US 2005.0004-049A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0004049 A1 Liversidge (43) Pub. Date: Jan. 6, 2005

(54) NOVEL GRISEOFULVIN COMPOSITIONS Related U.S. Application Data (75) Inventor: Gary G. Liversidge, West Chester, PA (63) Continuation-in-part of application No. 10/175,851, (US) filed on Jun. 21, 2002, now abandoned, which is a continuation of application No. 08/815,346, filed on Correspondence Address: Mar. 11, 1997, now Pat. No. 6,432,381. FOLEY AND LARDNER SUTE 500 Publication Classification 3000 KSTREET NW WASHINGTON, DC 20007 (US) (51) Int. Cl...... A61K 31/704 (52) U.S. Cl...... 514/35 (73) Assignee: Elan Pharma International Limited (57) ABSTRACT The present invention is directed to nanoparticulate compo (21) Appl. No.: 10/683,154 Sitions comprising griseofulvin. The griseofulvin particles of the composition preferably have an effective average par (22) Filed: Oct. 14, 2003 ticle Size of less than about 2 microns. US 2005/OOO4049 A1 Jan. 6, 2005

NOVEL GRISEOFULVIN COMPOSITIONS Agents. Using High Molecular Weight Non-ionic Surfac 0001 CROSS-REFERENCE TO RELATED APPLICA tants;" U.S. Pat. No. 5,451,393 for “X-Ray Contrast Com TIONS positions Useful in Medical Imaging; U.S. Pat. No. 5,466, 0002 This application is a continuation-in-part of U.S. 440 for “Formulations of Oral Gastrointestinal Diagnostic Application Ser. No. 10/175,851, filed on Jun. 21, 2002 X-Ray Contrast Agents in Combination with Pharmaceuti (pending), which is a continuation of U.S. Application Ser. cally Acceptable Clays;” U.S. Pat. No. 5,470,583 for No. 08/815,346, filed on Mar. 11, 1997, now U.S. Pat. No. “Method of Preparing Nanoparticle Compositions Contain 6.432,381. ing Charged Phospholipids to Reduce Aggregation; U.S. Pat. No. 5,472,683 for “Nanoparticulate Diagnostic Mixed FIELD OF THE INVENTION Carbamic Anhydrides as X-Ray Contrast Agents for Blood 0003. The present invention relates to a novel composi Pool and Lymphatic System Imaging; U.S. Pat. No. 5,500, tions of griseofulvin, comprising griseofulvin particles hav 204 for “Nanoparticulate Diagnostic Dimers as X-Ray Con ing an effective average particle size of less than about 2000 trast Agents for Blood Pool and Lymphatic System Imag nm and at least one Surface Stabilizer. ing.” U.S. Pat. No. 5,518,738 for “Nanoparticulate NSAID Formulations;” U.S. Pat. No. 5,521,218 for “Nanoparticu BACKGROUND OF THE INVENTION late Iododipamide Derivatives for Use as X-Ray Contrast 0004 I. Background Regarding Nanoparticulate Active Agents; U.S. Pat. No. 5,525,328 for “Nanoparticulate Diag Agent Compositions nostic Diatrizoxy Ester X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging; U.S. Pat. No. 5,543, 0005 Nanoparticulate active agent compositions, first 133 for “Process of Preparing X-Ray Contrast Compositions described in U.S. Pat. No. 5,145,684 (“the 684 patent”), are particles consisting of a poorly Soluble therapeutic or diag Containing Nanoparticles;” U.S. Pat. No. 5,552,160 for nostic agent having associated with the Surface thereof a “Surface Modified NSAID Nanoparticles;” U.S. Pat. No. non-crosslinked surface stabilizer. The 684 patent does not 5,560,931 for “Formulations of Compounds as Nanoparticu describe nanoparticulate griseofulvin compositions. late Dispersions in Digestible Oils or Fatty Acids; U.S. Pat. No. 5,565,188 for “Polyalkylene Block Copolymers as 0006 Methods of making nanoparticulate active agent compositions are described, for example, in U.S. Pat. Nos. Surface Modifiers for Nanoparticles;” U.S. Pat. No. 5,569, 5,518,187 and 5,862.999, both for “Method of Grinding 448 for "Sulfated Non-ionic Block Copolymer Surfactant as Pharmaceutical Substances.” U.S. Pat. No. 5,718,388, for Stabilizer Coatings for Nanoparticle Compositions; U.S. “Continuous Method of Grinding Pharmaceutical Sub Pat. No. 5,571,536 for “Formulations of Compounds as stances;” and U.S. Pat. No. 5,510,118 for “Process of Nanoparticulate Dispersions in Digestible Oils or Fatty Preparing Therapeutic Compositions Containing Nanopar Acids;” U.S. Pat. No. 5,573,749 for “Nanoparticulate Diag ticles.” These patents do not describe methods of making nostic Mixed Carboxylic Anydrides as X-Ray Contrast nanoparticulate griseofulvin. Agents for Blood Pool and Lymphatic System Imaging,” 0007 Nanoparticulate active agent compositions are also U.S. Pat. No. 5,573,750 for “Diagnostic Imaging X-Ray described, for example, in U.S. Pat. No. 5,298,262 for “Use Contrast Agents;” U.S. Pat. No 5,573,783 for “Redispersible of Ionic Cloud Point Modifiers to Prevent Particle Aggre Nanoparticulate Film Matrices With Protective Overcoats;” gation During Sterilization; U.S. Pat. No. 5,302,401 for U.S. Pat. No. 5,580,579 for “Site-specific Adhesion Within “Method to Reduce Particle Size Growth During Lyophiliza the GI Tract Using Nanoparticles Stabilized by High tion;” U.S. Pat. No. 5,318,767 for “X-Ray Contrast Com Molecular Weight, Linear Poly(ethylene Oxide) Polymers;” positions Useful in Medical Imaging; U.S. Pat. No. 5,326, U.S. Pat. No. 5,585,108 for “Formulations of Oral Gas 552 for “Novel Formulation For Nanoparticulate X-Ray trointestinal Therapeutic Agents in Combination with Phar Blood Pool Contrast Agents Using High Molecular Weight maceutically Acceptable Clays; U.S. Pat. No. 5,587,143 for Non-ionic Surfactants; U.S. Pat. No. 5,328,404 for “Butylene Oxide-Ethylene Oxide Block Copolymers Sur “Method of X-Ray Imaging Using Iodinated Aromatic Pro factants as Stabilizer Coatings for Nanoparticulate Compo panedioates;” U.S. Pat. No. 5,336,507 for “Use of Charged sitions;” U.S. Pat. No. 5,591,456 for “Milled Naproxen with Phospholipids to Reduce Nanoparticle Aggregation; U.S. Hydroxypropyl Cellulose as Dispersion Stabilizer; U.S. Pat. No. 5,340,564 for “Formulations Comprising Olin 10-G to Prevent Particle Aggregation and Increase Stability; U.S. Pat. No. 5,593,657 for “Novel Barium Salt Formulations Pat. No. 5,346,702 for “Use of Non-Ionic Cloud Point Stabilized by Non-ionic and Anionic Stabilizers; U.S. Pat. Modifiers to Minimize Nanoparticulate Aggregation During No. 5,622,938 for “Sugar Based Surfactant for Nanocrys Sterilization;” U.S. Pat. No. 5,349,957 for “Preparation and tals;” U.S. Pat. No. 5,628,981 for “Improved Formulations Magnetic Properties of Very Small Magnetic-Dextran Par of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents ticles; U.S. Pat. No. 5,352,459 for “Use of Purified Surface and Oral Gastrointestinal Therapeutic Agents; U.S. Pat. No. Modifiers to Prevent Particle Aggregation During Steriliza 5,643,552 for “Nanoparticulate Diagnostic Mixed Carbonic tion;' U.S. Pat. Nos. 5,399,363 and 5,494,683, both for Anhydrides as X-Ray Contrast Agents for Blood Pool and “Surface Modified Anticancer Nanoparticles; U.S. Pat. No. Lymphatic System Imaging; U.S. Pat. No. 5,718,388 for 5,401,492 for “Water Insoluble Non-Magnetic Manganese “Continuous Method of Grinding Pharmaceutical Sub Particles as Magnetic Resonance Enhancement Agents,” stances;” U.S. Pat. No. 5,718,919 for “Nanoparticles Con U.S. Pat. No. 5,429,824 for “Use of Tyloxapol as a Nano taining the R(-)Enantiomer of Ibuprofen.” U.S. Pat. No. particulate Stabilizer;” U.S. Pat. No. 5,447,710 for “Method 5,747,001 for “Aerosols Containing Beclomethasone Nano for Making Nanoparticulate X-Ray Blood Pool Contrast particle Dispersions;” U.S. Pat. No. 5,834,025 for “Reduc US 2005/OOO4049 A1 Jan. 6, 2005 tion of Intravenously Administered Nanoparticulate Formu

lation Induced Adverse Physiological Reactions; U.S. Pat. No. 6,045,829 “Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors. Using Cellulosic Surface Stabilizers; U.S. Pat. No. 6,068,858 for “Methods of Making Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers;” U.S. Pat. No. 6,153, 225 for “Injectable Formulations of Nanoparticulate Naproxen;” U.S. Pat. No. 6,165,506 for “New Solid Dose Form of Nanoparticulate Naproxen; U.S. Pat. No. 6,221, 400 for “Methods of Treating Mammals Using Nanocrys 0.011) See The Merck Index, 10" Edition, pp. 4433-34 talline Formulations of Human Immunodeficiency Virus (1983). (HIV) Protease Inhibitors;” U.S. Pat. No. 6,264,922 for 0012 Griseofulvin is given orally to treat dermatophyte “Nebulized Aerosols Containing Nanoparticle Dispersions;” and ringworm infections of the Scalp, hair, nails (fingernails U.S. Pat. No. 6,267,989 for “Methods for Preventing Crystal and toenails), and skin caused by specific fungi. Griseoful Growth and Particle Aggregation in Nanoparticle Compo Vin is used to treat Skin infections Such as jockitch, athlete's sitions.” U.S. Pat. No. 6,270.806 for “Use of PEG-Deriva foot, and ringworm. In particular, griseofulvin is useful in tized Lipids as Surface Stabilizers for Nanoparticulate Com treating Tinea capitis (ringworm of the Scalp), Tinea cor positions;” U.S. Pat. No. 6,316,029 for “Rapidly poris (ringworm of the body), Tinea pedis (athlete's foot), Disintegrating Solid Oral Dosage Form,” U.S. Pat. No. Tinea unguium (ringworm of the nails), Tinea cruris (ring 6,375,986 for “Solid Dose Nanoparticulate Compositions worm of the thigh), and Tinea barbae (barber's itch). Comprising a Synergistic Combination of a Polymeric Sur Griseofulvin is also used to the following fungal infections of the hair, skin, and nails: Trichophyton rubrum, Tricho face Stabilizer and Dioctyl Sodium Sulfosuccinate,” U.S. phyton tonsurans, Trichophyton mentagrophytes, Tricho Pat. No. 6,428,814 for “Bioadhesive nanoparticulate com phyton interdigitalis, Trichophyton verrucosum, Trichophy positions having cationic Surface Stabilizers, U.S. Pat. ton Sulphureum, Trichophyton Schoenleini, Trichophyton No.6,431,478 for “Small Scale Mill; U.S. Pat. No. 6,432, audouini, Trichophyton Canis, Trichophyton gypseum, Tri 381 for “Methods for Targeting Drug Delivery to the Upper chophyton floccosum, Trichophyton megnini, Trichophyton and/or Lower Gastrointestinal Tract,” and U.S. Pat. No. gallinae, and Trichophyton crateriform. This medication is 6,592,903 for “Nanoparticulate Dispersions Comprising a Sometimes prescribed for other uses, and it is used as an Synergistic Combination of a Polymeric Surface Stabilizer antifungal agent in Veterinary medicine. Griseofulvin may and Dioctyl Sodium Sulfosuccinate,” all of which are spe be taken alone or used along with medicines that are applied cifically incorporated by reference. In addition, U.S. patent to the skin for fungus infections. application No. 20020012675 A1, published on Jan. 31, 2002, for “Controlled Release Nanoparticulate Composi 0013 Griseofulvin stops fungal cells dividing (i.e., it is tions,” and WO 02/098565 for “System and Method for fungistatic) but does not kill them outright. This means Milling Materials, describe nanoparticulate active agent treatment needs to be continued for Several weeks or compositions, and are specifically incorporated by refer months. Griseofulvin is generally well tolerated in children. ence. None of these references describe nanoparticulate 0014 Griseofulvin is available as a tablet, capsule, and griseofulvin compositions. liquid to take by mouth. It is usually taken once a day or can be taken two to four times a day. Griseofulvin is usually 0008 Amorphous small particle compositions are taken for 2 to 4 weeks for skin infections, 4 to 6 weeks for described, for example, in U.S. Pat. No. 4,783,484 for hair and Scalp infections, 4 to 8 weeks for foot infections, 3 “Particulate Composition and Use Thereof as Antimicrobial to 4 months for fingernail infections, and at least 6 months Agent;” U.S. Pat. No. 4,826,689 for “Method for Making for toenail infections. Uniformly Sized Particles from Water-Insoluble Organic 0.015 The dose of griseofulvin will be different for dif Compounds;" U.S. Pat. No. 4,997,454 for “Method for ferent patients. In general, for adults the dose is 500 mg to Making Uniformly-Sized Particles From Insoluble Com 1 g daily, and for children it is 10-25 mg per kg body weight pounds;” U.S. Pat. No. 5,741,522 for “Ultrasmall, Non per day. aggregated Porous Particles of Uniform Size for Entrapping Gas Bubbles Within and Methods;” and U.S. Pat. No. 0016 Griseofulvin absorption from the gastrointestinal 5,776,496, for “Ultrasmall Porous Particles for Enhancing tract varies considerably among individuals, mainly because Ultrasound Back Scatter.” These references do not describe of insolubility of the drug in aqueous media of the upper GI nanoparticulate griseofulvin. tract. Physician's Desk Reference, 57" Edition, p. 2445 (2003). The peak serum level found in fasting adults given 0009 II. Background Regarding Griseofulvin 0.5g occurs at about 4 hours and ranges between 0.5 and 2.0 mcg/mL. 0.010 Griseofulvin is an antifungal antibiotic first iso lated from a Penicillium species in 1939. The compound is 0017 Thus, griseofulvin is not very well absorbed from insoluble in water, and Slightly Soluble in ethanol, methanol, the gut. The drug should be taken after a meal or drink of acetone, benzene, CHCl, ethyl acetate, and acetic acid. milk as fat increases the absorption. The medication is Griseofulvin has the chemical formula C7H,CIO and the carried into the Skin by Sweat and within a couple of weeks following chemical Structure: is concentrated in the Outer skin layers. US 2005/OOO4049 A1 Jan. 6, 2005

0018) Half the medication is cleared from the blood as it requires Solubilizing the active agent, which can change stream in 10 to 20 hours; the rest is eliminated in urine and the properties of the active agent. In addition, the Solvents faeces. This means the medication can be taken once daily. required to Solubilize the active agent can have undesirable Griseofulvin should be continued until the fungal infection side effects. has completely gone because the medication is quickly cleared from skin and hair when it is stopped. Side effects of 0023 U.S. Pat. No. 5,785,976 for “Solid lipid particles, griseofulvin include headache, gastrointestinal upset, particles of bioactive agents and methods for the manufac including nausea, vomiting, heartburn, cramps, flatulence, ture and use thereof,” issued on Jul. 28, 1998, describes a taste disturbance, diarrhea or loose Stools, and furred tongue; process for making Solid lipid particles (SLPs). The process thirst; fever, Sore throat; Skin rash (increased Sun Sensitiv comprises: (a) melting a Solid agent, Such as griseofulvin; ity); mouth Soreness or irritation; urinary disturbance, (b) heating a dispersion medium to approximately the same including increased frequency and bed wetting, nervous temperature as the molten Solid agent; (c) adding one or System disturbance, including blurred vision, dizziness, more highly mobile water-soluble or dispersible stabilizers depression, nightmares, faintness, and fatigue, menstrual to the dispersion medium in Such a way that the amount of highly mobile Stabilizers is, after emulsification, Sufficient to disturbance; and liver disturbance. Stabilize newly created Surfaces during recrystallization; (d) 0.019 Griseofulvin has exhibited interactions with dietary homogenizing the melted agent and dispersion medium by Supplements. In particular, adding 50 IU of Vitamin E per high-pressure homogenization, micro-fluidization and/or day was reported to increase blood levels of griseofulvin ultraSonication; and (d) cooling the homogenized dispersion within four weeks in children, allowing the drug dose to be until solid particles are formed by recrystallization of the cut in half. Reducing the amount of griseofulvin Should dispersed agents. This proceSS is undesirable as it requires decrease the likelihood of side effects. melting the active agent, which can change the properties of 0020 Griseofulvin is currently produced by different the active agent. companies. The microcystalline form is marketed as Griful 0024 U.S. Pat. Nos. 5,449,521 and 5,354,560, both for vin VTM (Ortho Dermatological). (Fulvicin U/FTM (Scher “Supported drugs with increased dissolution rate, and a ing) and GrisactinTM (Wyeth-Ayerst), the other two micro process for their preparation,” issued on Sep. 12, 1995, and crystalline products, are no longer marketed.) The Oct. 11, 1994, respectively, describe Supported drugs having ultramicrocrystalline form of griseofulvin is marketed as an increased dissolution rate and prepared by a process Gris-PEGTM (Pedinol). (Fulvicin P/GTM (Schering) and comprising mixing the drug With the Support material under Grisactin UltraTM (Wyeth-Ayerst), the other two ultramicro dry conditions, co-grinding the mixture in a mill with its crystalline products, are no longer marketed.) grinding chamber Saturated with the vapour of one or more solvents able to solubilize the drug or to be adsorbed on the 0021 U.S. Pat. No. 6,604,698 for “Media Milling.” Surface of the Support material, Vacuum-drying the product issued on Aug. 12, 2003, describes a process for preparing obtained, and Sieving. The drugs obtained in this manner a dispersion of Solid particles of a milled Substrate, which have a reduced heat of fusion, a reduced melting point, an can be griseofulvin, in a fluid carrier. The method comprises: increased dissolution rate and an increased Solubilization (a) providing a plurality of large size milling media to the kinetics. This proceSS is undesirable as it requires Solubiliz milling chamber of a media mill and forming a depth filter ing the active agent, which can change the properties of the on an exit Screen or separator in the milling chamber; (b) active agent. In addition, the Solvents required to Solubilize adding to the milling chamber a plurality of Small size the active agent can have undesirable Side effects. milling media, a conglomerate of a Solid Substance com prising a Substrate to be milled, Such as griseofulvin, and 0.025 Finally, U.S. Pat. No. 5,705,194 for “Pharmaceu optionally one or more than one Surface active Substance, tical compositions containing polyalkylene block copoly and a fluid carrier; (c) milling the conglomerate in the mers which gel at physiological temperature,” issued on Jan. milling chamber to produce very Small milled Substrate 6, 1998, describes a pharmaceutical composition which gels product particles; and (d) continuously removing or sepa at physiological temperature. The composition comprises a rating the milled Substrate particles Suspended in the fluid triblock copolymer containing one or more polyoxyethylene carrier from the media through the depth filter. The media blocks and one or more polyoxy (higher alkylene) blocks, are retained in the milling chamber. wherein at least Some of the blocks are linked together by a linking group characterized in that the linking group is an 0022 U.S. Pat. No. 6,569,463, for “Solid carriers for oxymethylene group, and a therapeutic agent. The therapeu improved delivery of hydrophobic active ingredients in tic agent, which can be griseofulvin, is present as: (a) pharmaceutical compositions” issued on May 27, 2003, particles having an average size of less than about 400 nm describes pharmaceutical compositions in the form of a Solid and having the block copolymer adsorbed on the Surface carrier comprising a Substrate and an encapsulation coat on thereof, (b) a Suspension in a Solution of the block copoly the Substrate. The encapsulation coat comprises an admix mer, or (c) as an aqueous Solution in a Solution of the block ture of a therapeutically effective amount of a hydrophobic copolymer. pharmaceutical active ingredient, Such as griseofulvin, an effective Solubilizing amount of at least one hydrophilic 0026. At concentrations as low as 2.5% w/v in phosphate Surfactant, and a lipophilic additive Selected from the group balance salt solution (PBS) or in water, the described block consisting of lipophilic Surfactants, triglycerides, and com copolymers have gel points close to physiological tempera binations thereof. The effective solubilizing amount of the at ture (37.4 C.). The viscosity of these block copolymers at least one hydrophilic Surfactant is an amount effective to 3.5% and 5.5% in PBS changes abruptly from less than 20 partially or fully Solubilize the pharmaceutical active ingre cpS at room temperature to more than 1500 cps at physi dient in the encapsulation coat. This process is undesirable ological temperature, while the pH and OSmolality of the US 2005/OOO4049 A1 Jan. 6, 2005 block copolymer solutions remain comparable to PBS. Thus, nanoparticulate composition. It was Surprisingly discovered compositions containing these block copolymers can be that stable nanoparticulate griseofulvin formulations can be administered (e.g., Subcutaneously or orally) as low Viscos made. ity compositions at room temperature and, when they reach 0036) The current formulations of griseofulvin Suffer physiological temperature, will tend to gel. from the following problems: (1) the poor solubility of the 0.027 Disadvantages of composition including such poly drug results in a relatively low bioavailability; (2) there is a alkylene block copolymers include potential problems with significant variability in the fed/fasted absorption of the IV administration, as well as potential difficulties in formu drug; (3) a wide variety of Side effects are associated with lating the nanoparticulate composition into dosage forms for the current dosage forms of the drug. administration. 0037. The present invention overcomes problems 0028. There is a need in the art for griseofulvin compo encountered with the prior art griseofulvin formulations. Sitions which can improve clinical efficacy, reduce fed/fasted Specifically, the nanoparticulate griseofulvin formulations variability, and potentially reduce Side effects. The present of the invention may offer the following advantages as invention Satisfies these needs. compared to prior griseofulvin compositions: (1) faster onset of action; (2) a potential decrease in the frequency of dosing; SUMMARY OF THE INVENTION (3) Smaller doses of griseofulvin required to obtain the same 0029. The present invention relates to nanoparticulate pharmacological effect; (4) increased bioavailability; (5) an griseofulvin compositions. The compositions comprise increased rate of dissolution; (6) improved performance characteristics for oral, intravenous, Subcutaneous, or intra griseofulvin and at least one Surface Stabilizer. The nano muscular injection, Such as higher dose loading and Smaller particulate griseofulvin particles have an effective average tablet or liquid dose volumes; (7) improved pharmacokinetic particle size of less than about 2 microns. profiles, such as improvedT, C, and AUC profiles; (8) 0.030. Another aspect of the invention is directed to Substantially similar or bioeduivalent pharmacokinetic pro pharmaceutical compositions comprising a nanoparticulate files of the nanoparticulate griseofulvin compositions when griseofulvin composition of the invention. The pharmaceu administered in the fed versus the fasted state; (9) bioadhe tical compositions preferably comprise griseofulvin, at least Sive griseofulvin formulations, which can coat the gut or the one Surface Stabilizer, and at least one pharmaceutically desired site of application and be retained for a period of acceptable carrier, as well as any desired excipients. Advan time, thereby increasing the efficacy of the drug as well as tages and properties of the compositions of the invention are eliminating or decreasing the frequency of dosing; (10) high described herein. redispersibility of the nanoparticulate griseofulvin particles present in the compositions of the invention following 0031. The invention further discloses a method of making administration; (11) the nanoparticulate griseofulvin com a nanoparticulate griseofulvin composition. Such a method positions can be formulated in a dried form which readily comprises contacting griseofulvin and at least one Surface redisperses; (12) low Viscosity liquid nanoparticulate Stabilizer for a time and under conditions Sufficient to griseofulvin dosage forms can be made; (13) for liquid provide a nanoparticulate griseofulvin composition. The one nanoparticulate griseofulvin compositions having a low vis or more Surface Stabilizers can be contacted with griseoful cosity-better Subject compliance due to the perception of a Vin either before, preferably during, or after Size reduction of lighter formulation which is easier to consume and digest; the griseofulvin. (14) for liquid nanoparticulate griseofulvin compositions 0.032 The present invention is also directed to methods of having a low Viscosity—ease of dispensing because one can treating fungal infections using the nanoparticulate griseof use a cup or a Syringe, (15) the nanoparticulate griseofulvin ulvin compositions. Such infections include, for example, compositions can be used in conjunction with other active Such as dermatophyte and ringworm infections of the Scalp, agents; (16) the nanoparticulate griseofulvin compositions hair, nails (fingernails and toenails), and skin caused by can be sterile filtered; (17) the nanoparticulate griseofulvin Specific fungi. compositions are Suitable for parenteral administration; and 0.033 Both the foregoing general description and the (18) the nanoparticulate griseofulvin compositions do not following detailed description are exemplary and explana require organic Solvents or pH extremes. tory and are intended to provide further explanation of the 0038 A preferred dosage form of the invention is a solid invention as claimed. Other objects, advantages, and novel dosage form, although any pharmaceutically acceptable features will be readily apparent to those skilled in the art dosage form can be utilized. Exemplary Solid dosage forms from the following detailed description of the invention. include, but are not limited to, tablets, capsules, Sachets, lozenges, powders, pills, or granules. DETAILED DESCRIPTION OF THE 0039 The dosage form of the invention can be, for INVENTION example, a fast melt dosage form, controlled release dosage 0034. The present invention is directed to nanoparticulate form, lyophilized dosage form, delayed release dosage form, griseofulvin compositions. The compositions comprise extended release dosage form, pulsatile release dosage form, griseofulvin and at least one Surface Stabilizer that is pref mixed immediate release and controlled release dosage erably adsorbed on or associated with the surface of the form, or a combination thereof. A Solid dose tablet formu drug. The nanoparticulate griseofulvin particles have an lation is preferred. effective average particle size of less than about 2 microns. 0040. The present invention is described herein using 0.035 AS taught in the 684 patent, not every combination several definitions, as set forth below and throughout the of Surface Stabilizer and active agent will result in a stable application. US 2005/OOO4049 A1 Jan. 6, 2005

0041 AS used herein, “about” will be understood by tically effective amount,” administered to a particular Sub perSons of ordinary skill in the art and will vary to Some ject in a particular instance will not always be effective in extent on the context in which it is used. If there are uses of treating the diseases described herein, even though Such the term which are not clear to perSons of ordinary skill in dosage is deemed a therapeutically effective amount by the art given the context in which it is used, “about” will those skilled in the art. It is to be further understood that drug mean up to plus or minus 10% of the particular term. dosages are, in particular instances, measured as oral dos 0.042 “Conventional” or “non-nanoparticulate active ages, or with reference to drug levels as measured in blood. agent' shall mean an active agent which is Solubilized or 0048 I. Preferred Characteristics of the Nanoparticulate which has an effective average particle size of greater than Griseofulvin Compositions of the Invention about 2 microns. Nanoparticulate active agents as defined 0049 A. Increased Bioavailability, Frequency of Dosing, herein have an effective average particle size of less than and Dosage Quantity about 2 microns. 0050. The nanoparticulate griseofulvin compositions of 0.043 “Pharmaceutically acceptable” as used herein the invention may preferably exhibit increased bioavailabil refers to those compounds, materials, compositions, and/or ity and require Smaller doses as compared to prior non dosage forms which are, within the Scope of Sound medical nanoparticulate griseofulvin compositions administered at judgment, Suitable for use in contact with the tissues of the same dose. human beings and animals without excessive toxicity, irri tation, allergic response, or other problem or complication, 0051) Any drug, including griseofulvin, can have adverse commensurate with a reasonable benefit/risk ratio. Side effects. Thus, lower doses of griseofulvin that can achieve the same or better therapeutic effects as those 0044) “Pharmaceutically acceptable salts' as used herein observed with larger doses of non-nanoparticulate griseof refers to derivatives wherein the parent compound is modi ulvin compositions are desired. Such lower doses may be fied by making acid or base Salts thereof. Examples of realized with the nanoparticulate griseofulvin compositions pharmaceutically acceptable Salts include, but are not lim of the invention because the nanoparticulate griseofulvin ited to, mineral or organic acid Salts of basic residues Such compositions may exhibit greater bioavailability as com as amines, alkali or organic Salts of acidic residues Such as pared to non-nanoparticulate griseofulvin formulations, carboxylic acids, and the like. The pharmaceutically accept which means that Smaller doses of griseofulvin are likely able Salts include the conventional non-toxic Salts or the required to obtain the desired therapeutic effect. quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For 0052 The griseofulvin compositions of the invention example, Such conventional non-toxic Salts include those may be administered less frequently and at lower doses in derived from inorganic acids Such as hydrochloric, hydro dosage forms Such as liquid dispersions, powders, SprayS, bromic, Sulfuric, Sulfamic, phosphoric, nitric, and the like; Solid re-dispersable dosage forms, ointments, creams, etc. and the Salts prepared from organic acids Such as acetic, Exemplary types of formulations useful in the present inven propionic, Succinic, glycolic, Stearic, lactic, malic, tartaric, tion include, but are not limited to, liquid dispersions, gels, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylace aerosols (pulmonary and nasal), ointments, creams, Solid tic, glutamic, benzoic, Salicylic, Sulfanilic, 2-acetoxyben dose forms, etc. of nanoparticulate griseofulvin. Lower dosages can be used because the Small particle Size of the Zoic, fumaric, toluenesulfonic, methaneSulfonic, ethane dis griseofulvin particles ensure greater absorption, and in the ulfonic, oxalic, isethionic, and the like. case of bioadhesive nanoparticulate griseofulvin composi 0.045 “Poorly water soluble drugs” as used herein means tions, the griseofulvin is retained at the desired site of those having a solubility of less than about 30 mg/ml, application for a longer period of time as compared to preferably less than about 20 mg/ml, preferably less than conventional griseofulvin dosage forms. about 10 mg/ml, or preferably less than about 1 mg/ml. Such 0053. In one embodiment of the invention, the therapeu drugs tend to be eliminated from the gastrointestinal tract tically effective amount of the nanoparticulate griseofulvin before being absorbed into the circulation. compositions is %, /s, 4,"/", or % of the therapeutically 0046. As used herein with reference to stable drug par effective amount of a non-nanoparticulate griseofulvin com ticles, “stable' includes, but is not limited to, one or more of position. the following parameters: (1) that the griseofulvin particles do not appreciably flocculate or agglomerate due to inter 0054. Such lower doses are preferred as they may particle attractive forces, or otherwise Significantly increase decrease or eliminate adverse effects of the drug. In addition, in particle size over time; (2) that the physical Structure of Such lower doses decrease the cost of the dosage form and the griseofulvin particles is not altered over time, Such as by may increase patient compliance. conversion from an amorphous phase to crystalline phase; 0055 B. Pharmacokinetic Profiles of the Nanoparticulate (3) that the griseofulvin particles are chemically stable; Griseofulvin Compositions of the Invention and/or (4) where the griseofulvin has not been Subject to a heating Step at or above the melting point of the griseofulvin 0056. The invention also preferably provides griseofulvin in the preparation of the nanoparticles of the invention. compositions having a desirable pharmacokinetic profile when administered to mammalian Subjects. The desirable 0047. “Therapeutically effective amount” as used herein pharmacokinetic profile of the griseofulvin compositions with respect to a drug dosage, Shall mean that dosage that preferably includes, but is not limited to: (1) a T for provides the Specific pharmacological response for which griseofulvin, when assayed in the plasma of a mammalian the drug is administered in a significant number of Subjects Subject following administration, that is preferably less than in need of Such treatment. It is emphasized that “therapeu the T for a non-nanoparticulate griseofulvin formulation US 2005/OOO4049 A1 Jan. 6, 2005 administered at the same dosage; (2) a C for griseofulvin, 0062) Any formulation giving the desired pharmacoki when assayed in the plasma of a mammalian Subject fol netic profile is Suitable for administration according to the lowing administration, that is preferably greater than the present methods. Exemplary types of formulations giving C. for a non-nanoparticulate griseofulvin formulation Such profiles are liquid dispersions, gels, aerosols, oint administered at the same dosage; and/or (3) an AUC for ments, creams, Solid dose forms, etc. of nanoparticulate griseofulvin, when assayed in the plasma of a mammalian griseofulvin. Subject following administration, that is preferably greater 0063 C. The Pharmacokinetic Profiles of the Nanopar than the AUC for a non-nanoparticulate griseofulvin formu ticulate Griseofulvin Compositions of the Invention are lation administered at the same dosage. Preferably not Substantially Affected by the Fed or Fasted 0057 The desirable pharmacokinetic profile, as used State of the Subject Ingesting the Compositions herein, is the pharmacokinetic profile measured after the 0064. The invention encompasses nanoparticulate initial dose of griseofulvin. The compositions can be for griseofulvin compositions wherein preferably the pharma mulated in any way as described below and as known to cokinetic profile of the griseofulvin is not Substantially those of skill in the art. affected by the fed or fasted State of a Subject ingesting the 0.058 A preferred griseofulvin composition of the inven composition. This means that there is no Substantial differ tion exhibits in comparative pharmacokinetic testing with a ence in the quantity of griseofulvin absorbed or the rate of non-nanoparticulate griseofulvin formulation administered griseofulvin absorption when the nanoparticulate griseoful at the same dosage, a T not greater than about 90%, not Vin compositions are administered in the fed versus the greater than about 80%, not greater than about 70%, not fasted State. Thus, the nanoparticulate griseofulvin compo greater than about 60%, not greater than about 50%, not Sitions of the invention can Substantially eliminate the effect greater than about 30%, not greater than about 25%, not of food on the pharmacokinetics of griseofulvin. greater than about 20%, not greater than about 15%, not 0065. In another embodiment of the invention, the phar greater than about 10%, or not greater than about 5% of the macokinetic profile of the griseofulvin compositions of the T exhibited by the non-nanoparticulate griseofulvin for invention, when administered to a mammal in a fasted State, mulation. is bioeduivalent to the pharmacokinetic profile of the same griseofulvin composition administered at the same dosage, 0059) This shorter T translates into a faster onset of when administered to a mammal in a fed State. “Bioecquiva therapeutic activity. The use of conventional formulations of lency” is preferably established by a 90% Confidence Inter griseofulvin is not ideal due to delayed onset of action. val (CI) of between 0.80 and 1.25 for both C, and AUC Specifically, conventional griseofulvin formulations exhibit under U.S. Food and Drug Administration (USFDA) regu a peak plasma concentration at 4 hours following adminis latory guidelines, or a 90% CI for AUC of between 0.80 to tration. In contrast, the nanoparticulate griseofulvin compo 1.25 and a 90% CI for C of between 0.70 to 1.43 under sitions of the invention exhibit faster therapeutic effects. the European Medicines Evaluation Agency (EMEA) regu 0060 A preferred griseofulvin composition of the inven latory guidelines (T is not relevant for bioeduivalency tion exhibits in comparative pharmacokinetic testing with a determinations under USFDA and EMEA regulatory guide non-nanoparticulate griseofulvin formulation of adminis lines). tered at the same dosage, a C, which is at least about 50%, 0066 Preferably the difference in AUC (e.g., absorption) at least about 100%, at least about 200%, at least about of the nanoparticulate griseofulvin composition of the inven 300%, at least about 400%, at least about 500%, at least tion, when administered in the fed versus the fasted State, is about 600%, at least about 700%, at least about 800%, at less than about 100%, less than about 90%, less than about least about 900%, at least about 1000%, at least about 80%, less than about 70%, less than about 60%, less than 1100%, at least about 1200%, at least about 1300%, at least about 50%, less than about 40%, less than about 35%, less about 1400%, at least about 1500%, at least about 1600%, than about 30%, less than about 25%, less than about 20%, at least about 1700%, at least about 1800%, or at least about less than about 15%, less than about 10%, less than about 1900% greater than the C exhibited by the non-nanopar 5%, or less than about 3%. ticulate griseofulvin formulation. 0067. In addition, preferably the difference in C, of the 0061 A preferred griseofulvin composition of the inven nanoparticulate griseofulvin composition of the invention, tion exhibits in comparative pharmacokinetic testing with a when administered in the fed versus the fasted State, is leSS non-nanoparticulate griseofulvin formulation administered than about 100%, less than about 90%, less than about 80%, at the same dosage, an AUC which is at least about 25%, at less than about 70%, less than about 60%, less than about least about 50%, at least about 75%, at least about 100%, at 50%, less than about 40%, less than about 35%, less than least about 125%, at least about 150%, at least about 175%, about 30%, less than about 25%, less than about 20%, less at least about 200%, at least about 225%, at least about than about 15%, less than about 10%, less than about 5%, or 250%, at least about 275%, at least about 300%, at least less than about 3%. about 350%, at least about 400%, at least about 450%, at 0068 Finally, preferably the difference in the T of the least about 500%, at least about 550%, at least about 600%, nanoparticulate griseofulvin compositions of the invention, at least about 750%, at least about 700%, at least about when administered in the fed versus the fasted State, is leSS 750%, at least about 800%, at least about 850%, at least than about 100%, less than about 90%, less than about 80%, about 900%, at least about 950%, at least about 1000%, at less than about 70%, less than about 60%, less than about least about 1050%, at least about 1100%, at least about 50%, less than about 40%, less than about 30%, less than 1150%, or at least about 1200% greater than the AUC about 20%, less than about 15%, less than about 10%, less exhibited by the non-nanoparticulate griseofulvin formula than about 5%, less than about 3%, or essentially no differ tion. CCC. US 2005/OOO4049 A1 Jan. 6, 2005

0069 Benefits of a dosage formn that substantially elimi or less, about 0.001M HCl or less, about 0.1M NaCl or less, nates the effect of food include an increase in Subject about 0.01 M NaCl or less, about 0.001M NaCl or less, and convenience, thereby increasing Subject compliance, as the mixtures thereof. Of these electrolyte solutions, 0.01 M HCl Subject does not need to ensure that they are taking a dose and/or 0.1M NaCl, are most representative of fasted human either with or without food. physiological conditions, owing to the pH and ionic Strength 0070) D. Redispersibility Profiles of the Nanoparticulate conditions of the proximal gastrointestinal tract. Griseofulvin Compositions of the Invention 0.077 Electrolyte concentrations of 0.001M HCl, 0.01 M 0071 An additional feature of the nanoparticulate HCl, and 0.1M HCl correspond to pH 3, pH 2, and pH 1, griseofulvin compositions of the invention is that the com respectively. Thus, a 0.01 M HCl solution simulates typical positions redisperse Such that the effective average particle acidic conditions found in the stomach. A Solution of 0.1 M Size of the redispersed griseofulvin particles is less than NaCl provides a reasonable approximation of the ionic about 2 microns. This is significant, as if upon administra Strength conditions found throughout the body, including the tion the nanoparticulate griseofulvin particles present in the gastrointestinal fluids, although concentrations higher than compositions of the invention did not redisperse to a Sub 0.1 M may be employed to simulate fed conditions within Stantially nanoparticulate particle size, then the dosage form the human GI tract. may lose the benefits afforded by formulating griseofulvin 0078 Exemplary solutions of salts, acids, bases or com into a nanoparticulate particle size. binations thereof, which exhibit the desired pH and ionic 0.072 This is because nanoparticulate griseofulvin com Strength, include but are not limited to phosphoric acid/ positions benefit from the Small particle Size of griseofulvin; phosphate Salts+Sodium, potassium and calcium Salts of if the nanoparticulate griseofulvin particles do not redisperse chloride, acetic acid/acetate Salts+Sodium, potassium and into the Small particle sizes upon administration, then calcium Salts of chloride, carbonic acid/bicarbonate Salts+ "clumps' or agglomerated griseofulvin particles are formed. Sodium, potassium and calcium Salts of chloride, and citric With the formation of Such agglomerated particles, the acid/citrate Salts+Sodium, potassium and calcium Salts of bioavailability of the dosage form may fall. chloride. 0.073 Moreover, the nanoparticulate griseofulvin compo 0079. In other embodiments of the invention, the redis sitions of the invention exhibit dramatic redispersion of the persed griseofulvin particles of the invention (redispersed in griseofulvin particles upon administration to a mammal, an aqueous, biorelevant, or any other Suitable media) have Such as a human or animal, as demonstrated by reconstitu an effective average particle size of less than about 1900 nm, tion in a biorelevant aqueous media. Such biorelevant acque less than about 1800 nm, less than about 1700 nm, less than ous media can be any aqueous media that exhibit the desired about 1600 nm, less than about 1500 nm, less than about ionic strength and pH, which form the basis for the biorel 1400 nm, less than about 1300 nm, less than about 1200 nm, evance of the media. The desired pH and ionic Strength are less than about 1100 nm, less than about 1000 nm, less than those that are representative of physiological conditions about 900 nm, less than about 800 nm, less than about 700 found in the human body. Such biorelevant acqueous media nm, less than about 600 nm, less than about 500 nm, less can be, for example, aqueous electrolyte Solutions or aque than about 400 nm, less than about 300 nm, less than about ous Solutions of any Salt, acid, or base, or a combination 250 nm, less than about 200 nm, less than about 150 nm, less thereof, which exhibit the desired pH and ionic strength. than about 100 nm, less than about 75 nm, or less than about 0074 Biorelevant pH is well known in the art. For 50 nm, as measured by light-scattering methods, microS example, in the Stomach, the pH ranges from Slightly leSS copy, or other appropriate methods. than 2 (but typically greater than 1) up to 4 or 5. In the Small 0080 Redispersibility can be tested using any suitable intestine the pH can range from 4 to 6, and in the colon it can means known in the art. See e.g., the example Sections of range from 6 to 8. Biorelevant ionic Strength is also well U.S. Pat. No. 6,375,986 for “Solid Dose Nanoparticulate known in the art. Fasted State gastric fluid has an ionic Compositions Comprising a Synergistic Combination of a strength of about 0.1M while fasted State intestinal fluid has Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuc an ionic Strength of about 0.14. See e.g., Lindahl et al., cinate.” “Characterization of Fluids from the Stomach and Proximal Jejunum in Men and Women.” Pharm. Res., 14(4): 497-502 0081 E. Bioadhesive Nanoparticulate Griseofulvin Com (1997). positions 0075). It is believed that the pH and ionic strength of the 0082 Bioadhesive nanoparticulate griseofulvin composi test Solution is more critical than the Specific chemical tions of the invention comprise at least one cationic Surface content. Accordingly, appropriate pH and ionic Strength stabilizer, which are described in more detail below. Bioad values can be obtained through numerous combinations of hesive formulations of griseofulvin exhibit exceptional bio Strong acids, Strong bases, Salts, Single or multiple conjugate adhesion to biological Surfaces, Such as mucous and skin. acid-base pairs (i.e., weak acids and corresponding Salts of 0083. In the case of bioadhesive nanoparticulate griseof that acid), monoprotic and polyprotic electrolytes, etc. ulvin compositions, the term “bioadhesion” is used to 0.076 Representative electrolyte solutions can be, but are describe the adhesion between the nanoparticulate griseof not limited to, HCl Solutions, ranging in concentration from ulvin compositions and a biological Substrate (i.e., gas about 0.001 to about 0.1 M, and NaCl Solutions, ranging in trointestinal mucin, lung tissue, nasal mucosa, etc.). See e.g., concentration from about 0.001 to about 0.1M, and mixtures U.S. Pat. No. 6,428,814 for “Bioadhesive Nanoparticulate thereof. For example, electrolyte Solutions can be, but are Compositions Having Cationic Surface Stabilizers,” which not limited to, about 0.1M HCl or less, about 0.01 M HCl is Specifically incorporated by reference. US 2005/OOO4049 A1 Jan. 6, 2005

0084. The bioadhesive griseofulvin compositions of the mPa.s, from about 1500 mPa.S to about 1 mPa.s, from about invention are useful in any situation in which it is desirable 1400 mPas to about 1 mPa.s, from about 1300 mPa.s to to apply the compositions to a biological Surface. The about 1 mPa.s, from about 1200 mPa.S to about 1 mPa.S, bioadhesive griseofulvin compositions preferably coat the from about 1100 mPa.S to about 1 mPa.s, from about 1000 targeted Surface in a continuous and uniform film that is mPa.S to about 1 mPa.s, from about 900 mPa.S to about 1 invisible to the naked human eye. mPa.s, from about 800 mPa.S to about 1 mPa.s, from about 0085. A bioadhesive nanoparticulate griseofulvin com 700 mPa.S to about 1 mPa.s, from about 600 mPa.S to about position Slows the transit of the composition, and Some 1 mPa.s, from about 500 mPa is to about 1 mPa.s, from griseofulvin particles would also most likely adhere to tissue about 400 mPa.S to about 1 mPa.s, from about 300 mPa.s other than the mucous cells and therefore give a prolonged to about 1 mPa.s, from about 200 mPa.S to about 1 mPa.s exposure to griseofulvin, thereby increasing absorption and , from about 175 mPa.S to about 1 mPa.s, from about 150 mPa.S to about 1 mPa.s, from about 125 mPa.S to about 1 the bioavailability of the administered dosage. mPa.s, from about 100 mPa.S to about 1 mPa.s, from about 0.086 F. Low Viscosity 75 mPa.S to about 1 mPa.s, from about 50 mPa.S to about 0.087 Aliquid dosage form of a conventional microcrys 1 mPa.s, from about 25 mPa is to about 1 mPa.s, from about talline or non-nanoparticulate griseofulvin composition 15 mPa.S to about 1 mPa.s, from about 10 mPa.S to about would be expected to be a relatively large Volume, highly 1 mPa.S, or from about 5 mPa.S to about 1 mPa.S. Such a viscous substance which would not be well accepted by Viscosity is much more attractive for Subject consumption patient populations. Moreover, Viscous Solutions can be and may lead to better overall Subject compliance. problematic in parenteral administration because these Solu 0092 Viscosity is concentration and temperature depen tions require a slow Syringe push and can Stick to tubing. In dent. Typically, a higher concentration results in a higher addition, conventional formulations of poorly water-Soluble Viscosity, while a higher temperature results in a lower active agents, Such as griseofulvin, tend to be unsafe for Viscosity. Viscosity as defined above refers to measurements intravenous administration techniques, which are used pri taken at about 20° C. (The viscosity of water at 20° C. is 1 marily in conjunction with highly water-Soluble Substances. mPa.s.) The invention encompasses equivalent Viscosities 0088 Liquid dosage forms of the nanoparticulate griseof measured at different temperatures. ulvin compositions of the invention provide significant 0093. Another important aspect of the invention is that advantages over a liquid dosage form of a conventional the nanoparticulate griseofulvin compositions of the inven microcrystalline or Solubilized griseofulvin composition. tion, formulated into a liquid dosage form, are not turbid. The low Viscosity and Silky texture of liquid dosage forms “Turbid,” as used herein refers to the property of particulate of the nanoparticulate griseofulvin compositions of the matter that can be seen with the naked eye or that which can invention result in advantages in both preparation and use. be felt as "gritty.” The nanoparticulate griseofulvin compo These advantages include, for example: (1) better Subject Sitions of the invention, formulated into a liquid dosage compliance due to the perception of a lighter formulation form, can be poured out of or extracted from a container as which is easier to consume and digest; (2) ease of dispensing easily as water, whereas a liquid dosage form of a non because one can use a cup or a Syringe; (3) potential for nanoparticulate or Solubilized griseofulvin is expected to formulating a higher concentration of griseofulvin resulting exhibit notably more "sluggish characteristics. in a Smaller dosage Volume and thus leSS Volume for the Subject to consume, and (4) easier overall formulation 0094. The liquid formulations of this invention can be COCCS. formulated for dosages in any Volume but preferably equiva 0089 Liquid griseofulvin dosage forms that are easier to lent or Smaller Volumes than a liquid dosage form of a consume are especially important when considering juvenile non-nanoparticulate griseofulvin composition. patients, terminally ill patients, and elderly patients. Viscous 0.095 G. Sterile Filtered Nanoparticulate Griseofulvin or gritty formulations, and those that require a relatively Compositions large dosage Volume, are not well tolerated by these patient populations. Liquid oral dosage forms can be particularly 0096. The nanoparticulate griseofulvin compositions of preferably for patient populations who have difficulty con the invention can be sterile filtered. This obviates the need Suming tablets, Such as infants and the elderly. for heat Sterilization, which can harm or degrade griseoful Vin, as well as result in crystal growth and particle aggre 0090 The viscosities of liquid dosage forms of nanopar gation. ticulate griseofulvin according to the invention are prefer ably less than about 1/200, less than about/175, less than about 0097 Sterile filtration can be difficult because of the /150, less than about/125, less than about /100, less than about required Small particle size of the composition. Filtration is /75, less than about /so, or less than about 1/25 of a liquid oral an effective method for Sterilizing homogeneous Solutions dosage form of a non-nanoparticulate griseofulvin compo when the membrane filter pore size is less than or equal to Sition, at about the same concentration per ml of griseoful about 0.2 microns (200 nm) because a 0.2 micron filter is W. sufficient to remove essentially all bacteria. Sterile filtration is normally not used to Sterilize Suspensions of micron-sized 0.091 Typically the viscosity of liquid nanoparticulate griseofulvin because the griseofulvin particles are too large griseofulvin dosage forms of the invention, at a shear rate of to pass through the membrane pores. 0.1 (1/s) measured at 20° C., is from about 2000 mPa is to about 1 mPa S, from about 1900 mPa.S to about 1 mPa.s, 0098 Asterile nanoparticulate griseofulvin dosage form from about 1800 mPa is to about 1 mPa.s, from about 1700 is particularly useful in treating immunocompromised mPa.S to about 1 mPa.s, from about 1600 mPa.S to about 1 patients, infants or juvenile patients, and the elderly, as these US 2005/OOO4049 A1 Jan. 6, 2005 patient groups are the most Susceptible to infection caused invention can be formulated Separately from the nanopar by a non-Sterile liquid dosage form. ticulate griseofulvin composition or co-formulated with the 0099 Because the nanoparticulate griseofulvin composi nanoparticulate griseofulvin composition. Where a nanopar tions of the invention, formulated into a liquid dosage form, ticulate griseofulvin composition is co-formulated with a can be Sterile filtered, and because the compositions can Second active agent, the Second active agent can be formu have a very Small griseofulvin effective average particle lated in any Suitable manner, Such as immediate-release, size, the compositions are Suitable for parenteral adminis rapid-onset, Sustained-release, or dual-release form. tration. 0109 Such non-griseofulvin active agents can be, for example, a therapeutic agent. A therapeutic agent can be a 0100 H. Combination Pharmacokinetic Profile Compo pharmaceutical agent, including a biologic. The active agent Sitions can be Selected from a variety of known classes of drugs, 0101. In yet another embodiment of the invention, a first including, for example, amino acids, proteins, peptides, nanoparticulate griseofulvin composition providing a nucleotides, anti-obesity drugs, central nervous System desired pharmacokinetic profile is co-administered, Sequen Stimulants, carotenoids, corticosteroids, elastase inhibitors, tially administered, or combined with at least one other anti-fungals, oncology therapies, anti-emetics, analgesics, griseofulvin composition that generates a desired different cardiovascular agents, anti-inflammatory agents, Such as pharmacokinetic profile. More than two griseofulvin com NSAIDs and COX-2 inhibitors, anthelmintics, anti-arrhyth positions can be co-administered, Sequentially administered, mic agents, antibiotics (including penicillins), anticoagul or combined. While the first griseofulvin composition has a lants, antidepressants, antidiabetic agents, antiepileptics, nanoparticulate particle size, the additional one or more antihistamines, antihypertensive agents, antimuscarinic griseofulvin compositions can be nanoparticulate, Solubi agents, antimycobacterial agents, antineoplastic agents, lized, or have a microparticulate particle size. immunosuppressants, antithyroid agents, antiviral agents, anxiolytics, Sedatives (hypnotics and neuroleptics), astrin 0102) For example, a first griseofulvin composition can gents, alpha-adrenergic receptor blocking agents, beta have a nanoparticulate particle size, conferring a short T. adrenoceptor blocking agents, blood products and Substi and typically a higher C. This first griseofulvin compo tutes, cardiac inotropic agents, contrast media, Sition can be combined, co-administered, or Sequentially corticosteroids, cough Suppressants (expectorants and administered with a second composition comprising: (1) mucolytics), diagnostic agents, diagnostic imaging agents, griseofulvin having a larger (but still nanoparticulate as diuretics, dopaminergicS (antiparkinsonian agents), haemo defined herein) particle size, and therefore exhibiting slower Statics, immunological agents, lipid regulating agents, absorption, a longer Ta, and typically a lower Cas, or (2) muscle relaxants, parasympathomimetics, parathyroid cal a microparticulate or Solubilized griseofulvin composition, citonin and biphosphonates, prostaglandins, radio-pharma exhibiting a longer T and typically a lower C. ceuticals, Sex hormones (including Steroids), anti-allergic 0103) The second, third, fourth, etc., griseofulvin com agents, Stimulants and anoretics, Sympathomimetics, thyroid positions can differ from the first, and from each other, for agents, vasodilators, and Xanthines. example: (1) in the effective average particle sizes of 0110. Examples of representative active agents useful in griseofulvin; or (2) in the dosage of griseofulvin. Such a this invention include, but are not limited to, acyclovir, combination composition can reduce the dose frequency alprazolam, altretamine, amiloride, amiodarone, benz required. tropine meSylate, bupropion, cabergoline, candesartan, 0104. If the second griseofulvin composition has a nano cerivastatin, chlorpromazine, ciprofloxacin, cisapride, particulate particle size, then preferably the griseofulvin clarithromycin, clonidine, clopidogrel, cyclobenzaprine, particles of the Second composition have at least one Surface cyproheptadine, delavirdine, desmopressin, diltiazem, dipy Stabilizer associated with the Surface of the drug particles. ridamole, dolasetron, enalapril maleate, enalaprilat, famoti The one or more Surface Stabilizers can be the same as or dine, felodipine, furazolidone, irbesartan, ketoconazole, lan different from the surface stabilizer(s) present in the first Soprazole, loratadine, loxapine, mebendazole, griseofulvin composition. mercaptopurine, milrinone lactate, minocycline, mitox antrone, nelfinavir meSylate, nimodipine, norfloxacin, olan 0105 Preferably where co-administration of a “fast-act Zapine, omeprazole, penciclovir, pimozide, tacolimus, ing formulation and a “longer-lastingss formulation is quazepam, raloxifene, rifabutin, rifampin, risperidone, riza desired, the two formulations are combined within a Single triptan, Saquinavir, Sertraline, Sildenafil, acetyl-Sulfisox composition, for example a dual-release composition. azole, temazepam, thiabendazole, thioguanine, trandolapril, triamterene, trimetrexate, troglitaZone, trovafloxacin, Vera 01.06) I. Combination Active Agent Compositions pamil, vinblastine Sulfate, mycophenolate, atovaquone, 0107 The invention encompasses the nanoparticulate atovaquone, proguanil, ceftazidime, cefuroxime, etoposide, griseofulvin compositions of the invention formulated or terbinafine, thalidomide, fluconazole, amsacrine, dacarba co-administered with one or more non-griseofulvin active Zine, teniposide, and acetylsalicylate. agents. Methods of using Such combination compositions are also encompassed by the invention. The non-griseoful 0111. A description of these classes of active agents and Vin active agents can be present in a crystalline phase, an a listing of Species within each class can be found in amorphous phase, a Semi-crystalline phase, a Semi-amor Martindale's The Extra Pharmacopoeia, 31 Edition (The Pharmaceutical Press, London, 1996), specifically incorpo phous phase, or a mixture thereof. rated by reference. The active agents are commercially 0108. The compound to be administered in combination available and/or can be prepared by techniques known in the with a nanoparticulate griseofulvin composition of the art. Exemplary nutraceuticals or dietary Supplements US 2005/OOO4049 A1 Jan. 6, 2005

include, but are not limited to, lutein, folic acid, fatty acids (in Solid, liquid, or aerosol (i.e., pulmonary) form), vaginal, (e.g., DHA and ARA), fruit and vegetable extracts, Vitamin nasal, rectal, ocular, local (powders, creams, ointments or and mineral Supplements, phosphatidylserine, lipoic acid, drops), buccal, intracisternal, intraperitoneal, topical admin melatonin, glucosamine/chondroitin, Aloe Vera, Guggul, istration, and the like. glutamine, amino acids (e.g., arginine, isoleucine, leucine, leucine, lysine, methionine, phenylanine, threonine, tryp 0119) A. Griseofulvin Particles tophan, and valine), green tea, lycopene, whole foods, food 0120 Griseofulvin as used herein includes the compound additives, herbs, phytonutrients, antioxidants, flavonoid con having the chemical formula C7H,ClO and the following Stituents of fruits, evening primrose oil, flax Seeds, fish and chemical Structure: marine animal oils, and probiotics. Nutraceuticals and dietary Supplements also include bio-engineered foods genetically engineered to have a desired property, also known as “pharmafoods.” Exemplary nutraceuticals and dietary Supplements are disclosed, for example, in Roberts et al., Nutraceuticals. The Complete Encyclopedia of Supple ments, Herbs, Vitamins, and Healing Foods (American Nutraceutical Association, 2001), which is specifically incorporated by reference. Dietary Supplements and nutra ceuticals are also disclosed in Physicians' Desk Reference for Nutritional Supplements, 1 Ed. (2001) and The Physi cians' Desk Reference for Herbal Medicines, 1 Ed. (2001), both of which are also incorporated by reference. A nutra 0121 and salts thereof. See The Merck Index, 10" Edi ceutical or dietary Supplement, also known as a phytochemi tion, pp.4433-34 (1983). cal or functional food, is generally any one of a class of 0.122 Griseofulvin can be in a crystalline phase, an dietary Supplements, Vitamins, minerals, herbs, or healing amorphous phase, a Semi-crystalline phase, a Semi-amor foods that have medical or pharmaceutical effects on the phous phase, or a mixture thereof. body. 0123 B. Surface Stabilizers 0112) In a preferred embodiment of the invention, the griseofulvin compositions of the invention are co-adminis 0.124. The choice of a Surface Stabilizer for griseofulvin is tered or combined with at least one other antifungal agent. non-trivial and required extensive experimentation to realize a desirable formulation. Accordingly, the present invention 0113. In another preferred embodiment of the invention, is directed to the Surprising discovery that nanoparticulate the griseofulvin compositions of the invention are co-ad griseofulvin compositions can be made. ministered or combined with vitamin E. 0.125 Combinations of more than one surface stabilizer 0114. J. Miscellaneous Benefits of the Nanoparticulate can be used in the invention. Useful Surface stabilizers that Griseofulvin Compositions of the Invention can be employed in the invention include, but are not limited 0115 The nanoparticulate griseofulvin compositions to, known organic and inorganic pharmaceutical excipients. preferably exhibit an increased rate of dissolution as com Such excipients include various polymers, low molecular pared to microcrystalline or non-nanoparticulate forms of weight oligomers, natural products, and Surfactants. Surface griseofulvin. In addition, the nanoparticulate griseofulvin Stabilizers include nonionic, anionic, cationic, Zwitterionic, compositions preferably exhibit improved performance and ionic Surfactants. characteristics for oral, intravenous, Subcutaneous, or intra 0.126 Representative examples of other useful surface muscular injection, Such as higher dose loading and Smaller Stabilizers include hydroxypropyl methylcellulose, hydrox tablet or liquid dose Volumes. Moreover, the nanoparticulate ypropylcellulose, polyvinylpyrrolidone, Sodium lauryl Sul griseofulvin compositions of the invention do not require fate, dioctylsulfoSuccinate, gelatin, casein, lecithin (phos organic Solvents or pH extremes. phatides), dextran, gum acacia, cholesterol, tragacanth, 0.116) II. Griseofulvin Compositions Stearic acid, benzalkonium chloride, calcium Stearate, glyc erol monoStearate, cetoStearyl alcohol, cetomacrogol emul 0117 The invention provides compositions comprising Sifying wax, Sorbitan esters, polyoxyethylene alkyl ethers nanoparticulate griseofulvin particles and at least one Sur (e.g., macrogol etherS Such as cetomacrogol 1000), poly face Stabilizer. The Surface Stabilizers are preferably asso oxyethylene castor oil derivatives, polyoxyethylene Sorbitan ciated with the Surface of the griseofulvin particles. Surface fatty acid esters (e.g., the commercially available TweenS(R) stabilizers useful herein do not chemically react with the such as e.g., Tween(R) and Tween 80R (ICI Speciality griseofulvin particles or itself. Preferably, individual mol Chemicals)); polyethylene glycols (e.g., Carbowaxs 3550(R) ecules of the Surface Stabilizer are essentially free of inter and 9340E (Union Carbide)), polyoxyethylene stearates, col molecular croSS-linkages. The compositions can comprise loidal Silicon dioxide, phosphates, carboxymethylcellulose two or more Surface Stabilizers. calcium, carboxymethylcellulose Sodium, methylcellulose, 0118. The present invention also includes nanoparticulate hydroxyethylcellulose, hydroxypropylmethylcellulose griseofulvin compositions together with one or more non phthalate, noncrystalline cellulose, magnesium aluminium toxic physiologically acceptable carriers, adjuvants, or silicate, triethanolamine, polyvinyl alcohol (PVA), 4-(1,1,3, vehicles, collectively referred to as carriers. The composi 3-tetramethylbutyl)-phenol polymer with ethylene oxide and tions can be formulated for parenteral injection (e.g., intra formaldehyde (also known as tyloxapol, Superione, and venous, intramuscular, or Subcutaneous), oral administration triton), poloxamers (e.g., Pluronics F68(R) and F1086, which US 2005/OOO4049 A1 Jan. 6, 2005 are block copolymers of ethylene oxide and propylene C-dimethyl hydroxyethyl ammonium chloride or bro oxide); poloxamines (e.g., Tetronic 9080E, also known as mide, coconut dimethyl hydroxyethyl ammonium chloride Poloxarnine 9080E), which is a tetrafunctional block copoly or bromide, myristyl trimethyl ammonium methyl Sulphate, mer derived from Sequential addition of propylene oxide and lauryl dimethyl benzyl ammonium chloride or bromide, ethylene oxide to ethylenediamine (BASF Wyandotte Cor lauryl dimethyl(ethenoxy) ammonium chloride or bromide, poration, Parsippany, N.J.)); Tetronic 15086) (T-1508) N-alkyl (Cs)dimethylbenzyl ammonium chloride, (BASF Wyandotte Corporation), Tritons X-2008), which is N-alkyl(Cs)dimethyl-benzyl ammonium chloride, N-tet an alkyl aryl polyether sulfonate (Rohm and Haas); Crod radecylidimethylbenzyl ammonium chloride monohydrate, estas F-110E), which is a mixture of Sucrose Stearate and dimethyl didecyl ammonium chloride, N-alkyl and (C- Sucrose distearate (Croda Inc.), p-isononylphenoxypoly 14)dimethyl 1-naphthylmethyl ammonium chloride, trim (glycidol), also known as Olin-1OG(R) or Surfactant 10-G(R) ethylammonium halide, alkyl-trimethylammonium Salts and (Olin Chemicals, Stamford, Conn.); Crodestas SL-40E dialkyl-dimethylammonium Salts, lauryl trimethyl ammo (Croda, Inc.); and SA90HCO, which is nium chloride, ethoxylated alkyamidoalkyldialkylammo CH,CH(CON(CH4)-CH(CHOH),(CHOH). (East nium Salt and/or an ethoxylated trialkyl ammonium Salt, man Kodak Co.); decanoyl-N-methylglucamide; n-decyl dialkylbenzene dialkylammonium chloride, N-didecyldim B-D-glucopyranoside; n-decyl B-D-maltopyranoside; ethyl ammonium chloride, N-tetradecyldimethylbenzyl n-dodecyl B-D-glucopyranoside; n-dodecyl B-D-maltoside; ammonium, chloride monohydrate, N-alkyl(C1-)dimethyl heptanoyl-N-methylglucamide; n-heptyl-B-D-glucopyrano 1-naphthylmethyl ammonium chloride and dodecyldimeth Side; n-heptyl B-D-thioglucoside; n-hexyl B-D-glucopyrano ylbenzyl ammonium chloride, dialkylbenzenealkyl ammo Side; nonanoyl-N-methylglucamide; n-noyl B-D-glucopyra nium chloride, lauryl trimethyl ammonium chloride, alkyl noside; octanoyl-N-methylglucamide; n-octyl-f-D- benzyl methyl ammonium chloride, alkylbenzyl dimethyl glucopyranoside; octyl B-D-thioglucopyranoside, PEG ammonium bromide, C2, Cs, C7 trimethyl ammonium derivatized phospholipid, PEG-derivatized cholesterol, bromides, dodecylbenzyl triethyl ammonium chloride, poly PEG-derivatized cholesterol derivative, PEG-derivatized diallyldimethylammonium chloride (DADMAC), dimethyl vitamin A, PEG-derivatized vitamin E, lysozyme, random ammonium chlorides, alkyldimethylammonium halo copolymers of vinyl pyrrollidone and vinyl acetate, and the genides, tricetyl methyl ammonium chloride, decyltrimethy like. lammonium bromide, dodecyltriethylammonium bromide, 0127 Depending upon the desired method of adminis tetradecyltrimethylammonium bromide, methyl trioctylam tration, bioadhesive formulations of nanoparticulate griseof monium chloride (ALIQUAT 336 TM), POLYQUAT 10TM, ulvin can be prepared by Selecting one or more cationic tetrabutylammonium bromide, benzyl trimethylammonium Surface Stabilizers that impart bioadhesive properties to the bromide, choline esters (such as choline esters of fatty resultant composition. Useful cationic Surface Stabilizers are acids), benzalkonium chloride, Stearalkonium chloride com described below. pounds (such as Stearyltrimonium chloride and Di-Stearyldi monium chloride), cetyl pyridinium bromide or chloride, 0128. Examples of useful cationic surface stabilizers halide Salts of quaternized polyoxyethylalkylamines, include, but are not limited to, polymers, biopolymers, MIRAPOLTM and ALKAQUATM (Alkaril Chemical Com polysaccharides, cellulosics, alginates, phospholipids, and pany), alkyl pyridinium salts, amines, such as alkylamines, nonpolymeric compounds, Such as Zwitterionic Stabilizers, dialkylamines, alkanolamines, polyethylenepolyamines, poly-n-methylpyridinium, anthryul pyridinium chloride, N,N-dialkylaminoalkyl acrylates, and vinyl pyridine, amine cationic phospholipids, chitosan, polylysine, polyvinylimi Salts, Such as lauryl amine acetate, Stearyl amine acetate, dazole, polybrene, polymethylmethacrylate trimethylammo alkylpyridinium Salt, and alkylimidazolium Salt, and amine niumbromide bromide (PMMTMABr), hexyldesyltrimethy oxides, imide azolinium Salts, protonated quaternary acry lammonium bromide (HDMAB), polyvinylpyrrolidone-2- lamides, methylated quaternary polymers, Such as poly dimethylaminoethyl methacrylate dimethyl Sulfate, 1.2 diallyl dimethylammonium chloride and poly-N-methyl Dipalmitoyl-sn-Glycero-3-Phosphoethanolamine-N-Ami vinyl pyridinium chloride; and cationic guar. no(Polyethylene Glycol)2000 (sodium salt) (also known as DPPE-PEG(2000)-Amine Na) (Avanti Polar Lipids, Alabas 0.130. Such exemplary cationic surface stabilizers and ter, A1), Poly(2-methacryloxyethyl trimethylammonium other useful cationic Surface Stabilizers are described in J. bromide) (Polysciences, Inc., Warrington, Pa.) (also known CroSS and E. Singer, Cationic Surfactants. Analytical and as S1001), poloxamines such as Tetronic 9080E), also known Biological Evaluation (Marcel Dekker, 1994); P and D. as Poloxamine 908E), which is a tetrafunctional block Rubingh (Editor), Cationic Surfactants. Physical Chemistry copolymer derived from Sequential addition of propylene (Marcel Dekker, 1991); and J. Richmond, Cationic Surfac oxide and ethylene oxide to ethylenediamine (BASF Wyan tants. Organic Chemistry, (Marcel Dekker, 1990). dotte Corporation, Parsippany, N.J.), lysozyme, long-chain 0131 Nonpolymeric cationic surface stabilizers are any polymerS Such as alginic acid, carrageenan (FMC Corp.), nonpolymeric compound, Such as benzalkonium chloride, a and POLYOX (Dow, Midland, Mich.). carbonium compound, a phosphonium compound, an OXO 0129. Other useful cationic stabilizers include, but are not nium compound, a halonium compound, a cationic organo limited to, cationic lipids, Sulfonium, phosphonium, and metallic compound, a quarternary phosphorous compound, a quarternary ammonium compounds, Such as Stearyltrim pyridinium compound, an anilinium compound, an ammo ethylammonium chloride, benzyl-di(2-chloroethyl)ethylam nium compound, a hydroxylammonium compound, a pri monium bromide, coconut trimethyl ammonium chloride or mary ammonium compound, a Secondary ammonium com bromide, coconut methyl dihydroxyethyl ammonium chlo pound, a tertiary ammonium compound, and quarternary ride or bromide, decyl triethyl ammonium chloride, decyl ammonium compounds of the formula NRRRR"). For dimethyl hydroxyethyl ammonium chloride or bromide, compounds of the formula NRRRR"): US 2005/OOO4049 A1 Jan. 6, 2005 12

0132) (i) none of R-R are CH, 0146 Preferred surface stabilizers include, but are not limited to, Tween(E) 80, Tetronic(R) T908, dioctylsulfosucci 0133) (ii) one of R-R is CH; nate, polyvinyl acetate, Pluronic(R) F127, or a mixture 0134) (iii) three of R-R are CH; thereof. 0135 (iv) all of R-R are CH; 0147 Tween(E) 80 is polyoxyethylene Sorbitan monooleate (polyoxyethylenesorbitan monooleat). 0136 (v) two of R-R are CH, one of R-R is Tetronic(R) T908 is a tetrafunctional block copolymer CHCH, and one of R-R is an alkyl chain of derived from Sequential addition of ethylene oxide and Seven carbon atoms or less, propylene oxide to ethylene-diamine available from BASF. 0137 (vi) two of R-R are CH, one of R-R is Pluronic(R) F127, which is a poloxamer, is a difunctional CHCH, and one of R-R is an alkyl chain of block copolymer Surfactant of ethylene oxide and propylene nineteen carbon atoms or more, oxide terminating in primary hydroxyl groups and having a molecular weight of about 12,600 daltons (see 0138 (vii) two of R-R are CH and one of 0.148 http://www.basf.com/businesses/chemicals/ R-R is the group C.H. (CH), where n>1; performance/pdfs/Pluronic F127.pdf. Pluronic(R) 0139 (viii) two of R-R are CH, one of R-R F127 has the chemical formula of is CHCH, and one of R-R comprises at least PEOPPOPEO. one heteroatom; 0149 Most of these surface stabilizers are known phar 0140 (ix) two of R-R are CH, one of R-R is maceutical excipients and are described in detail in the CHCH, and one of R-R comprises at least one Handbook of pharmaceutical Excipients, published jointly halogen; by the American Pharmaceutical Association and The Phar 0141 (x) two of R-R are CH, one of R-Ris maceutical Society of Great Britain (The Pharmaceutical CHCH, and one of R-R comprises at least one Press, 2000), specifically incorporated by reference. cyclic fragment; 0150 C. Pharmaceutical Excipients 0142) (xi) two of R-R are CH, and one of R-R, 0151 Pharmaceutical compositions according to the is a phenyl ring; or invention may also comprise one or more binding agents, 0143 (xii) two of R-R are CH and two of filling agents, lubricating agents, Suspending agents, Sweet R-R are purely aliphatic fragments. eners, flavoring agents, preservatives, buffers, wetting agents, disintegrants, effervescent agents, and other excipi 0144. Such compounds include, but are not limited to, ents. Such excipients are known in the art. behenalkonium chloride, benzethonium chloride, cetylpyri dinium chloride, behentrimonium chloride, lauralkonium 0152 Examples of filling agents are lactose monohy chloride, cetalkonium chloride, cetrimonium bromide, cet drate, lactose anhydrous, and various Starches, examples of rimonium chloride, cethylamine hydrofluoride, chlorallyl binding agents are various celluloses and croSS-linked poly methenamine chloride (Quaternium-15), distearyldimonium Vinylpyrrolidone, microcrystalline cellulose, Such as chloride (Quaternium-5), dodecyl dimethyl ethylbenzyl Avice1(R) PH101 and Avicel(R) PH102, microcrystalline cel ammonium chloride(Quaternium-14), Quaternium-22, Qua lulose, and silicified microcrystalline cellulose (ProSolv temium-26, Quatemium-18 hectorite, dimethylaminoethyl SMCCTM). chloride hydrochloride, cysteine hydrochloride, diethanola mmonium POE (10) oletyl ether phosphate, 0153 Suitable lubricants, including agents that act on the diethanolammonium POE (3)oleyl ether phosphate, tallow flowability of the powder to be compressed, are colloidal alkonium chloride, dimethyl dioctadecylammoniumbento Silicon dioxide, Such as AeroSilf) 200, talc, Stearic acid, nite, Stearalkonium chloride, domiphen bromide, denato magnesium Stearate, calcium Stearate, and Silica gel. nium benzoate, myristalkonium chloride, laurtrimonium 0154) Examples of Sweeteners are any natural or artificial chloride, ethylenediamine dihydrochloride, guanidine Sweetener, Such as Sucrose, Xylitol, Sodium Saccharin, cycla hydrochloride, pyridoxine HCl, iofetamine hydrochloride, mate, aspartame, and acSulfame. Examples of flavoring meglumine hydrochloride, methylbenzethonium chloride, agents are Magnasweet(R) (trademark of MAFCO), bubble myrtrimonium bromide, oleyltrimonium chloride, gum flavor, and fruit flavors, and the like. polyguaternium-1, procainehydrochloride, cocobetaine, Stearalkonium bentonite, Stearalkoniumhectonite, Stearyl tri O155 Examples of preservatives are potassium Sorbate, hydroxyethyl propylenediamine dihydrofluoride, tallowtri methylparaben, propylparaben, benzoic acid and its Salts, monium chloride, and hexadecyltrimethyl ammonium bro other esters of parahydroxybenzoic acid Such as butylpara mide. ben, alcohols Such as ethyl or benzyl alcohol, phenolic compounds Such as phenol, or quarternary compounds Such 0145. In a preferred embodiment, the compositions of the as benzalkonium chloride. invention do not contain as a Surface Stabilizer a polyalky lene block copolymer which gels at physiological tempera 0156 Suitable diluents include pharmaceutically accept ture, and which contains one or more polyoxyethylene able inert fillers, Such as microcrystalline cellulose, lactose, blocks and one or more polyoxy (higher alkylene) blocks, dibasic calcium phosphate, Saccharides, and/or mixtures of wherein at least Some of the blocks are linked together by an any of the foregoing. Examples of diluents include micro oxymethylene group. Such compounds are described in U.S. crystalline cellulose, such as Avice1(R) PH101 and Avicel(R) Pat. No. 5,705,194. PH102; lactose Such as lactose monohydrate, lactose anhy US 2005/OOO4049 A1 Jan. 6, 2005

drous, and Pharmatose(RDCL21; dibasic calcium phosphate greater than about 2 microns, by weight, when measured by Such as Emcompress(E); mannitol, Starch, Sorbitol; Sucrose; the above-noted techniques. In other embodiments of the and glucose. invention, at least about 70%, at least about 90%, at least O157 Suitable disintegrants include lightly crosslinked about 95%, or at least about 99%, by weight, of the polyvinyl pyrrollidone, corn Starch, potato Starch, maize microparticulate griseofulvin or non-griseofulvin active Starch, and modified Starches, croScarmelloSe Sodium, croSS agent particles have a particle size greater than about 2 poVidone, Sodium Starch glycolate, and mixtures thereof. microns. 0164. In the present invention, the value for D50 of a 0158 Examples of effervescent agents are effervescent nanoparticulate griseofulvin composition is the particle size couples Such as an organic acid and a carbonate or bicar bonate. Suitable organic acids include, for example, citric, below which 50% of the griseofulvin particles fall, by tartaric, malic, fumaric, adipic, Succinic, and alginic acids weight. Similarly, D90 and D99 are the particle sizes below and anhydrides and acid Salts. Suitable carbonates and which 90% and 99%, respectively, of the griseofulvin par bicarbonates include, for example, Sodium carbonate, ticles fall, by weight. Sodium bicarbonate, potassium carbonate, potassium bicar 01.65 E. Concentration of Nanoparticulate Griseofulvin bonate, magnesium carbonate, Sodium glycine carbonate, and Surface Stabilizers L-lysine carbonate, and arginine carbonate. Alternatively, 0166 The relative amounts of griseofulvin and one or only the Sodium bicarbonate component of the effervescent more Surface Stabilizers can vary widely. The optimal couple may be present. amount of the individual components can depend, for 0159) D. Nanoparticulate Griseofulvin Particle Size example, upon the hydrophilic lipophilic balance (HLB), melting point, and the Surface tension of water Solutions of 0160 AS used herein, particle size is determined on the basis of the weight average particle size as measured by the Stabilizer, etc. conventional particle size measuring techniques well known 0.167 The concentration of griseofulvin can vary from to those skilled in the art. Such techniques include, for about 99.5% to about 0.001%, from about 95% to about example, Sedimentation field flow fractionation, photon cor 0.1%, or from about 90% to about 0.5%, by weight, based relation spectroScopy, light Scattering, and disk centrifuga on the total combined dry weight of the griseofulvin and at tion. least one Surface Stabilizer, not including other excipients. 0.161 The compositions of the invention comprise 0.168. The concentration of the at least one Surface sta griseofulvin nanoparticles which have an effective average bilizer can vary from about 0.5% to about 99.999%, from particle size of less than about 2000 nm (i.e., 2 microns), less about 5.0% to about 99.9%, or from about 10% to about than about 1900 nm, less than less than about 1800 nm, less 99.5%, by weight, based on the total combined dry weight than about 1700 nm, less than about 1600 nm, less than of the griseofulvin and at least one Surface Stabilizer, not about 1500 nm, less than about 1400 nm, less than about including other excipients. 1300 nm, less than about 1200 nm, less than about 1100 nm, 0169 III. Methods of Making Nanoparticulate Griseof less than about 1000 nm, less than about 900 nm, less than ulvin Formulations about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less 0170 The nanoparticulate griseofulvin compositions can than about 300 nm, less than about 250 nm, less than about be made using, for example, milling, homogenization, or 200 nm, less than about 150 nm, less than about 140 nm, less precipitation techniques. Exemplary methods of making than about 130 nm, less than about 120 nm, less than about nanoparticulate compositions are described in the 684 110 nm, less than about 100 nm, less than about 90 nm, less patent. Methods of making nanoparticulate compositions are than about 80 nm, less than about 70 nm, less than about 60 also described in U.S. Pat. No. 5,518,187 for “Method of nm, or less than about 50 nm, when measured by the Grinding Pharmaceutical Substances; U.S. Pat. No. 5,718, above-noted techniques. 388 for “Continuous Method of Grinding Pharmaceutical Substances; U.S. Pat. No. 5,862.999 for “Method of Grind 0162 By “an effective average particle size of less than ing Pharmaceutical Substances;” U.S. Pat. No. 5,665,331 for about 2000 nm it is meant that at least 50% of the “Co-Microprecipitation of Nanoparticulate Pharmaceutical nanoparticulate griseofulvin particles have a weight average Agents with Crystal Growth Modifiers; U.S. Pat. No. particle size less than about 2000 nm, when measured by the 5,662.883 for “Co-Microprecipitation of Nanoparticulate above-noted techniques. In other embodiments of the inven Pharmaceutical Agents with Crystal Growth Modifiers;” tion, at least about 70%, at least about 90%, at least about U.S. Pat. No. 5,560,932 for “Microprecipitation of Nano 95%, or at least about 99% of the griseofulvin particles have particulate Pharmaceutical Agents; U.S. Pat. No. 5,543,133 a particle size less than the effective average, by weight, i.e., for “Process of Preparing X-Ray Contrast Compositions less than about 2000 nm, less than about 1900 nm, less than Containing Nanoparticles;” U.S. Pat. No. 5,534.270 for less than about 1800 nm, less than about 1700 nm, etc. “Method of Preparing Stable Drug Nanoparticles; U.S. Pat. 0163) If the nanoparticulate griseofulvin composition is No. 5,510,118 for “Process of Preparing Therapeutic Com combined with a microparticulate griseofulvin or non positions Containing Nanoparticles;” and U.S. Pat. No. griseofulvin active agent composition, then Such a compo 5,470,583 for “Method of Preparing Nanoparticle Compo Sition is either Solubilized or has an effective average particle Sitions Containing Charged Phospholipids to Reduce Aggre Size greater than about 2 microns. By “an effective average gation,” all of which are specifically incorporated by refer particle size of greater than about 2 microns' it is meant that CCC. at least 50% of the microparticulate griseofulvin or non 0171 Following milling, homogenization, precipitation, griseofulvin active agent particles have a particle size etc., the resultant nanoparticulate griseofulvin composition US 2005/OOO4049 A1 Jan. 6, 2005

can be utilized in Solid or liquid dosage formulations, Such after the size reduction process. Dispersions can be manu as controlled release formulations, Solid dose fast melt factured continuously or in a batch mode. formulations, aeroSol formulations, nasal formulations, lyo philized formulations, tablets, capsules, Solid lozenge, pow 0181 IV. Methods of Using Nanoparticulate Griseofulvin ders, creams, ointments, etc. Formulations 0182. The method of the invention comprises adminis 0172 A. Milling to Obtain Nanoparticulate Griseofulvin tering to a Subject an effective amount of a composition Dispersions comprising nanoparticulate griseofulvin. The griseofulvin 0173 Milling griseofulvin to obtain a nanoparticulate compositions of the present invention can be administered to dispersion comprises dispersing griseofulvin particles in a a Subject via any conventional means including, but not liquid dispersion media in which griseofulvin is poorly limited to, orally, rectally, ocularly, parenterally (e.g., intra Soluble, followed by applying mechanical means in the venous, intramuscular, or Subcutaneous), intracistemally, presence of grinding media to reduce the particle size of pulmonary, intravaginally, intraperitoneally, locally (e.g., griseofulvin to the desired effective average particle size. powders, ointments or drops), or as a buccal or nasal spray. The dispersion media can be, for example, water, Safflower AS used herein, the term “Subject' is used to mean an oil, ethanol, t-butanol, glycerin, polyethylene glycol (PEG), animal, preferably a mammal, including a human or non hexane, or glycol. human. The terms patient and Subject may be used inter changeably. 0.174. The griseofulvin particles can be reduced in size in the presence of at least one Surface Stabilizer. Alternatively, 0183 The griseofulvin compositions of the invention can the griseofulvin particles can be contacted with one or more be used to treat dermatophyte and ringworm infections of Surface Stabilizers after attrition. Other compounds, Such as the Scalp, hair, nails (fingernails and toenails), and skin. The a diluent, can be added to the griseofulvin/Surface Stabilizer griseofulvin compositions can be used to treat Skin infec composition during the size reduction proceSS. Dispersions tions Such as jock itch, athlete's foot, and ringworm. In can be manufactured continuously or in a batch mode. particular, the griseofulvin compositions of the invention can be used to treat Tinea capitis (ringworm of the Scalp), 0175 B. Precipitation to Obtain Nanoparticulate Griseof Tinea corporis (ringworm of the body), Tinea pedis (ath ulvin Compositions lete's foot), Tinea unguium (ringworm of the nails), Tinea 0176 Another method of forming the desired nanopar cruris (ringworm of the thigh), and Tinea barbae (barber's ticulate griseofulvin composition is by microprecipitation. itch). The griseofulvin compositions of the invention can This is a method of preparing Stable dispersions of poorly also used to the following fungal infections of the hair, Skin, Soluble active agents in the presence of one or more Surface and nails: Trichophyton rubrum, Trichophyton tonsurans, Stabilizers and one or more colloid Stability enhancing Trichophyton mentagrophytes, Trichophyton interdigitalis, Surface active agents free of any trace toxic Solvents or Trichophyton verrucosum, Trichophyton Sulphureum, Tri Solubilized heavy metal impurities. Such a method com chophyton Schoenleini, Trichophyton audouini, Trichophy prises, for example: (1) dissolving griseofulvin in a Suitable ton canis, Trichophyton gypseum, Trichophyton floccosum, Solvent; (2) adding the formulation from Step (1) to a Trichophyton megnini, Trichophyton gallinae, and Tricho Solution comprising at least one Surface Stabilizer; and (3) phyton crateriform. precipitating the formulation from Step (2) using an appro 0.184 Compositions suitable for parenteral injection may priate non-solvent. The method can be followed by removal comprise physiologically acceptable Sterile aqueous or non of any formed Salt, if present, by dialysis or diafiltration and aqueous Solutions, dispersions, Suspensions or emulsions, concentration of the dispersion by conventional means. and Sterile powders for reconstitution into Sterile injectable 0177) C. Homogenization to Obtain Nanoparticulate Solutions or dispersions. Examples of Suitable aqueous and Griseofulvin Compositions nonaqueous carriers, diluents, Solvents, or vehicles includ ing water, ethanol, polyols (propyleneglycol, polyethylene 0.178 Exemplary homogenization methods of preparing glycol, glycerol, and the like), Suitable mixtures thereof, active agent nanoparticulate compositions are described in vegetable oils (Such as olive oil) and injectable organic U.S. Pat. No. 5,510,118, for “Process of Preparing Thera esterS Such as ethyl oleate. Proper fluidity can be maintained, peutic Compositions Containing Nanoparticles.” for example, by the use of a coating Such as lecithin, by the 0179 Such a method comprises dispersing griseofulvin maintenance of the required particle size in the case of particles in a liquid dispersion media in which griseofulvin dispersions, and by the use of Surfactants. is poorly Soluble, followed by Subjecting the dispersion to 0185. The nanoparticulate compositions may also contain homogenization to reduce the particle size of the griseoful adjuvants Such as preserving, wetting, emulsifying, and Vin to the desired effective average particle size. The dis dispensing agents. Prevention of the growth of microorgan persion media can be, for example, water, Safflower oil, isms can be ensured by various antibacterial and antifungal ethanol, t-butanol, glycerin, polyethylene glycol (PEG), agents, Such as parabens, chlorobutanol, phenol, Sorbic acid, hexane, or glycol. and the like. It may also be desirable to include isotonic agents, Such as Sugars, Sodium chloride, and the like. Pro 0180. The griseofulvin particles can be reduced in size in longed absorption of the injectable pharmaceutical form can the presence of at least one Surface Stabilizer. Alternatively, be brought about by the use of agents delaying absorption, the griseofulvin particles can be contacted with one or more Surface stabilizers either before or after attrition. Other Such as aluminum monoStearate and gelatin. compounds, Such as a diluent, can be added to the griseof 0186 Solid dosage forms for oral administration include, ulvin/Surface Stabilizer composition either before, during, or but are not limited to, powder aerosols, capsules, tablets, US 2005/OOO4049 A1 Jan. 6, 2005

pills, powders, and granules. In Such Solid dosage forms, the invention is not to be limited to the Specific conditions or active agent is admixed with at least one of the following: (a) details described in these examples. Throughout the Speci one or more inert excipients (or carriers), Such as Sodium fication, any and all references to a publicly available citrate or dicalcium phosphate; (b) fillers or extenders, Such document, including a U.S. patent, are specifically incorpo as Starches, lactose, Sucrose, glucose, mannitol, and Silicic rated by reference. acid; (c) binders, Such as carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, Sucrose, and acacia; (d) EXAMPLE 1. humectants, Such as glycerol; (e) disintegrating agents, Such 0.192 The purpose of this example was to prepare a as agar-agar, calcium carbonate, potato or tapioca Starch, nanoparticulate griseofulvin composition. alginic acid, certain complex Silicates, and Sodium carbon ate, (f) Solution retarders, Such as paraffin, (g) absorption 0193 5.0% (w/w) griseofulvin and 2.5% (w/w) Plu accelerators, Such as quaternary ammonium compounds, (h) ronic E F68 were combined in an aqueous media (water). wetting agents, Such as cetyl alcohol and glycerol 3.75 mLs of this mixture was then charged into a /2 oz bottle monoStearate; (ii) adsorbents, Such as kaolin and bentonite; (15 ml) for roller milling on a Bench top roller mill (U.S. and () lubricants, Such as talc, calcium Stearate, magnesium Stoneware, East Palestine, Ohio) along with 1.0 mm zirco Stearate, Solid polyethylene glycols, Sodium lauryl Sulfate, or nium oxide milling media. The griseofulvin Slurry was then mixtures thereof. For capsules, tablets, and pills, the dosage milled for 2 days. forms may also comprise buffering agents. 0194 Following milling, the D50 particle size of the 0187 Liquid dosage forms for oral administration griseofulvin particles was 617 nm, and the D90 was 1000 include pharmaceutically acceptable aerosols, emulsions, nm. Particle size was determined on the Coulter Model Solutions, Suspensions, Syrups, and elixirs. In addition to the N4MD Submicron Particle Analyzer (Coulter Corp., Miami active agent, the liquid dosage forms may comprise inert Lakes, Fla.), and using the Microtrac Ultrafine Particle diluents commonly used in the art, Such as water or other Analyzer (Leeds and Northrup Co., St. Petersburg, Fla.). Solvents, Solubilizing agents, and emulsifiers. Exemplary emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl car 0.195 This example demonstrates that nanoparticulate bonate, ethyl acetate, benzyl alcohol, benzyl benzoate, pro compositions of griseofulvin can be made. pyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, Such as cottonseed oil, groundnut oil, corn germ oil, olive EXAMPLE 2 oil, castor oil, and Sesame oil, glycerol, tetrahydrofurfuryl 0196. The purpose of this example was to prepare a alcohol, polyethyleneglycols, fatty acid esters of Sorbitan, or nanoparticulate griseofulvin composition. mixtures of these Substances, and the like. 0197) 5.0% (w/w) griseofulvin and 2.5% (w/w) Plu 0188 Besides such inert diluents, the composition can ronic E 127 were combined in an aqueous media (water). also include adjuvants, Such as wetting agents, emulsifying 3.75 mLs of this mixture was then charged into a /2 oz bottle and Suspending agents, Sweetening, flavoring, and perfum (15 mL) for roller milling on a Bench top roller mill (U.S. ing agents. Stoneware, East Palestine, Ohio) along with 1.0 mm zir 0189 One of ordinary skill will appreciate that effective conium oxide milling media. The griseofulvin Slurry was amounts of griseofulvin can be determined empirically and then milled for 5 days. can be employed in pure form or, where Such forms exist, in 0198 Following milling, the D90 particle size of the pharmaceutically acceptable Salt, ester, or prodrug form. griseofulvin particles was 464 nm. Particle Size was deter Actual dosage levels of griseofulvin in the nanoparticulate mined on the Coulter Model N4MD Submicron Particle compositions of the invention may be varied to obtain an Analyzer (Coulter Corp., Miami Lakes, Fla.), and using the amount of griseofulvin that is effective to obtain a desired Microtrac Ultrafine Particle Analyzer (Leeds and Northrup therapeutic response for a particular composition and Co., St. Petersburg, Fla.). method of administration. The Selected dosage level there fore depends upon the desired therapeutic effect, the route of 0199 This example demonstrates that nanoparticulate administration, the potency of the administered griseofulvin, compositions of griseofulvin can be made. the desired duration of treatment, and other factors. EXAMPLE 3 0.190 Dosage unit compositions may contain such 0200. The purpose of this example was to prepare a amounts of Such Submultiples thereof as may be used to pharmaceutical composition utilizing the nanoparticulate make up the daily dose. It will be understood, however, that the Specific dose level for any particular patient will depend griseofulvin composition of Example 2. upon a variety of factors: the type and degree of the cellular 0201 The nanoparticulate griseofulvin composition of or physiological response to be achieved; activity of the Example 2 was combined with pharmaceutical excipients Specific agent or composition employed; the Specific agents and carriers as shown below in Table 1. or composition employed; the age, body weight, general health, Sex, and diet of the patient; the time of administra TABLE 1. tion, route of administration, and rate of excretion of the agent; the duration of the treatment; drugs used in combi Ingredient Quantity nation or coincidental with the Specific agent; and like Griseofulvin 5.0 g factors well known in the medical arts. Pluronic F127 2.5 g. Benzoate Sodium 0.2 g 0191 The following examples are given to illustrate the Saccharin Sodium 0.1 g present invention. It should be understood, however, that the US 2005/OOO4049 A1 Jan. 6, 2005 16

TABLE 1-continued TABLE 2-continued Ingredient Quantity Weight Average FD&C Red. No. 3 0.03 g Milling Griseofulvin Water, qs 100 mL. Surface Stabilizer and Time Particle Size D80 Quantity Thereof (days) (D50) (nm) (nm) D90 (nm) 2.5% PVP K15 - 2.5% 1O 270 215 464 0202) This example demonstrates the Successful prepa DOSS ration of a pharmaceutical composition comprising a nano particulate griseofulvin composition. 0206 All of the milled compositions were tested for EXAMPLE 4 Stability in water, simulated gastric fluid (SGF), and Simu lated intestinal fluid (SIF) (SGF and SIF were prepared 0203 The purpose of this example was to prepare nano according to the USP). In addition, the stability of the milled particulate griseofulvin compositions using various Surface compositions following Storage for one week at room tem stabilizers. perature was determined. 0204 An aqueous slurry of 5% (w/w) griseofulvin and 0207. The particle morphology of griseofulvin appears to 2.5% surface stabilizer(s) in water was prepared. The Sur be spherical in nature when observed by light microscopy. face stabilizer(s) are identified in Table 2, below. 3.75 mLS 0208 Based on the above data, and the lack of aggrega of each slurry was then charged into a % oz bottle (15 mL) tion in fluid stability tests and stable one week shelf stabili for roller milling on a Bench top roller mill (U.S. Stoneware, ties, the following Surface Stabilizers for Nanoparticulate East Palestine, Ohio) along with 1.0 mm zirconium oxide griseofulvin are preferred: milling media. Each slurry was then milled for the time period shown in Table 2. 0209 (1) Tween(E) 80: This surface stabilizer is Generally Recognized as Safe (GRAS) (see “Inac 0205 Following completion of milling, the average par tive Ingredient Guide, Division of Drug Information ticle Size, by weight, of the griseofulvin was determined. In Resources Food and Drug Administration, Center for addition, the D80 and/or D90 griseofulvin particle sizes Drug Evaluation and Research, Office of Manage were determined. Particle size was determined on the ment, January 1996). In addition, nanoparticulate Coulter Model N4MD Submicron Particle Analyzer griseofulvin compositions utilizing this Surface Sta (Coulter Corp., Miami Lakes, Fla.), and using the Microtrac bilizer exhibited Small size particles and were stable Ultrafine Particle Analyzer (Leeds and Northrup Co., St. in water, Simulated gastric fluid, and Simulated intes Petersburg, Fla.). tinal fluid; TABLE 2 0210 (2) Tetronic(R) T908: This surface stabilizer is GRAS, and nanoparticulate griseofulvin composi Weight tions utilizing this Surface Stabilizer exhibited Small Average Milling Griseofulvin Size particles and were stable in water, Simulated Surface Stabilizer and Time Particle Size D80 gastric fluid, and Simulated intestinal fluid; and Quantity Thereof (days) (D50) (nm) (nm) D90 (nm) 0211 (3) Dioctylsulfosuccinate: This surface stabi 2.5% polyvinyl acetate 2 459 464 lizer is GRAS, and nanoparticulate griseofulvin 70-100K (PVA) compositions utilizing this Surface Stabilizer exhib 2.5% PVA 70-1OOK+ 1O 276 215 464 2.5% dioctylsulfosuccinate ited Small size particles and were Stable in water, (DOSS) Simulated gastric fluid, and Simulated intestinal fluid. 2.5% DOSS 2 225 215 2.5% DOSS 2.5% DOSS 1O 224 215 464 0212 Less preferred but still useful are nanoparticulate 2.5%. Tetronic (E) 908 2 101 OO griseofulvin compositions comprising as a Surface Stabilizer 2.5%. Tetronic (E) 908 + 1O 310 464 polyvinyl acetate or Pluronic(R) 127. 2.5% DOSS 2.5% Pluronic (R) F127 5 519 464 0213 The following surface stabilizers performed poorly 2.5% Pluronic (R) F127- 1O 309 2150 during the milling assay, and exhibited poor Stability in 2.5% DOSS 2.5% tyloxapol 5 492 215 464 water, Simulated gastric fluid, and/or Simulated intestinal 2.5% tyloxapol + 2.5% 6 279 215 464 fluid: DOSS 2.5% Tween (E) 80 6 290 215 464 0214) (1) Pharmacoat(R) 603: Abimodal griseofulvin 2.5% Tween (E) 80+ 6 282 215 464 particle size distribution and large griseofulvin par 2.5% DOSS ticles were observed; 2.5%, Pharmacoat (E) 603 6 77.5 10,000 2.5%, Pharmacoat (E) 603 + 2 4.38 464 1OOO 2.5% DOSS 0215 (2) Pluronic(R) F68: A bimodal griseofulvin 2.5% Pluronic (R) F68 6 617 1OOO particle size distribution was observed; 2.5% Pluronic (R) F68 + 2 864 10,000 2.5% DOSS 0216 (3) Ponlyvinylpyrrollidone: The griseofulvin 2.5% Polyvinylpyrrollidone 2 455 10,000 composition comprising PVP as a Surface Stabilizer K15 (PVP) exhibited poor Stability in water, Simulated gastric fluid, and Simulated intestinal fluid; and US 2005/OOO4049 A1 Jan. 6, 2005

0217 (4) Tyloxapol: The griseofulvin composition 7. The composition of claim 1, wherein the composition comprising tyloxapol as a Surface Stabilizer exhib further comprises one or more pharmaceutically acceptable ited poor Stability in water, Simulated gastric fluid, excipients, carriers, or a combination thereof. and Simulated intestinal fluid. 8. The composition of claim 1, wherein griseofulvin or a 0218 While the latter four surface stabilizers were not Salt thereof is present in an amount Selected from the group Successful in producing a stable nanoparticulate griseofulvin consisting of from about 99.5% to about 0.001%, from about 95% to about 0.1%, and from about 90% to about 0.5%, by composition in this experiment, the Surface Stabilizers may weight, based on the total combined dry weight of the be useful at different concentrations of griseofulvin or griseofulvin or a Salt thereof and at least one Surface Surface Stabilizer, or when used in combination with one or Stabilizer, not including other excipients. more other Surface Stabilizers. 9. The composition of claim 1, wherein the at least one 0219. It will be apparent to those skilled in the art that Surface Stabilizer is present in an amount Selected from the various modifications and variations can be made in the group consisting of from about 0.5% to about 99.999% by methods and compositions of the present invention without weight, from about 5.0% to about 99.9% by weight, and departing from the Spirit or Scope of the invention. Thus, it from about 10% to about 99.5% by weight, based on the is intended that the present invention cover the modifications total combined dry weight of the griseofulvin or a Salt and variations of this invention provided they come within thereof and at least one Surface Stabilizer, not including other the Scope of the appended claims and their equivalents. excipients. 10. The composition of claim 1, comprising at least two We claim: Surface Stabilizers. 1. A composition comprising: 11. The composition of claim 1, wherein the surface (a) particles of griseofulvin or a Salt thereof, wherein the Stabilizer is Selected from the group consisting of an anionic griseofulvin particles have an effective average particle Surface Stabilizer, a cationic Surface Stabilizer, a Zwitterionic size of less than about 2000 nm, and Surface Stabilizer, and an ionic Surface Stabilizer. 12. The composition of claim 11, wherein the at least one (b) at least one Surface Stabilizer, wherein the Surface Surface Stabilizer is Selected from the group consisting of Stabilizer is not a polyalkylene block copolymer which cetyl pyridinium chloride, gelatin, casein, phosphatides, gels at physiological temperature, and which contains dextran, glycerol, gum acacia, cholesterol, tragacanth, one or more polyoxyethylene blocks and one or more Stearic acid, benzalkonium chloride, calcium Stearate, glyc polyoxy (higher alkylene) blocks, wherein at least erol monoStearate, cetoStearyl alcohol, cetomacrogol emul Some of the blocks are linked together by an oxymeth Sifying wax, Sorbitan esters, polyoxyethylene alkyl ethers, ylene group. polyoxyethylene castor oil derivatives, polyoxyethylene Sor 2. The composition of claim 1, wherein the griseofulvin is bitan fatty acid esters, polyethylene glycols, dodecyl trim Selected from the group consisting of a crystalline phase, an ethyl ammonium bromide, polyoxyethylene Stearates, col amorphous phase, a Semi-crystalline phase, a Semi-amor loidal Silicon dioxide, phosphates, Sodium dodecylsulfate, phous phase, and mixtures thereof. carboxymethylcellulose calcium, hydroxypropyl celluloses, 3. The composition of claim 1, wherein the effective hypromellose, carboxymethylcellulose Sodium, methylcel average particle Size of the griseofulvin particles is Selected lulose, hydroxyethylcellulose, hypromellose phthalate, non from the group consisting of less than about 1900 nm, leSS crystalline cellulose, magnesium aluminum Silicate, trietha than about 1800 nm, less than about 1700 nm, less than nolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1, about 1600 rum, less than about 1500 nm, less than about 3,3-tetramethylbutyl)-phenol polymer with ethylene oxide 1400 nm, less than about 1300 nm, less than about 1200 nm, and formaldehyde, poloxamers, poloxamines, a charged less than about 1100 nm, less than about 1000 nm, less than phospholipid, dioctylsulfoSuccinate, dialkylesters of Sodium about 900 nm, less than about 800 nm, less than about 700 SulfoSuccinic acid, Sodium lauryl Sulfate, alkyl aryl poly nm, less than about 600 nm, less than about 500 nm, less ether Sulfonates, mixtures of Sucrose Stearate and Sucrose than about 400 nm, less than about 300 nm, less than about distearate, p-isononylphenoxypoly-(glycidol), decanoyl-N- 250 nm, less than about 200 nm, less than about 100 nm, less methylglucamide; n-decyl B-D-glucopyranoside; n-decyl than about 75 nm, and less than about 50 nm. f-D-maltopyranoside; n-dodecyl 3-D-glucopyranoside; 4. The composition of claim 1, wherein the composition n-dodecyl B-D-maltoside, heptanoyl-N-methylglucamide; is formulated for administration Selected from the group n-heptyl-B-D-glucopyranoside; n-heptyl B-D-thioglucoside; consisting of oral, pulmonary, rectal, opthalmic, colonic, n-hexyl,f-D-glucopyranoside; nonanoyl-N-methylglucam parenteral, intracisternal, intravaginal, intraperitoneal, local, ide; n-noyl B-D-glucopyranoSide; octanoyl-N-methylgluca buccal, nasal, and topical administration. mide; n-octyl-B-D-glucopyranoside; octyl f-D-thioglu 5. The composition of claim 1 formulated into a dosage copyranoside; lysozyme, PEG-phospholipid, PEG form Selected from the group consisting of liquid disper cholesterol, PEG-cholesterol derivative, PEG-vitamin A, Sions, oral Suspensions, gels, aerosols, ointments, creams, and random copolymers of Vinyl acetate and vinyl pyrroli tablets, capsules, Sachets, lozenges, powders, pills, and done. granules. 13. The composition of claim 11, wherein the at least one 6. The composition of claim 1 formulated into a dosage cationic Surface Stabilizer is Selected from the group con form Selected from the group consisting of controlled release Sisting of a polymer, a biopolymer, a polysaccharide, a formulations, fast melt formulations, lyophilized formula cellulosic, an alginate, a nonpolymeric compound, and a tions, delayed release formulations, extended release formu phospholipid. lations, pulsatile release formulations, and mixed immediate 14. The composition of claim 11, wherein the surface release and controlled release formulations. Stabilizer is Selected from the group consisting of cationic US 2005/OOO4049 A1 Jan. 6, 2005 lipids, polymethylmethacrylate trimethylammonium bro 18. The composition of claim 1, additionally comprising mide, Sulfonium compounds, polyvinylpyrrollidone-2-dim one or more non-griseofulvin active agents. ethylaminoethyl methacrylate dimethyl Sulfate, hexadecyl 19. The composition of claim 18, wherein said additional trimethyl ammonium bromide, phosphonium compounds, one or more non-griseofulvin active agents are Selected from quarternary ammonium compounds, benzyl-di(2-chloroeth the group consisting of nutraceuticals, amino acids, proteins, yl)ethylammonium bromide, coconut trimethyl ammonium peptides, nucleotides, anti-obesity drugs, central nervous chloride, coconut trimethyl ammonium bromide, coconut System Stimulants, carotenoids, corticosteroids, elastase methyl dihydroxyethyl ammonium chloride, coconut methyl inhibitors, anti-fungals, oncology therapies, anti-emetics, dihydroxyethyl ammonium bromide, decyl triethyl ammo analgesics, cardiovascular agents, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics, antico nium chloride, decyl dimethyl hydroxyethyl ammonium agulants, antidepressants, antidiabetic agents, antiepileptics, chloride, decyl dimethyl hydroxyethyl ammonium chloride antihistamines, antihypertensive agents, antimuscarinic bromide, C2-s dimethyl hydroxyethyl ammonium chloride, agents, antimycobacterial agents, antineoplastic agents, Cs dimethyl hydroxyethyl ammonium chloride bromide, immunosuppressants, antithyroid agents, antiviral agents, coconut dimethyl hydroxyethyl ammonium chloride, coco anxiolytics, Sedatives, astringents, alpha-adrenergic receptor nut dimethyl hydroxyethyl ammonium bromide, myristyl blocking agents, beta-adrenoceptor blocking agents, blood trimethyl ammonium methyl Sulphate, lauryl dimethylben products, blood Substitutes, cardiac inotropic agents, con Zyl ammonium chloride, lauryl dimethylbenzyl ammonium trast media, corticosteroids, cough Suppressants, diagnostic bromide, lauryl dimethyl(ethenoxy) ammonium chloride, agents, diagnostic imaging agents, diuretics, dopaminergics, lauryl dimethyl(ethenoxy) ammonium bromide, haemostatics, immunological agents, lipid regulating agents, N-alkyl(Cs)dimethylbenzyl ammonium chloride, muscle relaxants, parasympathomimetics, parathyroid cal N-alkyl(Cs)dimethyl-benzyl ammonium chloride, N-tet citonin, parathyroid biphosphonates, prostaglandins, radio radecylidmethylbenzyl ammonium chloride monohydrate, pharmaceuticals, SeX hormones, anti-allergic agents, Stimu dimethyl didecyl ammonium chloride, N-alkyl and (C- lants, anoretics, Sympathomimetics, thyroid agents, 14)dimethyl 1-naphthylmethyl ammonium chloride, trim vasodilators, and Xanthines. ethylammonium halide, alkyl-trimethylammonium Salts, 20. The composition of claim 18, wherein said at least one dialkyl-dimethylammonium Salts, lauryl trimethyl ammo additional non-griseofulvin active agent is an anti-fungal nium chloride, ethoxylated alkyamidoalkyldialkylammo agent. nium Salt, an ethoxylated trialkyl ammonium Salt, dialkyl 21. The composition of claim 18, wherein said at least one benzene dialkylammonium chloride, N-didecyldimethyl additional non-griseofulvin active agent is vitamin E. ammonium chloride, N-tetradecyldimethylbenzyl ammo 22. The composition of claim 1, wherein upon adminis nium, chloride monohydrate, N-alkyl (C1-)dimethyl tration to a mammal the griseofulvin particles redisperse 1-naphthylmethyl ammonium chloride, dodecyldimethyl Such that the particles have an effective average particle size benzyl ammonium chloride, dialkyl benzenealkyl ammo of less than about 2 microns. nium chloride, lauryl trimethyl ammonium chloride, alkyl 23. The composition of claim 22, wherein upon admin benzyl methyl ammonium chloride, alkylbenzyl dimethyl istration the composition redisperses Such that the griseof ammonium bromide, C trimethyl ammonium bromides, ulvin particles have an effective average particle size C. trimethyl ammonium bromides, C17 trimethyl ammo selected from the group consisting of less than about 1900 nium bromides, dodecylbenzyl triethyl ammonium chloride, nm, less than about 1800 nm, less than about 1700 nm, less poly-diallyldimethylammonium chloride (DADMAC), dim than about 1600 nm, less than about 1500 nm, less than ethyl ammonium chlorides, alkyldimethylammonium halo about 1400 nm, less than about 1300 nm, less than about genides, tricetyl methyl ammonium chloride, decyltrimethy 1200 nm, less than about 1100 nm, less than about 1000 nm, lammonium bromide, dodecyltriethylammonium bromide, less than about 900 nm, less than about 800 nm, less than tetradecyltrimethylammonium bromide, methyl trioctylam about 700 nm, less than about 600 nm, less than about 500 monium chloride, POLYOUAT 10TM, tetrabutylammonium nm, less than about 400 nm, less than about 300 nm, less bromide, benzyl trimethylammonium bromide, choline than about 250 nm, less than about 200 nm, less than about esters, benzalkonium chloride, Stearalkonium chloride com 150 nm, less than about 100 nm, less than about 75 nm, and pounds, cetyl pyridinium bromide, cetyl pyridinium chlo less than about 50 nm. ride, halide Salts of quaternized polyoxyethylalkylamines, 24. The composition of claim 1, wherein the composition MIRAPOLTM, ALKAQUATTM, alkyl pyridinium salts; redisperses in a biorelevant media Such that the griseofulvin amines, amine Salts, amine oxides, imide azolinium Salts, particles have an effective average particle size of less than protonated quaternary acrylamides, methylated quaternary about 2 microns. polymers, and cationic guar. 25. The composition of claim 24, wherein the biorelevant 15. The composition of any of claims 11, 13, or 14, media is Selected from the group consisting of water, acque wherein the composition is bioadhesive. ous electrolyte Solutions, aqueous Solutions of a Salt, aque 16. The composition of claim 1, comprising as a Surface ous Solutions of an acid, aqueous Solutions of a base, and stabilizer Tween(& 80, Tetronic(R) T908, dioctylsulfosucci combinations thereof. nate, polyvinyl acetate, Pluronic(R) F127, or a mixture 26. The composition of claim 24, wherein the composi thereof. tion redisperses in a biorelevant media Such that the griseof 17. The composition of claim 1, further comprising at ulvin particles have an effective average particle size least one additional griseofulvin composition having an selected from the group consisting of less than about 1900 effective average particle size which is different that the nm, less than about 1800 nm, less than about 1700 nm, less effective average particle size of the griseofulvin composi than about 1600 nm, less than about 1500 nm, less than tion of claim 1. about 1400 nm, less than about 1300 nm, less than about US 2005/OOO4049 A1 Jan. 6, 2005

1200 nm, less than about 1100 nm, less than about 1000 nm, Selected from the group consisting of less than about 100%, less than about 900 nm, less than about 800 nm, less than less than about 90%, less than about 80%, less than about about 700 nm, less than about 600 nm, less than about 500 70%, less than about 60%, less than about 50%, less than nm, less than about 400 nm, less than about 300 nm, less about 40%, less than about 30%, less than about 25%, less than about 250 nm, less than about 200 nm, less than about than about 20%, less than about 15%, less than about 10%, 150 nm, less than about 100 nm, less than about 75 nm, and less than about 5%, and less than about 3%. less than about 50 nm. 35. The composition of claim 1, wherein administration of 27. The composition of claim 1, wherein the T of the the composition to a human in a fasted State is bioeduivalent griseofulvin, when assayed in the plasma of a mammalian to administration of the composition to a Subject in a fed Subject following administration, is less than the T for a non-nanoparticulate griseofulvin formulation, administered State. at the same dosage. 36. The composition of claim 35, wherein “bioeduiva 28. The composition of claim 27, wherein the T is lency” is established by a 90% Confidence Interval of Selected from the group consisting of not greater than about between 0.80 and 1.25 for both C and AUC. 90%, not greater than about 80%, not greater than about 37. The composition of claim 35, wherein “bioeduiva 70%, not greater than about 60%, not greater than about lency” is established by a 90% Confidence Interval of 50%, not greater than about 30%, not greater than about between 0.80 and 1.25 for AUC and a 90%. Confidence 25%, not greater than about 20%, not greater than about Interval of between 0.70 to 1.43 for C 15%, not greater than about 10%, and not greater than about 38. The composition of claim 1 formulated into a liquid 5% of the T exhibited by a non-nanoparticulate griseo dosage form, wherein the dosage form has a Viscosity of leSS fuilvin formulation, administered at the same dosage. than about 2000 mPa.s, measured at 20° C., at a shear rate 29. The composition of claim 1, wherein the C of the of 0.1 (1/s). griseofilvin, when assayed in the plasma of a mammalian 39. The composition of claim 38, having a viscosity at a Subject following administration, is greater than the C for shear rate of 0.1 (1/s), measured at 20° C., selected from the a non-nanoparticulate griseofulvin formulation, adminis group consisting of from about 2000 mPa.S to about 1 mpa.S, tered at the same dosage. from about 1900 mPa.s. to about 1 mPa.s, from about 1800 30. The composition of claim 29, wherein the C is mPa.S to about 1 mPa.s, from about 1700 mPa.S to about 1 Selected from the group consisting of at least about 50%, at mPa.s, from about 1600 mPa.S to about 1 mPa.s, from about least about 100%, at least about 200%, at least about 300%, 1500 mPa.s to about 1 mPa.s, from about 1400 mPas to at least about 400%, at least about 500%, at least about about 1 mPa.s, from about 1300 mPa.S to about 1 mPa.s, 600%, at least about 700%, at least about 800%, at least from about 1200 mPa.S to about 1 mPa.s, from about 1100 about 900%, at least about 1000%, at least about 1100%, at mPa.s to about 1 mPa.s, from about 1000 mpFs to about 1 least about 1200%, at least about 1300%, at least about mPa.s, from about 900 mPa.S to about 1 mPa.s, from about 1400%, at least about 1500%, at least about 1600%, at least 800 mPa.s. to about 1 mPa.s, from about 700 mPas to about about 1700%, at least about 1800%, or at least about 1900% 1 mPa.s, from about 600 mPa.S to about 1 mPa.s, from about greater than the C exhibited by a non-nanoparticulate 500 mPa.S to about 1 mPa.s, from about 400 mPa.S to about formulation of griseofulvin, administered at the same doS 1 mPa.s, from about 300 mPa.S to about 1 mPa.s, from about age. 200 mPa.S to about 1 mPa.s, from about 175 mPa.S to about 31. The composition of claim 1, wherein the AUC of the 1 mPa.s, from about 150 mPa.S to about 1 mPa.s, from about griseofulvin, when assayed in the plasma of a mammalian 125 mPa.S to about 1 mPa.s, from about 100 mPa.S to about Subject following administration, is greater than the AUC for 1 mPa.s, from about 75 mPa.S to about 1 mPa.s, from about a non-nanoparticulate griseofulvin formulation, adminis 50 mPa.S to about 1 mPa.s, from about 25 mPa.S to about tered at the same dosage. 1 mPa.s, from about 15 mPa is to about 1 mPa.s, from about 32. The composition of claim 31, wherein the AUC is 10 mPa.S to about 1 mPa.s, and from about S mPa.S to about Selected from the group consisting of at least about 25%, at 1 mPa...S. least about 50%, at least about 75%, at least about 100%, at 40. The composition of claim 38, wherein the viscosity of least about 125%, at least about 150%, at least about 175%, the dosage form is Selected from the group consisting of leSS at least about 200%, at least about 225%, at least about than about /200, less than about /100, less than about /50, leSS 250%, at least about 275%, at least about 300%, at least than about 1/35, and less than about /10 of the viscosity of a about 350%, at least about 400%, at least about 450%, at liquid dosage form of a non-nanoparticulate composition of least about 500%, at least about 550%, at least about 600%, griseofulvin, at about the same concentration per ml of at least about 750%, at least about 700%, at least about griseoftilvin. 750%, at least about 800%, at least about 850%, at least 41. The composition of claim 38, wherein the viscosity of about 900%, at least about 950%, at least about 1000%, at the dosage form is Selected from the group consisting of leSS least about 1050%, at least about 1100%, at least about than about 5%, less than about 10%, less than about 15%, 1150%, or at least about 1200% greater than the AUC less than about 20%, less than about 25%, less than about exhibited by the non-nanoparticulate formulation of griseof 30%, less than about 35%, less than about 40%, less than ulvin, administered at the same dosage. about 45%, less than about 50%, less than about 55%, less 33. The composition of claim 1 which does not produce than about 60%, less than about 65%, less than about 70%, Significantly different absorption levels when administered less than about 75%, less than about 80%, less than about under fed as comPared to fasting conditions. 85%, and less than about 90% of the viscosity of a liquid 34. The composition of claim 33, wherein the difference dosage form of a non-nanoparticulate composition of in absorption of the griseofulvin composition of the inven griseoftilvin, at about the same concentration per ml of tion, when administered in the fed versus the fasted State, is griseofulvin. US 2005/OOO4049 A1 Jan. 6, 2005

42. A method of making a griseofulvin composition weight of the griseofulvin or a Salt thereof and at least one comprising contacting particles of griseofulvin or a Salt Surface Stabilizer, not including other excipients. thereof with at least one Surface stabilizer for a time and 53. The method of claim 42, utilizing at least two surface under conditions Sufficient to provide a griseofulvin com stabilizers. position having an effective average particle size of less than 54. The method of claim 42, wherein the Surface stabilizer about 2000 nm, wherein the Surface stabilizer is not a is Selected from the group consisting of an anionic Surface polyalkylene block copolymer which gels at physiological Stabilizer, a cationic Surface Stabilizer, a Zwitterionic Surface temperature, and which contains one or more polyoxyeth Stabilizer, and an ionic Surface Stabilizer. ylene blocks and one or more polyoxy (higher alkylene) 55. The method of claim 54, wherein the at least one blocks, wherein at least Some of the blocks are linked Surface Stabilizer is Selected from the group consisting of together by an oxymethylene group. cetyl pyridinium chloride, gelatin, casein, phosphatides, 43. The method of claim 42, wherein said contacting dextran, glycerol, gum acacia, cholesterol, tragacanth, comprises grinding. Stearic acid, benzalkonium chloride, calcium Stearate, glyc 44. The method of claim 43, wherein said grinding erol monoStearate, cetoStearyl alcohol, cetomacrogol emul comprises wet grinding. Sifying wax, Sorbitan esters, polyoxyethylene alkyl ethers, 45. The method of claim 42, wherein said contacting polyoxyethylene castor oil derivatives, polyoxyethylene Sor comprises homogenizing. bitan fatty acid esters, polyethylene glycols, dodecyl trim 46. The method of claim 42, wherein said contacting ethyl ammonium bromide, polyoxyethylene Stearates, col comprises: loidal Silicon dioxide, phosphates, Sodium dodecylsulfate, carboxymethylcellulose calcium, hydroxypropyl celluloses, (a) dissolving the particles of a griseofulvin or a salt hypromellose, carboxymethylcellulose Sodium, methylcel thereof in a Solvent; lulose, hydroxyethylcellulose, hypromellose phthalate, non (b) adding the resulting griseofulvin Solution to a Solution crystalline cellulose, magnesium aluminum Silicate, trietha comprising at least one Surface Stabilizer; and nolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1, 3,3-tetramethylbutyl)-phenol polymer with ethylene oxide (c) precipitating the Solubilized griseofulvin having at and formaldehyde, poloxamers, poloxamines, a charged least one Surface Stabilizer adsorbed on the Surface phospholipid, dioctylsulfoSuccinate, dialkylesters of Sodium thereof by the addition thereto of a non-solvent. SulfoSuccinic acid, Sodium lauryl Sulfate, alkyl aryl poly 47. The method of claim 42, wherein the griseofulvin or ether Sulfonates, mixtures of Sucrose Stearate and Sucrose a Salt thereof is Selected from the group consisting of a distearate, p-isononylphenoxypoly-(glycidol), decanoyl-N- crystalline phase, an amorphous phase, a Semi-crystalline methylglucamide; n-decyl B-D-glucopyranoside; n-decyl phase, a Semi-amorphous phase, and mixtures thereof. B-D-maltopyranoside; n-dodecyl B-D-glucopyranoside; 48. The method of claim 42, wherein the effective average n-dodecyl 3-D-maltoside; heptanoyl-N-methylglucamide; particle size of the griseofulvin particles is Selected from the n-heptyl-B-D-glucopyranoside; n-heptyl B-D-thioglucoside; group consisting of less than about 1900 nm, less than about n-hexyl B-D-glucopyranoside; nonanoyl-N-methylglucam 1800 nm, less than about 1700 nm, less than about 1600 nm, ide; n-noyl B-D-glucopyranoSide; octanoyl-N-methylgluca less than about 1500 nm, less than about 1000 nm, less than mide; n-octyl-B-D-glucopyranoside; octyl B-D-thioglucopy about 1400 nm, less than about 1300 nm, less than about ranoside; lysozyme, PEG-phospholipid, PEG-cholesterol, 1200 nm, less than about 1100 nm, less than about 900 nm, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin less than about 800 nm, less than about 700 nm, less than E, and random copolymers of vinyl acetate and Vinyl pyr about 600 nm, less than about 500 nm, less than about 400 rolidone. nm, less than about 300 nm, less than about 250 nm, less 56. The method of claim 54, wherein the at least one than about 200 nm, less than about 100 nm, less than about cationic Surface Stabilizer is Selected from the group con 75 nm, and less than about 50 nm. Sisting of a polymer, a biopolymer, a polysaccharide, a 49. The method of claim 42, wherein the composition is cellulosic, an alginate, a nonpolymeric compound, and a formulated for administration Selected from the group con phospholipid. Sisting of oral, pulmonary, rectal, opthalmic, colonic, 57. The method of claim 54, wherein the Surface stabilizer parenteral, intracistemal, intravaginal, intraperitoneal, local, is Selected from the group consisting of cationic lipids, buccal, nasal, and topical administration. polymethylmethacrylate trimethylammonium bromide, Sul 50. The method of claim 42, wherein the composition fonium compounds, polyvinylpyrrollidone-2-dimethylami further comprises one or more pharmaceutically acceptable noethyl methacrylate dimethyl sulfate, hexadecyltrimethyl excipients, carriers, or a combination thereof. ammonium bromide, phosphonium compounds, quarternary 51. The method of claim 42, wherein griseofulvin or a salt ammonium compounds, benzyl-di(2-chloroethyl)ethylam thereof is present in an amount Selected from the group monium bromide, coconut trimethyl ammonium chloride, consisting of from about 99.5% to about 0.001%, from about coconut trimethyl ammonium bromide, coconut methyl 95% to about 0.1%, and from about 90% to about 0.5%, by dihydroxyethyl ammonium chloride, coconut methyl dihy weight, based on the total combined dry weight of the droxyethyl ammonium bromide, decyl triethyl ammonium griseofulvin or a Salt thereof and at least one Surface chloride, decyl dimethyl hydroxyethyl ammonium chloride, Stabilizer, not including other excipients. decyl dimethyl hydroxyethyl ammonium chloride bromide, 52. The method of claim 42, wherein the at least one C-dimethyl hydroxyethyl ammonium chloride, C Surface Stabilizer is present in an amount Selected from the 15 dimethyl hydroxyethyl ammonium chloride bromide, group consisting of from about 0.5% to about 99.999%, coconut dimethyl hydroxyethyl ammonium chloride, coco from about 5.0% to about 99.9%, and from about 10% to nut dimethyl hydroxyethyl ammonium bromide, myristyl about 99.5% by weight, based on the total combined dry trimethyl ammonium methyl Sulphate, lauryl dimethylben US 2005/OOO4049 A1 Jan. 6, 2005

Zyl ammonium chloride, lauryl dimethylbenzyl ammonium about 1300 nm, less than about 1200 nm, less than about bromide, lauryl dimethyl(ethenoxy) ammonium chloride, 1100 nm, less than about 1000 nm, less than about 900 nm, lauryl dimethyl(ethenoxy) ammonium bromide, less than about 800 nm, less than about 700 nm, less than N-alkyl(Cs)dimethylbenzyl ammonium chloride, about 600 nm, less than about 500 nm, less than about 400 N-alkyl(Cs)dimethyl-benzyl ammonium chloride, N-tet nm, less than about 300 nm, less than about 250 nm, less radecylidmethylbenzyl ammonium chloride monohydrate, than about 200 nm, less than about 100 nm, less than about dimethyl didecyl ammonium chloride, N-alkyl and (C- 75 nm, and less than about 50 nm. 14)dimethyl 1-naphthylmethyl ammonium chloride, trim 63. The method of claim 60, wherein the composition is ethylammonium halide, alkyl-trimethylammonium Salts, formulated for administration Selected from the group con dialkyl-dimethylammonium Salts, lauryl trimethyl ammo Sisting of oral, pulmonary, rectal, opthalmic, colonic, nium chloride, ethoxylated alkyamidoalkyldialkylammo parenteral, intracisternal, intravaginal, intraperitoneal, local, nium Salt, an ethoxylated trialkyl ammonium Salt, dialkyl buccal, nasal, and topical administration. benzene dialkylammonium chloride, N-didecyldimethyl 64. The method of claim 60, wherein the composition is ammonium chloride, N-tetradecyldimethylbenzyl ammo a dosage form Selected from the group consisting of liquid nium, chloride monohydrate, N-alkyl (C2-)dimethyl dispersions, oral Suspensions, gels, aeroSols, ointments, 1-naphthylmethyl ammonium chloride, dodecyldimethyl creams, controlled release formulations, fast melt formula benzyl ammonium chloride, dialkyl benzenealkyl ammo tions, lyophilized formulations, tablets, capsules, delayed nium chloride, lauryl trimethyl ammonium chloride, alkyl release formulations, extended release formulations, pulsa benzyl methyl ammonium chloride, alkylbenzyl dimethyl tile release formulations, and mixed immediate release and ammonium bromide, C2 trimethyl ammonium bromides, controlled release formulations. C. trimethyl ammonium bromides, C17 trimethyl ammo 65. The method of claim 60, wherein the composition nium bromides, dodecylbenzyl triethyl ammonium chloride, further comprises one or more pharmaceutically acceptable poly-diallyldimethylammonium chloride (DADMAC), dim excipients, carriers, or a combination thereof. ethyl ammonium chlorides, alkyldimethylammonium halo 66. The method of claim 60, wherein griseofulvin or a salt genides, tricetyl methyl ammonium chloride, decyltrimethy thereof is present in an amount Selected from the group lammonium bromide, dodecyltriethylammonium bromide, consisting of from about 99.5% to about 0.001%, from about tetradecyltrimethylammonium bromide, methyl trioctylam 95% to about 0.1%, and from about 90% to about 0.5%, by monium chloride, POLYOUAT 10TM, tetrabutylammonium weight, based on the total combined dry weight of the bromide, benzyl trimethylammonium bromide, choline griseofulvin or a salt thereof and at least one Surface esters, benzalkonium chloride, Stearalkonium chloride com Stabilizer, not including other excipients. pounds, cetyl pyridinium bromide, cetyl pyridinium chlo 67. The method of claim 60, wherein the at least one ride, halide Salts of quaternized polyoxyethylalkylamines, Surface Stabilizer is present in an amount Selected from the MIRAPOLTM, ALKAQUATTM, alkyl pyridinium salts; group consisting of from about 0.5% to about 99.999% by amines, amine Salts, amine oxides, imide azolinium Salts, weight, from about 5.0% to about 99.9% by weight, and protonated quaternary acrylamides, methylated quaternary from about 10% to about 99.5% by weight, based on the polymers, and cationic guar. total combined dry weight of the griseofulvin or a Salt 58. The method of any of claims 54,56, or 57, wherein the thereof and at least one Surface Stabilizer, not including other composition is bioadhesive. excipients. 59. The method of claim 42, comprising as a surface 68. The method of claim 60, utilizing at least two surface stabilizer Tween(E) 80, Tetronic(R) T908, dioctylsulfosucci stabilizers. nate, polyvinyl acetate, Pluronic(R) 127, or a mixture thereof. 69. The method of claim 60, wherein the Surface stabilizer 60. A method of treating a Subject in need comprising is Selected from the group consisting of an anionic Surface administering to the Subject an effective amount of a com Stabilizer, a cationic Surface Stabilizer, a Zwitterionic Surface position comprising: Stabilizer, and an ionic Surface Stabilizer. (a) particles of a griseofulvin or a Salt thereof, wherein the 70. The method of claim 69, wherein the at least one griseofulvin particles have an effective average particle Surface Stabilizer is Selected from the group consisting of size of less than about 2000 nm, and cetyl pyridinium chloride, gelatin, casein, phosphatides, dextran, glycerol, gum acacia, cholesterol, tragacanth, (b) at least one Surface Stabilizer, wherein the Surface Stearic acid, benzalkonium chloride, calcium Stearate, glyc Stabilizer is not a polyalkylene block copolymer which erol monoStearate, cetoStearyl alcohol, cetomacrogol emul gels at physiological temperature, and which contains Sifying wax, Sorbitan esters, polyoxyethylene alkyl ethers, one or more polyoxyethylene blocks and one or more polyoxyethylene castor oil derivatives, polyoxyethylene Sor polyoxy (higher alkylene) blocks, wherein at least bitan fatty acid esters, polyethylene glycols, dodecyl trim Some of the blocks are linked together by an oxymeth ethyl ammonium bromide, polyoxyethylene Stearates, col ylene group. loidal Silicon dioxide, phosphates, Sodium dodecylsulfate, 61. The method of claim 60, wherein the griseofulvin or carboxymethylcellulose calcium, hydroxypropyl celluloses, a Salt thereof is Selected from the group consisting of a hypromellose, carboxymethylcellulose Sodium, methylcel crystalline phase, an amorphous phase, a Semi-crystalline lulose, hydroxyethylcellulose, hypromellose phthalate, non phase, a Semi-amorphous phase, and mixtures thereof. crystalline cellulose, magnesium aluminum Silicate, trietha 62. The method of claim 60, wherein the effective average nolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1, particle size of the griseofulvin particles is Selected from the 3,3-tetramethylbutyl)-phenol polymer with ethylene oxide group consisting of less than about 1900 nm, less than about and formaldehyde, poloxamers, poloxamines, a charged 1800 nm, less than about 1700 nm, less than about 1600 nm, phospholipid, dioctylsulfoSuccinate, dialkylesters of Sodium less than about 1500 nm, less than about 1400 nm, less than SulfoSuccinic acid, Sodium lauryl Sulfate, alkyl aryl poly US 2005/OOO4049 A1 Jan. 6, 2005 22 ether Sulfonates, mixtures of Sucrose Stearate and Sucrose 10TM, tetrabutylammonium bromide, benzyl trimethylam distearate, p-isononylphenoxypoly-(glycidol), decanoyl-N- monium bromide, choline esters, benzalkonium chloride, methylglucamide; n-decyl B-D-glucopyranoside; n-decyl Stearalkonium chloride compounds, cetyl pyridinium bro B-D-maltopyranoside; n-dodecyl B-D-glucopyranoside; mide, cetyl pyridinium chloride, halide Salts of quaternized n-dodecyl 3-D-maltoside; heptanoyl-N-methylglucamide; polyoxyethylalkylamines, MIRAPOLTM, ALKAQUATTM, n-heptyl-B-D-glucopyranoside; n-heptyl f-D-thiogluco alkyl pyridinium Salts, amines, amine Salts, amine oxides, Side; n-hexyl B-D-glucopyranoside; nonanoyl-N-methylglu imide azolinium Salts, protonated quaternary acrylamides, camide; n-noyl B-D-glucopyranoside; octanoyl-N-methyl methylated quaternary polymers, and cationic guar. glucamide; n-octyl-, 3-D-glucopyranoside; octyl B-D- 73. The method of any of claims 69,71, or 72, wherein the thioglucopyranoside; lysozyme, PEG-phospholipid, PEG composition is bioadhesive. cholesterol, PEG-cholesterol derivative, PEG-vitamin A, 74. The method of claim 60, comprising utilizing as a PEG-vitamin E, and random copolymers of vinyl acetate surface stabilizer Tween(E) 80, Tetronic(R) T908, dioctylsul and vinyl pyrrollidone. fosuccinate, polyvinyl acetate, Pluronic(R) F127, or a mixture 71. The method of claim 69, wherein the at least one thereof. cationic Surface Stabilizer is Selected from the group con 75. The method of claim 60, additionally comprising Sisting of a polymer, a biopolymer, a polysaccharide, a administering one or more non-griseofulvin active agents. cellulosic, an alginate, a nonpolymeric compound, and a 76. The method of claim 75, wherein said additional one phospholipid. or more non-griseofulvin active agents are Selected from the 72. The method of claim 69, wherein the Surface stabilizer group consisting of nutraceuticals, amino acids, proteins, is Selected from the group consisting of benzalkonium peptides, nucleotides, anti-obesity drugs, central nervous chloride, polymethylmethacrylate trimethylammonium bro System Stimulants, carotenoids, corticosteroids, elastase mide, polyvinylpyrrollidone-2-dimethylaminoethyl meth inhibitors, anti-fungals, oncology therapies, anti-emetics, acrylate dimethyl Sulfate, hexadecyltrimethyl ammonium analgesics, cardiovascular agents, anti-inflammatory agents, bromide, cationic lipids, Sulfonium compounds, phospho anthelmintics, anti-arrhythmic agents, antibiotics, antico nium compounds, quarternary ammonium compounds, ben agulants, antidepressants, antidiabetic agents, antiepileptics, Zyl-di(2-chloroethyl) ethylammonium bromide, coconut tri antihistamines, antihypertensive agents, antimuscarinic methyl ammonium chloride, coconut trimethyl ammonium agents, antimycobacterial agents, antineoplastic agents, bromide, coconut methyl dihydroxyethyl ammonium chlo immunosuppressants, antithyroid agents, antiviral agents, ride, coconut methyl dihydroxyethyl ammonium bromide, anxiolytics, Sedatives, astringents, alpha-adrenergic receptor decyl triethyl ammonium chloride, decyl dimethyl hydroxy blocking agents, beta-adrenoceptor blocking agents, blood ethyl ammonium chloride, decyl dimethyl hydroxyethyl products, blood Substitutes, cardiac inotropic agents, con ammonium chloride bromide, C-dimethyl hydroxyethyl trast media, corticosteroids, cough Suppressants, diagnostic ammonium chloride, C2-sdimethyl hydroxyethyl ammo agents, diagnostic imaging agents, diuretics, dopaminergics, nium chloride bromide, coconut dimethyl hydroxyethyl haemostatics, immunological agents, lipid regulating agents, ammonium chloride, coconut dimethyl hydroxyethyl ammo muscle relaxants, parasympathomimetics, parathyroid cal nium bromide, myristyl trimethyl ammonium methyl Sul citonin, parathyroid biphosphonates, prostaglandins, radio phate, lauryl dimethyl benzyl ammonium chloride, lauryl pharmaceuticals, SeX hormones, anti-allergic agents, Stimu dimethyl benzyl ammonium bromide, lauryl dimethyl lants, anoretics, Sympathomimetics, thyroid agents, (ethenoxy), ammonium chloride, lauryl dimethyl(ethenoxy), vasodilators, and Xanthines. ammonium bromide, N-alkyl(Cs)dimethylbenzyl ammo 77. The method of claim 75, wherein said at least one nium chloride, N-alkyl(Cs)dimethyl-benzyl ammonium additional non-griseofulvin active agent is an anti-fungal chloride, N-tetradecylidmethylbenxyl ammonium chloride agent. monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C1-)dimethyl 1-naphthylmethyl ammonium 78. The method of claim 75, wherein at least one addi chloride, trimethylammonium halide, alkyl-trimethylammo tional non-griseofulvin active agent is vitamin E. nium Salts, dialkyl-dimethylammonium Salts, lauryl trim 79. The method of claim 60, wherein the T. of the ethyl ammonium chloride, ethoxylated alkyamidoalkyl griseofulvin, when assayed in the plasma of a mammalian dialkylammonium Salt, an ethoxylated trialkyl ammonium Subject following administration, is less than the T for a salt, dialkylbenzene dialkylammonium chloride, N-dide non-nanoparticulate griseofulvin formulation, administered cyldimethyl ammonium chloride, N-tetradecyldimethylben at the same dosage. Zyl ammonium, chloride monohydrate, N-alkyl(C-)dim 80. The method of claim 79, wherein the T is selected ethyl 1-naphthylmethyl ammonium chloride, from the group consisting of not greater than about 90%, not dodecyldimethylbenzyl ammonium chloride, dialkylbenze greater than about 80%, not greater than about 70%, not nealkyl ammonium chloride, lauryl trimethyl ammonium greater than about 60%, not greater than about 50%, not chloride, alkylbenzyl methyl ammonium chloride, alkyl greater than about 30%, not greater than about 25%, not benzyl dimethyl ammonium bromide, C2 trimethyl ammo greater than about 20%, not greater than about 15%, not nium bromides, Cs trimethyl ammonium bromides, C7 greater than about 10%, and not greater than about 5% of the trimethyl ammonium bromides, dodecylbenzyl triethyl T exhibited by a non-nanoparticulate griseofulvin formu ammonium chloride, poly-diallyldimethylammonium chlo lation, administered at the same dosage. ride (DADMAC), dimethyl ammonium chlorides, alkyldim 81. The method of claim 60, wherein the C. of the ethylammonium halogenides, tricetyl methyl ammonium griseofulvin, when assayed in the plasma of a mammalian chloride, decyltrimethylammonium bromide, dodecyltri Subject following administration, is greater than the C for ethylammonium bromide, tetradecyltrimethylammonium a non-nanoparticulate griseofulvin formulation, adminis bromide, methyl trioctylammonium chloride, POLYOUAT tered at the Same dosage. US 2005/OOO4049 A1 Jan. 6, 2005 23

82. The method of claim 81, wherein the C is selected less than about 90%, less than about 80%, less than about from the group consisting of at least about 50%, at least 70%, less than about 60%, less than about 50%, less than about 100%, at least about 200%, at least about 300%, at about 40%, less than about 30%, less than about 25%, less least about 400%, at least about 500%, at least about 600%, than about 20%, less than about 15%, less than about 10%, at least about 700%, at least about 800%, at least about less than about 5%, and less than about 3%. 900%, at least about 1000%, at least about 1100%, at least 87. The method of claim 60, wherein administration of the about 1200%, at least about 1300%, at least about 1400%, composition to a human in a fasted State is bioeduivalent to at least about 1500%, at least about 1600%, at least about administration of the composition to a human in a fed State. 1700%, at least about 1800%, or at least about 1900% 88. The method of claim 87, wherein “bioeduivalency” is greater than the C exhibited by a non-nanoparticulate established by a 90% Confidence Interval of between 0.80 formulation of griseofulvin, administered at the same doS and 1.25 for both C. and AUC. age. 89. The method of claim 87, wherein “bioeduivalency” is 83. The method of claim 60, wherein the AUC of the established by a 90% Confidence Interval of between 0.80 griseofulvin, when assayed in the plasma of a mammalian and 1.25 for AUC and a 90% Confidence Interval of between Subject following administration, is greater than the AUC for 0.70 to 1.43 for C. a non-nanoparticulate griseofulvin formulation, adminis 90. The method of claim 60, wherein the subject is a tered at the same dosage. human. 84. The method of claim 83, wherein the AUC is selected 91. The method of claim 60, used to treat a condition from the group consisting of at least about 25%, at least Selected from the group consisting of dermatophyte infec about 50%, at least about 75%, at least about 100%, at least tions and ringworm infections. about 125%, at least about 150%, at least about 175%, at 92. The method of claim 91, used to treat a condition least about 200%, at least about 225%, at least about 250%, Selected from the group consisting of ringworm infections of at least about 275%, at least about 300%, at least about the Scalp, hair, nails, and skin. 350%, at least about 400%, at least about 450%, at least 93. The method of claim 60, used to treat a condition about 500%, at least about 550%, at least about 600%, at Selected from the group consisting of Tinea capitis (ring least about 750%, at least about 700%, at least about 750%, worm of the Scalp), Tinea corporis (ringworm of the body), at least about 800%, at least about 850%, at least about Tinea pedis (athlete's foot), Tinea unguium (ringworm of the 900%, at least about 950%, at least about 1000%, at least nails), Tinea cruris (ringworm of the thigh), and Tinea about 1050%, at least about 1100%, at least about 1150%, or barbae (barber's itch). at least about 1200% greater than the AUC exhibited by the 94. The method of claim 60, used to treat a flngal infection non-nanoparticulate formulation of griseofulvin, adminis of an organism Selected from the group consisting of Tri tered at the same dosage. chophyton rubrum, Trichophyton tonsurans, Trichophyton 85. The method of claim 60, wherein the griseofulvin mentagrophytes, Trichophyton interdigitalis, Trichophyton composition does not produce significantly different absorp verrucosum, Trichophyton Sulphureum, Trichophyton tion levels when administered under fed as comPared to Schoenleini, Trichophyton audouini, Trichophyton canis, fasting conditions. Trichophyton gypseum, Trichophytonfioccosum, Trichophy 86. The method of claim 85, wherein the difference in ton megnini, Trichophyton gallinae, and Trichophyton cra absorption of the griseofulvin composition of the invention, teriform. when administered in the fed verSuS the fasted State, is Selected from the group consisting of less than about 100%,