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`2000 amino acids residues. The mean molecular weight of an aminoacid residue is
`about 110 daltons, and so the molecular weights of most polypeptide chains are
`between 5500 and 220,000. See e.g., L. Stryer, Biochemistry, 3" Edition, p. 22 (W.H.
`
`Freeman & Co., NY, 1988).
`
`A protein is a large macromolecule composed of one or more polypeptide
`chains. In the context of the present invention, a “peptide”refers to a peptide or a
`
`polypeptide, but not a protein.
`
`Preferably, the peptide surface stabilizers of the invention are water soluble.
`By “water soluble,” it is meant that the peptide has a water solubility of greater than
`about 1 mg/mL, greater than about 10 mg/mL, greater than about 20 mg/mL, or
`greater than about 30 mg/mL. Thisis in contrast to prior art compositions teaching
`the use of a peptide as an active agent in a nanoparticulate active agent composition.
`See e.g., U.S. Patent Nos. 6,270,806; 6,592,903; 6,428,814; and 6,375,986. In such
`prior art references, whena peptide is utilized as an active agent in a nanoparticulate
`composition, the peptide is poorly water soluble.
`
`Thereis an extensive catalog of commercially available peptides that can be
`used in the compositions of the invention. For example, the on-line peptide catalog
`http://www.peptide-catalog.com/PC/Peptides provides a list of hundreds of
`commercially available peptides, along with their structure and molecular weight. In
`addition, to the many commercially available peptides, custom peptides can be made
`
`10
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`15
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`20
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`and utilized in the compositions of the invention.
`
`A preferred peptide surface stabilizer is poly(Lysine, Tryptophan)) 4:1
`
`hydrobromide.
`
`B.
`
`Secondary or Auxiliary Surface Stabilizers
`
`25
`
`The compositions of the invention can also include one or more auxiliary non-
`peptide surfacestabilizers in addition to the at least one peptide surface stabilizer.
`
`The auxiliary surface stabilizers of the invention are preferably adsorbed on, or
`associated with, the surface of the active agent particles. The auxiliary surface
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`stabilizers especially useful herein preferably do not chemically react with the active
`agent particles or itself. Preferably, individual molecules of the auxiliary surface
`stabilizer are essentially free of intermolecular cross-linkages.
`
`Twoor more auxiliary surface stabilizers can be employed in the compositions
`
`and methods of the invention.
`
`Suitable surface stabilizers can preferably be selected from known organic and
`inorganic pharmaceutical excipients. Such excipients include various polymers, low
`molecular weight oligomers, natural products, and surfactants. Preferred auxiliary
`surface stabilizers include nonionic, anionic, cationic, zwitterionic, and ionic
`
`10
`
`surfactants.
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`15
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`20
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`25
`
`Representative examples of secondary surface stabilizers include gelatin,
`casein, lecithin (phosphatides), dextran, gum acacia, cholesterol, tragacanth, stearic
`acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl
`alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers
`(e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil
`derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., the commercially
`available Tweens® suchase.g. Tween 20° and Tween 80® (ICISpeciality
`Chemicals)); polyethylene glycols (e.g., Carbowaxs 3550° and 934° (Union
`Carbide)), polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium
`dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium,
`methylcellulose, hydroxyethylcellulose, hydroxypropylcelluloses(e.g., HPC, HPC-
`SL, and HPC-L), hydroxypropyl methylcellulose (HPMC), hydroxypropylmethyl-
`cellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate,
`triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), 4-(1,1,3,3-
`tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known
`as tyloxapol, superione, and triton), poloxamers(e.g., Pluronics F68°® and F108°,
`which are block copolymers of ethylene oxide and propylene oxide); poloxamines
`(e.g., Tetronic 908°, also known as Poloxamine 908°, which is a tetrafunctional block
`copolymerderived from sequential addition of propylene oxide and ethylene oxide to
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`ethylenediamine (BASF Wyandotte Corporation, Parsippany, N.J.)); Tetronic 1508°
`(T-1508) (BASF Wyandotte Corporation), dialkylesters of sodium sulfosuccinic acid
`(e.g., Aerosol OT®, which is a dioctyl ester of sodium sulfosuccinic acid (DOSS)
`(American Cyanamid)); Duponol P®, which is a sodium lauryl sulfate (DuPont);
`Tritons X-200®, whichis an alkyl aryl polyether sulfonate (Rohm and Haas);
`Crodestas F-110°, which is a mixture of sucrose stearate and sucrose distearate (Croda
`Inc.); p-isononylphenoxypoly-(glycidol), also known as Olin-10G®or Surfactant 10-
`G® (Olin Chemicals, Stamford, CT); Crodestas SL-40® (Croda, Inc.); and SA9OHCO,
`which is C1 gH37CH2C(O)N(CH3)-CH2(CHOH)4(CH20H)2 (Eastman Kodak Co.);
`
`decanoyl-N-methylglucamide; n-decyl B-D-glucopyranoside; n-decyl B-D-
`maltopyranoside; n-dodecyl B-D-glucopyranoside; n-dodecyl B-D-maltoside;
`heptanoyl-N-methylglucamide; n-heptyl-B-D-glucopyranoside; n-heptyl B-D-
`thioglucoside; n-hexyl B-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl B-
`D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-B-D-glucopyranoside; octyl
`§-D-thioglucopyranoside; lysozyme, PEG-derivatized phospholipid, PEG-derivatized
`cholesterol, PEG- derivatized cholesterol derivative, PEG-derivatized vitamin A,
`PEG-derivatized vitamin E, random copolymersof vinyl pyrrolidone and vinyl
`
`acetate, and the like.
`
`Examplesof useful cationic surface stabilizers include butare notlimited to
`polymers, biopolymers, polysaccharides, cellulosics, alginates, phospholipids, and
`nonpolymeric compounds, such as zwitterionic stabilizers, poly-n-methylpyridinium,
`anthryul pyridinium chloride, cationic phospholipids, a charged phospholipid such as
`dimyristoyl phophatidyl glycerol, chitosan, polylysine, polyvinylimidazole, polybrene,
`polymethylmethacrylate irimethylammoniumbromide bromide (PMMTMABr),
`hexyldesyltrimethylammonium bromide (HDMAB),and polyvinylpyrrolidone-2-
`dimethylaminoethyl methacrylate dimethyl sulfate.
`
`Otheruseful cationic stabilizers include, but are not limited to, cationic lipids,
`
`sulfonium, phosphonium, and quarternary ammonium compounds, such as
`stearyltrimethylammonium chloride, benzyl-di(2-chloroethyl)ethylammonium
`bromide, coconut trimethyl ammonium chloride or bromide, coconut methyl
`
`29
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`10
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`15
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`dihydroxyethyl ammoniumchlorideor bromide, dodecyl trimethyl ammonium
`bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium
`chloride or bromide, C12.;5dimethyl hydroxyethyl ammonium chloride or bromide,
`coconut dimethyl hydroxyethyl ammonium chloride or bromide, myristyl trimethyl
`ammonium methyl sulphate, lauryl dimethyl benzyl ammonium chloride or bromide,
`lauryl dimethyl (ethenoxy)4 ammonium chloride or bromide, N-alkyl (Ci2-
`13)dimethylbenzyl ammonium chloride, N-alkyl (Cj4-1s)dimethyl-benzyl ammonium
`chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl
`didecyl ammonium chloride, N-alkyl and (Cy2-14) dimethyl 1-napthylmethyl
`ammonium chloride, trimethylammonium halide, alkyl-trimethylammoniumsalts and
`dialkyl-dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated
`alkyamidoalkyldialkylammonium salt and/or an ethoxylated trialkyl ammonium salt,
`dialkylbenzene dialkylammonium chloride, N-didecyldimethyl ammonium chloride,
`N-tetradecyldimethylbenzyl ammonium, chloride monohydrate, N-alkkyl(C 12-14)
`dimethyl 1-naphthylmethyl ammonium chloride and dodecyldimethylbenzyl
`ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl
`ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl
`ammonium bromide, C12, Cis, Ci7 trimethyl ammonium bromides, dodecylbenzyl
`triethyl ammonium chloride, poly-diallyldimethylammonium chloride (DADMAC),
`dimethyl ammonium chlorides, alkyidimethylammonium halogenides, tricetyl methyl
`ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium
`bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride
`(ALIQUAT 336™), POLYQUAT10™,tetrabutylammonium bromide, benzyl
`trimethylammonium bromide, choline esters (such as choline esters of fatty acids),
`benzalkonium chloride, stearalkonium chloride compounds(such as stearyltrimonium
`chloride and Di-stearyldimonium chloride), cetyl pyridinium bromide or chloride,
`halidesalts of quaternized polyoxyethylalkylamines, MIRAPOL™and
`ALKAQUAT™(Alkaril Chemical Company), alkyl pyridinium salts; amines, such as
`alkylamines, dialkylamines, alkanolamines, polyethylenepolyamines, N,N-
`dialkylaminoalkyl acrylates, and vinyl pyridine, amine salts, such as lauryl amine
`
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`acetate, stearyl amine acetate, alkylpyridinium salt, and alkylimidazolium salt, and
`amine oxides; imide azolinium salts; protonated quaternary acrylamides; methylated
`quaternary polymers, such as poly[diallyl dimethylammonium chloride] and poly-[N-
`methyl vinyl pyridinium chloride]; and cationic guar.
`
`Such exemplary cationic surface stabilizers and other useful cationic surface
`stabilizers are described in J. Cross and E. Singer, Cationic Surfactants: Analytical
`and Biological Evaluation (Marcel Dekker, 1994); P. and D. Rubingh (Editor),
`Cationic Surfactants: Physical Chemistry (Marcel Dekker, 1991); and J. Richmond,
`Cationic Surfactants: Organic Chemistry, (Marcel Dekker, 1990).
`
`Particularly preferred nonpolymeric primary stabilizers are any nonpolymeric
`compound, such benzalkonium chloride, a carbonium compound,a phosphonium
`compound, an oxonium compound, a halonium compound, a cationic organometallic
`compound, a quarternary phosphorous compound, a pyridinium compound, an
`anilinium compound, an immonium compound, a hydroxylammonium compound,a
`primary ammonium compound, a secondary ammonium compound,a tertiary
`ammonium compound, and quarternary ammonium compoundsof the formula
`NR,RoR3R4y™. For compounds ofthe formula NRRoR3Ru™:
`(i)
`none of R;-Ry are CH;
`
`(ii)
`
`(iii)
`
`(iv)
`(v)
`
`(vi)
`
`(vii)
`
`(viii)
`
`one of Ri-Rg is CH3;
`
`‘three of R1-Ry are CH3;
`
`all of Ri-R4, are CH3;
`two of R,-Ry are CH3, one of R1-Ry is CsHsCHa2, and one of R-Ry is
`an alkyl chain of seven carbon atomsorless;
`two ofRi-Ry are CH, one ofRi-Ra is CéHsCH), and one ofRi-Rz is
`an alkyi chain of nineteen carbon atoms or more;
`two of Ry-R, are CH; and one of R)-R, is the group Co6Hs(CH2)n, where
`
`n>1;
`two of R1-Ry are CH3, one of Ri-Ry is CéHsCHo2, and one of Ri-R4
`
`comprises at least one heteroatom;
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`(x)
`
`(ix)
`
`two of R;-R, are CH, one of Ri-R, is CsHsCHp, and one of Ri-R4
`comprises at least one halogen;
`two of Ry-R, are CH3, one of Rj-R4 is CgHsCHp, and one of Ry-R4
`comprises at least one cyclic fragment;
`two ofR1-Ry are CH3 and one of Rj-R, is a phenyl ring; or
`(xi)
`two ofR,-R4 are CH; and two of R-Ry are purely aliphatic fragments.
`(xii)
`Such compoundsinclude,but are not limited to, behenalkonium chloride,
`benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride,
`
`lauralkonium chloride, cetalkonium chloride, cetrimonium bromide, cetrimonium
`
`10
`
`chloride, cethylamine hydrofluoride, chlorallylmethenamine chloride (Quaternium-
`15), distearyldimonium chloride (Quaternium-5), dodecyl dimethyl ethylbenzyl
`ammonium chloride(Quaternium-14), Quaternium-22, Quaternium-26, Quaternium-
`18 hectorite, dimethylaminoethylchloride hydrochloride, cysteine hydrochloride,
`diethanolammonium POE(10) oletyl ether phosphate, diethanolammonium POE
`
`15
`
`(3)oleyl ether phosphate, tallow alkonium chloride, dimethyl
`dioctadecylammoniumbentonite, stearalkonium chloride, domiphen bromide,
`
`denatonium benzoate, myristalkonium chloride, laurtrimonium chloride,
`
`20
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`25
`
`ethylenediamine dihydrochloride, guanidine hydrochloride, pyridoxine HCl,
`iofetamine hydrochloride, meglumine hydrochloride, methylbenzethonium chloride,
`myrtrimonium bromide, oleyltrimonium chloride, polyquaternium-1,
`procainehydrochloride, cocobetaine, stearalkonium bentonite, stearalkoniumhectonite,
`stearyl trihydroxyethyl propylenediamine dihydrofluoride, tallowtrimonium chloride,
`and hexadecyltrimethyl ammonium bromide.
`
`Mostof these surface stabilizers are known pharmaceutical excipients and are
`
`described in detail in the Handbook ofPharmaceutical Excipients, published jointly
`by the American Pharmaceutical Association and The Pharmaceutical Society of
`Great Britain (The Pharmaceutical Press, 1986), specifically incorporated by
`reference. The surface stabilizers are commercially available and/or can be prepared
`
`by techniques knownintheart.
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`Cc.
`
`Active Agents
`
`The nanoparticles of the invention comprise at least one active, therapeutic, or
`diagnostic agent, collectively referred to as a “drug.” A therapeutic agent can be a
`pharmaceutical agent, including biologics such as proteins, peptides, and nucleotides,
`or a diagnostic agent, such as a contrast agent, including x-ray contrast agents.
`
`The active agent exists as a crystalline phase, an amorphousphase, a semi-
`amorphousphase, a semi-crystalline phase, or mixtures thereof. The crystalline phase,
`differs from a non-crystalline or amorphous phase which results from precipitation
`
`techniques, such as those described in EP Patent No. 275,796.
`
`The invention can be practiced with a wide variety of active agents. The
`active agent is preferably present in an essentially pure form, is poorly soluble, and is
`dispersible in at least one liquid dispersion media. By "poorly soluble"it is meant that
`the active agent has a solubility in a liquid dispersion media of less than about 30
`mg/mL, less than about 20 mg/mL,less than about 10 mg/mL,orless than about 1
`mg/mL. Useful liquid dispersion medias include, but are not limited to, water,
`aqueoussalt solutions, safflower oil, and solvents such asethanol, t-butanol, hexane,
`and glycol. A preferred liquid dispersion media is water.
`
`Two or more active agents can be used in combination.
`
`1.
`
`Active Agents Generally
`
`The active agent can be selected from a variety of knownclassesof drugs,
`including, for example, nutraceuticals, COX-2 inhibitors, retinoids, anticancer agents,
`NSAIDS,proteins, peptides, nucleotides, anti-obesity drugs, nutraceuticals, dietary
`supplements, carotenoids, corticosteroids, elastase inhibitors, anti-fungals, oncology
`therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents,
`anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins),
`anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines,
`antihypertensive agents, antimuscarinic agents, antimycobacterial agents,
`antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents,
`
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`anxiolytics, sedatives (hypnotics and neuroleptics), astringents, beta-adrenoceptor
`blocking agents, blood products and substitutes, cardiac inotropic agents, contrast
`media, corticosteroids, cough suppressants (expectorants and mucolytics), diagnostic
`agents, diagnostic imaging agents, diuretics, dopaminergics (antiparkinsonian agents),
`haemostatics, immunological agents,lipid regulating agents, muscle relaxants,
`parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins,
`radio- pharmaceuticals, sex hormones(including steroids), anti-allergic agents,
`stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators, and
`
`xanthines.
`
`10
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`30
`
`Examples of representative active agents useful in this invention include, but
`are not limited to, acyclovir, alprazolam,altretamine, amiloride, amiodarone,
`benztropine mesylate, bupropion, cabergoline, candesartan, cerivastatin,
`chlorpromazine, ciprofloxacin,cisapride, clarithromycin, clonidine, clopidogrel,
`cyclobenzaprine, cyproheptadine, delavirdine, desmopressin,diltiazem, dipyridamole,
`dolasetron, enalapril maleate, enalaprilat, famotidine, felodipine, furazolidone,
`glipizide, irbesartan, ketoconazole, lansoprazole, loratadine, loxapine, mebendazole,
`mercaptopurine, milrinone lactate, minocycline, mitoxantrone, nelfinavir mesylate,
`nimodipine, norfloxacin, olanzapine, omeprazole, penciclovir, pimozide, tacolimus,
`quazepam,raloxifene, rifabutin, rifampin, risperidone, rizatriptan, saquinavir,
`sertraline, sildenafil, acetyl-sulfisoxazole, temazepam, thiabendazole, thioguanine,
`trandolapril, triamterene, trimetrexate, troglitazone, trovafloxacin, verapamil,
`vinblastine sulfate, mycophenolate, atovaquone, atovaquone, proguanil, ceftazidime,
`cefuroxime, etoposide,terbinafine, thalidomide, fluconazole, amsacrine, dacarbazine,
`
`teniposide, and acetylsalicylate.
`
`Exemplary nutraceuticals and dietary supplementsare disclosed, for example,
`in Robertset al., Nutraceuticals: The Complete Encyclopedia ofSupplements, Herbs,
`Vitamins, and Healing Foods (American Nutraceutical Association, 2001), which is
`specifically incorporated by reference. A nutraceutical or dietary supplement, also
`known as a phytochemical or functional food, is generally any one of a class of dietary
`supplements, vitamins, minerals, herbs, or healing foods that have medical or
`
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`pharmaceutical effects on the body. Exemplary nutraceuticals or dietary supplements
`include, but are notlimited to, lutein, folic acid, fatty acids (e.g., DHA and ARA),
`fruit and vegetable extracts, vitamin and mineral supplements, phosphatidylserine,
`lipoic acid, melatonin, glucosamine/chondroitin, Aloe Vera, Guggul, glutamine,
`amino acids (e.g., iso-leucine, leucine, lysine, methionine, phenylanine, threonine,
`tryptophan, and valine), green tea, lycopene, whole foods, food additives, herbs,
`phytonutrients, antioxidants, flavonoid constituents offruits, evening primroseoil,
`flax seeds, fish and marine animal oils, and probiotics. Nutraceuticals and dietary
`supplements also include bio-engineered foods genetically engineered to have a
`desired property, also known as “pharmafoods.”
`
`Active agents to be administered in an aerosol formulation are preferably
`
`selected from the group consisting of proteins, peptide, bronchodilators,
`corticosteroids, elastase inhibitors, analgesics, anti-fungals, cystic-fibrosis therapies,
`asthma therapies, emphysematherapies,respiratory distress syndrometherapies,
`chronic bronchitis therapies, chronic obstructive pulmonary disease therapies, organ-
`transplant rejection therapies, therapies for tuberculosis and other infections of the
`lung, fungal infection therapies, respiratory illness therapies associated with acquired.
`immunedeficiency syndrome, an oncology drug, an anti-emetic, an analgesic, and a
`
`cardiovascular agent.
`
`10
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`2.
`
`Anticancer Active Agents
`
`Useful anticancer agents are preferably selected from alkylating agents,
`
`antimetabolites, natural products, hormones and antagonists, and miscellaneous
`
`agents, such as radiosensitizers.
`
`25
`
`Examples ofalkylating agents include: (1) alkylating agents having the bis-(-
`chloroethyl)-amine group such as, for example, chlormethine, chlorambucile,
`melphalan, uramustine, mannomustine, extramustinephoshate, mechlore-thaminoxide,
`cyclophosphamide,ifosfamide, and trifosfamide; (2) alkylating agents having a
`substituted aziridine group such as, for example, tretamine, thiotepa, triaziquone, and
`mitomycine; (3) alkylating agents of the alkyl sulfonate type, such as, for example,
`
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`busulfan, piposulfan, and piposulfam; (4) alkylating N-alkyl-N-nitrosourea
`
`derivatives, such as, for example, carmustine, lomustine, semustine, or
`streptozotocine; and (5) alkylating agents of the mitobronitole, dacarbazine and
`
`procarbazine type.
`
`(1) folic acid analogs, such as, for
`Examples of antimetabolites include:
`example, methotrexate; (2) pyrimidine analogs such as, for example, fluorouracil,
`floxuridine, tegafur, cytarabine, idoxuridine, and flucytosine; and (3) purine
`derivatives such as, for example, mercaptopurine, thioguanine, azathioprine,
`
`tiamiprine, vidarabine, pentostatin, and puromycine.
`
`Examples of natural products include: (1) vinca alkaloids, such as, for
`example, vinblastine and vincristine; (2) epipodophylotoxins, such as, for example,
`etoposide and teniposide; (3) antibiotics, such as, for example, adriamycine,
`daunomycine, doctinomycin, daunorubicin, doxorubicin, mithramycin, bleomycin,
`and mitomycin; (4) enzymes, such as, for example, L-asparaginase; (5) biological
`response modifiers, such as, for example, alpha-interferon; (6) camptothecin;(7)
`taxol; and (8) retinoids, such as retinoic acid.
`
`(1) adrenocorticosteroids,
`Examples of hormones and antagonists include:
`such as, for example, prednisone; (2) progestins, such as, for example,
`hydroxyprogesterone caproate, medroxyprogesterone acetate, and megestrol acetate;
`(3) estrogens, such as, for example, diethylstilbestrol and ethinyl estradiol; (4)
`antiestrogens, such as, for example, tamoxifen; (5) androgens, such as, for example,
`testosterone propionate and fluoxymesterone; (6) antiandrogens, such as, for example,
`flutamide; and (7) gonadotropin-releasing hormone analogs, such as, for example,
`
`leuprolide.
`
`Examples of miscellaneous agents include: (1) radiosensitizers, such as, for
`example, 1,2,4-benzotriazin-3-amine 1,4-dioxide (SR 4889) and 1,2,4-benzotriazine-
`7-amine 1,4-dioxide (WIN 59075); (2) platinum coordination complexes such as
`cisplatin and carboplatin; (3) anthracenediones, such as, for example, mitoxantrone;
`
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`(4) substituted ureas, such as, for example, hydroxyurea; and (5) adrenocortical
`
`suppressants, such as, for example, mitotane and aminoglutethimide.
`
`In addition, the anticancer agent can be an immunosuppressive drug, such as,
`
`for example, cyclosporine, azathioprine, sulfasalazine, methoxsalen, and thalidomide.
`
`The anticancer agent can also be a COX-2 inhibitor.
`
`3.
`
`Analgesic Active Agents
`
`An analgesic can be, for example, an NSAID or a COX-2 inhibitor.
`
`Exemplary NSAIDSthat can be formulated in compositions of the invention
`
`include, but are not limited to, suitable nonacidic and acidic compounds. Suitable
`
`10
`
`nonacidic compoundsinclude, for example, nabumetone,tiaramide, proquazone,
`
`bufexamac, flumizole, epirazole, tinoridine, timegadine, and dapsone. Suitable acidic
`
`compoundsinclude, for example, carboxylic acids and enolic acids. Suitable
`carboxylic acid NSAIDsinclude, for example:
`(1) salicylic acids and esters thereof,
`such as aspirin, diflunisal, benorylate, and fosfosal; (2) acetic acids, such as
`
`15
`
`phenylacetic acids, including diclofenac, alclofenac, and fenclofenac; (3) carbo- and
`
`heterocyclic acetic acids such as etodolac, indomethacin, sulindac, tolmetin, fentiazac,
`
`20
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`25
`
`and tilomisole; (4) propionic acids, such as carprofen, fenbufen, flurbiprofen,
`
`ketoprofen, oxaprozin, suprofen, tiaprofenic acid, ibuprofen, naproxen, fenoprofen,
`
`indoprofen, and pirprofen; and (5) fenamic acids, such as flufenamic, mefenamic,
`meclofenamic, and niflumic. Suitable enolic acid NSAIDsinclude, for example: (1)
`pyrazolones such as oxyphenbutazone, phenylbutazone, apazone, and feprazone; and
`
`(2) oxicams such as piroxicam, sudoxicam, isoxicam, and tenoxicam.
`
`Exemplary COX-2 inhibitors that can be formulated in combination with the
`
`nanoparticulate nimesulide composition of the invention include, but are not limited
`to, celecoxib (SC-58635, CELEBREX®, Pharmacia/Searle & Co.), rofecoxib (MK-
`966, L-748731, VIOXX®, Merck & Co.), meloxicam (MOBIC®, co-marketed by
`
`Abbott Laboratories, Chicago, IL, and Boehringer Ingelheim Pharmaceuticals),
`valdecoxib (BEXTRA®, G.D.Searle & Co.), parecoxib (G.D. Searle & Co.),
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`etoricoxib (MK-663; Merck), SC-236 (chemical name of 4-[5-(4-chlorophenyl)-3-
`
`(trifluoromethyl)-1H-pyrazol-1-yl)] benzenesulfonamide; G.D. Searle & Co., Skokie,
`
`IL); NS-398 (N-(2-cyclohexyloxy-4-nitrophenyl)methane sulfonamide; Taisho
`
`Pharmaceutical Co., Ltd., Japan); SC-58125 (methyl sulfone spiro(2.4)hept-5-ene I;
`
`Pharmacia/Searle & Co.); SC-57666 (Pharmacia/Searle & Co.); SC-558
`(Pharmacia/Searle & Co.); SC-560 (Pharmacia/Searle & Co.); etodolac (Lodine®,
`Wyeth-Ayerst Laboratories, Inc.); DFU (5,5-dimethyl-3-(3-fluorophenyl)-4-(4-
`
`methylsulfonyl)phenyl 2(5H)-furanone); monteleukast (MK-476), L-745337 ((5-
`
`methanesulphonamide-6-(2,4-difluorothio-phenyl)-1-indanone), L-761066, L-761000,
`
`L-748780 (all Merck & Co.); DUP-697 (5-Bromo-2-(4-fluorophenyl)-3-(4-
`(methylsulfonyl)phenyl; DuPont Merck Pharmaceutical Co.); PGV 20229 (1-(7-tert.-
`butyl-2,3-dihydro-3,3-dimethylbenzo(b)furan-5-yl)-4-cyclopropylbutan-1-one; Procter
`
`& Gamble Pharmaceuticals); iguratimod (T-614; 3-formylamino-7-
`
`methylsulfonylamino-6-phenoxy-4H-1- benzopyran-4-one; Toyama Corp., Japan); BF
`
`389 (Biofor, USA); CL 1004 (PD 136095), PD 136005, PD 142893, PD 138387, and
`PD 145065(all Parke-Davis/Warner-Lambert Co.); flurbiprofen (ANSAID®;
`Pharmacia & Upjohn); nabumetone (FELAFEN®; SmithKline Beecham,plc);
`flosulide (CGP 28238; Novartis/Ciba Geigy); piroxicam (FELDANE®;Pfizer);
`diclofenac (VOLTAREN® and CATAFLAM®,Novartis); lumiracoxib (COX-189;
`Novartis); D 1367 (Celltech Chiroscience, plc); R 807 (3 benzoyldifluoromethane
`sulfonanilide, diflumidone); JTE-522 (Japan Tobacco, Japan); FK-3311 (4'-Acetyl-2'-
`(2,4-difluorophenoxy)methanesulfonanilide), FK 867, FR 140423, and FR 115068(all
`Fujisawa, Japan); GR 253035 (Glaxo Wellcome); RWJ 63556 (Johnson & Johnson);
`RWI 20485 (Johnson & Johnson); ZK 38997 (Schering); S 2474 ((E)-(5)-(3,5-di-tert-
`butyl-4-hydroxybenzylidene)-2-ethyl-1,2-isothiazolidine-1,1-dioxide indomethacin;
`
`Shionogi & Co., Lid., Japan); zomepirac analogs, such as RS 57067 and RS 104897
`(Hoffmann La Roche); RS 104894 (Hoffmann La Roche); SC 41930 (Monsanto);
`pranlukast (SB 205312, Ono-1078, ONON®, ULTAIR®; SmithKline Beecham); SB
`209670 (SmithKline Beecham); and APHS (heptinylsulfide).
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`10
`
`15
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`20
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`D.
`
`Nanoparticulate Active Agent Particle Size
`
`The compositions of the invention contain nanoparticulate active agent
`particles which have an effective average particle size of less than about 2000 nm (.e.,
`2 microns). In other embodiments of the invention, the active agent particles have a
`
`size of less than about 1900 nm,less than about 1800 nm,less than about 1700 nm,
`
`less than about 1600 nm, less than about 1500 nm,less than about 1400 nm,less than
`
`about 1300 nm,less than about 1200 nm, less than about 1100 nm,less than about
`1000 nm, less than about 900 nm, less than about 800 nm,less than about 700 nm,
`
`less than about 600 nm,less than about 500 nm,less than about 400 nm,less than
`
`10
`
`about 300 nm,less than about 250 nm, less than about 200 nm, less than about 150
`
`nim, less than about 100 nm,less than about 75 nm,or less than about 50 nm,as
`
`measured bylight-scattering methods, microscopy, or other appropriate methods.
`
`By “an effective average particle size of less than about 2000 nm”it is meant
`
`that at least 50% by weight of the active agent particles have a particle size less than
`
`15
`
`the effective average, i.e., less than about 2000 nm, 1900 nm, 1800 nm,efc., when
`
`measured by the above-noted techniques. In other embodiments of the invention,at
`
`least about 70%, at least about 90%, at least about 95%, or at least about 99% of the
`
`active agent particles have a particle size less than the effective average,i.e., less than
`
`about 2000 nm, 1900 nm, 1800 nm,ee.
`
`20
`
`If the nanoparticulate active agent composition is combined with a
`
`conventional active agent composition, then such a composition is either solubilized
`
`or has an effective average particle size greater than about 2 microns. By “an effective
`
`average particle size of greater than about 2 microns”it is meant that at least 50% of
`the microparticulate active agent particles have a particle size greater than about 2
`
`25
`
`microns, by weight, when measured by the above-noted techniques. In other
`embodiments of the invention, at least about 70%, at least about 90%, at least about
`95%, or at least about 99%, by weight, of the microparticulate active agent particles
`
`havea particle size greater than about 2 microns.
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`In the present invention, the value for D50 of a nanoparticulate active agent
`composition is the particle size below which 50% ofthe active agentparticles fall, by
`weight. Similarly, D90 and D99are the particle sizes below which 90% and 99%,
`respectively, of the active agent particles fall, by weight.
`
`5.
`
`Concentration of Nanoparticulate
`Active Agent and Peptide Stabilizer
`
`Therelative amounts of active agent and peptide surface stabilizer, and
`
`optionally one or more secondary surface stabilizers, can vary widely. The optimal
`amount of the individual components can depend, for example, upon the particular
`active agentselected, the hydrophilic lipophilic balance (HLB), melting point, and the
`surface tension of water solutions of the stabilizer, etc.
`
`10
`
`The concentration of the peptide surface stabilizer can vary from about 0.5%
`
`to about 99.999%, from about 5.0% to about 99.9%, or from about 10% to about
`
`99.5%, by weight, based on the total combined dry weight of the at least one active
`agent and at least one peptide surface stabilizer, not including other excipients.
`
`15
`
`The concentration of the at least one active agent can vary from about 99.5%
`
`to about 0.001%, from about 95% to about 0.1%, or from about 90% to about 0.5%,
`
`by weight, based on the total combined dry weight of the active agent andat least one
`peptide surface stabilizer, not including other excipients.
`
`20
`
`B.
`
`Methods of Making Nanoparticulate Active Agent Formulations
`
`The nanoparticulate active agent compositions of the invention, comprising at
`least one peptide as a surface stabilizer, can be made using, for example, milling,
`homogenization, or precipitation techniques. Exemplary methods of making
`nanoparticulate compositions are described in the '684 patent. Methods ofmaking
`nanoparticulate active agent compositions are also described in U.S. Patent No.
`5,518,187 for “Method of Grinding Pharmaceutical Substances;” U.S. Patent No.
`5,718,388 for “Continuous Method of Grinding Pharmaceutical Substances;” U.S.
`Patent No. 5,862,999 for “Method of Grinding Pharmaceutical Substances;” U.S.
`
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`PCT/US2004/036337
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`Patent No. 5,665,331 for “Co-Microprecipitation of Nanoparticulate Pharmaceutical
`Agents with Crystal Growth Modifiers;” U.S. Patent No. 5,662,883 for “Co-
`Microprecipitation of Nanoparticulate Pharmaceutical Agents with Crystal Growth
`Modifiers;” U.S. Patent No. 5,560,932 for “Microprecipitation of Nanoparticulate
`Pharmaceutical Agents;” U.S. Patent No. 5,543,133 for “Process of Preparing X-Ray
`Contrast Compositions Containing Nanoparticles,” U.S. Patent No. 5,534,270 for
`“Method ofPreparing Stable Drug Nanoparticles;” U.S. Patent No. 5,510,118 for
`“Process of Preparing Therapeutic Compositions Containing Nanoparticles;” and U.S.
`Patent No. 5,470,583 for “Method of Preparing Nanoparticle Compositions
`
`10
`
`Containing Charged Phospholipids to Reduce Aggregation,”all of which are
`
`specifically incorporated by reference.
`
`The resultant nanoparticulate active agent compositions can be utilized in any
`
`desired dosage form.
`
`1.
`
`Millin