(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2006/0159628 A1
`(43) Pub. Date:
`Jul. 20, 2006
`Liversidge et al.
`
`US 20060159628A1
`
`(54)
`
`NANOPARTICULATE BENZOTHIOPHENE
`FORMULATIONS
`
`(75)
`
`Inventors: Gary Liversidge, West Chester, PA
`(US); Scott Jenkins, DoWningtoWn, PA
`(Us)
`
`Correspondence Address:
`ELAN DRUG DELIVERY, INC.
`C/O FOLEY & LARDNER LLP
`3000 K STREET, N.W.
`SUITE 500
`WASHINGTON, DC 20007-5109 (US)
`
`(73)
`
`(21)
`
`(22)
`
`Assignee: Elan Pharma International Limited
`
`Appl. No.:
`
`11/292,314
`
`Filed:
`
`Dec. 2, 2005
`
`Related US. Application Data
`
`(60) Provisional application No. 60/633,003, ?led on Dec.
`3, 2004.
`
`Publication Classi?cation
`
`(51) Int. Cl.
`(2006.01)
`A61K 31/453
`(2006.01)
`A61K 9/14
`(2006.01)
`A61L 9/04
`(52) US. Cl. .......................... .. 424/46; 514/320; 977/906;
`424/489
`
`(57)
`
`ABSTRACT
`
`The present invention is directed to benZothiophene com
`positions, preferably nanoparticulate raloxifene hydrochlo
`ride compositions having improved pharmacokinetic pro
`?les, improved bioavailability, dissolution rates and ef?cacy.
`In one embodiment, the raloxifene hydrochloride nanopar
`ticulate composition have an e?‘ective average particle siZe
`of less than about 2000 nm.
`
`Page 1
`
`LUPIN EX. 1017
`Lupin v. iCeutica
`US Patent No. 9,017,721
`
`

`
`US 2006/0159628 A1
`
`Jul. 20, 2006
`
`NANOPARTICULATE BENZOTHIOPHENE
`FORMULATIONS
`
`FIELD OF THE INVENTION
`[0001] This invention relates to the ?elds of pharmaceu
`tical and organic chemistry and provides a benzothiophene
`compound, such as a raloxifene hydrochloride compound, in
`nanoparticulate form, Which is useful for the treatment of
`various medical indications, including osteoporosis.
`BACKGROUND OF THE INVENTION
`[0002] Background Regarding Nanoparticulate Composi
`tions
`
`[0003] Osteoporosis describes a group of diseases Which
`arise from diverse etiologies, but Which are characterized by
`the net loss of bone mass per unit volume. The consequence
`of this loss of bone mass and resulting bone fracture is the
`failure of the skeleton to provide adequate structural support
`for the body. One of the most common types of osteoporosis
`is that associated With menopause. Most Women lose from
`about 20% to about 60% of the bone mass in the trabecular
`compartment of the bone Within 3 to 6 years after the
`cessation of menses. This rapid loss is generally associated
`With an increase of bone resorption and formation. HoWever,
`the resorptive cycle is more dominant and the result is a net
`loss of bone mass. Osteoporosis is a common and serious
`disease among post-menopausal Women.
`
`[0004] There are an estimated 25 million Women in the
`United States, alone, Who are a?licted With this disease. The
`results of osteoporosis are personally harmful and also
`account for a large economic loss due to its chronicity and
`the need for extensive and long term support (hospitalization
`and nursing home care) from the disease sequelae. This is
`especially true in more elderly patients. Additionally,
`although osteoporosis is not generally thought of as a life
`threatening condition, a 20% to 30% mortality rate is related
`With hip fractures in elderly Women. A large percentage of
`this mortality rate can be directly associated With post
`menopausal osteoporosis.
`[0005] Before menopause time, most Women have less
`incidence of cardiovascular disease than age-matched men.
`Following menopause, hoWever, the rate of cardiovascular
`disease in Women sloWly increases to match the rate seen in
`men. This loss of protection has been linked to the loss of
`estrogen and, in particular, to the loss of estrogen’s ability to
`regulated the levels of serum lipids. The nature of estrogen’s
`ability to regulate serum lipids is not Well understood, but
`evidence to date indicates that estrogen can up regulate the
`loW density lipid (LDL) receptors in the liver to remove
`excess cholesterol. Additionally, estrogen appears to have
`some e?fect on the biosynthesis of cholesterol, and other
`bene?cial e?fects on cardiovascular health.
`
`[0006] It has been reported in the literature that post
`menopausal Women having estrogen replacement therapy
`have a return of serum lipid levels to concentrations to those
`of the pre-menopausal state. Thus, estrogen Would appear to
`be a reasonable treatment for this condition. HoWever, the
`side-elfects of estrogen replacement therapy are not accept
`able to many Women, thus limiting the use of this therapy.
`An ideal therapy for this condition Would be an agent Which
`Would regulate the serum lipid level as does estrogen, but
`Would be devoid of the side-elfects and risks associated With
`estrogen therapy.
`
`[0007] Preclinical ?ndings With a structurally distinct
`“anti-estrogen”, raloxifene hydrochloride, have demon
`strated potential for improved selectivity of estrogenic
`e?fects in target tissues. Similar to tamoxifen, raloxifene
`hydrochloride Was developed originally for treatment of
`breast cancer; hoWever, the benzothiophene nucleus of ral
`oxifene hydrochloride represented a signi?cant structural
`deviation from the triphenylethylene nucleus of tamoxifen.
`Raloxifene hydrochloride binds With high a?inity to the
`estrogen receptor, and inhibits estrogen-dependent prolifera
`tion in MCF-7 cells (human mammary tumor derived cell
`line) in cell culture. In vivo estrogen antagonist activity of
`raloxifene hydrochloride Was furthermore demonstrated in
`carcinogen-induced models of mammary tumors in rodents.
`Signi?cantly, in uterine tissue raloxifene hydrochloride Was
`more e?‘ective than tamoxifen as an antagonist of the
`uterotrophic response to estrogen in immature rats and, in
`contrast to tamoxifen, raloxifene hydrochloride displayed
`only minimal uterotrophic response that Was not dose
`dependent in ovariectomized (OVX) rats. Thus, raloxifene
`hydrochloride is unique as an antagonist of the uterine
`estrogen receptor, in that it produces a nearly complete
`blockage of uterotrophic response of estrogen due to mini
`mal agonist e?fect of raloxifene hydrochloride in this tissue.
`Indeed, the ability of raloxifene hydrochloride to antagonize
`the uterine stimulatory e?fect of tamoxifen Was recently
`demonstrated in OVX rats. Raloxifene hydrochloride is
`more properly characterized as a Selective Estrogen Recep
`tor Modulator (SERM), due to its unique pro?le. The
`chemical structure of raloxifene hydrochloride is:
`
`FORMULA l
`
`ow
`
`The chemical designation is methanone, [6-hydroxy-2-(4
`hydroxyphenyl)benzo[b]thien-3 -yl]-[4-[2-(l -piperidi
`nyl)ethoxy]phenyl]-, hydrochloride. Raloxifene hydrochlo
`ride (CH1) has the empirical formula C 28 H 27 NO 4S.CHl,
`Which corresponds to a molecular Weight of 510.05. Ralox
`ifene CHl is an off-White to pale-yelloW solid that is very
`slightly soluble in Water.
`
`[0008] Raloxifene HCL is commercially available in tablet
`dosage form for oral administration (Eli Lilly, Indianapolis,
`Ind.). Each tablet is the molar equivalent of 55.71 mg free
`base With inactive ingredients that include anhydrous lac
`tose, camuba Wax, crospovidone, FD&C Blue #2, aluminum
`lake, hypromellose, lactose monohydrate, and magnesium
`stearate, as Well as other commercially available excipients
`Well knoW to the art.
`
`Page 2
`
`

`
`US 2006/0159628 A1
`
`Jul. 20, 2006
`
`[0009] Raloxifene hydrochloride and processes for its
`preparation are described and claimed in US. Pat. Nos.
`5,393,763 and 5,457,117 to Black et al, US. Pat. No.
`5,478,847 to Draper; US. Pat. Nos. 5,812,120 and 5,972,
`383 to Gibson et al., and US. Pat. Nos. 6,458,811 and
`6,797,719 to Arbuthnat et al., all of Which are incorporated
`herein by reference.
`[0010] Nanoparticulate compositions, ?rst described in
`US. Pat. No. 5,145,684 (“the ’684 patent”), are particles
`consisting of a poorly soluble therapeutic or diagnostic agent
`having adsorbed onto, or associated With, the surface thereof
`a non-crosslinked surface stabilizer. The ’684 patent does
`not describe nanoparticulate compositions of a ben
`zothiophene.
`[0011] Methods of making nanoparticulate compositions
`are described in, for example, US. Pat. Nos. 5,518,187 and
`5,862,999, both for “Method of Grinding Pharmaceutical
`Substances,” US. Pat. No. 5,718,388, for “Continuous
`Method of Grinding Pharmaceutical Substances,” and US.
`Pat. No. 5,510,118 for “Process of Preparing Therapeutic
`Compositions Containing Nanoparticles.”
`[0012] Nanoparticulate compositions are also described,
`for example, in US. Pat. Nos. 5,298,262 for “Use of Ionic
`Cloud Point Modi?ers to Prevent Particle Aggregation Dur
`ing Sterilization,” US. Pat. No. 5,302,401 for “Method to
`Reduce Particle Size GroWth During Lyophilization,” US.
`Pat. No. 5,318,767 for “X-Ray Contrast Compositions Use
`ful in Medical Imaging,” US. Pat. No. 5,326,552 for “Novel
`Formulation For Nanoparticulate X-Ray Blood Pool Con
`trast Agents Using High Molecular Weight Non-ionic Sur
`factants,” US. Pat. No. 5,328,404 for “Method of X-Ray
`Imaging Using Iodinated Aromatic Propanedioates,” US.
`Pat. No. 5,336,507 for “Use of Charged Phospholipids to
`Reduce Nanoparticle Aggregation,” US. Pat. No. 5,340,564
`for “Formulations Comprising Olin 10-G to Prevent Particle
`Aggregation and Increase Stability,” US. Pat. No. 5,346,
`702 for “Use of Non-Ionic Cloud Point Modi?ers to Mini
`mize Nanoparticulate Aggregation During Sterilization,”
`US. Pat. No. 5,349,957 for “Preparation and Magnetic
`Properties of Very Small Magnetic-Dextran Particles,” US.
`Pat. No. 5,352,459 for “Use of Puri?ed Surface Modi?ers to
`Prevent Particle Aggregation During Sterilization,” US. Pat.
`Nos. 5,399,363 and 5,494,683, both for “Surface Modi?ed
`Anticancer Nanoparticles,” US. Pat. No. 5,401,492 for
`“Water Insoluble Non-Magnetic Manganese Particles as
`Magnetic Resonance Enhancement Agents,” US. Pat. No.
`5,429,824 for “Use of Tyloxapol as a Nanoparticulate Sta
`bilizer,” US. Pat. No. 5,447,710 for “Method for Making
`Nanoparticulate X-Ray Blood Pool Contrast Agents Using
`High Molecular Weight Non-ionic Surfactants,” US. Pat.
`No. 5,451,393 for “X-Ray Contrast Compositions Useful in
`Medical Imaging,” US. Pat. No. 5,466,440 for “Formula
`tions of Oral Gastrointestinal Diagnostic X-Ray Contrast
`Agents in Combination With Pharmaceutically Acceptable
`Clays,” US. Pat. No. 5,470,583 for “Method of Preparing
`Nanoparticle Compositions Containing Charged Phospho
`lipids to Reduce Aggregation,” US. Pat. No. 5,472,683 for
`“Nanoparticulate Diagnostic Mixed Carbamic Anhydrides
`as X-Ray Contrast Agents for Blood Pool and Lymphatic
`System Imaging,” US. Pat. No. 5,500,204 for “Nanopar
`ticulate Diagnostic Dimers as X-Ray Contrast Agents for
`Blood Pool and Lymphatic System Imaging,” US. Pat. No.
`5,518,738 for “Nanoparticulate NSAID Formulations,” U.S.
`
`Pat. No. 5,521,218 for “Nanoparticulate Iododipamide
`Derivatives for Use as X-Ray Contrast Agents,” US. Pat.
`No. 5,525,328 for “Nanoparticulate Diagnostic Diatrizoxy
`Ester X-Ray Contrast Agents for Blood Pool and Lymphatic
`System Imaging,” US. Pat. No. 5,543,133 for “Process of
`Preparing X-Ray Contrast Compositions Containing Nano
`particles,” US. Pat. No. 5,552,160 for “Surface Modi?ed
`NSAID Nanoparticles,” US. Pat. No. 5,560,931 for “For
`mulations of Compounds as Nanoparticulate Dispersions in
`Digestible Oils or Fatty Acids,” US. Pat. No. 5,565,188 for
`“Polyalkylene Block Copolymers as Surface Modi?ers for
`Nanoparticles,” US. Pat. No. 5,569,448 for “Sulfated Non
`ionic Block Copolymer Surfactant as Stabilizer Coatings for
`Nanoparticle Compositions,” US. Pat. No. 5,571,536 for
`“Formulations of Compounds as Nanoparticulate Disper
`sions in Digestible Oils or Fatty Acids,” US. Pat. No.
`5,573,749 for “Nanoparticulate Diagnostic Mixed Carboxy
`lic Anydrides as X-Ray Contrast Agents for Blood Pool and
`Lymphatic System Imaging,” US. Pat. No. 5,573,750 for
`“Diagnostic Imaging X-Ray Contrast Agents,” US. Pat. No.
`5,573,783 for “Redispersible Nanoparticulate Film Matrices
`With Protective Overcoats,” US. Pat. No. 5,580,579 for
`“Site-speci?c Adhesion Within the GI Tract Using Nano
`particles Stabilized by High Molecular Weight, Linear Poly
`(ethylene Oxide)Polymers,” US. Pat. No. 5,585,108 for
`“Formulations of Oral Gastrointestinal Therapeutic Agents
`in Combination With Pharmaceutically Acceptable Clays,”
`US. Pat. No. 5,587,143 for “Butylene Oxide-Ethylene
`Oxide Block Copolymers Surfactants as Stabilizer Coatings
`for Nanoparticulate Compositions,” US. Pat. No. 5,591,456
`for “Milled Naproxen With Hydroxypropyl Cellulose as
`Dispersion Stabilizer,” US. Pat. No. 5,593,657 for “Novel
`Barium Salt Formulations Stabilized by Non-ionic and
`Anionic Stabilizers,” US. Pat. No. 5,622,938 for “Sugar
`Based Surfactant for Nanocrystals,” US. Pat. No. 5,628,981
`for “Improved Formulations of Oral Gastrointestinal Diag
`nostic X-Ray Contrast Agents and Oral Gastrointestinal
`Therapeutic Agents,” US. Pat. No. 5,643,552 for “Nano
`particulate Diagnostic Mixed Carbonic Anhydrides as
`X-Ray Contrast Agents for Blood Pool and Lymphatic
`System Imaging,” US. Pat. No. 5,718,388 for “Continuous
`Method of Grinding Pharmaceutical Substances,” US. Pat.
`No. 5,718,919 for “Nanoparticles Containing the R(—)Enan
`tiomer of Ibuprofen,” US. Pat. No. 5,747,001 for “Aerosols
`Containing Beclomethasone Nanoparticle Dispersions,”
`US. Pat. No. 5,834,025 for “Reduction of Intravenously
`Administered Nanoparticulate
`Formulation
`Induced
`Adverse Physiological Reactions,” US. Pat. No. 6,045,829
`“Nanocrystalline Formulations of Human Immunode?
`ciency Virus (HIV) Protease Inhibitors Using Cellulosic
`Surface Stabilizers,” US. Pat. No. 6,068,858 for “Methods
`of Making Nanocrystalline Formulations of Human Immu
`node?ciency Virus (HIV) Protease Inhibitors Using Cellu
`losic Surface Stabilizers,” US. Pat. No. 6,153,225 for
`“Injectable Formulations of Nanoparticulate Naproxen,”
`US. Pat. No. 6,165,506 for “NeW Solid Dose Form of
`Nanoparticulate Naproxen,” US. Pat. No. 6,221,400 for
`“Methods of Treating Mammals Using Nanocrystalline For
`mulations of Human Immunode?ciency Virus (HIV) Pro
`tease Inhibitors,” US. Pat. No. 6,264,922 for “Nebulized
`Aerosols Containing Nanoparticle Dispersions,” US. Pat.
`No. 6,267,989 for “Methods for Preventing Crystal GroWth
`and Particle Aggregation in Nanoparticle Compositions,”
`US. Pat. No. 6,270,806 for “Use of PEG-Derivatized Lipids
`
`Page 3
`
`

`
`US 2006/0159628 A1
`
`Jul. 20, 2006
`
`as Surface Stabilizers for Nanoparticulate Compositions,”
`US. Pat. No. 6,316,029 for “Rapidly Disintegrating Solid
`Oral Dosage Form,” US. Pat. No. 6,375,986 for “Solid Dose
`Nanoparticulate Compositions Comprising a Synergistic
`Combination of a Polymeric Surface Stabilizer and Dioctyl
`Sodium Sulfosuccinate,” US. Pat. No. 6,428,814 for “Bio
`adhesive Nanoparticulate Compositions Having Cationic
`Surface Stabilizers,” US. Pat. No. 6,431,478 for “Small
`Scale Mill,” and US. Pat. No. 6,432,381 for “Methods for
`Targeting Drug Delivery to the Upper and/or LoWer Gas
`trointestinal Tract,” US. Pat. No. 6,592,903 for “Nanopar
`ticulate Dispersions Comprising a Synergistic Combination
`of a Polymeric Surface Stabilizer and Dioctyl Sodium
`Sulfosuccinate,” US. Pat. No. 6,582,285 for “Apparatus for
`sanitary Wet milling,” US. Pat. No. 6,656,504 for “Nano
`particulate
`Compositions
`Comprising
`Amorphous
`Cyclosporine,” US. Pat. No. 6,742,734 for “System and
`Method for Milling Materials,” US. Pat. No. 6,745,962 for
`“Small Scale Mill and Method Thereof,” US. Pat. No.
`6,811,767 for “Liquid droplet aerosols of nanoparticulate
`drugs,” and US. Pat. No. 6,908,626 for “Compositions
`having a combination of immediate release and controlled
`release characteristics,” all of Which are speci?cally incor
`porated by reference. In addition, US. Patent Application
`No. 20020012675 A1, published on Jan. 31, 2002, for
`“Controlled Release Nanoparticulate Compositions,” and
`WO 02/098565 for “System and Method for Milling Mate
`rials,” describe nanoparticulate compositions, and are spe
`ci?cally incorporated by reference.
`
`[0013] Amorphous small particle compositions are
`described, for example, in US. Pat. No. 4,783,484 for
`“Particulate Composition and Use Thereof as Antimicrobial
`Agent,” US. Pat. No. 4,826,689 for “Method for Making
`Uniformly Sized Particles from Water-Insoluble Organic
`Compounds,” US. Pat. No. 4,997,454 for “Method for
`Making Uniformly-Sized Particles From Insoluble Com
`pounds,” US. Pat. No. 5,741,522 for “Ultrasmall, Non
`aggregated Porous Particles of Uniform Size for Entrapping
`Gas Bubbles Within and Methods,” and US. Pat. No.
`5,776,496, for “Ultrasmall Porous Particles for Enhancing
`Ultrasound Back Scatter.”
`
`SUMMARY OF THE INVENTION
`
`[0014] The present invention relates to nanoparticulate
`compositions comprising a benzothiophene, preferably ral
`oxifene hydrochloride. The compositions comprise a ben
`zothiophene, preferably raloxifene hydrochloride, and at
`least one surface stabilizer adsorbed on or associated With
`the surface of the benzothiophene particles. The nanopar
`ticulate benzothiophene, preferably raloxifene hydrochlo
`ride, particles have an effective average particle size of less
`than about 2000 nm. A preferred dosage form of the inven
`tion is a solid dosage form, although any pharrnaceutically
`acceptable dosage form can be utilized.
`
`[0015] Another aspect of the invention is directed to
`pharmaceutical compositions comprising a nanoparticulate
`benzothiophene, preferably raloxifene hydrochloride, com
`position of the invention. The pharmaceutical compositions
`comprise a benzothiophene, preferably raloxifene hydro
`chloride, at least one surface stabilizer, and a pharmaceuti
`cally acceptable carrier, as Well as any desired excipients.
`
`[0016] Another aspect of the invention is directed to a
`nanoparticulate benzothiophene, preferably raloxifene
`hydrochloride, composition having improved pharmacoki
`netic pro?les as compared to conventional microcrystalline
`or solubilized benzothiophene formulations.
`
`[0017] In yet another embodiment, the invention encom
`passes a benzothiophene, preferably raloxifene hydrochlo
`ride, composition, Wherein administration of the composi
`tion to a subject in a fasted state is bioequivalent to
`administration of the composition to a subject in a fed state.
`
`[0018] Another embodiment of the invention is directed to
`nanoparticulate benzothiophene, preferably raloxifene
`hydrochloride, compositions additionally comprising one or
`more compounds useful in treating osteoporosis, breast
`cancer, or related conditions.
`
`[0019] This invention further discloses a method of mak
`ing a nanoparticulate benzothiophene, preferably raloxifene
`hydrochloride, composition according to the invention. Such
`a method comprises contacting a benzothiophene, preferably
`raloxifene hydrochloride, and at least one surface stabilizer
`for a time and under conditions suf?cient to provide a
`nanoparticulate benzothiophene composition, and prefer
`ably a raloxifene hydrochloride composition. The one or
`more surface stabilizers can be contacted With a ben
`zothiophene, preferably raloxifene hydrochloride, either
`before, during, or after size reduction of the benzothiophene.
`
`[0020] The present invention is also directed to methods of
`treatment using the nanoparticulate benzothiophene, prefer
`ably raloxifene hydrochloride, compositions of the invention
`for conditions such as osteoporosis, carcinomas of the breast
`and lymph glands, and the like.
`[0021] Both the foregoing general description and the
`folloWing detailed description are exemplary and explana
`tory and are intended to provide further explanation of the
`invention as claimed. Other objects, advantages, and novel
`features Will be readily apparent to those skilled in the art
`from the folloWing detailed description of the invention.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`A. Introduction
`
`[0022] The present invention is directed to nanoparticulate
`compositions comprising a benzothiophene, preferably ral
`oxifene hydrochloride. The compositions comprise a ben
`zothiophene, preferably raloxifene hydrochloride, and pref
`erably at least one surface stabilizer adsorbed on or
`associated With the surface of the drug. The nanoparticulate
`benzothiophene, preferably raloxifene hydrochloride, par
`ticles have an effective average particle size of less than
`about 2000 nm.
`
`[0023] Advantages of a nanoparticulate benzothiophene,
`preferably a nanoparticulate raloxifene hydrochloride, for
`mulation of the invention include, but are not limited to: (1)
`smaller tablet or other solid dosage form size, or less
`frequent administration of the formulation, (2) smaller doses
`of drug required to obtain the same pharmacological effect
`as compared to conventional microcrystalline or solubilized
`forms of a benzothiophene, (3) increased bioavailability as
`compared to conventional microcrystalline or solubilized
`forms of a benzothiophene, (4) improved pharmacokinetic
`
`Page 4
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`

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`US 2006/0159628 A1
`
`Jul. 20, 2006
`
`pro?les, such as Tmax, Cmax, and AUC pro?les as com
`pared to conventional microcrystalline or solubiliZed forms
`of a benZothiophene; (5) substantially similar pharmacoki
`netic pro?les of the nanoparticulate benZothiophene com
`positions When administered in the fed versus the fasted
`state; (6) bioequivalent pharmacokinetic pro?les of the
`nanoparticulate benZothiophene compositions When admin
`istered in the fed versus the fasted state; (7) an increased rate
`of dissolution for the nanoparticulate benZothiophene com
`positions as compared to conventional microcrystalline or
`solubiliZed forms of the same benZothiophene; (8) bioadhe
`sive benZothiophene compositions; and (9) use of the nano
`particulate benZothiophene compositions in conjunction
`With other active agents useful in treating osteoporosis,
`carcinomas of the breast and lymph glands and, related
`conditions.
`[0024] The present invention also includes nanoparticulate
`benZothiophene, preferably nanoparticulate raloxifene
`hydrochloride compositions, together With one or more
`non-toxic physiologically acceptable carriers, adjuvants, or
`vehicles, collectively referred to as carriers. The composi
`tions can be formulated for parenteral injection (e.g., intra
`venous, intramuscular, or subcutaneous), oral administration
`in solid, liquid, or aerosol form, vaginal, nasal, rectal, ocular,
`local (poWders, ointments or drops), buccal, intracistemal,
`intraperitoneal, or topical administration, and the like.
`[0025] A preferred dosage form of the invention is a solid
`dosage form, although any pharmaceutically acceptable
`dosage form can be utiliZed. Exemplary solid dosage forms
`include, but are not limited to, tablets, capsules, sachets,
`loZenges, poWders, pills, or granules, and the solid dosage
`form can be, for example, a fast melt dosage form, con
`trolled release dosage form, lyophiliZed dosage form,
`delayed release dosage form, extended release dosage form,
`pulsatile release dosage form, mixed immediate release and
`controlled release dosage form, or a combination thereof. A
`solid dose tablet formulation is preferred.
`
`B. De?nitions
`
`[0026] The present invention is described herein using
`several de?nitions, as set forth beloW and throughout the
`application.
`[0027] The term “e?‘ective average particle siZe”, as used
`herein means that at least 50% of the nanoparticulate ben
`Zothiophene, or preferably raloxifene hydrochloride par
`ticles, have a Weight average siZe of less than about 2000
`nm, When measured by, for example, sedimentation ?eld
`?oW fractionation, photon correlation spectroscopy, light
`scattering, disk centrifugation, and other techniques knoWn
`to those of skill in the art.
`
`[0028] As used herein, “about” Will be understood by
`persons of ordinary skill in the art and Will vary to some
`extent on the context in Which it is used. If there are uses of
`the term Which are not clear to persons of ordinary skill in
`the art given the context in Which it is used, “about” Will
`mean up to plus or minus 10% of the particular term.
`
`[0029] As used herein With reference to a stable ben
`Zothiophene or a stable raloxifene hydrochloride particle
`connotes, but is not limited to one or more of the folloWing
`parameters: (1 ), benZothiophene or raloxifene hydrochloride
`particles do not appreciably ?occulate or agglomerate due to
`interpar‘ticle attractive forces or otherWise signi?cantly
`
`increase in particle siZe over time; (2) that the physical
`structure of the benZothiophene or raloxifene hydrochloride
`particles is not altered over time, such as by conversion from
`an amorphous phase to a crystalline phase; (3) that the
`benZothiophene or raloxifene hydrochloride particles are
`chemically stable; and/or (4) Where the benZothiophene or
`raloxifene hydrochloride has not been subject to a heating
`step at or above the melting point of the benZothiophene or
`raloxifene hydrochloride in the preparation of the nanopar
`ticles of the present invention.
`
`[0030] The term “conventional” or “non-nanoparticulate
`active agent” shall mean an active agent Which is solubiliZed
`or Which has an e?‘ective average particle siZe of greater than
`about 2000 nm. Nanopar‘ticulate active agents as de?ned
`herein have an e?‘ective average particle siZe of less than
`about 2000 nm.
`
`[0031] The phrase “poorly Water soluble drugs” as used
`herein refers to those drugs that have a solubility in Water of
`less than about 30 mg/ml, preferably less than about 20
`mg/ml, preferably less than about 10 mg/ml, or preferably
`less than about 1 mg/ml.
`[0032] As used herein, the phrase “therapeutically effec
`tive amount” shall mean that drug dosage that provides the
`speci?c pharmacological response for Which the drug is
`administered in a signi?cant number of subjects in need of
`such treatment. It is emphasiZed that a therapeutically effec
`tive amount of a drug that is administered to a particular
`subject in a particular instance Will not always be effective
`in treating the conditions/diseases described herein, even
`though such dosage is deemed to be a therapeutically
`e?‘ective amount by those of skill in the art.
`C. The Nanopar‘ticulate Composition
`
`[0033] There are a number of enhanced pharmacological
`characteristics of nanoparticulate benZothiophene composi
`tions of the present invention.
`[0034]
`1. Increased Bioavailability
`[0035] The benZothiophene formulations of the present
`invention, preferably raloxifene hydrochloride formulations
`of the invention, exhibit increased bioavailability at the
`same dose of the same benZothiophene, and require smaller
`doses as compared to prior conventional benZothiophene
`formulations, including conventional raloxifene hydrochlo
`ride formulations. Thus, a nanoparticulate raloxifene hydro
`chloride tablet, if administered to a patient in a fasted state
`is not bioequivalent to administration of a conventional
`microcrystalline raloxifene hydrochloride tablet in a fasted
`state.
`
`[0036] The non-bioequivalence is signi?cant because it
`means that the nanoparticulate raloxifene hydrochloride
`dosage form exhibits signi?cantly greater drug absorption.
`And for the nanoparticulate raloxifene hydrochloride dosage
`form to be bioequivalent to the conventional microcrystal
`line raloxifene hydrochloride dosage form, the nanoparticu
`late raloxifene hydrochloride dosage form Would have to
`contain signi?cantly less drug. Thus, the nanoparticulate
`raloxifene hydrochloride dosage form signi?cantly increases
`the bioavailability of the drug.
`
`[0037] Moreover, a nanoparticulate raloxifene hydrochlo
`ride dosage form requires less drug to obtain the same
`pharmacological e?fect observed With a conventional micro
`
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`Jul. 20, 2006
`
`crystalline raloxifene hydrochloride dosage form (e.g.,
`EVISTA®). Therefore, the nanoparticulate raloxifene
`hydrochloride dosage form has an increased bioavailability
`as compared to the conventional microcrystalline raloxifene
`hydrochloride dosage form.
`
`[0038] 2. The Pharmacokinetic Pro?les of the Ben
`Zothiophene Compositions of the Invention are not Affected
`by the Fed or Fasted State of the Subject Ingesting the
`Compositions
`
`[0039] The compositions of the present invention encom
`pass a benZothiophene, preferably raloxifene hydrochloride,
`Wherein the pharmacokinetic pro?le of the benZothiophene
`is not substantially affected by the fed or fasted state of a
`subject ingesting the composition. This means that there is
`little or no appreciable difference in the quantity of drug
`absorbed or the rate of drug absorption When the nanopar
`ticulate benZothiophene, preferably raloxifene hydrochlo
`ride, compositions are administered in the fed versus the
`fasted state.
`
`[0040] Bene?ts of a dosage form Which substantially
`eliminates the effect of food include an increase in subject
`convenience, thereby increasing subject compliance, as the
`subject does not need to ensure that they are taking a dose
`either With or Without food. This is signi?cant, as With poor
`subject compliance an increase in the medical condition for
`Which the drug is being prescribed may be observed, i.e.,
`osteoporosis or cardiovascular problems for poor subject
`compliance With a benZothiophene such as raloxifene hydro
`chloride.
`
`[0041] The invention also preferably provides ben
`Zothiophene compositions, such as raloxifene hydrochloride
`compositions, having a desirable pharmacokinetic pro?le
`When administered to mammalian subjects. The desirable
`pharmacokinetic pro?le of the benZothiophene compositions
`preferably includes, but is not limited to: (1) a Cmax for
`benZothiophene, When assayed in the plasma of a mamma
`lian subject folloWing administration, that is preferably
`greater than the Cmax for a non-nanoparticulate ben
`Zothiophene formulation (e.g., EVISTA®), administered at
`the same dosage; and/or (2) an AUC for benZothiophene,
`When assayed in the plasma of a mammalian subject fol
`loWing administration, that is preferably greater than the
`AUC for a non-nanoparticulate benZothiophene formulation
`(e.g., EVISTA®), administered at the same dosage; and/or
`(3) a Tmax for benZothiophene, When assayed in the plasma
`of a mammalian subject folloWing administration, that is
`preferably less than the Tmax for a non-nanoparticulate
`benZothiophene formulation (e. g., EVISTA®), administered
`at the same dosage. The desirable pharmacokinetic pro?le,
`as used herein, is the pharmacokinetic pro?le measured after
`the initial dose of benZothiophene.
`
`[0042] In one embodiment, a preferred benZothiophene
`composition of the invention is a nanoparticulate raloxifene
`hydrochloride composition that exhibits in comparative
`pharmacokinetic testing With a non-nanoparticulate ben
`Zothiophene formulation (e.g., EVISTA®), administered at
`the same dosage, a Tmax not greater than about 90%, not
`greater than about 80%, not greater than about 70%, not
`greater than about 60%, not greater than about 50%, not
`greater than about 30%, not greater than about 25%, not
`greater than about 20%, not greater than about 15%, not
`
`greater than about 10%, or not greater than about 5% of the
`Tmax exhibited by the non-nanoparticulate benZothiophene
`formulation.
`
`[0043] In another embodiment, the benZothiophene com
`position of the invention is a nanoparticulate raloxifene
`hydrochloride composition that exhibits in comparative
`pharmacokinetic testing With a non-nanoparticulate ben
`Zothiophene formulation of (e.g., EVISTA®, administered
`at the same dosage, a Cmax Which is at least about 50%, at
`least about 100%, at least about 200%, at least about 300%,
`at least about 400%, at least about 500%, at least about
`600%, at least about 700%, at least about 800%, at least
`about 900%, at least about 1000%, at least about 1100%, at
`least about 1200%, at least about 1300%, at least about
`1400%, at least about 1500%, at least about 1600%, at least
`about 1700%, at least about 1800%, or at least about 1900%
`greater than the Cmax exhibited by the non-nanoparticulate
`benZothiophene formulation.
`
`[0044] In yet another embodiment, the benZothiophene
`composition of the invention is a raloxifene hydrochloride
`nanoparticulate composition exhibits in comparative phar
`macokinetic testing With a non-nanoparticulate ben
`Zothiophene formulation (e.g., EVISTA®), administered at
`the same dosage, an AUC Which is at least about 25%, at
`least about 50%, at least about 75%, at least about 100%, at
`least about 125%, at least about 150%, at least about 175%,
`at least about 200%, at least a