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`(12) INTERNATIONAT. APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`
`
`(43) International Publication Daic
`19 May 2005 (19.05.2005)
`
`(10) International Publication Number
`WO 2005/044234 A2
`
`(51) International Patent Classification’:
`
`A6I1K 9/14
`
`(21) Loternalional Application Number:
`PCT/LUS2004/036337
`
`(22) International Filing Dale:
`2 November2004 (02.11.2004)
`
`(25) Filing Language:
`
`(26) Publicalion Language:
`
`linglish
`
`English
`
`(30) Priority Data:
`60/317, 106
`
`3 November 2003 (05.11.2003)
`
`US
`
`(71) Applicant (fer at! designated States except US KLAN
`PHARMA INTERNATIONAL, LTD.
`[TEE];
`‘WTI.
`House, Shannon Business Park, Shannon, County Clare
`(I).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): CUNNINGHAM,
`James [US/US]; 903 Charleston Greene, Malvemm, PA
`19355 (US). LIVERSIDGE, Elaine, Merisko [US/US]:
`258 Colwyn Terrace, West Chesicr, PA 19380 (US).
`
`(74) Agents: STIMKIN, Michele, Ml.ct al.; Foley & Tardner
`LI.P, Washington Harbour, 3000 K Street, NW. Suite 500,
`Washington, DC 20007-5101 (US).
`
`(81) Designated States (arnfess otherwise érelicated, for every
`hind of national protection available}: AT AG, AT, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, LC, EL, LG, ES, TT,
`GB, GD, GU, GH, GM, AR, HU, ID, IL, IN, IS, JP, KL,
`KG, KP, KR, K4, LC, LK, LR, LS, LI LU, LY, MA, MD,
`MG, MR, MN, MW. MX, M4, NA, NI, NO, NZ, OM, PG,
`PL, PL, PT, RO, RU, SC, SD, SH, SG, SK, SI, SY, TI, "TM,
`TN, TR, VT, TA, UA, OG, US, O04, WC, YN, YO, AA, AM,
`AW,
`
`(84) Designated States (unless otherwise indicaied, for every
`kind of regional proieciton avaiable}: ARIPO (BW, GH,
`GM, KE, LS, MW, M#, NA, SD, SL, $4, ‘TZ, UG, 2M,
`AW), Eurasian (AM, AZ. BY, KG, KZ, MD, ROU, ‘TJ, TM),
`European (Al, BE, BG, Cl, CY, CZ, DE, DK, BE, ES, BL,
`ER, GB, GR, IU, [E, 18, Il, LU, MC, NI, PL. PT, RO, SE,
`SI, SK, TR), OAPT(BF, BI, CF, CG, Cl, CM, GA, GN, GQ,
`GW, MI, MR, NI. SN, TD, TG).
`
`Declarations under Rule 4.17:
`
`— as to applicant's entitlement to apply for and be granted
`a patent (Rute 4.7 7(ii}) for the following designations AF,
`AG, AL, AM. AT. AU. AZ. BA. BB, BG. BR. BW. BY. B7,
`
`{Continued on next page]
`
`(54) Titles NANGPARTICULATE COMPOSTTIONS DAVING A PEPTIDE AS A SURFACE STABILIZER
`
`>
`
`
`
`(87) Abstraed: ‘he present invention is directed Lo nanoparticulate active agent compositions comprising al least one peptide as a
`surface stabilizer. Also encompassed by the invention are pharmaccutical compositions comprising a nanoparticulate active agent
`composition ofthe invention and methods of making and using such nanopariiculate and pharmaccutical compositions.
`AQUESTIVE EXHIBIT 1007
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`2005/044234A2IMVMIINURNIANIINANATTTATNAMTTATAMIYAA
`
`WwO
`
`

`

`WO 2005/044234 A2
`
`CA, CH, CN, CO, CR, CU C4, DE, DK, DM, DZ, EC, EF,
`EG, &S, FL, G8, OD, GE, GOL, OM, LK, fil) BD, IL, IN, ES,
`JP KEL KG, RP ER, KZ, EC, LK, ER, LS, ET) LO), EV MA,
`MD, MG, MK, MN, MW, MX, MZ, NA, NIL NO, NZ OM,
`PG, PH, PL. PT. RO. RU. SC, SD. SE, SG. SK. SL, SY. TI.
`TM, TN, TR. TT, TZ, UA, UG, UZ. VC, VN, YU, ZA, ZM,
`AW. ARIPO patent (BW, GA, CE, KEL LS. MW. MZ, NA,
`SD, SE SA, TA UG, 4M. AW), Burasican patent fAM, AZ.
`BY KO, KZ, MD, RU Td, 1M), European pateni (AL BE,
`8G, CH, CY CZ, DE, DK, EE, BS, Fl, FR, GB, GR, Litt
`fh ES, 2EOLU MC, NE, PL, PE ORO, SE, SE SK, TR), OAPI
`patent (BF BF CE CG, Ch CM, GA, GN, GO, GH ME,
`MR, NE, SN, TD, TG}
`as to the applicant's entitlement to claim the priority of the
`earlier application (Rule 4.17(iii}) for the following desig-
`nations AB, AG, AL AM, AT, AU. AZ, BA, BB, BG, BR, BW.
`BY BA CA, CH, CN, CO, CR, CU. C4, DR, DK, DM, DA,
`EC, EE,GO, BS, FL GB, GD, GE, GU, GM, LERLit! ED.
`EL UNESP RE, KG, KP ORR, KZ LC, LK, ER, ES, LLU,
`
`LV, MA, AAD, MG, AK, MN, MW MX, MZ, NA. NE NO, NZ,
`OM, PG. PL PL, PT RO, RU SC, SO, SE, SG, SK, SE, S¥.
`Td, TM, TN, TR, TT T#, UA, UG, UZ, VC. VN, YU, ZA,
`2M, ZW, ARIPO patent (BW GH, GM, KE, ES, MW, MZ,
`NA, SD, SE, SA. 74, UG, 2M, ZW), Eurasian patent (AM,
`AZ, BY, KG, KZ, MD, RUT, TM), European patent (AT,
`BE, AG, CA, CY C4, DR OK, EK, ES, FE, FR, GB, GR,
`HU 1K, IS, EE LUMO, NL, PL. PT. RO, SE. SLSK, TR),
`OAPT patent (BE BU, CE CG, Ci, CM, GA, GN, GG, CW.
`ML, MR, NE, SN, TD, TG)
`
`Published:
`
`— without international search report and to be republished
`upon receipt of that report
`
`For two-letter cadey and ather abbreviations, refer io the “Crid-
`ance Notes on Codes and Abbreviations” appearing ai the begin-
`ning of each regular issue ofthe PCT Guzeiie.
`
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`

`

`WO 2005/044234
`
`PCT/US2004/036337
`
`NANOPARTICULATE COMPOSITIONS HAVING
`
`A PEPTIDE AS A SURFACE STABILIZER
`
`FIELD OF THE INVENTION
`
`The present invention ts 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
`
`Nanoparticulate 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
`
`nom-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 compositionsis not described bythe “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.
`Notall surface stabilizers will function to produce a stable, non-agglomerated
`
`15
`
`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 theart to identify 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 U.S. Patent Nos. 5,518,187 and 5,862,999, both for “Method of
`
`Grinding Pharmaceutical Substances;” U.S. Patent No. 5,718,388, for “Continuous
`
`23
`
`Method of Grinding Pharmaceutical Substances;” and U.S. Patent No. 5,510,118 for
`
`“Process of Preparing Therapeutic Compositions Containing Nanoparticles.”
`
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`WO 2005/044234
`
`PCT/US2004/036337
`
`Nanoparticulate active agent compositions are also described, for example, in
`
`U.S. Patent Nos. 5,298,262 for “Use of Jonic 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-ienic
`
`Surfactants;” 5,328,404 for “Method of X-Ray Imaging Using Iodinated Aromatic
`
`Propanedioates;” 5,336,507 for “Use of Charged Phospholipids ta Reduce
`
`Nanoparticle Ageregation;” 5,340,564 for “Formulations Comprising Olin 10-G to
`
`10
`
`Prevent Particle Aggregation and Increase Stability;” 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 ofPurified Surface Modifiers to
`
`Prevent Particle Aggregation During Sterilization;” 5,399,363 and 5,494,683, both for
`
`15
`
`“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 Stabilizer;” 5,447,710 for
`“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 “Formulations of Oral
`
`Gastrointestinal Diagnostic X-Ray Contrast Agents in Combination with
`Pharmaceutically Acceptable Clays;” 5,470,583 for “Method ofPreparing
`Nanoparticle Compositions Containing Charged Phospholipids to Reduce
`
`Ageregation;” 5,472,683 for “Nanoparticulate Diagnostic Mixed Carbamic
`
`25
`
`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
`
`“Nanoparticulate NSAID Formulations;” 5,521,218 for “Nanoparticulate
`
`Iododipamide Derivatives for Use as X-Ray Contrast Agents;” 5,525,328 for
`
`30
`
`“Nanoparticulate Diagnostic Diatrizoxy Ester X-Ray Contrast Agents for Blood Poo!
`
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`

`

`WO 2005/044234
`
`PCT/US2004/036337
`
`and Lymphatic System Imaging;” 5,543,133 for “Process ofPreparing X-Ray Contrast
`Compositions Containing Nanoparticles;” 5,552,160 for “Surface Modified NSAID
`Nanoparticles;” 5,560,931 for “Formulations of Compounds as Nanoparticulate
`Dispersions in Digestible Oils or Fatty Acids;” 5,565,188 for “Polyalkylene Block
`Copolymers as Surface Modifiers for Nanoparticles;” 5,569,448 for “Sulfated Non-
`ionic Block Copolymer Surfactant as Stabilizer Coatings for Nanoparticle
`Compositions;” 5,571,536 for “Formulations of Compounds as Nanoparticulate
`Dispersions in Digestible Oils or Fatty Acids;” 5,573,749 for “Nanoparticulate
`Diagnostic Mixed Carboxylic Anydrides as X-Ray Contrast Agents for Blood Pool
`and Lymphatic System Imaging;” 5,573,750 for “Diagnostic Imaging X-Ray Conirast
`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}
`Polymers;” 5,585,108 for “Formulations ofOral Gastrointestinal Therapeutic Agents
`in Combination with Pharmaceutically Acceptable Clays;” 5,587,143 for “Butylene
`Oxide-Ethylene Oxide Block Copolymers Surfactants as Stabilizer Coatings for
`Nanoparticulate Compositions;” 5,591,456 for “Milled Naproxen with Hydroxypropyl
`Cellulose as Dispersion Stabilizer;” 5,593,657 for “Novel Barium Salt Formulations
`Stabilized by Non-ionic and Anionic Stabilizers,” 5,622,938 for “Sugar Based
`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 Pooland Lymphatic System
`Imaging;”5,718,388 for “Continuous Method of Grinding Pharmaceutical
`Substances;” 5,718,919 for “Nanoparticles Containing the R(-)Enantiomer of
`Tbuprofen;” 5,747,001 for “Aerosols Containing Beclomethasone Nanoparticle
`Dispersions;” 5,834,025 for “Reduction ofIntravenously Administered
`Nanoparticulate Formulation Induced Adverse Physiological Reactions;” 6,045,829
`“Nanocrystalline Formulations ofHuman Immunodeficiency Virus (HIV) Protease
`Inhibitors Using Cellulosic Surface Stabilizers;” 6,068,858 for “Methods of Making
`
`10
`
`15
`
`20
`
`25
`
`30
`
`AQUESTIVE EXHIBIT 1007
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`AQUESTIVE EXHIBIT 1007 page 1238
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`

`

`WO 2005/044234
`
`PCT/US2004/036337
`
`Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease
`Inhibitors Using Cellulosic Surface Stabilizers;” 6,153,225 for “Injectable
`Formulations of Nanoparticulate Naproxen;”6,165,506 for “New Solid Dose Form of
`Nanoparticulate Naproxen;”6,221,400 for “Methods of Treating Mammals Using
`Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease
`Inhibitors;” 6,264,922 for “Nebulized Aerosols Containing Nanoparticle
`Dispersions;” 6,267,989 for “Methods for Preventing Crystal Growth and Particle
`Aggregation in Nanoparticle Compositions;” 6,270,806 for “Use of PEG-Derivatized
`Lipids as Surface Stabilizers for Nanoparticulate Compositions;” 6,316,029 for
`“Rapidly Disintegrating Solid Oral Dosage Form,”6,375,986 for “Solid Dose
`Nanoparticulate Compositions Comprising a Synergistic Combination of a Polymeric
`Surface Stabilizer and Dioctyl Sodium Sulfosuccinate,” 6,428,814 for “Bioadhesive
`nanoparticulate compositions having cationic surface stabilizers;” 6,431,478 for
`“Small Scale Mill.” 6,432,381 for “Methods for Targeting Drug Delivery to the Upper
`and/or 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
`incorporated by reference. In addition, U.S. Patent Application No. 20020012675 AJ,
`published on January 31, 2002, for “Controlled Release Nanoparticulate
`Compositions,” and WO 02/098565 for “System and Method for Milling Materials,”
`describe nanoparticulate active agent compositions, and are specifically incorporated
`by reference. Noneofthese references describe nanoparticulate active agent
`compositions comprising a peptide surface stabilizer.
`
`10
`
`15
`
`29
`
`Amorphous small particle compositions are described, for example, in U.S.
`Patent Nos. 4,783,484 for “Particulate Composition and Use Thereof as Antimicrobial
`Agent;” 4,826,689 for “Method for Making Uniformly Sized Particles from Water-
`Insoluble Organic Compounds;” 4,997,454 for “Method for Making Uniformly-Sized
`Particles From Insoluble Compounds;” 5,741,522 for “Ulirasmall, Non-aggregated
`
`30
`
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`WO 2005/044234
`
`PCT/US2004/036337
`
`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 theart for new surface stabilizers useful in preparing
`
`nanoparticulate active agent compositions. The present invention satisfies this need.
`
`SUMMARY OF THE INVENTION
`
`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.
`
`10
`
`Another aspect of the invention is directed to pharmaceutical compositions
`
`comprising a nanoparticulate active agent composition of the invention. The
`
`pharmaceutical compositions preferably comprise at least one active agent, at least
`
`one peptide, and a pharmaceutically acceptable carrier, as well as any desired
`
`excipients.
`
`15
`
`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 onc 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 oftime, 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
`
`25
`
`the surface of the active agent. Such a method comprises contacting an active agent
`withat least one peptide for a time and under conditions sufficient to provide a
`Nanoparticle active agent/peptide composition. The peptide surface stabilizer can be
`
`contacted with the active agenteither before, preferably during, or after size reduction
`
`of the active agent.
`
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`

`WO 2005/044234
`
`PCT/US2004/036337
`
`The present invention is further directed to a method of treatment comprising
`administering to a mammal a therapeutically effective amount of a nanoparticulate
`
`active agent/peptide composition according to the invention.
`
`5
`
`Both the foregoing general description and the following detailed description
`are exemplary and explanatory and are intendedto 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.
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`10
`
`FIGURE 1:
`
`Showsrepresentative photomicrographs of nystatin crystals
`
`before (Fig. 1A) and after (Fig. 1B) milling;
`
`FIGURE 2:
`
`Showstheresults of monitoring the particle size stability over
`
`time at 5°C (solid line), 25°C (dashed line), and 40°C (dotted line) for a
`nanoparticulate nystatin composition comprising the peptide poly(Lysine, Tryptophan)
`
`15
`
`4:1 hydrobromide as a surface stabilizer; and
`
`FIGURE 3:
`
`Showsrepresentative micrographsof cells with anionic
`
`particles (Fig. 3A) and cationic particles (Fig. 3B).
`
`DETAILED DESCRIPTION OF THE INVENTION
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`20
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`The present inventionis directed to compositions comprising nanoparticulate
`active agents having at least one peptide as a surface stabilizer adsorbed on or
`associated with the surface thereof, and methods of making and using such
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`nanoparticulate compositions.
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`Astaught in the ‘684 patent, not every combination of surface stabilizer and
`active agent will result in a stable nanoparticulate composition. The discovery of the
`present inventionis surprising in that peptides are biological compounds having
`secondary and tertiary structures which are critical to the activity of the peptide. It
`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
`peptide surfacestabilizer 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
`acids where the alpha carboxyl group of one is bound to the alpha amino group of
`another. A polypeptide is a long peptide chain. A protein is a large macromolecule
`composed of one or more polypeptide chains. In the context of the present invention,
`“peptide” refers to a peptide or a polypeptide, but not a protein.
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`A striking characteristic ofpeptides is that they have well-defined three
`dimensional structures. Peptides fold into compactstructures with nominal bond
`lengths. The strong tendency of hydrophobic aminoacid residuesto 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 from conformation, which is
`the three dimensional arrangement of atoms in a structure. See e.g., L. Stryer,
`Biochemistry, 3" Edition, p. 1-41 (WH. Freeman & Co., NY, 1988). Amino acid
`sequences are important because they specify the conformation of peptides. Jd.
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`Peptides have several different defined structures, including a primary,
`secondary, andtertiary structure. The primary structure of a peptide is generally the
`amino acid sequenceof the peptide and the location of disulfides. See e.g., L. Stryer,
`Biochemistry, 3" Edition, p. 31 (W.H. Freeman & Co., NY, 1988). Secondary
`structure refers to the spatial arrangement of aminoacid residuesthat are near one
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`another in the linear sequence. Examples of thesesteric relationships are structures
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`known as an alphahelix, a beta pleated sheet, and a collagen helix.
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`/d. Tertiary
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`structure refers to the spatial arrangement of aminoacid residuesin 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. Ja.
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`It was very surprising that such complex compoundsas peptides and
`polypeptides could be successfully utilized as a surface stabilizer for a nanoparticulate
`active agent. In addition to enabling the use of a newclass of surfacestabilizers for
`nanoparticulate active agents, this discovery is significant as the peptide surface
`stabilizer in the compositions of the invention may also have therapeutic or diagnostic
`properties. This is in contrast to prior art nanoparticulate active agent compositions,
`in which the surfacestabilizer is generally a surfactant, which lacks such therapeutic
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`or diagnostic properties.
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`The nanoparticulate active agent compositions ofthe invention mayalso offer
`. the following advantages as compared to prior conventional or non-nanoparticulate
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`(1) faster onset of action; (2) a potential decrease in the
`active agent compositions:
`frequency of dosing; (3) smaller doses ofactive agent required to obtain the same
`pharmacologicaleffect; (4) increased bioavailability; (5) an increased rate of
`dissolution; (6) improved performancecharacteristics fororal, intravenous,
`subcutaneous, orintramuscular injection, such as higher active agent dose loading and
`smaller tablet or liquid dose volumes; (7) improved pharmacokinetic profiles, such as
`improved Trax; Cmax, aud AUC profiles; (8) substantially similar or bioequivalent
`pharmacokinetic profiles of the nanoparticulate active agent compositions when
`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
`for a period of time, thereby increasing the efficacy of the active agent as well as
`_ eliminating or decreasingthe frequency of dosing; (10) high redispersibility of the
`nanoparticulate active agentparticles present in the compositions of the invention
`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 hquid
`nanoparticulate active agent dosage forms can be made; (13) for liquid nanoparticulate
`active agent compositions having a low viscosity - better subject compliance due to
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`the perception of a lighter formulation whichis easier to consume and digest; (14) for
`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
`nanoparticulate active agent compositions can besterile filtered; (17) the
`nanoparticulate active agent compositionsare suitable for parenteral administration;
`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 ofthe invention is a solid dosage form,although any
`pharmaceutically acceptable dosage form can be utilized. Exemplary dosage forms
`include, but are notlimited to, tablets, capsules, sachets, lozenges, powders,pills,
`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,
`controlled release dosage form,lyophilized dosage form, delayed release dosage form,
`extended release dosage form,pulsatile releasc 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 formulatedfor any
`suitable administration route, such as oral, pulmonary, rectal, opthalmic, colonic,
`parenteral, intracisternal, 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 throughoutthe application.
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`Asused herein, “about” will be understood by personsof 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
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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
`than about 2 microns. Nanoparticulate active agents as defined herein have an
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`effective averageparticle size of less than, about 2 microns.
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`“Pharmaceutically acceptable” as used herein refers to those compounds,
`materials, compositions, and/or dosage forms whichare, within the scope of sound
`medical judgment, suitable for use in contact with the tissues ofhuman beings and
`animals without excessive toxicity, irritation, allergic response, or other problem or
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`complication, commensurate with a reasonable benefit/risk ratio.
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`“Pharmaceutically acceptable salts” as used herein refers to derivatives
`wherein the parent compoundis modified by making acid or base salts thereof.
`Examples ofpharmaceutically acceptablesalts include, but are not limited to, mineral
`or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidic
`residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts
`include the conventional non-toxic salts or the quaternary ammonium salts of the
`parent compound formed, for example, from non-toxic inorganic or organic acids.
`For example, such conventional non-toxic salts include those derived from inorganic
`acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the
`like; and the salts prepared from organic acids such as acetic, propionic, succinic,
`glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, malcic,
`hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-
`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
`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. Such drugs tendto be
`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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`(1) that the active agent
`notlimited to, one or moreofthe following parameters:
`particles do not appreciably flocculate or agglomerate due to interparticle attractive
`forces, or otherwise significantly increase in particle size over time; (2) that the
`physical structure of the active agentparticles is not altered over time, such as by
`conversion from an amorphousphaseto 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
`to a heating siep at or above the melting point ofthe active agent in the preparation of
`the nanoparticles of the invention.
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`“Therapeutically effective amount”as used herein with respect to an active
`agent dosage, shall mean that dosage that provides the specific pharmacological
`response for which the active agent is administered in a significant number of subjects
`in need of such treatment. It is emphasized that “therapeutically effective amount,”
`administered to a particular subject in a particular instance will not always be effective
`in treating the diseases described herein, even though such dosage is deemed a
`‘therapeutically effective amount’ by those skilled in the art. It is to be further
`understoodthat active agent dosages are, in particular instances, measured as oral
`dosages, or with reference to active agent levels as measured in blood.
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`L
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`Preferred Characteristics of the Nanoparticulate
`Active Agent Compositions of the Invention
`
`A.
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`Increased Bioavailability, Frequency
`of Dosing, and Dosage Quantity
`The nanoparticulate active agent compositions ofthe invention, having atleast
`one peptide as a surface stabilizer, may preferably exhibit increased bioavailability
`and require smaller doses as compared to prior non-nanoparticulate compositions of
`the same active agent administered at the same dose.
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`Any active agent can have adverse side effects. Thus, lower dosesof an active
`agent that can achieve the sameor better therapeutic effects as those observed with
`larger doses of a non-nanoparticulate composition ofthe same active agent are
`desired. Such lower doses may berealized with the nanoparticulate active agent
`compositions ofthe invention because the nanoparticulate active agent compositions
`may exhibit greater bioavailability as compared to non-nanoparticulate compositions
`of the same active agent, which meansthat smaller doses of the active agentare likely
`required to obtain the desired therapeutic effect.
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`The nanopatticulate active agent compositionsof the invention may be
`administered less frequently and at lower doses, as compared to conventional non-
`nanoparticulate compositions ofthe same active agent, in dosage forms such as liquid
`dispersions, powders, sprays, aerosols (pulmonary and nasal), solid re-dispersable
`dosage forms,gels, ointme