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`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`
`
`(43) International Publication Date
`19 May 2005 (19.05.2005)
`
`(10) International Publication Number
`WO 2005/044234 A2
`
`(51') International Patent Classification”:
`
`A61K 9.114
`
`[74)
`
`(21) International Application Number:
`PC’I‘HJS20041036337
`
`(31)
`
`(22) International Filing Date:
`2 November 2004 (02.1 1.2004)
`
`(2.5) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60511106
`
`5 November 2003 (05.11.2003)
`
`US
`
`(.34)
`
`(71) Applicant (for alt! designated States except US): ELAN
`PHARNIA INTERNATIONAL, LTD. HEM-7.]; WIT.
`House, Shannon Business Park, Shannon, County Clare
`([13).
`
`(72) Inventors; and
`(75) InventorstApplieants (for US catty): CUNNINGHAM,
`.Iumes [USIUS]; 903 Charleston Greene, Malvern, PA
`19355 (US). LIVERSIDGE, Elaine, Nlerisko |_US.-’US]:_
`258 (Iolwyn Terrace, West Chester, PA 19380 (US).
`
`Agents: SIMKIN, Michele, M. et al.; Pole}-r & Lardner
`LLP, Washington Harbour, 3000 K Street, N.W. Suite 500,
`Washington, DC 20007—5 101 (US).
`
`Designated States (unless when-vise indicated, flJt' every
`kind (if-national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, BI}, ES, PT,
`GB, GD, GLi, GH, GM, HR, HU, ID, IL, IN, IS, .113, KE,
`KG, KP, KR, KZ, LC. LK, LR, LS. LT, LU, LV, IVIA, IVID,
`MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG,
`P11, PL, PT, R0, RU, SC, SD, SH, SG, SK, -SI., SY, TJ, TM,
`TN, ’I‘R,'1"I',’I"/., UA, UG, US, [17,, VC, VN, YU, ZA, ZM,
`ZVV.
`
`Designated States (unless otherwise indicated, for every
`kt'nd of regional protection drrtt't’rtble): ARIPO (BW, GH,
`GM, KB, LS, MW, NIX, NA, SD, SL, SZ, TZ, UG, ZNI,
`VAN), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, (:1 I, (:Y, (17., DE, UK, on, as, H[,
`HR,GB,GR,11LI, [11,13,1'1', I.U,M(1,Nl.,Pl., P'l‘,R(),-SH,
`SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, Mi, MR, NT. SN, TD, TG).
`
`Declarations under Rule 4.17:
`
`as to appt't‘cant’s entitlement to apply for and be granted
`a patent (Rate 4. I7{'it_1)for thefatt'on-‘tng designations .4 E.
`AG, AL, AM, AT AU.
`.47. BA, BB, HG. BR, BW, BY, 32,
`
`[Contmaed on next page]
`
`{54) Title: NANOPAR’I‘ICUI.ATl-E COMPOSITIONS HAVING A PEI-YI‘IDH AS A SURFACE S’l‘ABllJZl-tR
`
`
`
`(57) Abstract: The present invention is directed to nanoparticulate active agent compositions comprising at least one peptide as a
`surface stabilizer. Also encompassed by the invention are pharmaceutical compositions comprising a nanoparticulate active agent
`composition of the invention and methods o [' making and using such nanoparticul ate and pharmaceutical compositions.
`
`AQUESTIVE EXHIBIT 1007
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`AQUESTIVE EXHIBIT 1007 page 1234
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`
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`2005/044234A2|||||||||||||||||||||||||||||||||||||||||||||||||l|||||||||||||||||||||||||||||||||||||||||||||
`
`W0
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`

`

`WO 2005/044234 A2
`
`CA. CH, CN, CO. CR. CU. CZ, DE, UK, DM'. DZ, EC, EE,
`EG.ES.F1. GB, GD, Cit-.0111. GM. HR, HU, ID. IL. IN, IS,
`JP, KE. KG. KP, KR. KZ. LC, LK. LR, LS, LT. LU. L'r’. M'A,
`MD, MG, MK, MN, MW, MX, MZ, N4. NI, NO, NZ. OM,
`PG, PH, Pt, P7? RO, RU, SC, SD, SE, SG, SK, 5!, SY, rt,
`TM, TN, TR, T7, 77,, UA, UG, UZ, VC, VN, YU, 2A, 2M,
`ZWC ARH’U patent (SW; GH, GM", KE, LS, MW, MZ, NH,
`SD, SL, SZ, TZ, UG, ZM', XIV), Eurasian patent (AM, AZ,
`BY, KG, KZ. M'D, RU,
`'11}. TIM), European patent (AI, BE,
`BU. CH. CY, CZ, DE. UK, EE. ES. FI, FR, GB. GR, HU,
`IE. IS, LI, LU. MC, NL, PL, PI. RO, SE, SI. SK. IR). OAPI
`patent (BE Bf. CE CG, CI, CM, GA, GN, GQ, 011*: ML,
`MR, NE, SN, TD. TG)
`as to the cwpiicantic entitlement to claim the priority of the
`earlier application (Rule 4. 1'7(iiij,J for thefiliimving desig—
`tttltitmx Ah, AG, ,‘JLL, AM, AT, AU, AZ, BA, 83, RH, BR, HW,
`BY, BZ, CA, CH, CN, CO, CR, CU, CZ,
`.r'JE, DR, DM, DZ,
`EC, EE, EG, ES, 1“}. GB, GD, GE, GH, GM‘, HR, HU, ID,
`IL. IN, IS. JP, KE, KG. KP. KR, KZ. LC, LK. LR, LS. LI. LU,
`
`LV. M11, MD. MG, MK. MN. M W: MX. MZ, NA. N1. NO. NZ.
`OM. PG, PH, PL, PI, R0, RU. SC, SD, SE, SG, SK. 51., 5!.
`TJ’. TM. TN, TR. TE". 1'2. UA. UG, UZ. VC. VN, YU. ZA.
`ZM. ZW, ARIPO patent (BW. GH, GM, KE, LS, MW, MZ.
`NA, SD, SL, 52, TZ, UG, ZM, ZW), Eurasian patent (AM,
`AZ, BY, KG, KZ, MD, RU, TI, TM), European Jpatent (.47:
`BE, HG, CH, CY: CZ, DE, UK, EE, ES, Ft, FR, GB, GR,
`HU, IE, tS, rt: LU, MC, NL, PL, P’t, no, SE, St, SK, TR),
`OAPI patent (BE BJ. CF. CG, CI, CM, GA. GN, (IQ, GW.
`ML. MR, NE, SN, TD. TU)
`
`Published:
`
`— without international search report and to be republished
`upon receipt of that report
`
`For t urn—fetter code; and other abbre'nr‘iatimix, refer In the "Guid—
`ance Notes on Code; and Abbreviations " appearing at the begin—
`ning (breach regular ia'stte ofthe PCT Gazette.
`
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`AQUESTIVE EXHIBIT 1007 page 1235
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`W0 2005HH4234
`
`PCTIUS2IMI4UII36337
`
`NANOPARTICULATE COMPOSITIONS HAVING
`
`A PEPTIDE AS A SURFACE STABILIZER
`
`FIELD OF THE INVENTION
`
`The present invention is directed to nanoparticulate active agent compositions
`
`having a peptide adsorbed onto or associated with the surface of the active agent as a
`
`surface stabilizer, and methods of making and using such compositions.
`
`BACKGROUND OF THE INVENTION
`
`Nancparticulate active agent compositions, first described in U.S. Patent 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 describes the use of a variety of
`
`10
`
`surface stabilizers for nanoparticulate compositions. The use of a peptide as a surface
`
`stabilizer for nanoparticulate active agent compositions is not described by the ‘684
`
`patent.
`
`The ‘684 patent describes a method of screening active agents to identify
`
`useful surface stabilizers that enable the production of a nanoparticulate composition.
`
`15
`
`Not all surface stabilizers will function to produce a stable, non-agglomerated
`
`nanoparticulate composition for all active agents. Moreover, known surface
`
`stabilizers may be unable to produce a stable, non—agglomerated nanOparticulate
`
`composition for certain active agents. Thus, there is a need in the art to identifi! new
`
`surface stabilizers useful in making nanoparticulate active agent compositions.
`
`20
`
`Additionally, such new surface stabilizers may have superior properties over prior
`
`known surface stabilizers.
`
`Methods of making nanoparticulate active agent compositions are described,
`
`for example, in US. Patent Nos. 5,518,187 and 5,862,999, both for “Method of
`
`Grinding Pharmaceutical Substances ;” US. Patent No. 5,718,3 88, for “Continuous
`
`25
`
`Method of Grinding Pharmaceutical Substances;” and US. Patent No. 5,510,118 for
`
`“Process of Preparing Therapeutic Compositions Containing Nanoparticles.”
`
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`AQUESTIVE EXHIBIT 1007 page 1236
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`W0 2005HH4Z3J
`
`PCTIUS2IMI4UII36337
`
`Nanoparticulate active agent compositions are also described, for example, in
`
`U.S. Patent Nos. 5,298,262 for “Use of Ionic Cloud Point Modifiers to Prevent
`
`Particle Aggregation During Sterilization;” 5,302,401 for “Method to Reduce Particle
`
`Size Growth During Lyophilization;” 5,318,767 for “X-Ray Contrast Compositions
`
`Useful in Medical imaging” 5,326,552 for “Novel Formulation For Nanoparticulate
`
`X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic
`
`Surfactants,” 5,328,404 for “Method of X~Ray Imaging Using Iodinated Aromatic
`
`Propanedioates;” 5,336,507 for “Use of Charged Phospholipids to Reduce
`
`Nanoparticle Aggregationf’ 5,340,564 for “Formulations Comprising Olin lO-G to
`
`Prevent Particle Aggregation and Increase Stabilityf’ 5,346,702 for “Use of Non-Ionic
`
`Cloud Point Modifiers to Minimize Nanoparticulate Aggregation During
`
`Sterilization;” 5,349,957 for “Preparation and Magnetic Properties of Very Small
`
`Magnetic-Dextran Particles;” 5,352,459 for “Use of Purified Surface Modifiers to
`
`Prevent Particle Aggregation During Sterilizationf’ 5,399,363 and 5,494,683, both for
`
`“Surface Modified Anticancer Nanoparticles;” 5,401,492 for “Water Insoluble Non»
`
`Magnetic Manganese Particles as Magnetic Resonance Enhancement Agents;”
`
`5,429,824 for “Use of Tyloxapol as a Nanoparticulate Stabilizerf’ 5,447,710 for
`
`10
`
`15
`
`“Method for Making Nanoparticulate X—Ray Blood Pool Contrast Agents Using High
`
`Molecular Weight Non-ionic Surfactants;” 5,451,393 for “X-Ray Contrast
`
`20
`
`Compositions Useful in Medical Imaging” 5,466,440 for ‘Ponnulations of Oral
`
`Gastrointestinal Diagnostic X—Ray Contrast Agents in Combination with
`Phannaceutically Acceptable Claysg” 5,470,583 for “Method ofPreparing
`
`Nanoparticle Compositions Containing Charged PhosPholipids to Reduce
`
`Aggregationg” 5,422,683 for ‘Nanoparticulate Diagnostic Mixed Carbamic
`
`Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System
`
`Imaging,” 5,500,204 for “Nanoparticulate Diagnostic Dimers as X—Ray Contrast
`
`Agents for Blood Pool and Lymphatic System Imaging” 5,518,738 for
`
`‘Nauopaiticulate NSAJD Fonnulationsg” 5,521,218 for ‘Nanoparticulate
`
`Iododipamide Derivatives for Use as X—Ray Contrast Agents;” 5,525,328 for
`
`“Nanoparticulate Diagnostic Diatn'zoxy Ester X~Ray Contrast Agents for Blood Pool
`
`25
`
`30
`
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`AQUESTIVE EXHIBIT 1007 page 1237
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`

`W0 20057044234
`
`PCTIU820047036337
`
`and Lymphatic 33’5th Imaging” 535411 33 for “Process of Preparing X-Ray Contrast
`
`Compositions Containing Nanoparticles;” 5,5 52,160 for “Surface Modified NSAID
`Nanoparticlesf’ 5,560,931 'for ‘Tonnulations of Compounds as Nanoparticulate
`
`Dispersions in Digestible Oils or Fatty Acids;” 5,565,188 for “Polyalkylene Block
`
`5
`
`Copolymers as Surface Modifiers for Nanoparticles;” 5,569,448 for “Sulfated Non-
`
`ionic Block Copolymer Surfactant as Stabilizer Coatings for Nanoparticle
`
`Compositions,” 5,571,536 for ‘Tonnulations of Compounds as Nanoparticulate
`
`Dispersions in Digestible Oils or Fatty Acids;” 5,573,749 for “Nanoparticulate
`
`Diagnostic Mixed Carboxylic Anydrides as X-Ray Contrast Agents for Blood Pool
`
`10
`
`and Lymphatic System Imagiugf’ 5,573,750 for “Diagnostic Imaging X-Ray Contrast
`
`Agents;” 5,573,783 for ‘Redispersible Nanoparticulate Film Matrices With Protective
`
`Overcoats;” 5,580,579 for “Site-specific Adhesion Within the GI Tract Using
`
`Nanoparticles Stabilized by‘High Molecular Weight, Linear Poly(ethylene Oxide)
`Polymersf’ 5,585,108 for ‘Tonnulations of Oral Gastrointestinal Therapeutic Agents
`
`15
`
`in Combination with Pharmaceutically Acceptable Clays;” 5,5 87,143 for “Butylene
`OxideuEthylene Oxide Block Copolymers Surfactants as Stabilizer Coatings for
`
`Nanoparticulate Compositions," 5,591,456 for “Milled Napl'OXBIl with Hydroxypropyl
`
`Cellulose as Dispersion Stabilizer,” 5,593,657 for “Novel Barium Salt Formulations
`
`Stabilized by Nonuionic and Anionic Stabilizers;” 5,622,938 for “Sugar Based
`
`20
`
`Surfactant for Nanocrystals;” 5,628,981 for “Improved Formulations of Oral
`
`Gastrointestinal Diagnostic X-Ray Contrast Agents and Oral Gastrointestinal
`
`Therapeutic Agents;” 5,643,552 for ‘Nanoparticulate Diagnostic Mixed Carbonic
`
`Anhydrides as X—Ray Contrast Agents for Blood Pool and Lymphatic System
`
`Imaging,” 5,718,388 for “Continuous Method of Grinding Pharmaceutical
`
`25
`
`Substances ;” 5,718,919 for “Nanoparticles Containing the R(-)Enantiomer of
`
`Ibuprofenf’ 5,747,001 for “Aerosols Containing Beclomethasone Nanoparticle
`
`Dispersions;” 5,834,025 for “Reduction of Intravenoust Administered
`
`Nanoparticulate Formulation Induced Adverse Physiological Reactions;” 6,045,829
`
`‘Nanocrystalline Formulations of Human Irmnunodeficiency Vitus (HIV) Protease
`
`30
`
`Inhibitors Using Cellulosic Surface Stabilizers,” 6,068,858 for “Methods of Making
`
`AQUESTIVE EXHIBIT 1007
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`AQUESTIVE EXHIBIT 1007 page 1238
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`W0 20057044234
`
`PCTIUSZIIID-‘l-flll36337
`
`Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease
`
`Inhibitors Using Cellulosic Surface Stabilizers;” 6,153,225 for “lnjectable
`
`Formulations of Nanoparticulate Naproxen;” 6,165,506 for “New Solid Dose Form of
`
`Nanoparticulate Naproxen;” 6,221,400 for “Methods of Treating Mammals Using
`
`Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease
`
`Inhibitor-sf” 6,264,922 for “Nebulized Aerosols Containing Nanoparticle
`
`Dispersions;” 6,267,989 for “Methods for Preventing Crystal Growth and Particle
`
`Aggregation in Nanoparticle Compositions;” 6,270,806 for “Use of PEG—Derivatized
`
`Lipids as Surface Stabilizers for Nanoparticulate Compositions,” 6,316,029 for
`
`10
`
`“Rapidly Disintegrating Solid Oral Dosage Form,” 6,375,986 for “Solid Dose
`
`Nanoparticulate Compositions Comprising a Synergistic Combination of a Polymeric
`
`Surface Stabilizer and Dioctyl Sodium Sulfosuccinate,” 6,428,814 for “Bioadhesive
`
`nanoparticulate compositions having cationic surface stabilizers,” 6,431,478 for
`
`“Small Scale Mill;” 6,432,381 for “Methods for Targeting Drug Delivery to the Upper
`
`15
`
`andfor Lower Gastrointestinal Tract,” Patent No. 6,582,285 for “Apparatus for
`
`Sanitary Wet Milling? 6,592,903 for ‘Nanoparticulate Dispersions Comprising a
`Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium
`
`Sulfosuccinate,” 6,742,734 for “System and Method for Milling Materials,” and
`
`6,745,962 for “Small Scale Mill and Method Thereof,” all of which are specifically
`
`20
`
`incorporated by reference. In addition, US. Patent Application No. 20020012675 A1,
`
`published on January 31, 2002, for “Controlled Release Nanoparticuiate
`
`Compositions,” and W0 0270985 65 for “System and Method for Milling Materials,”
`
`describe nanoparticulate active agent compositions, and are specifically incorporated
`
`by reference. None of these references describe nanoparticulate active agent
`
`compositions comprising a peptide surface stabilizer.
`
`Amorphous small particle compositions are described, for example, in US.
`
`Patent Nos. 4,783,484 for “Particulate Composition and Use Thereof as Antimicrobial
`
`Agent,” 4,826,689 for ‘Mcthod for Making Uniformly Sized Particles from Water-
`Insoluble Organic Compounds;” 4,997,454 for “Method for Making Uniformly-Sized
`
`30
`
`Particles From Insoluble Compounds;” 5,741,522 for “Ultrasmall, Non-aggregated
`
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`W0 2l|05i044234
`
`PCTflISZIIIM-i03633?
`
`Porous Particles of Uniform Size for Entrapping Gas Bubbles Within and Methods;”
`
`and 5,776,496, for “Ultrasmall Porous Particles for Enhancing Ultrasound Back
`
`Scatter.”
`
`There is a need in the art for new surface stabilizers useful in preparing
`
`nanoparticulate active agent compositions. The present invention satisfies this need.
`
`SUMMARY OF THE INVENTION
`
`10
`
`15
`
`The present invention is directed to nanoparticulate compositions comprising
`
`at least one active agent and at least one peptide as a surface stabilizer adsorbed onto,
`
`or associated with, the surface of the active agent.
`
`Another aspect of the invention is directed to pharmaceutical compositions
`
`compri sing a nanoparticulate active agent composition of the invention. The _
`
`pharmaceutical compositions preferably comprise at least one active agent, at least
`
`one peptide, and a phannaceutically acceptable carrier, as well as any desired
`
`excipients.
`
`In yet another embodiment, the invention is directed to bioadhesive
`
`nanoparticulate active agent compositions comprising at least one cationic peptide as a
`
`surface stabilizer, or at least one non-cationic peptide surface stabilizer in combination
`
`with at least one secondary cationic surface stabilizer. Such compositions can coat the
`
`gut, or the desired site of application, and be retained for a period of time, thereby
`
`20
`
`increasing the efficacy of the active agent as well as eliminating or decreasing the
`
`frequency of dosing.
`
`This invention further discloses a method of making a nanoparticulate active
`
`agent composition having a peptide surface stabilizer adsorbed on or associated with
`
`the surface of the active agent. Such a method comprises contacting an active agent
`with at least one peptide for a time and under conditions sufficient to provide a
`
`25
`
`Nanoparticle active agenflpeptide composition. The peptide surface stabilizer can be
`
`contacted with the active agent either before, preferably during, or after size reduction
`
`of the active agent.
`
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`The present invention is further directed to a method of treatment comprising
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`administering to a mammal a therapeutically effective amount of a nanoparticulate
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`active agentfpeptide composition according to the invention.
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`Both the foregoing general description and the following detailed description
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`are exemplary and explanatory and are intended to provide further explanation of the
`invention as claimed. Other objects, advantages, and novel features will be readily
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`apparent to those skilled in the art from the following detailed description of the
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`invention.
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`BRIEF DESCRIPTION OF THE FIGURES
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`FIGURE 1:
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`Shows representative photomierographs of nystatin crystals
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`before (Fig. 1A) and aficr (Fig. 1B) milling;
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`FIGURE 2:
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`Shows the results of monitoring the particle size stability over
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`time at 5°C (solid line), 25°C (dashed line), and 40°C (dotted line) for a
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`nanoparticulate nystatin composition comprising the peptide poly(Lysine, Tryptophan)
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`4:1 hydrobromide as a surface stabilizer; and
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`FIGURE 3:
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`Shows representative micrographs of cells with anionic
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`particles (Fig. 3A) and cationic particles (Fig. 3B).
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`DETAILED DESCRIPTION OF THE INVENTION
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`The present invention is directed to compositions comprising nanopartieulate
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`active agents having at least one peptide as a surface stabilizer adsorbed on or
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`associated with the surface thereof, and methods of making and using such
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`nanoparticulate compositions.
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`As taught in the “684 patent, not every combination of surface stabilizer and
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`active agent will result in a stable nanoparticulate composition. The discovery of the
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`present invention is surprising in that peptides are biological compounds having
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`secondary and tertiary structures which are critical to the activity of the peptide. It
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`was surprising that such a compound could be successfully used to stabilize a
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`nanoparticulate active agent. Moreover, it was even more surprising that milling of a
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`peptide surface stabilizer did not change the activity or function of the peptide.
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`A “peptide” is defined as any compound consisting of two or more amino
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`acids where the alpha carboxyl group of one is bound to the alpha amino group of
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`another. A polypeptide is a long peptide chain. A protein is a large macromolecule
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`composed of one or more polypeptide chains. In the context of the present invention,
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`“peptide” refers to a peptide or a polypeptide, but not a protein.
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`A striking characteristic of peptides is that they have well-defined three
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`dimensional structures. Peptides fold into compact structures with nominal bond
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`lengths. The strong tendency of hydrophobic amino acid residues to flee from water
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`drives the folding of soluble peptides.
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`A stretched-out or randomly arranged polypeptide chain is devoid of biological
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`activity. This is because the function of a peptide arises flom confomiation, which is
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`the three dimensional arrangement of atoms in a structure. See e.3., L. Stryer,
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`Biochemistry, 3rd Edition, p. 1—41 (WH. Freeman a. 00., NY, 1988). Amino acid
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`sequences are important because they specify the couformation of peptides. Id.
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`Peptides have several different defined structures, including a primary,
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`secondary, and tertiary structure. The primary structure of a peptide is generally the
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`amino acid sequence of the peptide and the location of disulfides. See e.g., L. Stryer,
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`Biochemistry, 3rd Edition, p. 31 (WH. Freeman & (30., NY, 1988). Secondary
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`structure refers to the spatial arrangement of amino acid residues that are near one
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`another in the linear sequence. Examples of these steric relationships are structures
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`known as an alpha helix, a beta pleated sheet, and a collagen helix. Id. Tertiary
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`structure refers to the spatial arrangement of amino acid residues in a peptide or
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`polypeptide that are far apart in the linear sequence.
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`Proteins, comprising multiple polypeptide chains, also have a quaternary
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`structure, which refers to the spatial arrangement of the polypeptide subunits and the
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`nature of their contacts. Id.
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`It was very snipiising that such complex compounds as peptides and
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`polypeptides could be succeSSfully utilized as a surface stabilizer for a nanoparticulate
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`active agent. In addition to enabling the use of a new class of surface stabilizers for
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`nanoparticulate active agents, this discovery is significant as the peptide surface
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`stabilizer in the compositions of the invention may also have therapeutic or diagnostic
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`properties. This is in contrast to prior art nanopaiticulate active agent compositions,
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`in which the surface stabilizer is generally a surfactant, which lacks such therapeutic
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`or diagnostic properties.
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`The nanoparticulate active agent compositions of the invention may also offer
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`- the following advantages as compared to prior conventional or non-nanoparticulate
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`active agent compositions:
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`(1) faster onset of action; (2) a potential decrease in the
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`frequency of dosing; (3) smaller doses of active agent required to obtain the same
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`pharmacological effect; (4) increased bioavailability; (5) an increased rate of
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`dissolution; (6) improved performance characteristics for oral, intravenous,
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`subcutaneous, or intramuscular inj ection; such as higher active agent dose loading and
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`smaller tablet or liquid dose volumes; (7) improved pharmacokinetic profiles, such as
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`improved Tmax, CHM; and AUC profiles; (8) substantially similar or bioequivalent
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`pharmacokinetic profiles of the nanoparticulate active agent compositions when
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`administered in the fed versus the fasted state; (9) bioadhesive active agent
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`compositions, which can coat the gut or the desired site of application and be retained
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`for a period of time, thereby increasing the efficacy of the active agent as well as
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`. eliminating or decreasing the frequency of dosing; (10) high redispersibility of the
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`nanoparticulate active agent particles present in the compositions of the invention
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`following administration; (11) the nanoparticulate active agent compositions can be
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`formulated in a dried form which readily redisperses; (12) low viscosity liquid
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`nanoparticulate active agent dosage forms can be made; (13) for liquid nanoparticulate
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`active agent compositions having a low viscosity - better subject compliance due to
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`the perception of a lighter formulation which is easier to consume and digest; (14) for
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`liquid nanoparticulate active agent compositions having a low viscosity - ease of
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`dispensing because one can use a cup or a syringe; (15) the nanoparticulate active
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`agent compositions can be used in conjunction with other active agents; (16) the
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`nanoparticulate active agent compositions can be sterile filtered; (17) the
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`nanoparticulate active agent compositions are suitable for parenteral administration;
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`and (18) the nanoparticulate active agent compositions do not require organic solvents
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`or pH extremes.
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`A preferred dosage form of the invention is a solid dosage form, although any
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`phannaceutically acceptable dosage form can be utilized. Exemplary dosage forms
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`include, but are not limited to, tablets, capsules, sachets, lozenges, powders, pills,
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`granules, liquid dispersions, oral suspensions, gels, aerosols (including nasal and
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`pulmonary), ointments, and creams.
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`The dosage form ofthe invention can be, for example, a fast melt dosage form,
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`controlled release dosage form, lyophilized dosage form, delayed release dosage form,
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`extended release dosage form, pulsatile release dosage form, mixed immediate release
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`and controlled release dosage form, or a combination thereof.
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`In addition, the compositions ofthe invention can be formulated for any
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`suitable administration route, such as oral, pulmonary, rectal, opthahnic, colonic,
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`parenteral, intracistemal, intravaginal, intraperitoneal, local, buccal, nasal, or topical
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`administration.
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`The present invention is described herein using several definitions, as set forth
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`below and throughout the application.
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`As used herein, “about” will be understood by persons of ordinary skill in the
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`art and will vary to some extent on the context in which it is used. If there are uses of
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`the term which are not clear to persons of ordinary skill in the art given the context in
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`which it is used, “about” will mean up to plus or minus 10% of the particular term.
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`“Conventional” or “non-nanoparticulate active agent” shall mean an active
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`agent which is solubilized or which has an effective average particle size of greater
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`than about 2 microns. Nanoparticulate active agents as defined herein have an
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`effective average particle size of less than about 2 microns.
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`“Pharmaceutically acceptable” as used herein refers to those compounds,
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`materials, compositions, andfor dosage forms which are, within the scope of sound
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`medical judgment, suitable for use in contact with the tissues of human beings and
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`animals without excessive toxicity, irritation, allergic response, or other problem or
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`complication, commensurate with a reasonable benefitfrisk ratio.
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`“Pharmaceutically acceptable salts” as used herein refers to derivatives
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`wherein the parent compound is modified by making acid or base salts thereof.
`Examples ofpharmaceutically acceptable salts include, but are not limited to, mineral
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`or organic acid salts of basic residues such as amines; alkali or organic salts of acidic
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`residues such as carboxylic acids; and the like. The pharmaceutically acceptable saits
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`include the conventional non-toxic salts or the quaternary ammonium salts of the
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`parent compound formed, for example, from non-toxic inorganic or organic acids.
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`For example, such conventional non—toxic salts include those derived from inorganic
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`acids such as hydrochloric, hydrobromic, sulfuric, sulfarnic, phosphoric, nitric, and the
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`like; and the salts prepared from organic acids such as acetic, propionic, succinic,
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`glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, malcic,
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`hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-
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`acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic,
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`isethionic, and the like.
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`“Poorly water soluble drugs” as used herein means those having a solubility of
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`less than about 30 mg/ml, preferably less than about 20 mg/ml, preferably less than
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`about 10 mg/ml, or preferably less than about 1 mg/ml. Such drugs tend to be
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`eliminated from the gastrointestinal tract before being absorbed into the circulation.
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`As used herein with reference to stable drug particles, “stable” includes, but is
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`not limited to, one or more of the following parameters:
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`(1) that the active agent
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`particles do not appreciably flocculate or agglomerate due to interparticle attractive
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`forces, or otherwise significantly increase in particle size over time; (2) that the
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`physical structure of the active agent particles is not altered over time, such as by
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`conversion from an amorphous phase to crystalline phase; (3) that the active agent
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`particles are chemically stable; and!or (4) where the active agent has not been subject
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`to a heating step at or above the melting point of the active agent in the preparation of
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`the nanoparticles of the invention.
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`“Therapeutically effective amount” as used herein with respect to an active
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`agent dosage, shall mean that dosage that provides the specific pharmacological
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`response for which the active agent is administered in a significant number of subjects
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`in need of such treatment. It is emphasized that “therapeutically effective amount,”
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`administered to a particular subject in a particular instance will not always be effective
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`in treating the diseases described herein, even though such dosage is deemed a
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`‘therapeutically effective amount“ by those skilled in the art. It is to be further
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`understood that active agent dosages are, in particular instances, measured as oral
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`dosages, or with reference to active agent levels as measured in blood.
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`I.
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`Preferred Characteristics of the Nanoparticulate
`Active Agent Compositions of the Invention
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`A.
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`Increased Bio-availability, Frequency
`of Dosing, and Dosage Quantity
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`The nanoparticulate active agent compositions of the invention, having at least
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`one peptide as a surface stabilizer, may preferably exhibit increased bioavailability
`and require smaller doses as compared to prior non—nanoparticulate compositions of
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`the same active agent administered at the same dose.
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`Any active agent can have adverse side effects. Thus, lower doses of an active
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`agent that can achieve the same or better therapeutic effects as those observed with
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`larger doses of a non-nanoparticulate composition of the same active agent are
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`desired. Such lower doses may be realized with the nanoparticulate active agent
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`compositions of the invention because the nanoparticulate active agent compositions
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`may exhibit greater bioavailability as compared to non-nanoparticulate compositions
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`of the same active agent, which means that smaller doses of the active agent are likely
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`require