a formulation and/or when adsorbed onto compound surfaces.
  • a surface stabilizer on the surface of a compound or otherwise in a formulation of the invention is essentially free of covalent crosslinkages.
  • a first surface stabilizer is present in an amount sufficient to maintain an effective average particle size of the compound.
  • one or more surface stabilizers are present in an amount sufficient to maintain an effective particle size of the compound.
  • a surface stabilizer is a surfactant.
  • a surface stabilizer is a crystallization inhibitor.
  • surfactant refers to amphipathic molecules that consist of a non-polar hydrophobic portion, exemplified by a straight or branched hydrocarbon or fluorocarbon chain containing 8-18 carbon atoms, which is attached to a polar or ionic portion (hydrophilic).
  • the hydrophilic portion may be nonionic, ionic or zwitterionic and accompanied by counter ions.
  • surfactants anionic, cationic, amphoteric, nonionic and polymeric.
  • a single surfactant may be properly classified as a member of both categories.
  • An exemplary group of surfactants that may be properly classified in this manner are the ethylene oxide-propylene oxide copolymers, referred to as Pluronics® (Wyandotte), Synperonic PE ®(ICI) and Poloxamers® (BASF).
  • Pluronics® Wideandotte
  • Synperonic PE ®(ICI) Synperonic PE ®(ICI)
  • Poloxamers® BASF
  • Polymers such as HPMC and PVP may be classified as polymeric surfactants.
  • Exemplary classes of surfactants include, without limitation: carboxylates, sulphates, sulphonates, phosphates, sulphosuccinates, isethionates, taurates, quarternary ammonium compounds, N-alkyl betaines, N-alkyl amino propionates, alcohol ethoxylates, alkyl phenol ethoxylates, fatty acid ethoxylates, monoalkaolamide ethoxylates, sorbitan ester ethoxylates, fatty amine ethoxylates, ethylene oxide-propylene oxide co-polymers, glycerol esters, glycol esters, glucosides, sucrose esters, amino oxides, sulphinyl surfactants, polyoxyethylene allcyl ethers, polyoxyethylene alkyl ethers, polyglycolized glycerides, short-chain glyceryl mono- alkylates, alkyl aryl poly
  • Exemplary surfactants include, without limitation: dodecyl hexaoxyethylene glycol monoether, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan mono-oleate, sorbitan tristearate, sorbitan trioleate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan mono-oleate, polyoxyethylene (20) sorbitan tristearate, polyoxyethylene (20) sorbitan trioleate, linolin, castor oil ethoxylates, Pluronic® F108, Pluronic® F68, Pluronic® F127, benzalkonium chloride, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxyprop
  • Pluronic® F108 refers to the polyoxyethylene-polyoxypropylene block copolymer that conforms generally to the formula
  • crystallization inhibitor refers to a polymer or other substances that can substantially inhibit precipitation and/or crystallization of a poorly water-soluble drug.
  • a polymeric surfactant is a crystallization inhibitor.
  • the crystallization inhibitor is a cellulosic or non-cellulosic polymer and is substantially water- soluble.
  • the crystallization inhibitor is HPMC.
  • a crystallization inhibitor is polyvinylpyrrolidone (PVP).
  • a technician performing Test I will readily find a suitable polymer concentration for the test within the polymer concentration range provided above, by routine experimentation.
  • a concentration of the polymer is selected such that when Test I is performed, the apparent absorbance of the second sample solution is not greater than about 50% of the apparent absorbance of the first sample solution.
  • pKa and “Dissociation Constant” refer to a measure of the strength of an acid or a base. The pKa allows the determination of the charge on a molecule at any given pH.
  • logP and "Partition Coefficient” refer to a measure of how well a substance partitions between a lipid (oil) and water.
  • the Partition Coefficient is also a very useful parameter which may be used in combination with the pKa to predict the distribution of a compound in a biological system. Factors such as absorption, excretion and penetration of the CNS may be related to the Log P value of a compound and in certain cases predictions made.
  • low aqueous solubility refers to a therapeutic or diagnostic agent with a solubility in water of less than about 10 mg/mL In another embodiment, the solubility in water is less than about 1 mg/mL.
  • particle size refers to effective diameter, in the longest dimension, of compound particles. Particle size is believed to be an important parameter affecting the clinical effectiveness of therapeutic or diagnostic agents of low aqueous solubility.
  • average particle size and “mean particle size” refer to compound particle size of which at least 50% or more of the compound particles are, when measured by dynamic light scattering.
  • an average particle size of from about 120 nm to about 400 nm means that at least 50% of the compound particles have a particle size from about 120 nm to about 400 nm when measured by standard techniques, as indicated in other embodiments herein.
  • at least 70% of the particles, by weight have a particle size of less than the indicated size.
  • at least 90% of the particles have the defined particle size.
  • at least 95% of the particles have the defined particle size.
  • at least 99% of the particles have the defined particle size.
  • the present invention comprises, in part, novel injectable depot formulations of low solubility drugs.
  • the present invention also comprises a method of treating disorders suitable for treatment with low solubility drugs.
  • an injectable depot formulation comprises: a) a pharmaceutically effective amount of a compound selected from the group consisting of a low solubility drug and a pharmaceutically acceptable salt thereof, the compound in the form of nanoparticles having an average particle size of less than about 2000 nm; b) a pharmaceutically acceptable carrier; and c) at least two surface stabilizers; wherein at least one of the surface stabilizers is adsorbed on the surface of the nanoparticles; and wherein the combined amount of the surface stabilizers is effective to maintain the average particle size of the nanoparticles (Formulation 1).
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, ste
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • suitable salts see Handbook of Pharmaceutical Salts: Properties. Selection, and Use by Stahl and Wermuth (Wiiey-VCH, 2002).
  • the compound may also exist in unsolvated and solvated forms.
  • 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • 'hydrate' is employed when said solvent is water.
  • Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules.
  • channel hydrates the water molecules lie in lattice channels where they are next to other water molecules.
  • metal-ion coordinated hydrates the water molecules are bonded to the metal ion.
  • compositions When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
  • Pharmaceutically acceptable salts of a low solubility drug may be prepared by one or more of three methods:
  • the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionization in the resulting salt may vary from completely ionized to almost non-ionized.
  • the compound is crystalline.
  • the pharmaceutically acceptable carrier is water.
  • the nanoparticles of the compound have an average particle size of less than about 1500 nm. In still another embodiment, the nanoparticles have an average particle size of less than about 1000 nm. In still another embodiment, the nanoparticles have an average particle size of less than about 500 nm. In still another embodiment, the nanoparticles have an average particle size of less than about 350 nm.
  • the nanoparticles have an average particle size from about 120 nm to about 400 nm. In still another embodiment, the nanoparticles have an average particle size from about 220 nm to about 350 nm.
  • the nanoparticles have an average particle size of about 250 nm.
  • nanoparticles have an average particle size of about 120 nm. In still another embodiment, the nanoparticles have an average particle size of about
  • the amount by weight of the compound is less than about 60% by weight of the total volume of the formulation. In still another embodiment, the amount by weight of the compound is less than about 40% by weight of the total volume of the formulation. In another embodiment of Formulation 1 , the amount by weight of the compound is at least about 1 % by weight of the total volume of the formulation. In still another embodiment, the amount by weight of the compound is at least about 3% by weight of the total volume of the formulation. In still another embodiment, the amount by weight of the compound is at least about 15% by weight of the total volume of the formulation. In still another embodiment, the.
  • the amount by weight of the compound is at least about 20% by weight of the total volume of the formulation In still another embodiment, the amount by weight of the compound is at least about 40% by weight of the total volume of the formulation. In another embodiment of Formulation 1 , the amount by weight of the compound is from about 1 % by weight to about 60% by weight of the total volume of the formulation. In still another embodiment, the amount by weight of the compound is from about 3% by weight to about 60% by weight of the total volume of the formulation. In still another embodiment, the amount by weight of the compound is from about 15% by weight to about 60% by weight of the total volume of the formulation. In still another embodiment, the amount by weight of the compound is from about 20% by weight to about 60% by weight of the total volume of the formulation.
  • the amount by weight of the compound is from about 1% by weight to about 40% by weight of the total volume of the formulation. In still another embodiment, wherein the amount by weight of the compound is from about 3% by weight to about 40% by weight of the total volume of the formulation. In still another embodiment, the amount by weight of the compound is from about 15% by weight to about 40% by weight of the total volume of the formulation. In still another embodiment, the amount by weight of the compound is from about 20% by weight to about 40% by weight of the total volume of the formulation.
  • a first surface stabilizer is a surfactant.
  • a first surface stabilizer is selected from the group consisting of anionic surfactants, cationic surfactants, amphoteric surfactants, non-ionic surfactants and polymeric surfactants.
  • a first surface stabilizer is an anionic surfactant.
  • a first surface stabilizer is a cationic surfactant.
  • a first surface stabilizer is an amphoteric surfactant.
  • a first surface stabilizer is a non-ionic surfactant.
  • a first surface stabilizer is a polymeric surfactant.
  • a second surface stabilizer is selected from the group consisting of anionic surfactants, cationic surfactants, amphoteric surfactants, non- ionic surfactants and polymeric surfactants.
  • a second surface stabilizer is an anionic surfactant. In another embodiment, a second surface stabilizer is a cationic surfactant. In another embodiment, a second surface stabilizer is an amphoteric surfactant. In another embodiment, a second surface stabilizer is a non-ionic surfactant. In another embodiment, a second surface stabilizer is a polymeric surfactant.
  • a first surface stabilizer and a second surface stabilizer are independently selected from the group consisting of anionic surfactants, cationic surfactants, amphoteric surfactants, non-ionic surfactants and polymeric surfactants.
  • a first surface stabilizer is ' an anionic surfactant and a second surface stabilizer is an anionic surfactant.
  • a first surface stabilizer is an anionic surfactant and a second surface stabilizer is a cationic surfactant.
  • a first surface stabilizer is an anionic surfactant and a second surface stabilizer is an amphoteric surfactant.
  • a first surface stabilizer is an anionic surfactant and a second surface stabilizer is a non-ionic surfactant.
  • a first surface stabilizer is an anionic surfactant and a second surface stabilizer is a polymeric surfactant.
  • a first surface stabilizer is a cationic surfactant and a second surface stabilizer is an anionic surfactant.
  • a first surface stabilizer is an cationic surfactant and a second surface stabilizer is a cationic surfactant.
  • a first surface stabilizer is a cationic surfactant and a second surface stabilizer is an amphoteric surfactant.
  • a first surface stabilizer is a cationic surfactant and a second surface stabilizer is a non-ionic surfactant.
  • a first surface stabilizer is a cationic surfactant and a second surface stabilizer is a polymeric surfactant.
  • a first surface stabilizer is an amphoteric surfactant and a second surface stabilizer is an anionic surfactant.
  • a first surface stabilizer is an amphoteric surfactant and a second surface stabilizer is a cationic surfactant.
  • a first surface stabilizer is an amphoteric surfactant and a second surface stabilizer is an amphoteric surfactant.
  • a first surface stabilizer is an amphoteric surfactant and a second surface stabilizer is a non-ionic surfactant.
  • a first surface stabilizer is an amphoteric surfactant and a second surface stabilizer is a polymeric surfactant.
  • a first surface stabilizer is a non-ionic surfactant and a second surface stabilizer is an anionic surfactant.
  • a first surface stabilizer is a non-ionic surfactant and a second surface stabilizer is a cationic surfactant.
  • a first surface stabilizer is a non-ionic surfactant and a second surface stabilizer is am amphoteric surfactant.
  • a first surface stabilizer is a non-ionic surfactant and a second surface stabilizer is a non-ionic surfactant.
  • a first surface stabilizer is a non-ionic surfactant and a second surface stabilizer is a polymeric surfactant.
  • a first surface stabilizer is a polymeric surfactant and a second surface stabilizer is an anionic surfactant.
  • a first surface stabilizer is a polymeric surfactant and a second surface stabilizer is a cationic surfactant.
  • a first surface stabilizer is a polymeric surfactant and a second surface stabilizer is an amphoteric surfactant.
  • a first surface stabilizer is a polymeric surfactant and a second surface stabilizer is a non-ionic surfactant.
  • a first surface stabilizer is a polymeric surfactant and a second surface stabilizer is a polymeric surfactant.
  • a first surface stabilizer is selected from the group consisting of Pluronic® F108 and Tween® 80 and a second surface stabilizer is selected from the group consisting of Pluronic ® F108, Tween® 80, and SLS.
  • a first surface stabilizer is PVP and a second surface stabilizer is Pluronic® F108.
  • a first surface stabilizer is PVP and a second surface stabilizer is Pluronic® F68.
  • a first surface stabilizer is PVP and a second surface stabilizer is SLS.
  • a first surface stabilizer is Pluronic® F108 and a second surface stabilizer is Tween® 80.
  • a first surface stabilizer is PVP and a second surface stabilizer is Tween® 80.
  • the amount by weight of a first surface stabilizer is from about 0.5% to about 3.0% by weight of the total volume of the formulation. In another embodiment, the amount by weight of a first surface stabilizer is from about 0.5% to about 2.0% by weight of the total volume of the formulation. In yet another embodiment of Formulation 1 , the amount by weight of a first surface stabilizer is about 0.5% by weight of the total volume of the formulation. In yet another embodiment of Formulation 1 , the amount by weight of a first surface stabilizer is about 1.0 % by weight of the total volume of the formulation. In yet another embodiment of Formulation 1 , the amount by weight of a first surface stabilizer is about 2.0 % by weight of the total volume of the formulation.
  • the amount by weight of a second surface stabilizer is from about 0.1 % to about 3.0%, preferably about 0.1 % to about 2.0 %, by weight of the total volume of the formulation. In another embodiment of Formulation 1 , the amount by weight of a second surface stabilizer is from about 0.1 % to about 1.0% by weight of the total volume of the formulation. In another embodiment of Formulation 1 , the amount by weight of a second surface stabilizer is about 2.0 % by weight of the total volume of the formulation. In still another embodiment of Formulation 1 , the amount by weight of a second surface stabilizer is about 0.5% by weight of the total volume of the formulation. In still another embodiment of Formulation 1 , the amount by weight of a second surface stabilizer is about 0.1 % by weight of the total volume of the formulation.
  • a third surface stabilizer is present, wherein the amount by weight of the third surface stabilizer is from about 0.018% to about 1.0 % by weight of the total volume of the formulation. In another embodiment of Formulation 1 , the amount by weight of the third surface stabilizer is about 0.018% by weight of the total volume of the formulation. In still another embodiment, the amount by weight of the third surface stabilizer is about 0.1% by weight of the total volume of the formulation. In still another embodiment, the amount by weight of the third surface stabilizer is about 0.02% by weight of the total volume of the formulation. In still another embodiment, the amount by weight of the third surface stabilizer is about 0.5% by weight of the total volume of the formulation.
  • a third surface stabilizer is a surfactant.
  • the third surfactant is selected from the group consisting of Pluronic® F68, benzalkonium chloride, lecithin and SLS.
  • a third surface stabilizer is Pluronic® F68.
  • a third surface stabilizer is benzalkonium chloride.
  • a third surface stabilizer is lecithin.
  • a third surface stabilizer is SLS.
  • the total amount by weight of surface stabilizers in a formulation is about 6% or less, more preferably about 5% or less.
  • a bulking agent is present, wherein the amount by weight of the third surface stabilizer is from about 1.0% to about 10.0 % by weight of the total volume of the formulation. In another embodiment of Formulation 1 , the amount by weight of the bulking agent is about 1.0% by weight of the total volume of the formulation. In another embodiment, the amount by weight of the third surface stabilizer is about 5.0% by weight of the total volume of the formulation. In another embodiment, the amount by weight of the third surface stabilizer is about 10.0% by weight of the total volume of the formulation. In another embodiment of Formulation 1 , a bulking agent is present, the bulking agent selected from the group consisting of trehalose, mannitol and PEG400. In another embodiment, the bulking agent is trehalose. In another embodiment, the bulking agent is mannitol. In another embodiment, the bulking agent is PEG400.
  • the formulation consists essentially of a compound, a carrier, a first surface stabilizer and a second surface stabilizer, as previously defined herein.
  • the formulation consists essentially of a compound, a carrier, a first surface stabilizer, a second surface stabilizer and a third surface stabilizer, as previously defined herein.
  • the formulation consists essentially of a compound, a carrier, a first surface stabilizer, a second surface stabilizer and a bulking agent, as previously defined herein.
  • the compound nanoparticles can be made using several different methods, including, for example, milling, precipitation and high pressure homogenization. Exemplary methods of making compound nanoparticles are described in U.S. Patent No. 5,145, 684, the entire content of which is incorporated by reference herein.
  • the optimal effective average particle size of the invention can be obtained by controlling the process of particle size reduction, such as controlling the milling time and the amount of surface stabilizer added. Crystal growth and particle aggregation can also be minimized by milling or precipitating the composition under colder temperatures, and by storing the final composition at colder temperatures. 1. Aqueous Milling
  • a method of preparing the injectable depot formulation of the compound according to Formulation 1 Milling of compound in aqueous solution to obtain a nanoparticulate dispersion comprises dispersing compound in water, followed by applying mechanical means in the presence of grinding media to reduce the particle size of the compound to the desired effective average particle size, the optimal sizes as provided in other embodiments herein.
  • the compound can be effectively reduced in size in the presence of two or more surface stabilizers.
  • the compound can be contacted with two or more surface stabilizers after attrition.
  • Other compounds, such as a bulking agent, can be added to the compound/surface stabilizer mixture during the size reduction process.
  • Dispersions can be manufactured continuously or in a batch mode. The resultant nanoparticulate drug dispersion can be utilized in solid or liquid dosage formulations.
  • the nanoparticulate dispersion may be utilized in intramuscular depot formulations suitable for injection.
  • Exemplary useful mills include low energy mills, such as a roller mill, attritor mill, vibratory mill and ball mill, and high energy mills, such as Dyno mills, Netzsch mills, DC mills, and Planetary mills.
  • Media mills include sand ills and bead mills.
  • the compound is placed into a reservoir along with a dispersion medium (for example, water) and at least two surface stabilizers.
  • the mixture is recirculated through a chamber containing media and a rotating shaft/impeller.
  • the rotating shaft agitates the media which subjects the compound to impacting and sheer forces, thereby reducing particle size. 2. Grinding Media
  • Exemplary grinding media comprises particles that are substantially spherical in shape, such as beads, consisting essentially of polymeric resin.
  • the grinding media comprises a core having a coating of a polymeric resin adhered thereon.
  • Other examples of grinding media comprise essentially spherical particles comprising glass, metal oxide, or ceramic.
  • suitable polymeric resins are chemically and physically inert, substantially free of metals, solvent, and monomers, and of sufficient hardness and friability to enable them to avoid being chipped or crushed during grinding.
  • Suitable polymeric resins include, without limitation: crosslinked polystyrenes, such as polystyrene crosslinked with divinylbenzene; styrene copolymers; polycarbonates; polyacetals, for example, Delrin® (E.I. du Pont de Nemours and Co.); vinyl chloride polymers and copolymers; polyurethanes; polyamides; poly(tetrafluoroethylenes), for example, Teflon® (E.I.
  • du Pont de Nemours and Co. and other fluoropolymers
  • high density polyethylenes polypropylenes
  • cellulose ethers and esters such as cellulose acetate
  • polyhydroxymethacrylate polyhydroxyethyl acrylate
  • silicone- containing polymers such as polysiloxanes.
  • the polymer can be biodegradable.
  • biodegradable polymers include poly(Iactides), poly(glycolide) copolymers of lactides and glycolide, polyanhydrides, poly(hydroxyethyl methacylate), poly(imino carbonates), poly(N- acylhydroxyproline)esters, poly(N-palmitoyl hydroxyproline) esters, ethylene-vinyl acetate copolymers, poly(orthoesters), poly(caprolactones), and poly(phosphazenes).
  • contamination from the media itself advantageously can metabolize in vivo into biologically acceptable products that can be eliminated from the body.
  • the grinding media preferably ranges in size from about 10 ⁇ m to about 3 mm.
  • exemplary grinding media is from about 20 ⁇ m to about 2 mm.
  • exemplary grinding media is from about 30 ⁇ m to about 1 mm in size.
  • the grinding media is about 500 ⁇ m in size.
  • the polymeric resin can have a density from about 0.8 to about 3.0 g/ml.
  • the particles are made continuously.
  • Such a method comprises continuously introducing compound into a milling chamber, contacting the compound with grinding media while in the chamber to reduce the compound particle size, and continuously removing the nanoparticulate compound from the milling chamber.
  • the grinding media is separated from the milled nanoparticulate compound using conventional separation techniques in a secondary process, including, without limitation, simple filtration, sieving through a mesh filter or screen, and the like. Other separation techniques such as centrifugation may also be employed.
  • Another method of forming the desired nanoparticulate dispersion is by microprecipitation.
  • This is a method of preparing stable dispersions of drugs in the presence of two or more surface stabilizers and one or -more colloid stability enhancing surface active agents free of any trace toxic solvents or solubilized heavy metal impurities.
  • An exemplary method comprises: (1) dissolving the compound in a suitable solvent; (2) adding the formulation from step (1 ) to a solution comprising at least two surface stabilizers to form a clear solution; and (3) precipitating the formulation from step (2) using an appropriate non- solvent.
  • the method can be followed by removal of any formed salt, if present, by dialysis or diafiltration and concentration of the dispersion by conventional means.
  • the resultant nanoparticulate drug dispersion can be utilized in solid or liquid dosage formulations.
  • the nanoparticulate dispersion may be utilized in intramuscular depot formulations suitable for injection.
  • Another method of forming the desired nanoparticulate dispersion is by homogenization. Like precipitation, this technique does not use milling media. Instead, compound, surface stabilizers and carrier - the "mixture" (or, in an alternative embodiment, compound and carrier with the surface stabilizers added following reduction in particle size) constitute a process stream propelled into a process zone, which in a Microfluidizer® (Microfluidics Corp.) is called the Interaction Chamber.
  • the mixture to be treated is inducted into the pump and then forced out.
  • the priming valve of the Microfluidizer® purges air out of the pump. Once the pump is filled with the mixture, the priming valve is closed and the mixture is forced through the Interaction Chamber.
  • the geometry of the Interaction Chamber produces powerful forces of sheer, impact and cavitation which reduce particle size.
  • the pressurized mixture is split into two streams and accelerated to extremely high velocities.
  • the formed jets are then directed toward each other and collide in the interaction zone.
  • the resulting product has very fine and uniform particle size. 5.
  • terminal sterilization As indicated by the optional steps in parentheses, some of the processing is dependent upon the method of particle size reduction and/or method of sterilization. For example, media conditioning 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. Terminal sterilization can be by steam sterilization or by high energy irradiation of the product.
  • the conditions that can be treated in accordance with the present invention include one or more disorders selected from the group consisting of: arthritis, including rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, and other arthritic conditions; central nervous system disorders (including, but not limited to, central nervous system disorders having an inflammatory or apoptotic component), such as Alzheimer's disease, Parkinson's disease, Huntington's Disease, amyotrophic lateral sclerosis, spinal cord injury, and peripheral neuropathy; peripheral nervous system disorders; cardiovascular diseases including atherosclerosis, myocardial infarction (including post-myocardial infarction indications), thrombosis, congestive heart failure, and cardiac reperfusion injury, as well as complications associated with hypertension and/or heart failure such as vascular organ damage, restenosis; gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastriti
  • liver disease and nephritis include liver disease and nephritis;ulcerative diseases such as gastric ulcer; periodontal disease; diabetes; diabetic nephropathy;viral and bacterial infections, including sepsis, septic shock, gram negative sepsis, malaria, meningitis, HIV infection, opportunistic infections, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), pneumonia, and herpes virus; myalgias due to infection; influenza; endotoxic shock and sepsis; toxic shock syndrome; autoimmune disease including graft vs. host reaction and allograft rejections; treatment of bone resorption diseases, such as osteoporosis; multiple sclerosis; and disorders of the female reproductive system such as endometriosis.
  • diseases such as gastric ulcer; periodontal disease; diabetes; diabetic nephropathy;viral and bacterial infections, including sepsis,
  • a formulation described in this specification is administered in an amount effective to treat conditions listed herein.
  • the depot formulations of the present invention are administered by injection, whether subcutaneously or intramuscularly, and in a dose effective for the treatment intended.
  • Therapeutically effective doses of the compounds required to prevent or arrest the progress of or to treat the medical condition are readily ascertained by one of ordinary skill in the art using preclinical and clinical approaches familiar to the medicinal arts.
  • An effective dose for injection of a formulation of the invention can be generally determined by a physician of ordinary skill in the art.
  • the effective dose can be determined taking into consideration factors know to those of skill in the art, such as the indication being treated, the weight of the patient, and the duration of treatment (e.g. days or weeks) desired.
  • the percentage of drug present in the formulation is also a factor.
  • An example of an effective dose for injection of a formulation of the present invention is from about 0.1 ml to about 2.5 ml injected once every 1 , 2, 3 or 4 weeks.
  • the dose for injection is about 2 ml or less, for example from about 1 ml to about 2 ml.
  • the present invention comprises methods for the preparation of a formulation (or "medicament') comprising the Formulations of other embodiments herein disclosed, in combination with one or more pharmaceutically-acceptable carriers and at least two surface stabilizers, wherein at least one surface stabilizer is adsorbed on to the surface of the compound nanoparticles and wherein the combined amount of the surface stabilizers is effective to maintain the average particle size of the nanoparticles (Formulation 1 ), in which such formulation is suitable in treating one or more conditions selected from the group consisting of:
  • the conditions that can be treated in accordance with the present invention include one or more disorders selected from the group consisting of: arthritis, including rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, and other arthritic conditions; central nervous system disorders (including, but not limited to, central nervous system disorders having an inflammatory or apoptotic component), such as
  • liver disease and nephritis include liver disease and nephritis;ulcerative diseases such as gastric ulcer; periodontal disease; diabetes; diabetic nephropathy;viral and bacterial infections, including sepsis, septic shock, gram negative sepsis, malaria, meningitis, HIV infection, opportunistic infections, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), pneumonia, and herpes virus; myalgias due to infection; influenza; endotoxic shock and sepsis; toxic shock syndrome; autoimmune disease including graft vs. host reaction and allograft rejections; treatment of bone resorption diseases, such as osteoporosis; multiple sclerosis; and disorders of the female reproductive system such as endometriosis.
  • AIDS acquired immune deficiency syndrome
  • AIDS AIDS
  • ARC AIDS related complex
  • a coarse suspension was prepared by placing 8.86 gm of ziprasidone free base in a 100 ml milling chamber with 48.90 gm of milling media (500 micron polystyrene beads). To this, 4.2 ml each of 10% solutions of Pluronic® F108 and Tween® 80 were added. In addition, 27.8 ml of water for injection was added to the milling chamber. The above mixture was stirred until uniform suspension was obtained. This suspension was then milled for 30 minutes at 2100 RPM in a Nanomill-1 (Manufacturer Elan Drug Delivery, Inc.) and the temperature during milling was maintained at 4°C.
  • the resulting suspension was filtered under vacuum to remove the milling media and the suspension characterized by microscopy and light scattering (Brookhaven). For microscopic observation, a drop of diluted suspension was placed between a cover slip and slide and observed under both bright and dark field. For particle size determination by light scattering, a drop of suspension was added to a sample cuvette filled with water and particle size measured. The reported values are effective diameter in nm.
  • the above suspension after milling was free flowing and did not show any large crystals under the microscope at 400X and dispersed particles could not be seen individually due to the rapid Brownian motion.
  • the effective diameter of the 21 % ziprasidone free base nanosuspension was 235 nm.
  • a coarse suspension was prepared by placing 8.82 gm of ziprasidone free base in the 100 ml milling chamber with 48.87 gm of milling media (500 micron polystyrene beads). To this, 4.2 ml of 10% solution of PVP-K30 was added. In addition, 32 ml of water for injection was added to the milling chamber. The above mixture was milled under identical conditions as in example 1.
  • a coarse suspension was prepared by placing 9.69 gm of ziprasidone hydrochloride in a 100 ml milling chamber with 48.96 gm of milling media (500 micron polystyrene beads).
  • a coarse suspension was prepared by placing 11.78 gm of ziprasidone mesylate in a
  • Example 7 100 ml milling chamber with 48.89 gm of milling media (500 micron polystyrene beads). To this, 8.4 ml of 10% PVP and 2.1 ml of 10% of Pluronic® F108 solutions were added. In addition, 24.2 ml of water for injection was added to the milling chamber. The above mixture was milled under identical conditions for 3 hours as in example 1. When the milling was stopped at 3 hours, the above suspension after filtration was free flowing and did not show any large crystals under the microscope and the rapid Brownian motion was observed of the particles. The effective diameter of the 28% ziprasidone mesylate nanosuspension was 406 nm.
  • Example 7 100 ml milling chamber with 48.89 gm of milling media (500 micron polystyrene beads). To this, 8.4 ml of 10% PVP and 2.1 ml of 10% of Pluronic® F108 solutions were added. In addition, 24.2 ml of water for injection was added to the milling chamber
  • a coarse suspension was prepared by placing 8.85 gm of ziprasidone free base in the 100 ml milling chamber with 48.89 gm of milling media (500 micron polystyrene beads).
  • a coarse suspension was prepared by placing 8.87 gm of ziprasidone free base in the 100 ml milling chamber with 48.9 gm of milling media (500 micron polystyrene beads). To this, 4.2 ml of 10% Tween® 80 solution and 8.4 ml of 10% Pluronic® F108 solution were added. In addition, 23.6 ml of water for injection was added to the milling chamber. The above mixture was stirred until uniform suspension was obtained. This suspension was then milled for 30 minutes at 2100 RPM in a Nanomill-1 (Manufacturer Elan Drug Delivery, Inc.) and the temperature during milling was maintained at 4°C. The resulting suspension was filtered under vacuum to remove the milling media and the suspension characterized by microscopy and light scattering as described in example 1.
  • Example 7 The filtered suspension of Example 7 was filled (3 ml) into flint vials.
  • the vials were sealed with a rubber stopper and an aluminum seal was crimped on the stopper.
  • the filled vials were sterilized for 15 min at 121 "C in a steam sterilizer.
  • the suspension after sterilization was characterized and particle size measured by light scattering.
  • the filled vials were stored at 5°C and sampled at various times to determine particle size and stability of the suspension.
  • the following table shows particle size stability of Formulation G during autoclaving and upon storage of the sterilized formulation.
  • Example 8 The filtered suspension of Example 8 was filled (3 ml) into flint vials.
  • the vials were sealed with a rubber stopper and an aluminum seal was crimped on the stopper.
  • the filled vials were sterilized for 15 min at 121 °C in a steam sterilizer.
  • the suspension after sterilization was characterized and particle size measured by light scattering.
  • the filled vials were stored at 5°C and sampled at various times to determine particle size and stability of the suspension.
  • the following table shows particle size stability of Formulation ⁇ H during autoclaving and upon storage of the sterilized formulation.
  • Table D-5 Effective Particle Diameter of Formulation H after Autoclaving and upon Storage at 5°C.
  • the combination of two or more surface stabilizers provide enhanced surface stability and improve the ability of the crystal to maintain its nanoparticulate size without aggregation.
  • the addition of a different, second surface stabilizer may allow for the reduction in total amount of surface stabilizers by % w/v, which supports a synergistic interaction between surface stabilizers. That is, the use of at least two surface stabilizers in a formulation with a compound of low water solubility seems to maintain particle size and, therefore, provide a foundation for an IM depot formulation of interest.
  • This suspension was then milled for 80 minutes at 2100 RPM in a Nanomill-1 (Manufacturer Elan Drug Delivery, Inc.) and the temperature during milling was maintained at 4 0 C.
  • the resulting suspension was filtered under vacuum to remove the milling media and the suspension characterized by microscopy and light scattering as described in example 1.
  • the filtered suspension was filled (2.5 ml) into flint vials.
  • the vials were sealed with a rubber stopper and an aluminum seal was crimped on the stopper.
  • the filled vials were sterilized for 15 min at 121 0 C in a steam sterilizer.
  • the suspension after sterilization was characterized and particle size measured by light scattering.
  • the following table shows particle size stability of the 42% ziprasidone free base formulation after milling and following autoclaving.
  • Table D-7 Mean Particle Size of 42% Formulation I After Milling and Following Autoclaving.
  • Formulation J was prepared as described in example 15.
  • the filtered suspension was filled (3 ml) into flint vials.
  • the vials were sealed with a rubber stopper and an aluminum seal was crimped on the stopper.
  • the filled vials were sterilized for 15 min at 121 0 C in a steam sterilizer.
  • the suspension after sterilization was characterized and particle size measured by light diffraction.
  • the filled vials were stored at 5, 25, and 40 0 C and sampled at various times to determine particle size and stability of the suspension.
  • the following table shows particle size stability of Formulation J during autoclaving and upon storage of the sterilized formulation.
  • Table D-8 Mean Particle Size of Formulation J after Autoclaving and Upon Storage at 5, 25 and 40°C.
  • a coarse suspension was prepared by placing pre-ground 17.71 gm ziprasidone freebase in 250 mL bottle with 8.4 mL of each, 10%w/v Pluronic F108 and 10%w/v Tween 80 and 55.6 mL of water. The suspension was placed in a cooling bath set to 5°C. The high pressure homogenizer (Manufacturer Avestin, Inc.) was cleaned and primed with water at full open setting. The suspension was pumped for three minutes under the full open condition of the homogenizer during which time it flowed smoothly. The pressure drop across the gap was then slowly increased until to 10,000 psi, and held for 5 minutes. The pressure drop across the gap was then increased to15,000 psi, and was held here for 22 minutes.
  • Manufacturer Avestin, Inc. Manufacturer Avestin, Inc.
  • Table D-9 Particle size stability of autoclaved 21 % ziprasidone free base nanosuspension prepared by high pressure homogenization.
  • the 21%w/v Ziprasidone freebase nanosuspension was prepared by methods described in examples 7 and 8. Batch of 27%w/v Trehalose, 1%w/v F108, 1%w/v Tween 80, and 0.5%w/v Lecithin in water was used as diluent to prepare the samples for lyophilization. The formulation and diluent were combined in a ratio of 3 volumes of diluent to 1 volume of 21 % formulation and were gently mixed. This resultant suspension was filled using a 0.5 mL fill volume into 5 mL and 10 mL glass vials and stoppered at the lyophilization position. These vials were then placed into the FTS LyoStar freeze-drying unit, and the following thermal program was run:
  • Shelves were warmed at 1 °C/min (for 20 min) to 30 0 C and 150 mTorr and held for 720 min. 5) Shelves were cooled at 1 °C/min (for 15 min) to 15 °C and 150 mTorr and held until cycle could be manually ended.
  • the freeze-drying cycle was manually stopped, and the vials were stoppered and crimped. They were then placed in the refrigerator for storage.
  • the dry cake in the vials were reconstituted with the same volume as the initial fill with either 0.5 mL of water or 0.5 mL of 1%w/v F108, 1 %w/v Tween ⁇ O, 0.5%w/v Lecithin in water (the formulation vehicle). These vials were swirled, upon which the cake wetted and reconstituted into a milky white suspension easily.

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