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`PCT/US2004/036337
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`2000 amino acids residues. The mean molecular weight of an amino acid 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, 3rd 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
`
`10
`
`about 1 mg/mL, greater than about 10 mg/mL, greater than about 20 mg/mL, or
`
`greater than about 30 mg/mL. This is 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., US. Patent Nos. 6,270,806; 6,592,903; 6,428,814; and 6,375,986. In such
`
`prior art references, when a peptide is utilized as an active agent in a nanoparticulate
`
`15
`
`composition, the peptide is poorly water soluble.
`
`There is 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
`
`20
`
`addition, to the many commercially available peptides, custom peptides can be made
`
`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 surface stabilizers 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
`
`27
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`stabilizers especially usefiil 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.
`
`Two or 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
`
`1,0
`
`surfactants.
`
`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
`
`15
`
`(e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil
`
`derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., the commercially
`
`available Tweens® such as e.g Tween 20® and Tween 80® (ICI Speciality
`
`Chemicals»; polyethylene glycols (e.g., Carbowaxs 3550® and 934® (Union
`
`Carbide)), polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium
`
`20
`
`dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium,
`
`methylcellulose, hydroxyethylcellulose, hydroxypropyl celluloses (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 ,l,3,3—
`
`25
`
`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 tetrafiinctional block
`
`copolymer derived from sequential addition of propylene oxide and ethylene oxide to
`
`28
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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®, which is 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-4O® (Croda, Inc.); and SA9OHCO,
`
`which is C18H37CH2C(O)N(CH3)-CH2(CHOH)4(CH20H)2 (Eastman Kodak Co.);
`
`10
`
`decanoyl—N—methylglucamide; n—decyl B—D—glucopyranoside; n—decyl [3—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 fi-D-glucopyranoside; nonanoyl—N—methylglucamide; n—noyl [3—
`
`D~glucopyranoside; octanoyl—N—methylglucamide; n—octyl—B-D-glucopyranoside; octyl
`
`15
`
`B-D-thioglucopyranoside; lysozyme, PEG-derivatized phospholipid, PEG-derivatized
`
`cholesterol, PEG— derivatized cholesterol derivative, PEG—derivatized Vitamin A,
`
`PEG-derivatized Vitamin E, random copolymers of vinyl pyrrolidone and Vinyl
`
`acetate, and the like.
`
`Examples of useful cationic surface stabilizers include but are not limited to
`
`20
`
`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 trimethylammoniumbromide bromide (PMMTMABr),
`
`25
`
`hexyldesyltrimethylammonium bromide (HDMAB), and polyvinylpyrrolidone—Z—
`
`dimethylaminoethyl methacrylate dimethyl sulfate.
`
`Other useful cationic stabilizers include, but are not limited to, cationic lipids,
`
`sulfonium, phosphonium, and quartemary ammonium compounds, such as
`
`stearyltrimethylammonium chloride, benzyl—di(2—chloroethyl)ethylammonium
`
`30
`
`bromide, coconut trimethyl ammonium chloride or bromide, coconut methyl
`
`29
`
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`page 0403
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`dihydroxyethyl ammonium chloride or bromide, dodecyl trimethyl ammonium
`
`bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium
`
`chloride or bromide, (312-15dimethyl 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 (C12-
`
`18)dimethylbenzyl ammonium chloride, N—alkyl (C14_1g)dimethyl—benzy1 ammonium
`
`chloride, N—tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl
`
`didecyl ammonium chloride, N—alkyl and (€12-14) dimethyl l-napthylmethyl
`
`10
`
`ammonium chloride, trimethylammonium halide, alkyl—trimethylammonium‘ salts 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-alkyl(C12_14)
`
`15
`
`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, C15, C17 trimethyl ammonium bromides, dodecylbenzyl
`
`triethyl ammonium chloride, poly—diallyldimethylammonium chloride (DADMAC),
`
`20
`
`dimethyl ammonium chlorides, alkyldimethylammonium halogenides, tricetyl methyl
`
`ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium
`
`bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride
`
`(ALIQUAT 336TM), POLYQUAT 10TM, tetrabutylammonium bromide, benzyl
`
`trimethylammonium bromide, choline esters (such as choline esters of fatty acids),
`
`25
`
`benzalkonium chloride, stearalkonium chloride compounds (such as stearyltrimonium
`
`chloride and Di—stearyldimonium chloride), cetyl pyridinium bromide or chloride,
`
`halide salts of quaternized polyoxyethylalkylamines, MIRAPOLTM and
`
`ALKAQUATTM (Alkaril Chemical Company), alkyl pyridinium salts; amines, such as
`
`alkylamines, dialkylamines, alkanolamines, polyethylenepolyamines, N,N-
`
`30
`
`dialkylaminoalkyl acrylates, and vinyl pyridine, amine salts, such as lauryl amine
`
`3O
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`acetate, stearyl amine acetate, alkylpyridinium salt, and alkylimidazolium salt, and
`
`amine oxides; imide azolinium salts; protonated quaternary acrylainides; 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).
`
`10
`
`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 hydroxylarnmonium compound, a
`
`15
`
`primary ammonium compound, a secondary ammonium compound, a tertiary
`
`ammonium compound, and quarternary ammonium compounds of the formula
`
`NR1R2R3R4(+). For compounds of the formula NR1R2R3R4(+):
`
`(i)
`
`(ii)
`
`(iii)
`
`(iv)
`
`(V)
`
`(vi)
`
`20
`
`25
`
`none of R1-R4 are CH3;
`
`one of Rl—R4 is CH3;
`
`three of R1-R4 are CH3;
`
`all of R1 —R4 are CH3;
`
`two of Rl-R4 are CH3, one of R1—R4 is C5H5CH2, and one of R1—R4 is
`
`an alkyl chain of seven carbon atoms or less;
`two of 111—114 aro CH3, one of Rl-R4 is C5H50H2, and one ole—R4 is
`
`an alkyl chain of nineteen carbon atoms or more;
`
`(Vii)
`
`two of Rl—R4 are CH3 and one of Rl—R4 is the group C6H5(CH2)n, where
`
`n>1;
`
`(viii)
`
`two of R1—R4 are CH3, one of Rl—R4 is €5H5CH2, and one of R1-R4
`
`comprises at least one heteroatom;
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`31
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`(ix)
`
`two of Rl-R4 are CH3, one of R1—R4 is C5H5CH2, and one of R1—R4
`
`comprises at least one halogen;
`
`(X)
`
`two of Rl—R4 are CH3, one of R1-R4 is C6H5CH2, and one of R1 -R4
`
`comprises at least one cyclic fragment;
`
`(Xi)
`
`(xii)
`
`two of R1 —R4 are CH3 and one of Rl—R4 is a phenyl ring; or
`
`two of P1—R4 are CH3 and two of Rl-R4 are purely aliphatic fragments.
`
`Such compounds include, but are not limited to, behenalkonium chloride,
`
`benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride,
`
`lauralkonium chloride, cetalkonium chloride, cetrimoniurn bromide, cetrimonium
`
`10
`
`chloride, cethylamine hydrofluoride, chlorallylmethenamine chloride (Quaternium—
`
`15), distearyldimonium chloride (Quaternium—S), dodecyl dimethyl ethylbenzyl
`
`ammonium chloride(Quaternium—14), Quaternium—ZZ, Quaternium-26, Quaternium—
`18 hectorite, dimethylaminoethylchloride hydrochloride, {cysteine hydrochloride,
`
`diethanolammonium POE (10) oletyl ether phosphate, diethanolammonium POE
`
`15
`
`(3)01eyl ether phosphate, tallow alkonium chloride, dimethyl
`
`dioctadecylarnmoniumbentonite, stearalkonium chloride, domiphen bromide,
`
`denatonium benzoate, myristalkonium chloride, laurtrimoniurn chloride,
`
`ethylenediamine dihydrochloride, guanidine hydrochloride, pyridoxine HCl,
`
`iofetamine hydrochloride, meglurnine hydrochloride, methylbenzethonium chloride,
`
`20
`
`myrtrimonium bromide, oleyltrimonium chloride, polyquaternium—l,
`
`procainehydrochloride, cocobetaine, stearalkonium bentonite, stearalkoniumhectonite,
`
`stearyl trihydroxyethyl propylenediamine dihydrofluoride, tallowtrimonium chloride,
`
`and hexadecyltrimethyl ammonium bromide.
`
`Most of these surface stabilizers are known pharmaceutical excipients and are
`
`25
`
`described in detail in the Handbook ofPharmaceutical Excz'pients, 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 known in the art.
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`32
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`C.
`
`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 amorphous phase, a semi-
`
`amorphous phase, 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.
`
`10
`
`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, or less than about 1
`
`15
`
`mg/mL. Useful liquid dispersion medias include, but are not limited to, water,
`
`aqueous salt solutions, safflower oil, and solvents such as ethanol, 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
`
`20
`
`The active agent can be selected from a variety of known classes of 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,
`
`25
`
`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,
`
`33
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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
`
`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,
`
`15
`
`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,
`
`20
`
`sertraline, sildenafll, 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.
`
`25
`
`Exemplary nutraceuticals and dietary supplements are disclosed, for example,
`
`in Roberts et 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
`
`30
`
`supplements, Vitamins, minerals, herbs, or healing foods that have medical or
`
`34
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`pharmaceutical effects on the body. Exemplary nutraceuticals or dietary supplements
`
`include, but are not limited 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 of fruits, evening primrose oil,
`
`flax seeds, fish and marine animal oils, and probiotics. Nutraceuticals and dietary
`
`supplements also include bio—engineered foods genetically engineered to have a
`
`10
`
`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, emphysema therapies,” respiratory distress syndrome therapies,
`
`15
`
`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
`
`immune deficiency syndrome, an oncology drug, an anti—emetic, an analgesic, and a
`
`cardiovascular agent.
`
`20
`
`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.
`
`Examples of alkylating agents include: (1) alkylating agents having the bis—(2-
`
`25
`
`chloroethy1)-amine group such as, for example, chlormethine, chlorambucile,
`
`melphalan, uramustine, marmomustine, extrarnustinephoshate, mechlore-thaminoxide,
`
`cyclophosphamide, ifosfamide, and tn'fosfamide; (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,
`
`35
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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.
`
`Examples of antimetabolites include:
`
`(1) folic acid analogs, such as, for
`
`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.
`
`10
`
`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
`
`15
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`response modifiers, such as, for example, alpha—interferon; (6) camptothecin; (7)
`
`taxol; and (8) retinoids, such as retinoic acid.
`
`Examples of hormones and antagonists include:
`
`(1) adrenocorticosteroids,
`
`such as, for example, prednisone; (2) progestins, such as, for example,
`
`hydroxyprogesterone caproate, medroxyprogesterone acetate, and megestrol acetate;
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`20
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`(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.
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`25
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`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.
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`5
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`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 NSAIDS that can be formulated in compositions of the invention
`
`include, but are not limited to, suitable nonacidic and acidic compounds. Suitable
`
`10
`
`nonacidic compounds include, for example, nabumetone, tiaramide, proquazone,
`
`bufexamac, flumizole, epirazole, tinoridine, timegadine, and dapsone. Suitable acidic
`
`compounds include, for example, carboxylic acids and enolic acids. Suitable
`carboxylic acid NSAle include, 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,
`
`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,
`
`20 meclofenamic, and niflumic. Suitable enolic acid NSAIDS include, 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
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`25
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`to, celecoxib (SC—58635, CELEBREX®, Pharmacia/Searle & Co.), rofecoxib (MK-
`
`966, L—74873 1, VIOXX®, Merck & Co.), meloxicam (MOBIC®, co—marketed by
`
`Abbott Laboratories, Chicago, IL, and Boehringer Ingelheim Pharmaceuticals),
`
`valdecoxib (BEXTRA®, GD. 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-y1)] benzenesulfonamide; G.D. Searle & Co., Skokie,
`
`IL); NS—398 (N—(2—cyclohexyloxy-4-nitrophenyl)methane sulfonamide; Taisho
`
`Pharmaceutical Co., Ltd., Japan); SC—58 125 (methyl sulfone spiro(2.4)hept-5—ene I;
`
`Pharmacia/Searle & Co.); SC—57666 (Pharmacia/Searle & Co.); SC—558
`
`(Pharmacia/Searle & Co.); SC-56O (Pharmacia/Searle & Co.); etodolac (Lodine®,
`
`Wyeth—Ayerst Laboratories, Inc.); DFU (5 ,5—dimethyl-3-(3-fluorophenyl)—4—(4-
`
`methylsulfonyl)pheny1 2(5H)—furanone); monteleukast (MK—476), L—745337 ((5—
`
`methanesulphonamide-6-(2,4—difluorothio—phenyl)—1-indanone), L—761066, L-761000,
`
`10
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`L—74878O (all Merck & Co.); DUP-697 (5—Bromo-2-(4-fluoropheny1)—3-(4-
`(methylsulfonyl)phenyl; DuPont Merck Pharmaceutical Co.); PGV 20229 (1—(7-tert.-
`
`buty1—2,3 -dihydro-3 ,3 -dimethylbenzo(b)furan—5 -y1)-4—cyclopropy1butan— 1 —one; Procter
`
`& Gamble Pharmaceuticals); iguratimod (T-614; 3-formylamino—7-
`
`methylsulfonylamino-6-phenoxy—4H—1— benzopyran—4-one; Toyama Corp., Japan); BF
`
`15
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`389 (Biofor, USA); CL 1004 (PD 136095), PD 136005, PD 142893, PD 138387, and
`
`PD 145065 (all Parke—Davistarner—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;
`
`20
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`Novartis); D 1367 (Celltech Chiroscience, plc); R 807 (3 benzoyldifluoromethane
`
`sulfonanilide, diflumidone); JTE-522 (Japan Tobacco, Japan); FK—33 11 (4'-Acety1—2'-
`
`(2,4—difluorophenoxy)methanesu1fonanilide), FK 867, FR 140423, and FR 1 15068 (all
`
`Fujisawa, Japan); GR 253035 (Glaxo Wellcome); RWJ 63556 (Johnson & Johnson);
`
`RWJ 20485 (Johnson & Johnson); ZK 38997 (Schering); S 2474 ((E)—(5)—(3,5—di—tert—
`
`25
`
`buty1—4-hydroxybenzylidene)—2-ethy1— 1 ,2-isothiazolidine- 1 , 1 -dioxide indomethacin;
`
`Shionogi & Co., Ltd., Japan); zomepirac analogs, such as RS 57067 and RS 104897
`
`(Hoffinann La Roche); RS 104894 (Hoffmann La Roche); SC 41930 (Monsanto);
`
`pranlukast (SB 205312, Ono-1078, ONON®, ULTAlR®; SmithKline Beecham); SB
`
`209670 (SmithKline Beecham); and API-IS (heptinylsulfide).
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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 (i.e.,
`
`2 microns). In other embodiments of the invention, the active agent particles have a
`
`size of less than about 1900 mn, 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
`
`nm, less than about 100 nm, less than about 75 nm, or less than about 50 nm, as
`
`measured by light-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 mm, 1900 nm, 1800 nm, etc., when
`
`measured by the above—noted techniques. In other embodiments of the invention, at
`
`least about 7 0%, 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, etc.
`
`20
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`25
`
`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 5 0% of
`
`the microparticulate active agent particles have a particle size greater than about 2
`
`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
`
`have a 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% of the active agent particles fall, by
`
`weight. Similarly, D90 and D99 are 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
`
`The relative 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
`
`10
`
`active agent selected, the hydrophilic lipophilic balance (HLB), melting point, and the
`
`surface tension of water solutions of the stabilizer, etc.
`
`The concentration of the peptide surface stabilizer can vary from about 0.5%
`
`to about 99.999%, fiom 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
`
`15
`
`agent and at least one peptide surface stabilizer, not including other excipients.
`
`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 and at least one
`
`peptide surface stabilizer, not including other excipients.
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`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 of making
`
`25
`
`nanoparticulate active agent compositions are also described in US. Patent No.
`5,518,187 for “Method of Grinding Pharmaceutical Substances;” US. Patent No.
`
`5,718,388 for “Continuous Method of Grinding Pharmaceutical Substances g” US.
`
`Patent No. 5,862,999 for “Method of Grinding Pharmaceutical Substancesg” US
`
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`Patent No. 5,665,33 1 for “Co-Microprecipitation of Nanoparticulate Pharmaceutical
`
`Agents with Crystal Growth M0difl61‘S;” US. Patent No. 5,662,883 for “Co-
`
`Microprecipitation of NanOp articulate Pharmaceutical Agents with Crystal Growth
`
`Modifiers,” US. Patent No. 5,560,932 for “Microprecipitation of Nanoparticulate
`
`Pharmaceutical Agents;” US. Patent No. 5,543,133 for “Process of Preparing X—Ray
`
`Contrast Compositions Containing Nanoparticlesg” US. Patent No. 5,534,270 for
`“Method ofPreparing Stable Drug Nanopartic