US20050004002A1 - Compositions and methods of delivery of pharmacological agents - Google Patents

Compositions and methods of delivery of pharmacological agents Download PDF

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Publication number
US20050004002A1
US20050004002A1 US10/731,224 US73122403A US2005004002A1 US 20050004002 A1 US20050004002 A1 US 20050004002A1 US 73122403 A US73122403 A US 73122403A US 2005004002 A1 US2005004002 A1 US 2005004002A1
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US
United States
Prior art keywords
pharmaceutical composition
albumin
pharmaceutical
agents
administration
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/731,224
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English (en)
Inventor
Neil Desai
Andrew Yang
Tapas De
Sherry Ci
Patrick Soon-Shiong
Vuong Trieu
Oiang Yao
Bridget Grim
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abraxis Bioscience LLC
Original Assignee
American Bioscience Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=34891317&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20050004002(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to US10/731,224 priority Critical patent/US20050004002A1/en
Application filed by American Bioscience Inc filed Critical American Bioscience Inc
Assigned to AMERICAN BIOSCIENCE, INC. reassignment AMERICAN BIOSCIENCE, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SOON-SHIONG, PATRICK, CI, SHERRY XIAOPEI, DE, TAPAS, DESAI, NEIL P., GRIM, BRIDGET BEALS, TRIEU, VUONG, YANG, ANDREW, YAO, QIANG
Publication of US20050004002A1 publication Critical patent/US20050004002A1/en
Assigned to MERRILL LYNCH PROFESSIONAL CLEARING CORP. reassignment MERRILL LYNCH PROFESSIONAL CLEARING CORP. SECURITY AGREEMENT Assignors: AMERICAN BIOSCIENCE, INC.
Assigned to AMERICAN BIOSCIENCE, INC. reassignment AMERICAN BIOSCIENCE, INC. RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: MERRILL LYNCH PROFESSIONAL CLEARING CORP.
Priority to US11/553,339 priority patent/US7820788B2/en
Priority to US11/553,350 priority patent/US20070129448A1/en
Assigned to ABRAXIS BIOSCIENCE, INC. reassignment ABRAXIS BIOSCIENCE, INC. MERGER (SEE DOCUMENT FOR DETAILS). Assignors: AMERICAN BIOSCIENCE, INC.
Assigned to ABRAXIS BIOSCIENCE, LLC reassignment ABRAXIS BIOSCIENCE, LLC MERGER (SEE DOCUMENT FOR DETAILS). Assignors: ABRAXIS BIOSCIENCE, INC.
Priority to US12/758,413 priority patent/US7923536B2/en
Priority to US12/910,693 priority patent/US8138229B2/en
Priority to US13/038,287 priority patent/US8314156B2/en
Priority to US13/368,250 priority patent/US20120283205A1/en
Priority to US13/649,987 priority patent/US8846771B2/en
Priority to US13/777,988 priority patent/US9012519B2/en
Priority to US13/777,980 priority patent/US9012518B2/en
Priority to US14/626,678 priority patent/US20150165047A1/en
Abandoned legal-status Critical Current

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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00—Nanotechnology
    • Y10S977/902—Specified use of nanostructure
    • Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
    • Y10S977/906—Drug delivery
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00—Nanotechnology
    • Y10S977/902—Specified use of nanostructure
    • Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
    • Y10S977/908—Mechanical repair performed/surgical
    • Y10S977/911—Cancer cell destruction

Definitions

  • This invention pertains to pharmaceutical compositions comprising pharmaceutically active agents for parenteral or other internal use, which have the effect of reducing certain undesirable side effects upon administration when compared with available formulations of similar drugs.
  • drugs for parenteral use especially those administered intravenously, cause undesirable side effects such as venous irritation, phlebitis, burning and pain on injection, venous thrombosis, extravasation, and other administration related side effects.
  • Many of these drugs are insoluble in water, and are thus formulated with solubilizing agents, surfactants, solvents, and/or emulsifiers that are irritating, allergenic, or toxic when administered to patients (see, e.g., Briggs et al., Anesthesis 37, 1099 (1982), and Waugh et al., Am. J. Hosp. Pharmacists , 48, 1520 (1991)).
  • the free drug present in the formulation induces pain or irritation upon administration.
  • phlebitis was observed in 50% of patients who received peripheral vein administration of ifosfamide and vinorelbine as first-line chemotherapy for advanced non-small cell lung carcinoma.
  • ifosfamide and vinorelbine as first-line chemotherapy for advanced non-small cell lung carcinoma.
  • vancomycin has been shown to induce side effects such as phlebitis (see, e.g., Lopes Rocha et al., Braz. J. Infect. Dis ., 6(4), 196-200 (2002)).
  • Taxol paclitaxel
  • codarone amiodarone hydrochloride
  • T3 or liothyronine commercially available as Triostat
  • thiotepa thiotepa
  • bleomycin a drug that exhibit administration-associated side effects
  • diagnostic radiocontrast agents include, for example, Taxol (paclitaxel) (see, e.g., package insert for Taxol I.V.), codarone (amiodarone hydrochloride) (see, e.g., package insert for Codarone I.V.), the thyroid hormone T3 or liothyronine (commercially available as Triostat), thiotepa, bleomycin, and diagnostic radiocontrast agents.
  • Taxol paclitaxel
  • codarone amiodarone hydrochloride
  • T3 or liothyronine commercially available as Triostat
  • thiotepa thiote
  • propofol for example, methods for reducing propofol-induced pain include increasing the fat content of the solvent (e.g., long chain triglycerides (LCT)), premedication, pretreatment with non-steroidal drugs, local anaesthetics, opioids, the addition of lidocaine, the addition of cyclodextrin, and microfiltration (see, e.g., Mayer et al., Anaesthesist , 45(11), 1082-4 (1996), Davies, et al. Anaesthesia , 57, 557-61 (2002), Doenicke, et al., Anaesth.
  • solvent e.g., long chain triglycerides (LCT)
  • propofol formulations have been developed with antibacterial agents, such as an EDTA equivalent (e.g., edetate), pentetate, or sulfite-containing agents, or they have been have been formulated with a lower pH (see, e.g., U.S. Pat. Nos. 5,714,520, 5,731,355, 5,731,356, 6,028,108, 6,100,302, 6,147,122, 6,177,477, 6,399,087, 6,469,069, and International Patent Application No. WO 99/39696).
  • an EDTA equivalent e.g., edetate
  • pentetate pentetate
  • sulfite-containing agents e.g., sulfite-containing agents
  • edetate and pentetate are metal ion chelators, however, they have the potential to be dangerous by scavenging the essential metal ions from the body system. Moreover, the addition of sulphites to drug formulations presents potential adverse effects to the pediatric population and for those in the general population who are allergic to sulphur.
  • compositions and methods that reduce or eliminate the side effects associated with the parenteral or in vivo administration of drugs.
  • a pharmaceutical composition that is sterile, and methods of preparing such a composition.
  • a pharmaceutical composition and method that reduce or eliminate oxidation of pharmaceutical formulations to prevent drug destabilization.
  • the invention provides various embodiments of pharmaceutical compositions. One, some, or all of the properties of the various embodiments can be found in different embodiments of the invention and still fall within the scope of the appended claims.
  • the invention provides a pharmaceutical composition comprising a pharmaceutical agent and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises a protein, such as albumin, more preferably human serum albumin, in an amount effective to reduce one or more side effects of administration of the pharmaceutical composition into a human, and wherein the pharmaceutically acceptable carrier comprises deferoxamine in an amount effective to inhibit microbial growth in the pharmaceutical composition.
  • the pharmaceutically acceptable carrier comprises a protein, such as albumin, in an amount effective to reduce one or more side effects of administration of the pharmaceutical composition into a human, and wherein the pharmaceutically acceptable carrier comprises deferoxamine in an amount effective to inhibit oxidation in the pharmaceutical composition.
  • the invention provides a method for reducing one or more side effects associated with administration of a pharmaceutical composition to a human comprising (a) administering to a human a pharmaceutical composition comprising a pharmaceutical agent and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises albumin and deferoxamine.
  • a pharmaceutical composition comprising a pharmaceutical agent and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises deferoxamine in an amount effective for inhibiting microbial growth or in an amount effective for inhibiting oxidation in the pharmaceutical composition.
  • the invention also provides a method for enhancing transport of a pharmaceutical agent to the site of an infirmity, which method comprises administering to a human a pharmaceutical composition comprising a pharmaceutical agent and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises albumin, and wherein the ratio of albumin to pharmaceutical agent in the pharmaceutical composition is about 18:1 or less.
  • the invention further provides a method for enhancing binding of a pharmaceutical agent to a cell in vitro or in vivo, which method comprises administering to said cell in vitro or in vivo a pharmaceutical composition comprising a pharmaceutical agent and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises albumin, and wherein the ratio of albumin to pharmaceutical agent in the pharmaceutical composition is about 18:1 or less.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutical agent and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises albumin in an amount effective to increase transport of the drug to the site of infirmity in a human, and wherein the ratio of albumin to pharmaceutical agent is about 18:1 or less.
  • the invention further provides a method for increasing the transport of a pharmaceutical agent to a cell in vitro or in vivo by combining said agent with a protein, wherein said protein binds a specific cell-surface receptor on said cell, wherein said binding of the protein-pharmaceutical agent combination with the said receptor causes the transport to occur, and wherein the ratio of protein to pharmaceutical agent is about 18:1 or less.
  • the invention provides a pharmaceutical composition comprising a pharmaceutical agent and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises a protein such as albumin, preferably human serum albumin, in an amount effective to reduce one or more side effects of administration of the pharmaceutical composition to a human, and wherein the pharmaceutically acceptable carrier comprises deferoxamine in an amount effective to inhibit microbial growth in the pharmaceutical composition.
  • the pharmaceutically acceptable carrier comprises a protein such as albumin, preferably human serum albumin, in an amount effective to reduce one or more side effects of administration of the pharmaceutical composition to a human, and wherein the pharmaceutically acceptable carrier comprises deferoxamine in an amount effective to inhibit oxidation in the pharmaceutical composition.
  • Suitable pharmaceutical agents include, but are not limited to, anticancer agents or antineoplastics, antimicrotubule agents, immunosuppressive agents, anesthetics, hormones, agents for use in cardiovascular disorders, antiarrythmics, antibiotics, antifungals, antihypertensives, antiasthmatics, analgesics, anti-inflammatory agents, anti-arthritic agents, and vasoactive agents.
  • the invention is useful with many other drug classes as well.
  • suitable pharmaceutical agents include, but are not limited to, taxanes, (e.g., Taxol® (paclitaxel), and TaxotereTM (docetaxel)), epothilones, camptothecin, colchicine, amiodarone, thyroid hormones, vasoactive peptides (e.g., vasoactive intestinal peptide), amphotericin, corticosteroids, propofol, melatonin, cyclosporine, rapamycin (sirolimus), tacrolimus, mycophenolic acids, ifosfamide, vinorelbine, vancomycin, gemcitabine, SU5416, thiotepa, bleomycin, diagnostic radiocontrast agents, and derivatives thereof.
  • taxanes e.g., Taxol® (paclitaxel), and TaxotereTM (docetaxel)
  • epothilones camptothecin
  • colchicine amio
  • the pharmaceutical agent is propofol, paclitaxel, or docetaxel. More preferably, the pharmaceutical agent is propofol or paclitaxel. Most preferably, the pharmaceutical agent is propofol.
  • Taxol® (paclitaxel) (Bristol-Myers Squibb) is active against carcinomas of the ovary, breast, lung, esophagus and head and neck. Taxol, however, has been shown to induce toxicities associated with administration, as well significant acute and cumulative toxicity, such as myelosuppression, neutropenic fever, anaphylactic reaction, and peripheral neuropathy. Because paclitaxel is poorly soluble in water, cremophor typically is used as a solvent, requiring large infusion volumes and special tubing and filters.
  • Cremophor is associated with side effects that can be severe, including anaphylaxis and other hypersensitivity reactions that can require pretreatment with corticosteroids, antihistamines, and H 2 blockers (see, e.g., Gelderblom et al., Eur. J. of Cancer , 37, 1590-1598, (2001)).
  • TaxotereTM docetaxel
  • Epothilone and derivatives thereof
  • Cremophor also typically is administered in cremophor, and has been shown to induce severe neutropenia, hypersensitivity, and neuropathy.
  • Propofol (2,6-diisopropylphenol) is a hydrophobic, water-insoluble oil, which is widely used as an intravenous anesthetic agent to induce and maintain general anesthesia and sedation of humans and animals. Propofol typically is administered directly into the bloodstream and crosses the blood-brain barrier. Pharmaceutical compositions comprising propofol must have sufficient lipid solubility to cross this barrier and depress the relevant mechanisms of the brain. Propofol has a maximum solubility in water of 1.0+/ ⁇ 0.02 ⁇ M at 22.5° C. (see, e.g., Tonner et al., Anesthesiology , 77, 926-931 (1992)).
  • propofol is generally formulated as an emulsion containing solubilizing agents, surfactants, solvents, or as an oil-in-water emulsion (see, e.g., U.S. Pat. Nos. 6,150,423, 6,326, 406, and 6,362,234).
  • the compositions of the present invention include pharmaceutical carriers, or excipients.
  • the choice of carrier is not necessarily critical, and any of the carriers known in the art can be used in the composition.
  • the choice of carrier is preferably determined, in part, by the particular site to which the pharmaceutical composition is to be administered and the particular method used to administer the pharmaceutical composition.
  • the pharmaceutically acceptable carrier comprises proteins. Any suitable protein can be used.
  • suitable proteins include, but are not limited to albumin, immunoglobulins including IgA, lipoproteins, apolipoprotein B, beta-2-macroglobulin, thyroglobulin and the like.
  • the pharmaceutically acceptable carrier comprises albumin, most preferably human serum albumin. Proteins, including albumin, suitable for the invention may be natural in origin or synthetically prepared.
  • HSA Human serum albumin
  • HSA solution Intravenous use of HSA solution has been indicated for the prevention and treatment of hypovolumic shock (see, e.g., Tullis, JAMA , 237, 355-360, 460-463, (1977)) and Houser et al., Surgery, Gynecology and Obstetrics , 150, 811-816 (1980)) and in conjunction with exchange transfusion in the treatment of neonatal hyperbilirubinemia (see, e.g., Finlayson, Seminars in Thrombosis and Hemostasis , 6, 85-120, (1980)).
  • HSA Human serum albumin
  • hydrophobic binding sites a total of eight for fatty acids, an endogenous ligand of HSA
  • binds a diverse set of drugs, especially neutral and negatively charged hydrophobic compounds Goodman et al., The Pharmacological Basis of Therapeutics , 9 th ed, McGraw-Hill New York (1996).
  • Two high affinity binding sites have been proposed in subdomains IIA and IIIA of HSA, which are highly elongated hydrophobic pockets with charged lysine and arginine residues near the surface which function as attachment points for polar ligand features (see, e.g., Fehske et al., Biochem. Pharmcol ., 30, 687-92 (1981), Vorum, Dan.
  • the inclusion of proteins such as albumin in the inventive pharmaceutical compositions results in a reduction in side effects associated with administration of the pharmaceutical composition that is due, at least in part, to the binding of human serum albumin to any free drug that is present in the composition.
  • the amount of albumin included in the pharmaceutical composition of the present invention will vary depending on the pharmaceutical active agent, other excipients, and the route and site of intended administration. Desirably, the amount of albumin included in the composition is an amount effective to reduce one or more side effects the active pharmaceutical agent due to the of administration of the inventive pharmaceutical composition to a human.
  • the pharmaceutical composition is prepared in liquid form, and the albumin is then added in solution.
  • the pharmaceutical composition, in liquid form comprises from about 0.1% to about 25% by weight (e.g. about 0.5% by weight, about 5% by weight, about 10% by weight, about 15% by weight, or about 20% by weight) of albumin.
  • the pharmaceutical composition, in liquid form comprises about 0.5% to about 5% by weight of albumin.
  • the pharmaceutical composition can be dehydrated, for example, by lyophilization, spray-drying, fluidized-bed drying, wet granulation, and other suitable methods known in the art.
  • the albumin preferably is applied to the active pharmaceutical agent, and other excipients if present, as a solution.
  • the HSA solution preferably is from about 0.1% to about 25% by weight (about 0.5% by weight, about 5% by weight, about 10% by weight, about 15% by weight, or about 20% by weight) of albumin.
  • compositions of the present invention preferably comprise deferoxamine.
  • Deferoxamine is a natural product isolated from Streptomyces pilosus, and is capable of forming iron complexes.
  • Deferoxamine mesylate for injection USP for example, is approved by the Food and Drug Administration as an iron-chelating agent and is available for intramuscular, subcutaneous, and intravenous administration.
  • Deferoxamine mesylate USP is a white to off-white powder. It is freely soluble in water and its molecular weight is 656.79.
  • deferoxamine mesylate is N-[5-[3-[(5-aminopentyl)-hydroxycarbamoyl]-propion-amido]pentyl]-3[[5-((N-hydroxyacetamido)pentyl]-carbamoyl]propionohydroxamic acid monomethanesulfonate (salt), and its structural formula is C 25 H 48 N 6 O 8 .CH 3 SO 3 H.
  • deferoxamine, or analogs, derivatives, or salts e.g., mesylate salts thereof inhibits microbial growth and oxidation in the pharmaceutical composition, and it is believed to bind to free drug in the composition.
  • Deferoxamine also has been shown to bind to phenolic compounds (see, e.g., Juven et al., J. Appl. Bacteriol ., 76(6), 626-31 (1994)).
  • Paclitaxel, docetaxel, propofol, and the like are either phenolic like or have phenolic or phenyl substituents. Therefore, it is believed that deferoxamine can bind to or reduce the amount of free drug in the inventive pharmaceutical composition, thereby also reducing or alleviating irritation or pain upon injection.
  • the amount of deferoxamine, or its preferred salt, i.e., a mesylate salt of deferoxamine, included in the composition will depend on the active pharmaceutical agent and other excipients. Desirably, the amount of deferoxamine, its salts, and analogs thereof in the composition is an amount effective to inhibit microbial growth and/or inhibit oxidation. As described above, typically the pharmaceutical composition is prepared in liquid form, and deferoxamine, it salts, and analogs thereof, is then added in solution.
  • the pharmaceutical composition in liquid form, comprises from about 0.0001% to about 0.5% by weight (e.g., about 0.005% by weight, about 0.1%, or about 0.25% by weight) of deferoxamine, its salts, or its analogs. More preferably, the composition, in liquid form, comprises like amounts of the preferred deferoxamine salt, deferoxamine mesylate. Most preferably, the pharmaceutical composition, in liquid form, comprises about 0.1% by weight of deferoxamine mesylate.
  • deferoxamine mesylate When the composition is prepared in solid form, as described above, such as by wet granulation, fluidized-bed drying, and other methods known to those skilled in the art, deferoxamine mesylate preferably is applied to the active pharmaceutical agent, and other excipients if present, as a solution.
  • the deferoxamine mesylate solution preferably is from about 0.0001% to about 0.5% by weight (e.g., about 0.005% by weight, about 0.1%, or about 0.25% by weight) of deferoxamine.
  • the pharmaceutical composition can include other agents, excipients, or stabilizers to improve properties of the composition.
  • certain negatively charged components include, but are not limited to bile salts of bile acids consisting of glycocholic acid, cholic acid, chenodeoxycholic acid, taurocholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, litocholic acid, ursodeoxycholic acid, dehydrocholic acid and others; phospholipids including Lecithin (Egg yolk) based phospholipids which include the following phosphatidylcholines: palmitoyloleoylphosphatidylcholine, palmitoyllinoleoylphosphatidylcholine, stearoyllinoleoylphosphatidylcholine stearoyloleoylphosphatid
  • phospholipids including L- ⁇ -dimyristoylphosphatidylcholine (DMPC), dioleoylphosphatidylcholine (DOPC), distearyolphosphatidylcholine (DSPC), hydrogenated soy phosphatidylcholine (HSPC), D- ⁇ -phosphatidylcholine, ⁇ -acetyl- ⁇ -O-hexadecyl, L- ⁇ -phosphatidylcholine, ⁇ -acetyl- ⁇ -O-hexadecyl, DL- ⁇ -phosphatidylcholine, ⁇ -acetyl- ⁇ -O-hexadecyl, L- ⁇ -phosphatidylcholine, ⁇ -acetyl- 65 -O-octadecyl, L- ⁇ -phosphatidylcholine, ⁇ -arachidonoyl- 65 -O-hexadecyl, L- ⁇ -phosphatidylcholine,
  • the pharmaceutical agent e.g., propofol
  • a water-immiscible solvent such as soybean, safflower, cottonseed, corn, sunflower, arachis, castor, or olive oil may be used.
  • the preferred oil is a vegetable oil, wherein soybean oil is most preferred.
  • Soybean oil may be used in a range of 1% to 10% by weight of the composition.
  • soybean oil is present in the pharmaceutical composition in an amount of about 3% by weight.
  • the inventive pharmaceutical composition can be stabilized with a pharmaceutically acceptable surfactant.
  • surfactants refers to surface active group(s) of amphiphile molecules.
  • Surfactants can be anionic, cationic, nonionic, and zwitterionic. Any suitable surfactant can be included in the inventive pharmaceutical composition.
  • Suitable surfactants include non-ionic surfactants such as phosphatides, polyoxyethylene sorbitan esters, and tocopheryl polyethylene glycol succinate.
  • Preferable surfactants are egg lecithin, tween 80, and vitamin E-t d- ⁇ -tocopheryl polyethylene glycol-1000 succinate (TPGS).
  • egg lecithin is preferred and is no more than 1.2% by weight for a formulation containing 3% soybean oil, preferably at 1.1% by weight of the composition.
  • tween 80 or vitamin E-TPGS are the preferred surfactants.
  • 0.1 to 1.5% by weight of tween 80 or 0.5 to 4% by weight of vitamin E-TPGS is suitable.
  • 1.5% by weight of tween 80 or 1% by weight of vitamin E-TPGS is used.
  • suitable surfactants are described in, for example, Becher, Emulsions: Theory and Practice , Robert E. Krieger Publishing, Malabar, Fla. (1965).
  • Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice, (b) capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as solids or granules, (c) suspensions in an appropriate liquid, and (d) suitable emulsions.
  • Tablet forms can include one or more of lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, acacia, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible excipients.
  • Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such excipients as are known in the art.
  • a flavor usually sucrose and acacia or tragacanth
  • pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such excipients as are known in the art.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the formulations can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described. Injectable formulations are preferred.
  • Formulations suitable for aerosol administration comprise the inventive pharmaceutical composition include aqueous and non-aqueous, isotonic sterile solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes, as well as aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives, alone or in combination with other suitable components, which can be made into aerosol formulations to be administered via inhalation.
  • These aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also can be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.
  • suppositories can be prepared by use of a variety of bases such as emulsifying bases or water-soluble bases.
  • bases such as emulsifying bases or water-soluble bases.
  • Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.
  • the pharmaceutical composition is formulated to have a pH range of 4.5 to 9.0, and more preferably a pH of 5.0 to 8.0.
  • the pharmaceutical composition can also be made to be isotonic with blood by the addition of a suitable tonicity modifier, such as glycerol.
  • the pharmaceutically acceptable carrier preferably also comprises pyrogen-free water or water for injection, USP.
  • the inventive pharmaceutical composition is prepared as a sterile aqueous formulation, a nanoparticle, an oil-in-water emulsion, or a water-in-oil emulsion. Most preferably, the pharmaceutical composition is an oil-in-water emulsion.
  • an oil-in-water emulsion is prepared by dissolving propofol in a water-immiscible solvent alone, and preparing an aqueous phase containing albumin, deferoxamine, a surfactant, and other water-soluble ingredients, and mixing the oil with the aqueous phase.
  • the crude emulsion is high pressure homogenized at pressures of 10,000 to 25,000 psi and recirculated for 5 to 20 cycles to form an ideal emulsion.
  • the preferred pressure is 15,000 to 20,000 psi., and more preferably 10,000 psi.
  • the crude emulsion may be recirculated from 7 to 15 cycles and is preferably recirculated at 15 cycles. Alternatively, discrete passes through a homogenizer may be used.
  • the inventive pharmaceutical composition can have a particle or droplet size less than about 200 nanometers (nm).
  • nm nanometers
  • the mean size of these dispersions is less than 200 nm.
  • the invention further provides a method for reducing one or more side effects associated with administration of a pharmaceutical composition to a human.
  • the method comprises administering to a human a pharmaceutical composition comprising a pharmaceutical agent and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises albumin and deferoxamine.
  • a pharmaceutical composition comprising a pharmaceutical agent and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises albumin and deferoxamine.
  • the dose of the inventive pharmaceutical composition administered to a human will vary with the particular pharmaceutical composition, the method of administration, and the particular site being treated.
  • the dose should be sufficient to effect a desirable response, such as a therapeutic or prophylactic response against a particular disease, or, when the pharmaceutical agent is an anaesthesia, such as propofol, an anesthetic response, within a desirable time frame.
  • the inventive pharmaceutical composition is administered to the human via intravenous administration, intra-arterial administration, intrapulmonary administration, oral administration, inhalation, intravesicular administration, intramuscular administration, intra-tracheal administration, subcutaneous administration, intraocular administration, intrathecal administration, or transdermal administration.
  • the inventive pharmaceutical composition can be administered by inhalation to treat conditions of the respiratory tract.
  • albumin is a natural component in the lining and secretions of the respiratory tract.
  • the inventive composition can be used to treat respiratory conditions such as pulmonary fibrosis, broncheolitis obliterans, lung cancer, bronchoalveolar carcinoma, and the like.
  • the inventive method results in the reduction of one or more side effects associated with administration of a pharmaceutical composition to a human.
  • side effects include, for example, myelosuppression, neurotoxicity, hypersensitivity, inflammation, venous irritation, phlebitis, pain, skin irritation, and combinations thereof.
  • side effects are merely exemplary, and other side effects, or combination of side effects, associated with various pharmaceutical agents can be reduced or avoided by the use of the novel compositions and methods of the present invention.
  • the invention further provides a method for inhibiting microbial growth in a pharmaceutical composition.
  • inhibiting microbial growth is meant either a complete elimination of microbes from the pharmaceutical composition, or a reduction in the amount or rate of microbial growth in the pharmaceutical composition.
  • the method comprises preparing a pharmaceutical composition comprising a pharmaceutical agent and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises deferoxamine, its salts, its analogs, and combinations thereof, in an amount effective for inhibiting microbial growth in the pharmaceutical composition.
  • the invention provides a method for inhibiting oxidation of a pharmaceutical composition.
  • This method comprises preparing a pharmaceutical composition comprising a pharmaceutical agent and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises deferoxamine, its salts, its analogs, and combinations thereof, in an amount effective for inhibiting oxidation of the pharmaceutical composition.
  • the pharmaceutical composition, pharmaceutical agent, and pharmaceutically acceptable carrier, and components thereof set forth above in connection with the inventive pharmaceutical composition also are applicable to those same aspects of the inventive method.
  • the amount of deferoxamine, or its preferred salt, a mesylate salt of deferoxamine, included in the composition will depend on the active pharmaceutical agent and other excipients. Desirably, the amount of deferoxamine, its salts, and analogs thereof in the composition is an amount effective to inhibit microbial growth and/or inhibit oxidation.
  • the pharmaceutical composition is prepared in liquid form, and deferoxamine, it salts, and analogs thereof, is then added in solution.
  • the pharmaceutical composition, in liquid form comprises from about 0.0001% to about 0.5% by weight (e.g., about 0.005% by weight, about 0.1%, or about 0.25% by weight) of deferoxamine, its salts, or its analogs.
  • the composition, in liquid form comprises like amounts of the preferred deferoxamine salt, deferoxamine mesylate.
  • the pharmaceutical composition, in liquid form comprises about 0.5% by weight of deferoxamine mesylate.
  • deferoxamine mesylate preferably is applied to the active pharmaceutical agent, and other excipients if present, as a solution.
  • the deferoxamine mesylate solution preferably is from about 0.0001% to about 0.5% by weight (e.g., about 0.005% by weight, about 0.1%, or about 0.25% by weight) of deferoxamine.
  • the invention also provides a method for enhancing transport of a pharmaceutical agent to the site of an infirmity, which method comprises administering to a human a pharmaceutical composition comprising a pharmaceutical agent and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises albumin, and wherein the ratio of albumin to pharmaceutical agent in the pharmaceutical composition is about 18:1 or less.
  • the invention further provides a method for enhancing binding of a pharmaceutical agent to a cell in vitro or in vivo, which method comprises administering to said cell in vitro or in vivo a pharmaceutical composition comprising a pharmaceutical agent and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises albumin, and wherein the ratio of albumin to pharmaceutical agent in the pharmaceutical composition is about 18:1 or less.
  • Descriptions of the pharmaceutical composition, pharmaceutical agent, pharmaceutically acceptable carrier, administration routes, and components thereof set forth above in connection with the inventive pharmaceutical composition and inventive method also are applicable to those same aspects of the transport and binding methods.
  • the pharmaceutically acceptable carrier preferably comprises albumin, most preferably human serum albumin.
  • albumin most preferably human serum albumin.
  • the ratio of protein, e.g., human serum albumin, to pharmaceutical agent in the pharmaceutical composition affects the ability of the pharmaceutical agent to bind and transport the pharmaceutical agent to a cell.
  • higher ratios of protein to pharmaceutical agent generally are associated with poor cell binding and transport of the pharmaceutical agent, which possibly is the result of competition for receptors at the cell surface.
  • the ratio of protein, e.g., albumin, to active pharmaceutical agent must be such that a sufficient amount of pharmaceutical agent binds to, or is transported by, the cell.
  • Exemplary ranges for protein-drug preparations are protein to drug ratios (w/w) of 0.01:1 to about 100:1. More preferably, the ratios are in the range of 0.02:1 to about 40:1. While the ratio of protein to pharmaceutical agent will have to be optimized for different protein and pharmaceutical agent combinations, generally the ratio of protein, e.g., albumin, to pharmaceutical agent is about 18:1 or less (e.g., about 15:1, about 10:1, about 5:1, or about 3:1). More preferably, the ratio is about 0.2:1 to about 12:1.
  • the ratio is about 1:1 to about 9:1.
  • the formulation is essentially free of cremophor, and more preferably free of Cremophor EL® (BASF).
  • Cremophor EL® is a non-ionic emulsifying agent that is a polyether of castor oil and ethylene oxide.
  • cremophor typically is used as a solvent for paclitaxel, and is associated with side effects that can be severe (see, e.g., Gelderblom et al., supra).
  • the pharmaceutical agent can be any suitable pharmaceutical agent described herein (e.g., propofol, paclitaxel, or docetaxel).
  • the pharmaceutical agent can be a nucleic acid sequence, most preferably a DNA sequence.
  • the inventive pharmaceutical composition can be used to transport genes to a cell by way of a receptor mediated/caveolar/vescicular transport.
  • DNA sequences such as genes or other genetic material, including but not limited to plasmids or c-DNA
  • a cell e.g. an endothelial cell or a tumor cell
  • pharmaceutical compositions comprising albumin in combination with genetic material can be prepared.
  • a pharmaceutical composition comprising the nucleic acid sequence encoding ⁇ -galactosidase or green fluorescent protein (GFP) and albumin can be prepared and contacted with endothelial cells derived from human umbilical vein or human lung microvessels to facilitate incorporation of the nucleic acid sequence into the endothelial cells. Incorporation of the nucleic acid sequence can be detected using methods known in the art, such as, for example, fluorescence or staining.
  • the infirmity can be any suitable disease or condition.
  • the infirmity is cancer, cardiovascular disease, or arthritis.
  • the pharmaceutical composition is administered to a cell in vitro or in vivo.
  • the cell is an animal cell. More preferably the cell is a mammalian cell, and most preferably the cell is a human cell.
  • the pharmaceutical composition preferably is administered to a cell in vivo.
  • the cell can be any suitable cell that is a desirable target for administration of the pharmaceutical composition.
  • the cell can be located in or derived from tissues of the digestive system including, for example, the esophagus, stomach, small intestine, colon, rectum, anus, liver, gall bladder, and pancreas.
  • the cell also can be located in or derived from tissues of the respiratory system, including, for example, the larynx, lung, and bronchus.
  • the cell can be located in or derived from, for example, the uterine cervix, the uterine corpus, the ovary vulva, the vagina, the prostate, the testis, and the penis, which make up the male and female genital systems, and the urinary bladder, kidney, renal pelvis, and ureter, which comprise the urinary system.
  • the cell can be located in or derived from tissues of the cardiovascular system, including, for example, endothelial cells and cardiac muscle cells.
  • the cell also can be located in or derived from tissues of the lymphoid system (e.g., lymph cells), the nervous system (e.g., neurons or glial cells), and the endocrine system (e.g., thyroid cells).
  • the cell is located in or derived from tissues of the cardiovascular system.
  • the cell is an endothelial cell.
  • the pharmaceutical composition desirably contacts more than one cell.
  • the inventive methods for enhancing transport and enhancing binding of a pharmaceutical agent to a cell can be used to treat tumor cells.
  • Tumor cells exhibit an enhanced uptake of proteins including, for example, albumin and transferrin, as compared to normal cells. Since tumor cells are dividing at a rapid rate, they require additional nutrient sources compared to normal cells.
  • Tumor studies of the inventive pharmaceutical compositions containing paclitaxel and human serum albumin showed high uptake of albumin-paclitaxel into tumors. This has been found to be due to the previously unrecognized phenomenon of the albumin-drug transport by glycoprotein 60 (“gp60”) receptors, which are specific for albumin.
  • gp60 glycoprotein 60
  • the albumin-specific gp60 receptor and other protein transport receptors that are present on tumor cells can be used as a target to inhibit tumor growth.
  • blocking the gp60 receptor using antibodies against the gp60 receptor or other large or small molecule compounds that bind, block, or inactivate gp60 and other protein transport receptors on tumor cells or tumor endothelial cells, it is possible to block the transport of proteins to these cells and thereby reduce their growth rate and cause cell death. Blocking of this mechanism thus results in the treatment of a subject (e.g., a human) with cancer or another disease.
  • Identification of blocking/binding of the specific protein receptor is done by screening any number of compounds against the isolated gp60 or other receptors, such as gp16 orgp30, or by using a whole cell preparation.
  • suitable animal models also can be used for this purpose, such as, for example, mice containing “knock-out” mutations of the genes encoding gp60 or caveolin-1, or other proteins that are specific for transport.
  • method of identification of compounds that block or bind gp60, gp16, gp30, or other protein receptors are within the scope of the invention.
  • compounds that block or bind the gp60 receptor or other protein receptors can be used in the treatment of several diseases, including cancer.
  • the blocking or binding compound may be used as a single agent or in combination with other standard chemotherapy or chemotherapies.
  • Blocking compounds can be administered prior to, or in conjunction with, other chemotherapeutic or anticancer agents.
  • any compounds that can block or bind the gp60 receptor, or other protein receptors are within the scope of the present invention.
  • the inventive albumin-drug compositions such as e.g., albumin-paclitaxel, albumin-docetaxel, albumin-epothilone, albumin-camptothecin, or albumin-rapamycin, and others, are useful in the treatment of diseases. It is believed that such drug compositions are effective due to increased receptor mediated transport of the protein-drug composition to the required site, for example a tumor. Without wishing to be bound to any particular theory, the transport of a protein-drug composition by receptor mediated transport resulting in a therapeutic effect is believed to be the mechanism for transport of for example, albumin-paclitaxel compositions to a tumor, as well as albumin-paclitaxel and albumin-rapamycin transport across the lung.
  • Transport is effected by the presence of gp60, gp16, or gp30 in such tissues. Accordingly, drugs and protein-drug compositions whose transport to sites of disease, e.g., inflammation (e.g., arthritis) or tumors is associated with gp60, gp16, or gp30 receptors and that result in a therapeutic effect are contemplated as compositions of the present invention.
  • sites of disease e.g., inflammation (e.g., arthritis) or tumors
  • gp60, gp16, or gp30 receptors that result in a therapeutic effect
  • endothelial cells can be co-cultured with cells having a specific function. Incubation of endothelial cells with other cell types such as islet cells, hepatocytes, neuroendocrine cells, and others allows for required transport of components such as proteins and other beneficial components to these cells.
  • the endothelial cells provide for transport of these components to the cultured cell types in order to simulate in vivo conditions, i.e., where these cell types would normally be in close proximity to endothelial cells and would depend on the endothelial cells for transport of nutrients, growth factors, hormone signals, etc. that are required for their proper function.
  • endothelial cells have previously not been possible to adequately culture these different cell types and obtain physiological performance when endothelial cells were absent.
  • the presence of endothelial cells in culture with desired cell types allows for differentiation and proper functioning of islets, hepatocytes, or neuroendocrine tissue in vitro or ex vivo.
  • coculture of endothelial cells with islets results in islets with improved physiological properties e.g., ability to secrete insulin, when compared with those cultured in the absence of endothelial cells.
  • This tissue can then be used ex vivo or transplanted in vivo to treat diseases caused by lack of adequate cellular function (e.g., diabetes in the case of islet cells, hepatic dysfunction in the case of hepatocytes, and neuroendocrine disorders or pain relief in the case of neuroendocrine cells).
  • diseases caused by lack of adequate cellular function e.g., diabetes in the case of islet cells, hepatic dysfunction in the case of hepatocytes, and neuroendocrine disorders or pain relief in the case of neuroendocrine cells.
  • Cells originating from other tissues and organs may also be cocultured with endothelial cells to provide the same benefit.
  • the coculture may be utilized to incorporate genetic material into the target cell types. The presence of albumin in these cultures is found to be greatly beneficial.
  • This example demonstrates the preparation of pharmaceutical compositions comprising paclitaxel and albumin.
  • Preparation of paclitaxel-albumin compositions is described in U.S. Pat. Nos. 5,439,686 and 5,916,596, which are incorporated in their entirety by reference.
  • 30 mg of paclitaxel was dissolved in 3.0 ml methylene chloride.
  • the solution was added to 27.0 ml of human serum albumin solution (2% w/v).
  • Deferoxamine was added as necessary.
  • the mixture was homogenized for 5 minutes at low RPM (Vitris homogenizer, model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer (Avestin).
  • the emulsification was performed at 9000-40,000 psi while recycling the emulsion for at least 5 cycles.
  • the resulting system was transferred into a rotary evaporator, and methylene chloride was rapidly removed at 40° C., at reduced pressure (30 mm Hg) for 20-30 minutes.
  • the resulting dispersion was translucent, and the typical average diameter of the resulting paclitaxel particles was in the range 50-220 nm (Z-average, Malvern Zetasizer).
  • the dispersion was further lyophilized for 48 hrs.
  • the resulting cake could be easily reconstituted to the original dispersion by addition of sterile water or saline.
  • the particle size after reconstitution was the same as before lyophilization.
  • the amounts, types and proportions of drug, solvents, proteins used in this example are not limiting in any way.
  • the inventive pharmaceutical composition containing albumin showed substantially lower toxicity.
  • This example demonstrates the preparation of a pharmaceutical composition comprising amiodarone and albumin.
  • 30 mg of amiodarone was dissolved in 3.0 ml methylene chloride.
  • the solution was added to 27.0 ml of human serum albumin solution (1% w/v).
  • Deferoxamine was added as necessary.
  • the mixture was homogenized for 5 minutes at low RPM (Vitris homogenizer, model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer (Avestin).
  • the emulsification was performed at 9000-40,000 psi while recycling the emulsion for at least 5 cycles.
  • the resulting system was transferred into a rotary evaporator, and methylene chloride was rapidly removed at 40° C., at reduced pressure (30 mm Hg) for 20-30 minutes.
  • the resulting dispersion was translucent, and the typical average diameter of the resulting amiodarone particles was in the range 50-220 nm (Z-average, Malvern Zetasizer).
  • the dispersion was further lyophilized for 48 hrs.
  • the resulting cake was easily reconstituted to the original dispersion by addition of sterile water or saline.
  • the particle size after reconstitution was the same as before lyophilization.
  • the amounts, types and proportions of drug, solvents, proteins used in this example are not limiting in anyway.
  • the inventive pharmaceutical composition with albumin showed substantially lower toxicity.
  • This example demonstrates the preparation of pharmaceutical compositions comprising liothyronine and albumin compositions.
  • Liothyronine (or suitable salt) was dissolved in an aqueous alcoholic solution or alkaline solution at a concentration of 0.5-50 mg/ml.
  • the alcoholic (or alkaline) solution was added to an albumin solution (0.1-25% w/v) and agitated. Agitation was low shear with a stirrer or high shear using a sonicator or a homogenizer.
  • concentrations of liothyronine (5-1000 ⁇ g/ml) clear solutions were obtained. As the concentration was increased, a milky stable suspension was obtained. These solutions or suspensions were filtered through a sterilizing filter. Organic solvents were removed by evaporation or other suitable method.
  • This example demonstrates the preparation of pharmaceutical compositions comprising rapamycin and albumin.
  • 30 mg of rapamycin was dissolved in 2 ml chloroform/ethanol. The solution was then added into 27.0 ml of a human serum albumin solution (3% w/v). The mixture was homogenized for 5 minutes at low RPM (Vitris homogenizer model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer (Avestin). The emulsification was performed at 9000-40,000 psi while recycling the emulsion for at least 5 cycles. The resulting system was transferred into a Rotavap and solvent was rapidly removed at 40° C., at reduced pressure (30 mm Hg) for 20-30 minutes.
  • the resulting dispersion was translucent and the typical average diameter of the resulting particles was in the range 50-220 nm (Z-average, Malvern Zetasizer).
  • the dispersion was further lyophilized for 48 hours.
  • the resulting cake was easily reconstituted to the original dispersion by addition of sterile water or saline.
  • the particle size after reconstitution was the same as before lyophilization. It should be recognized that the amounts, types and proportions of drug, solvents, proteins used in this example are not limiting in anyway.
  • This example demonstrates the preparation of a pharmaceutical composition comprising epothilone B and albumin.
  • 30 mg of epothilone B was dissolved in 2 ml chloroform/ethanol. The solution was then added into 27.0 ml of a human serum albumin solution (3% w/v). Deferoxamine was added as necessary. The mixture was homogenized for 5 minutes at low RPM (Vitris homogenizer model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer (Avestin). The emulsification was performed at 9000-40,000 psi while recycling the emulsion for at least 5 cycles.
  • the resulting system was transferred into a Rotavap and solvent was rapidly removed at 40° C., at reduced pressure (30 mm Hg) for 20-30 minutes.
  • the resulting dispersion was translucent and the typical average diameter of the resulting particles was in the range 50-220 nm (Z-average, Malvern Zetasizer).
  • the dispersion was further lyophilized for 48 hours.
  • the resulting cake was easily reconstituted to the original dispersion by addition of sterile water or saline.
  • the particle size after reconstitution was the same as before lyophilization. It should be recognized that the amounts, types and proportions of drug, solvents, proteins used in this example are not limiting. When compared to toxicity of epothilone B dissolved in cremophor formulations, the pharmaceutical composition comprising albumin showed substantially lower toxicity.
  • This example demonstrates the preparation of pharmaceutical compositions comprising colchicine dimer and albumin.
  • 30 mg of colchicine-dimer was dissolved in 2 ml chloroform/ethanol. The solution was then added into 27.0 ml of human serum albumin solution (3% w/v). Deferoxamine was added as necessary. The mixture was homogenized for 5 minutes at low RPM (Vitris homogenizer model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer (Avestin). The emulsification was performed at 9000-40,000 psi while recycling the emulsion for at least 5 cycles.
  • the resulting system was transferred into a Rotavap and solvent was rapidly removed at 40° C., at reduced pressure (30 mm Hg) for 20-30 minutes.
  • the resulting dispersion was translucent and the typical average diameter of the resulting particles was in the range 50-220 nm (Z-average, Malvern Zetasizer).
  • the dispersion was further lyophilized for 48 hours.
  • the resulting cake was easily reconstituted to the original dispersion by addition of sterile water or saline.
  • the particle size after reconstitution was the same as before lyophilization. It should be recognized that the amounts, types and proportions of drug, solvents, proteins used in this example are not limiting. When compared to toxicity of the colchicines dimer dissolved in tween, the pharmaceutical composition comprising albumin showed substantially lower toxicity.
  • This example demonstrates the preparation of pharmaceutical compositions comprising docetaxel and albumin.
  • 30 mg of docetaxel was dissolved in 2 ml chloroform/ethanol. The solution was then added into 27.0 ml of human serum albumin solution (3% w/v). Deferoxamine was added as necessary. The mixture was homogenized for 5 minutes at low RPM (Vitris homogenizer model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer (Avestin). The emulsification was performed at 9000-40,000 psi while recycling the emulsion for at least 5 cycles.
  • the resulting system was transferred into a Rotavap and solvent was rapidly removed at 40° C., at reduced pressure (30 mm Hg) for 20-30 minutes.
  • the resulting dispersion was translucent and the typical average diameter of the resulting particles was in the range 50-220 run (Z-average, Malvern Zetasizer).
  • the dispersion was further lyophilized for 48 hours.
  • the resulting cake was easily reconstituted to the original dispersion by addition of sterile water or saline.
  • the particle size after reconstitution was the same as before lyophilization. It should be recognized that the amounts, types and proportions of drug, solvents, and proteins used in this example are not limiting. When compared to toxicity of the docetaxel dissolved in tween/ethanol which is the standard solvent for this drug, the pharmaceutical composition comprising albumin showed substantially lower toxicity.
  • This example demonstrates the preparation of pharmaceutical compositions comprising docetaxel and albumin.
  • 150 mg of docetaxel was dissolved in 1 ml ethyl acetate/butyl acetate and 0.5 ml of an oil for example soybean oil or vitamin E oil. Other ratios of solvents and oils were used and these compositions are also contemplated as part of the invention.
  • a small quantity of a negatively charged component was also optionally added, e.g., benzoic acid (0.001%-0.5%)
  • the solution was then added into 27.0 ml of human serum albumin solution (5% w/v). Deferoxamine was added as necessary.
  • the mixture was homogenized for 5 minutes at low RPM (Vitris homogenizer model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer (Avestin).
  • the emulsification was performed at 9000-40,000 psi while recycling the emulsion for at least 5 cycles.
  • the resulting system was transferred into a Rotavap and solvent was rapidly removed at 40° C., at reduced pressure (30 mm Hg) for 20-30 minutes.
  • the resulting dispersion was translucent and the typical average diameter of the resulting particles was in the range 50-220 nm (Z-average, Malvern Zetasizer).
  • the dispersion was further lyophilized for 48 hours.
  • the resulting cake was easily reconstituted to the original dispersion by addition of sterile water or saline.
  • the particle size after reconstitution was the same as before lyophilization. It should be recognized that the amounts, types and proportions of drug, solvents, proteins used in this example are not limiting. When compared to toxicity of the docetaxel dissolved in tween/ethanol which is the standard solvent for this drug, the pharmaceutical composition comprising albumin showed substantially lower toxicity.
  • This example demonstrates the preparation of pharmaceutical compositions comprising a taxane IDN5390 and albumin.
  • 150 mg of IDN5390 was dissolved in 1 ml ethyl acetatelbutyl acetate and 0.5 ml of an oil for example soybean oil or vitamin E oil. Other ratios of solvents and oils were used and these compositions are also contemplated as part of the invention.
  • a small quantity of a negatively charged component was also optionally added, e.g., benzoic acid (0.001%-0.5%) The solution was then added into 27.0 ml of human serum albumin solution (5% w/v). Deferoxamine was added as necessary.
  • the mixture was homogenized for 5 minutes at low RPM (Vitris homogenizer model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer (Avestin).
  • the emulsification was performed at 9000-40,000 psi while recycling the emulsion for at least 5 cycles.
  • the resulting system was transferred into a Rotavap and solvent was rapidly removed at 40° C., at reduced pressure (30 mm Hg) for 20-30 minutes.
  • the resulting dispersion was translucent and the typical average diameter of the resulting particles was in the range 50-220 nm (Z-average, Malvern Zetasizer).
  • the dispersion was further lyophilized for 48 hours.
  • the resulting cake was easily reconstituted to the original dispersion by addition of sterile water or saline.
  • the particle size after reconstitution was the same as before lyophilization. It should be recognized that the amounts, types and proportions of drug, solvents, proteins used in this example are not limiting.
  • the pharmaceutical composition comprising albumin showed substantially lower toxicity.
  • This example demonstrates the preparation of pharmaceutical compositions comprising a taxane IDN5109 and albumin.
  • 150 mg of IDN5109 was dissolved in 2 ml chloroform/ethanol. Other ratios of solvents and oils were used and these compositions are also contemplated as part of the invention.
  • a small quantity of a negatively charged component was also optionally added, e.g., benzoic acid (0.001%-0.5%) The solution was then added into 27.0 ml of human serum albumin solution (5% w/v). Deferoxamine was added as necessary.
  • the mixture is homogenized for 5 minutes at low RPM (Vitris homogenizer model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer (Avestin).
  • the emulsification was performed at 9000-40,000 psi while recycling the emulsion for at least 5 cycles.
  • the resulting system was transferred into a Rotavap and solvent was rapidly removed at 40° C., at reduced pressure (30 mm Hg) for 20-30 minutes.
  • the resulting dispersion was translucent and the typical average diameter of the resulting particles was in the range 50-220 nm (Z-average, Malvern Zetasizer).
  • the dispersion was further lyophilized for 48 hours.
  • the resulting cake was easily reconstituted to the original dispersion by addition of sterile water or saline.
  • the particle size after reconstitution was the same as before lyophilization. It should be recognized that the amounts, types and proportions of drug, solvents, and proteins used in this example are not limiting.
  • the pharmaceutical composition comprising albumin showed substantially lower toxicity.
  • This example demonstrates the preparation of a pharmaceutical composition comprising 10-hydroxy camptothecin (10HC) and albumin.
  • 10HC 10-hydroxy camptothecin
  • albumin 30 mg
  • 30 mg of 10-HC was dissolved in 2.0 ml DMF/methylene chloride/soybean oil.
  • the solution was then added into 27.0 ml of a human serum albumin solution (3% w/v).
  • the mixture was homogenized for 5 minutes at low RPM (Vitris homogenizer model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer (Avestin).
  • the emulsification was performed at 9000-40,000 psi while recycling the emulsion for at least 5 cycles.
  • the resulting system was transferred into a Rotavap and solvent was rapidly removed at 40° C., at reduced pressure (30 mm Hg) for 20-30 minutes.
  • the resulting dispersion was translucent and the typical average diameter of the resulting particles was in the range 50-220 nm (Z-average, Malvern Zetasizer).
  • the dispersion was further lyophilized for 48 hours.
  • the resulting cake was easily reconstituted to the original dispersion by addition of sterile water or saline.
  • the particle size after reconstitution was the same as before lyophilization. It should be recognized that the amounts, types and proportions of drug, solvents, proteins used in this example are not limiting in anyway.
  • This example demonstrates the preparation of a pharmaceutical composition comprising cyclosporine and albumin.
  • 30 mg of cyclosporine was dissolved in 3.0 ml methylene chloride. The solution was then added into 27.0 ml of a human serum albumin solution (1% w/v). The mixture was homogenized for 5 minutes at low RPM (Vitris homogenizer model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer (Avestin). The emulsification was performed at 9000-40,000 psi while recycling the emulsion for at least 5 cycles.
  • the resulting system was transferred into a Rotavap and methylene chloride was rapidly removed at 40° C., at reduced pressure (30 mm Hg) for 20-30 minutes.
  • the resulting dispersion was translucent and the typical average diameter of the resulting particles was in the range 50-220 nm (Z-average, Malvern Zetasizer).
  • the dispersion was further lyophilized for 48 hours.
  • the resulting cake was easily reconstituted to the original dispersion by addition of sterile water or saline.
  • the particle size after reconstitution was the same as before lyophilization.
  • This example demonstrates the preparation of a pharmaceutical composition containing oil and comprising cyclosporine and albumin.
  • 30 mg of cyclosporine was dissolved in 3.0 ml of a suitable oil (sesame oil containing 10% orange oil).
  • the solution was then added into 27.0 ml of a human serum albumin solution (1% v/w).
  • the mixture was homogenized for 5 minutes at low RPM (Vitris homogenizer, model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer (Avestin).
  • the emulsification as performed at 9000-40,000 psi while recycling the emulsion for at least 5 cycles.
  • the resulting dispersion had a typical average diameter in range of 50-220 nm (Z-average, Malvern Zetasizer).
  • the dispersion was used directly or lyophilized for 48 hours by optionally adding a suitable cryoprotectant.
  • the resulting cake was easily reconstituted to the original dispersion by addition of sterile water or saline. It should be recognized that the amounts, types and proportions of drug, solvents, and proteins used in this example are not limiting in anyway.
  • This example demonstrates the preparation of a pharmaceutical composition comprising amphotericin and albumin.
  • 30 mg of amphotericin was dissolved in 3.0 ml methyl pyrrolidinone/methylene chloride.
  • the solution was added to 27.0 ml of a human serum albumin solution (1% w/v).
  • the mixture was homogenized for 5 minutes at low RPM (Vitris homogenizer, model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer (Avestin).
  • the emulsification was performed at 9000-40,000 psi while recycling the emulsion for at least 5 cycles.
  • the resulting system was transferred into a rotary evaporator, and solvent was rapidly removed at 40° C., at reduced pressure (30 mm Hg) for 20-30 minutes.
  • the resulting dispersion was translucent, and the typical average diameter of the resulting amphotericin particles was between 50-220 nm (Z-average, Malvern Zetasizer).
  • the dispersion was further lyophilized for 48 hrs.
  • the resulting cake could be easily reconstituted to the original dispersion by addition of sterile water or saline.
  • the particle size after reconstitution was the same as before lyophilization. It should be recognized that the amounts, types and proportions of drug, solvents, and proteins used in this example are not limiting in anyway. Addition of other components such as lipids, bile salts, etc., also resulted in suitable formulations.
  • This example demonstrates preclinical pharmacokinetics and pharmacodynamics of a pharmaceutical composition comprising albumin and paclitaxel.
  • This example demonstrates reduced side effects and reduced toxicity associated with pharmaceutical compositions comprising paclitaxel and albumin.
  • toxicity of pharmaceutical compositions comprising paclitaxel and albumin is substantially lower than Taxol.
  • a single dose acute toxicity study in mice showed an LD 50 dose approximately 59 times greater for pharmaceutical compositions comprising paclitaxel and albumin than for Taxol.
  • the LD 50 dose was approximately 10-fold greater for pharmaceutical compositions comprising paclitaxel and albumin than for Taxol.
  • a further study evaluated the degree of myelosuppression in rats treated with pharmaceutical compositions comprising paclitaxel and albumin and Taxol.
  • This example demonstrates the clinical effects of a pharmaceutical composition comprising paclitaxel and albumin in humans.
  • the maximum tolerated dose of albumin-paclitaxel given on a weekly schedule was 125-150 mg/m 2 . This is substantially higher than the generally administered dose of cremophor-paclitaxel which is 80 mg/m 2 when given on a weekly schedule.
  • the hematological toxicities in these patients were mild with no hypersensitivities, mild neuropathies, and no administration related side effects such as venous irritation, etc.
  • This example demonstrates enhanced preclinical efficacy using a pharmaceutical composition comprising albumin and paclitaxel.
  • This example demonstrates enhanced clinical efficacy using a pharmaceutical composition comprising albumin and paclitaxel administered intra-arterially.
  • This example demonstrates the preparation of a pharmaceutical composition containing 3% oil and comprising propofol and albumin.
  • An oil-in-water emulsion containing 1% (by weight) of propofol was prepared as follows.
  • the aqueous phase was prepared by adding glycerol (2.25% by weight) and human serum albumin (0.5% by weight) into water for injection and stirred until dissolved.
  • the aqueous phase was passed through a filter (0.2 um filter).
  • the oil phase was prepared by dissolving egg lecithin (0.4% by weight) and propofol (1% by weight) into soybean oil (3% by weight) at about 50° C.-60° C. and was stirred until dissolved.
  • the oil phase was added to the aqueous phase and homogenized at 10,000RPM for 5 min.
  • the crude emulsion was high pressure homogenized at 20,000 psi and recirculated for 15 cycles at 5° C. Alternately, discrete passes through the homogenizer were used. The final emulsion was filtered (0.2 ⁇ m filter) and stored under nitrogen.
  • the resulting pharmaceutical composition contained the following general ranges of components (weight %): propofol 0.5-5%; human serum albumin 0.5-3%; soybean oil 0.5-3.0%; egg lecithin 0.12-1.2%; glycerol 2.25%; water for injection q.s. to 100; pH 5-8. Suitable chelators, e.g., deferoxamine (0.001-0.1%), were optionally added.
  • This example demonstrates the preparation of a pharmaceutical composition containing 5% oil and comprising propofol and albumin.
  • An oil-in-water emulsion containing 1% (by weight) of propofol was prepared as follows.
  • the aqueous phase was prepared by adding glycerol (2.25% by weight) and human serum albumin (0.5% by weight) into water for injection and was stirred until dissolved.
  • the aqueous phase was passed through a filter (0.2 um filter).
  • the oil phase as prepared by dissolving egg lecithin (0.8% by weight) and propofol (1% by weight) into soybean oil (5% by weight) at about 50° C.-60° C. and was stirred until dissolved.
  • the oil phase was added to the aqueous phase and homogenized at 10,000RPM for 5 min.
  • the crude emulsion was high pressure homogenized at 20,000 psi and recirculated for 15 cycles at 5° C. Alternately, discrete passes through the homogenizer were used. The final emulsion was filtered (0.2 ⁇ m filter) and stored under nitrogen.
  • the resulting pharmaceutical composition contained the following general ranges of components (weight %): propofol 0.5-5%; human serum albumin 0.5-3%; soybean oil 0.5-10.0%; egg lecithin 0.12-1.2%; glycerol 2.25%; water for injection q.s. to 100; pH 5-8.
  • Suitable chelators e.g., deferoxamine (0.001-0.1%), were optionally added
  • This example demonstrates the preparation of a pharmaceutical composition comprising propofol and albumin that is free of oil.
  • propofol compositions containing albumin and tween 80 were prepared.
  • the aqueous phase was prepared by adding glycerol (2.25% by weight), human serum albumin (0.5% by weight), tween 80 (1.5% by weight) and deferoxamine mesylate (0.1% by weight) into water for injection and stirred until dissolved.
  • the aqueous phase was passed through a filter (0.2 ⁇ m filter).
  • Propofol (1% by weight) was added to the aqueous phase and homogenized at 10,000 RPM for 5 min.
  • the crude emulsion was high pressure homogenized at 20,000 psi and recirculated for 15 cycles at 5° C.
  • the resulting pharmaceutical composition contained the following general ranges of components (weight %): propofol 0.5-5; human serum albumin 0.5-3%; tween 80 0.1-1.5%; deferoxamine mesylate 0.0001-0.1%; glycerol 2.25%; water for injection q.s. to 100; pH 5-8.
  • This example demonstrates the preparation of a pharmaceutical composition comprising propofol, albumin, and vitamin E-TPGS, which is free of oil.
  • propofol compositions containing albumin and vitamin E-TPGS were prepared.
  • the aqueous phase was prepared by adding glycerol (2.25% by weight), human serum albumin (0.5% by weight), vitamin E-TPGS (1% by weight) and deferoxamine mesylate (0.1% by weight) into water for injection and was stirred until dissolved.
  • the aqueous phase was passed through a filter (0.2 um filter).
  • Propofol (1% by weight) was added to the aqueous phase and homogenized at 10,000 RPM for 5 min.
  • the crude emulsion was high pressure homogenized at 20,000 psi and recirculated for 15 cycles at 5° C.
  • the resulting pharmaceutical composition contained the following general ranges of components (weight %): propofol 0.5-5; human serum albumin 0.5-3%; vitamin E-TPGS 0.5-4.0%; optionally deferoxamine mesylate 0.0001-0.1%; glycerol 2.25%; water for injection q.s. to 100; pH 5-8.
  • This example demonstrates the preparation of a pharmaceutical composition comprising propofol, albumin, vitamin E-TPGS, and 1% oil.
  • An emulsion containing 1% (by weight) of propofol was prepared by the following method.
  • the aqueous phase was prepared by adding glycerol (2.25% by weight) and human serum albumin (0.5% by weight) into water for injection and stirred until dissolved.
  • the aqueous phase was passed through a filter (0.2 ⁇ m filter).
  • Surfactant e.g., Vitamin E-TPGS (0.5%), was added to aqueous phase.
  • the oil phase consisted of propofol (1% by weight) and 1% soybean oil. The oil phase was added to the aqueous phase and homogenized at 10,000 RPM for 5 min.
  • the crude emulsion was high pressure homogenized at 20,000 psi and recirculated for up to 15 cycles at 5° C. Alternatively, discrete passes through the homogenizer were used. The final emulsion was filtered (0.2 ⁇ m filter) and stored under nitrogen.
  • the resulting pharmaceutical composition contained the following general ranges of components (weight %): propofol 0.5-5%; human serum albumin 0.01-3%; Vitamin E-TPGS 0.1-2%; soybean or other oil (0.1%-5%); glycerol 2.25%; water for injection q.s. to 100; pH 5-8. Deferoxamine was optionally added (0.001%-0.1% by weight).
  • This example demonstrates the preparation of a pharmaceutical composition comprising propofol, albumin, vitamin E-TPGS, 1% oil, and a negatively charged component.
  • An emulsion containing 1% (by weight) of propofol was prepared by the following method.
  • the aqueous phase was prepared by adding glycerol (2.25% by weight) and human serum albumin (0.5% by weight) into water for injection and was stirred until dissolved.
  • the aqueous phase was passed through a filter (0.2 ⁇ m filter).
  • Surfactant e.g., Vitamin E-TPGS (0.5%), was added to aqueous phase.
  • the oil phase consisted of propofol (1% by weight) and 1% soybean oil.
  • a small quantity of negatively charged component 0.001%-1%
  • a phospholipid or bile salt was added.
  • the oil phase was added to the aqueous phase and homogenized at 10,000 RPM for 5 min.
  • the crude emulsion was high pressure homogenized at 20,000 psi and recirculated for up to 15 cycles at 5° C. Alternatively, discrete passes through the homogenizer were used.
  • the final emulsion was filtered (0.2 ⁇ m filter) and stored under nitrogen.
  • the resulting pharmaceutical composition contained the following general ranges of components (weight %): propofol 0.5-5%; human serum albumin 0.01-3%; Vitamin E-TPGS 0.1-2%; soybean or other oil (0.1%-5%); glycerol 2.25%; water for injection q.s. to 100; pH 5-8. Deferoxamine was optionally added (0.001%-0.1% by weight).
  • This example demonstrates the preparation of a pharmaceutical composition
  • a pharmaceutical composition comprising propofol, albumin, vitamin E-TPGS, 1% oil, and a negatively charged component (sodium deoxycholate).
  • An emulsion containing 1% (by weight) of propofol was prepared by the following method.
  • the aqueous phase was prepared by adding glycerol (2.25% by weight) and human serum albumin (0.5% by weight) into water for injection and stirred until dissolved.
  • the aqueous phase was passed through a filter (0.2 ⁇ m filter).
  • Surfactant e.g., Vitamin E-TPGS (0.5%), was added to aqueous phase.
  • the oil phase consisted of propofol (1% by weight) and 1% soybean oil.
  • a small quantity of negatively charged component 0.001%-1%
  • sodium deoxycholate was added.
  • the oil phase was added to the aqueous phase and homogenized at 10,000 RPM for 5 min.
  • the crude emulsion was high pressure homogenized at 20,000 psi and recirculated for up to 15 cycles at 5° C. Alternately, discrete passes through the homogenizer were used. The final emulsion was filtered (0.2 ⁇ m filter) and stored under nitrogen.
  • the resulting pharmaceutical composition contained the following general ranges of components (weight %): propofol 0.5-5%; human serum albumin 0.01-3%; Vitamin E-TPGS 0.1-2%; soybean or other oil (0.1%-5%); glycerol 2.25%; water for injection q.s. to 100; pH 5-8. Deferoxamine was optionally added (0.001%-0.1% by weight).
  • This example demonstrates the preparation of a pharmaceutical composition
  • a pharmaceutical composition comprising propofol, albumin, vitamin E-TPGS, 1% oil, and a negatively charged component (phospholipids, bile salts, polyaminoacids etc).
  • An emulsion containing 1% (by weight) of propofol was prepared as follows.
  • the aqueous phase was prepared by adding glycerol (2.25% by weight) and human serum albumin (0.5% by weight) into water for injection and stirred until dissolved.
  • the aqueous phase was passed through a filter (0.2 ⁇ m filter).
  • Surfactant e.g., Vitamin E-TPGS (0.5%), was added to aqueous phase.
  • the oil phase consisted of propofol (1% by weight) and 1% soybean oil.
  • a small quantity of negatively charged component 0.001%-1%
  • phosphatidyl choline was added.
  • the oil phase was added to the aqueous phase and homogenized at 10,000 RPM for 5 min.
  • the crude emulsion was high pressure homogenized at 20,000 psi and recirculated for up to 15 cycles at 5° C. Alternatively, discrete passes through the homogenizer were used. The final emulsion was filtered (0.21 ⁇ m filter) and stored under nitrogen.
  • the resulting pharmaceutical composition contained the following general ranges of components (weight %): propofol 0.5-5%; human serum albumin 0.01-3%; Vitamin E-TPGS 0.1-2%; soybean or other oil (0.1%-5%); glycerol 2.25%; water for injection q.s. to 100; pH 5-8. Deferoxamine was optionally added (0.001%-0.1% by weight).
  • This example demonstrates the binding of propofol to albumin.
  • the binding of propofol to albumin was determined as follows. Solubility of propofol was tested in water and in solutions containing albumin. 250 ⁇ L of propofol was added to 10 mL of a water or albumin solution and stirred for 2 hours in a scintillation vial. The solution was then transferred to a 15 mL polyethylene centrifuge tube and kept at 40° C. for about 16 hours. Samples of water and albumin solutions were assayed for propofol. Solubility of propofol in water was determined to be 0.12 mg/ml. Solubility of propofol in albumin solutions was dependent on the concentration of albumin and increased to 0.44 mg/ml when the albumin concentration was 2% (20 mg/ml).
  • This example demonstrates the reduction of free propofol in a pharmaceutical composition by filtration/membrane contact.
  • filtration or ultrafiltration of pharmaceutical compositions comprising propofol results in a reduction in the amount of free propofol.
  • Diprivan and a pharmaceutical composition prepared in accordance with the present invention containing albumin, each of which contained 1% propofol (10 mg/ml) were ultrafiltered using a 30 kD membrane.
  • the amount of free propofol was measured in the filtrate using HPLC.
  • the concentration of free propofol in the filtrate was about 17 ⁇ g/ml for Diprivan, while the concentration of free propofol in the filtrate was about 7 ⁇ g/ml for the inventive pharmaceutical composition.
  • the results correspond to an effective reduction of free propofol by greater than a factor of 2 for pharmaceutical composition comprising propofol and albumin.
  • This example demonstrates administration of a pharmaceutical composition comprising propofol and albumin to humans.
  • a randomized, double-blind clinical trial was conducted to compare adverse skin sensations of a pharmaceutical composition comprising propofol and albumin with that of a commercially available propofol formulation, Diprivan. Trials were conducted in compliance with Good Clinical Practices and informed consent was taken from the subjects.
  • This example demonstrates the use of deferoxamine as antioxidant in a pharmaceutical composition comprising propofol.
  • compositions comprising propofol and deferoxamine mesylate, and containing tween or TPGS were stored at 4°, 25°, or 40° C. to test the effect of deferoxamine mesylate in preventing oxidation of propofol.
  • concentration of propofol was measured for these formulations over time to determine the antioxidant activity of deferoxamine. The data is reported below in Tables 2 and 3 as % potency relative to time zero.
  • TABLE 2 Albumin/tween formulation 1 month Storage Temp 4° C. 25° C. 40° C. CONTROL 100% 88% 48% 0.01% Def 101% 89% 61% 0.1% Def 103% 89% 64%
  • This example demonstrates intrapulmonary delivery of a pharmaceutical composition comprising paclitaxel and albumin (ABI-007).
  • the target volume of the intratracheal dose formulation to be administered to the animals was calculated based on a dose volume of 1.5 mL per kg body weight.
  • the dosing apparatus consisted of a Penn-Century microsprayer (Model 1A-1B; Penn-Century, Inc., Philadelphia, Pa.; purchased from DeLong Distributors, Long Branch, N.J.) attached to a 1-mL gas-tight, luer-lock syringe. The appropriate volume of dose preparation was drawn into the dosing apparatus, the filled apparatus was weighed and the weight-recorded.
  • a catheter was placed in the trachea of the anesthetized animal, the microsprayer portion of the dosing apparatus was placed into the trachea through the catheter, and the dose was administered. After dose administration the empty dosing apparatus was reweighed and the administered dose was calculated as the difference in the weights of the dosing apparatus before and after dosing. The average dose for all animals was 4.7738 ⁇ 0.0060 (CV 1.5059) mg paclitaxel per kg body weight.
  • Blood samples of approximately 250 ⁇ L were collected from the indwelling jugular cannulas of JVC rats at the following predetermined post-dosing time points: 1, 5, 10, 15, 30, and 45 minutes (min), and 1, 4, 8, and 24 hours (h).
  • the 24-h blood samples, as well as blood samples collected from animals sacrificed at 10 min, 45 min, and 2 h, were collected via cardiac puncture from anesthetized rats at sacrifice. All blood samples analyzed for total radioactivity were dispensed into pre-weighed sample tubes, and the sample tubes were reweighed, and the weight of each sample was calculated by subtraction.
  • the blood samples collected from the jugular vein as well as the 250- ⁇ L aliquots of blood collected from each animal at sacrifice were assayed for total tritium content.
  • the mean blood concentration of [ 3 H]ABI-007-derived radioactivity after an intravenous dose to rats was analyzed as a function of time in order to evaluate the bioavailability of tritium derived from an intratracheal dose of [ 3 H]ABI-007.
  • This analysis resulted in a 24-hour AUC (AUClast) of 6.1354 mg-eq ⁇ hr/L.
  • AUClast AUClast
  • Tritium derived from [ 3 H]ABI-007 is rapidly absorbed after intratracheal instillation.
  • the average absorption and elimination half-lives (k01 half-life and k10 half-life, respectively) for tritium in blood after an intratracheal dose of [ 3 H]ABI-007 (mean +/ ⁇ SD) were 0.0155+/ ⁇ 0.0058 hr and 4.738+/ ⁇ 0.366 hr, respectively.
  • the average apparent clearance of tritium from blood was 0.1235+/ ⁇ 0.0180 L/hr (see Table 4 above).
  • Tritium derived from [ 3 H]ABI-007 was absorbed and distributed after intratracheal administration. The time course of tritium in blood was well described by a two-compartment model, with mean absorption and elimination half-lives of 0.0155 and 4.738 hr, respectively. Approximately 28% of the administered dose was recovered in the lung at 10 min after the intratracheal dose. A maximum of less than 1% of the dose was recovered in other tissues, excluding the gastrointestinal tract, at all time points examined.
  • a fair amount of radioactivity was present in the gastrointestinal tract (including contents) at 24 hr post dosing (27% for the intratracheal dose).
  • the presence of tritium in the gastrointestinal tract may be due to biliary excretion or clearance of tritium from the respiratory tract via mucociliary clearance with subsequent swallowing.
  • This example demonstrates an investigation of Aerotech II and Pari nebulizers for pulmonary delivery of pharmaceutical compositions comprising paclitaxel and albumin.
  • Aerotech II and Pari nebulizers provided acceptable overall efficiency (30%-60%) when ABI-007 was reconstituted at a concentration range of 5-15 mg/mL.
  • the Pari nebulizer efficiency had higher nebulizer efficiency than the Aerotech II nebulizer.
  • the Pari nebulizer efficiency decreased somewhat as ABI-007 concentration increased. Excellent fine particle fraction was observed (74%-96%).
  • the Aerotech II nebulizer had higher fine particle fraction than the Pari nebulizer. The fine particle fraction was independent of concentration.
  • the Pari nebulizer delivered 100 mg of paclitaxel in less than 30 minutes using a 15 mg/mL solution of ABI-007.
  • the Aerotech II nebulizer delivered 100 mg of paclitaxel in about 65 min using either a 10 mg/mL or 15 mg/mL solution of ABI-007. Performance stability was tested for both Aerotech II and Pari nebulizers. Aerosol concentration and efficiency of both nebulizers were stable until the drug was exhausted. At 15 mg/mL, the Pari nebulizer consumed the drug at twice the rate of the Aerotech II nebulizer and produced higher aerosol concentrations than that of the Aerotech II nebulizer.
  • the nanoparticle/albumin formulation of paclitaxel shows excellent bioavailability in rats when administered by the pulmonary route. There were no overt signs of early toxicity at the administered dose.
  • Pulmonary delivery of nanoparticle paclitaxel (ABI-007) may be achieved using conventional nebulizers.
  • This example describes intrapulmonary delivery of a pharmaceutical composition comprising albumin and rapamycin.
  • the purpose of this study was to determine the pulmonary absorption of rapamycin in blood following intratracheal instillation to Sprague Dawley rats as compared to intravenous installation.
  • the target volume of the intratracheal dose formulation that was administered to the animals was calculated based on a dose volume of 1 mL per kg body.
  • the intratracheal dosing apparatus consisted of a Penn-Century microsprayer (Model 1A-1B; Penn-Century, Inc., Philadelphia, Pa.; purchased from DeLong Distributors, Long Branch, N.J.) attached to a 1 mL gas-tight, luer-lock syringe.
  • the appropriate volume of dose preparation was drawn into the dosing apparatus, the filled apparatus was weighed and the weight-recorded.
  • a catheter was placed in the trachea of the anesthetized animal, the microsprayer portion of the dosing apparatus was placed into the trachea through the catheter, and the dose was administered. After dose administration the empty dosing apparatus was reweighed and the administered dose was calculated as the difference in the weights of the dosing apparatus before and after dosing.
  • samples were collected from the indwelling jugular cannulas of rats at the following predetermined post-dosing time points: 1, 5, 10, 15, 30, and 45 minutes (min) and 1, 4, 8, and 24 hours (h). All blood samples analyzed were dispensed into pre-weighed sample tubes, and the sample tubes were reweighed, and the weight of each sample was calculated by subtraction. The blood samples collected were assayed for total rapamycin concentration using LC/MS/MS.
  • This example demonstrates tissue distribution of albumin-rapamycin after intrapulmonary administration of a pharmaceutical composition comprising rapamycin and albumin prepared in accordance with the present invention.
  • the purpose of this study was to determine the pulmonary absorption of rapamycin in tissue following intratracheal instillation to Sprague Dawley rats as compared to intravenous installation.
  • the target volume of the intratracheal dose formulation that was administered to the animals was calculated based on a dose volume of 1 mL per kg body.
  • the dosing apparatus consisted of a Penn-Century microsprayer (Model 1A-1B; Penn-Century, Inc., Philadelphia, Pa.; purchased from DeLong Distributors, Long Branch, N.J.) attached to a 1-mL gas-tight, luer-lock syringe. The appropriate volume of dose preparation was drawn into the dosing apparatus, the filled apparatus was weighed and the weight-recorded.
  • a catheter was placed in the trachea of the anesthetized animal, the microsprayer portion of the dosing apparatus was placed into the trachea through the catheter, and the dose was administered. After dose administration the empty dosing apparatus was reweighed and the administered dose was calculated as the difference in the weights of the dosing apparatus before and after dosing.
  • rapamycin concentration is greater in lung tissue when delivered via pulmonary as compared to intravenous delivery.
  • the total concentration of rapamycin in the brain is lower when delivered via intratracheal (IT) as compared to intravenous (IV).
  • IT intratracheal
  • IV intravenous
  • pulmonary delivery of rapamycin may be suitable for the treatment of a condition (i.e., lung transplantation), wherein high local concentration of rapamycin would be beneficial.
  • This example demonstrates oral delivery of a pharmaceutical composition comprising paclitaxel and albumin (ABI-007).
  • Tritiated ABI-007 was utilized to determine oral bioavailability of paclitaxel following oral gavage in rats. Following overnight fasting, 5 rats were given 5.5 mg/kg paclitaxel in ABI-007 (Group A) and another 5 rats (Group B) were pretreated with cyclosporine (5.0 mg/kg) followed by 5.6 mg/kg paclitaxel in ABI-007.
  • a pharmacokinetic analysis of blood samples drawn at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours was performed after determination of radioactivity in the blood samples by combustion. Oral bioavailability was determined by comparison with intravenous data previously obtained. The results are set forth below in Table 5.
  • AUC 0-24 IV (6.06 ⁇ g ⁇ hr./mL) and IV dose (5.1 mg/kg) were used for calculation of percent absorption (data based on IV dose of ABI-007).
  • CsA cyclosporine
  • This example demonstrates improved penetration of paclitaxel into red blood cells and tumor cells upon administration of a pharmaceutical composition comprising paclitaxel and albumin.
  • Human MX-1 breast tumor fragments were implanted subcutaneously in athymic mice.
  • a pharmaceutical composition comprising paclitaxel and albumin (“paclitaxel-albumin”), as described previously, and Taxol were prepared with 3 H paclitaxel to a specific activity of 25 ⁇ Ci/mg paclitaxel.
  • 20 mg/kg radiolabeled paclitaxel-albumin or Taxol was administered intravenously in saline when tumor volume reached approximately 500 mm 3 .
  • Plasma, blood, and tumor tissue were sampled and analyzed for radioactivity at 5, 15, and 30 minutes and at 1, 3, 8, and 24 hours after administration. Tumor pharmacokinetic (AUC and absorption constant) was analyzed using WinNonlin, Pharsight, USA.
  • Paclitaxel-albumin exhibited rapid partitioning into red blood cells (RBCs) as shown by a rapid drop of the plasma/blood radioactivity ratio to unity after intravenous administration of the drug. Complete partitioning into RBCs occurred as early as 1 hr after administration of paclitaxel-albumin. In contrast, the partitioning of paclitaxel formulated as Taxol into RBCs was much slower and was not completed until more than 8 hrs.
  • RBCs red blood cells
  • Paclitaxel-albumin exhibited a rapid partitioning into tumor tissue with an absorption constant (K a ) that was 3.3 ⁇ greater than Taxol.
  • K a absorption constant
  • the K a were 0.43 hr ⁇ 1 and 0.13 hr ⁇ 1 for paclitaxel-albumin and Taxol, respectively. Rapid uptake of paclitaxel resulted in 33% higher tumor AUC for paclitaxel-albumin than for Taxol.
  • the AUC were 3632 nCi*hr/g and 2739 nCi*hr/g for paclitaxel-albumin and Taxol, respectively.
  • This example demonstrates the safety of a pharmaceutical composition comprising paclitaxel and albumin administered to mice.
  • the LD 50 for paclitaxel-albumin and Taxol were calculated to be 47 mg/kg/day and 30 mg/kg/day for a qld ⁇ 5 schedule, respectively. At a dose level of 13.4 mg/kg/day, both paclitaxel-albumin and Taxol were well tolerated with mortality of 1% (1 death out of 72 mice) and 4% (2 deaths out of 47 mice), respectively.
  • This example demonstrates a novel paclitaxel transport mechanism across microvessel endothelial cells (EC) for paclitaxel-albumin compositions.
  • Nanoparticles and albumin-paclitaxel compositions can accumulate in tumor tissue due to EPR effect resulting from ‘leaky’ vessels in a tumor.
  • An albumin specific gp60 receptor (albondin) transported albumin across EC by transcytosis of the receptors within caveolae at the cell surface. This transcytosis mechanism allows for the transport of albumin-paclitaxel to the underlying interstitial space.
  • cremophor in Taxol inhibited binding of paclitaxel to albumin, greatly reducing paclitaxel transport to the tumor.
  • gp16 and gp30 receptors also were involved in intracellular transport of modified albumins containing bound paclitaxel, resulting in increased binding of paclitaxel to endothelial cells with a greater anti-angiogenic effect as compared to Taxol.
  • This example demonstrates an increase in endothelial transcytosis of pharmaceutical compositions comprising paclitaxel and albumin as compared to Taxol.
  • HLMVEC Human lung microvessel endothelial cells
  • inventive pharmaceutical composition comprising paclitaxel and albumin, or Taxol containing fluorescent paclitaxel (Flutax) at a concentration of 20 ⁇ g/mL, was added to the upper transwell chamber.
  • the transport of paclitaxel by transcytosis from the upper chamber to the lower chamber was monitored continuously using a fluorometer. A control containing only Flutax without albumin was also used. The control with Flutax showed no transport, validating the integrity of the confluent HLMVEC monolayer. Transport of paclitaxel from the albumin-paclitaxel composition was much faster than paclitaxel from Taxol in the presence of 5% HSA (physiological concentration). Transport rate constants (K t ) for the albumin-paclitaxel composition and Taxol were 1.396 hr ⁇ 1 and 0.03 hr ⁇ 1 , respectively. The total amount of paclitaxel transported across the monolayer was three times higher for the albumin-paclitaxel composition than Taxol.
  • This example demonstrates improved endothelial cell (EC) binding by pharmaceutical compositions comprising paclitaxel and albumin as compared to Taxol.
  • paclitaxel Flutax-Oregon Green labeled paclitaxel
  • Cremophor EL/EtOH which is the vehicle for Taxol
  • a pharmaceutical composition comprising albumin and Flutax and a Taxol-Flutax composition were reacted to the HUVEC at various final concentrations. Binding of paclitaxel to cells was inhibited by Cremophor. Inhibition was exhibited by an IC 50 of 0.02% of Cremophor EL/EtOH.
  • Cremophor This concentration of Cremophor has been shown to persist during Taxol chemotherapy for at least 24 hours. Therefore, it is a relevant process in vivo. At all concentrations tested, a significant amount of paclitaxel from the albumin-paclitaxel composition became bound to cells. In comparison, little or no binding was observed for Taxol.
  • This example demonstrates improved albumin binding by pharmaceutical compositions comprising paclitaxel and albumin as compared to Taxol.
  • HSA Human Serum Albumin
  • Paclitaxel Flutax-Oregon Green labeled paclitaxel
  • Cremophor EL/EtOH Cremophor EL/EtOH
  • an albumin-paclitaxel-Flutax composition and a Taxol-Flutax composition were reacted to immobilized HSA at a final concentration of 20 ⁇ g paclitaxel/mL. Binding of paclitaxel to albumin was inhibited by Cremophor. Inhibition was exhibited by an IC 50 of 0.003% of Cremophor EL/EtOH.
  • Cremophor This concentration of Cremophor has been shown to persist during Taxol chemotherapy for at least 24 hours. Therefore, it is a relevant process in vivo. At a relevant pharmacologic paclitaxel concentration (20 ⁇ g/mL), a significant amount of paclitaxel from the albumin-paclitaxel composition became bound to immobilized HSA. In comparison, no binding was observed for Taxol.
  • This example demonstrates increased transfer of paclitaxel to albumin for pharmaceutical compositions comprising paclitaxel and albumin as compared to Taxol.
  • Taxol-Flutax and albumin-paclitaxel-Flutax compositions were mixed with either 5% HSA in Hanks buffer or serum, at 20 ⁇ g/mL, 40 ⁇ g/ml, and 80 ⁇ g/ml. The mixtures were immediately separated on a native 3-14% polyacrylamide gel and the amount of paclitaxel bound to albumin was determined by a scanning fluorometer. The transfer of paclitaxel to HSA was more rapid for the albumin-paclitaxel composition versus Taxol. More paclitaxel co-electrophoresed with HSA when either serum or 5% HSA was incubated with the albumin-paclitaxel-Flutax composition or the Taxol-Flutax composition.
  • glycoprotein receptor gp60 is responsible for binding and transcytosis of albumin-paclitaxel.
  • Fluorescent labeled paclitaxel (Flutax) albumin compositions were contacted with microvessel endothelial cells in culture. Fluorescent staining was observed under a microscope with evidence of punctuate areas that were postulated to be the gp60 receptor binding the albumin-paclitaxel. This was confirmed by using rhodamine labeled albumin which colocalized with the punctuate fluorescence of paclitaxel.
  • Albumin was immobilized on a microtiter plate. Fluorescent paclitaxel was added into the wells and the binding of paclitaxel was measured using a scanning fluorometer. Increasing amounts of albumin were added to the wells and the level of inhibiton of paclitaxel binding to immobilized albumin was measured. The data showed that as the amount of albumin added was increased, a corresponding decrease in binding was seen. A similar effect was seen with binding to endothelial cells. This indicated that higher albumin concentration inhibited binding of paclitaxel. Thus invention compositions having lower amounts of albumin are preferred.
  • albumin-paclitaxel compositions with low amounts of albumin were prepared. It was found that these compositions were as stable as compositions with higher quantities of albumin when examined for several months at different temperatures (2-8° C., 25° C. and 40° C.) for potency of paclitaxel, impurity formation, particle size, pH and other typical parameters of stability. Thus compositions with lower amounts of albumin are preferred as this can greatly reduce cost as well as allow increased binding and transport to cells.
  • This example demonstrates a pharmaceutical composition comprising albumin and paclitaxel having a high albumin to paclitaxel ratio.
  • paclitaxel 30 mg was dissolved in 3.0 ml methylene chloride. The solution was added to 27.0 ml of human serum albumin solution (3% w/v) (corresponding to a ratio of albumin to paclitaxel of 27). Deferoxamine was added as necessary. The mixture was homogenized for 5 minutes at low RPM (Vitris homogenizer, model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer (Avestin). The emulsification was performed at 9000-40,000 psi while recycling the emulsion for at least 5 cycles.
  • the resulting system was transferred into a rotary evaporator, and methylene chloride was rapidly removed at 40° C., at reduced pressure (30 mm Hg) for 20-30 minutes.
  • the resulting dispersion was translucent, and the typical average diameter of the resulting paclitaxel particles was in the range 50-220 nm (Z-average, Malvern Zetasizer).
  • the dispersion was further lyophilized for 48 hrs.
  • the resulting cake was easily reconstituted to the original dispersion by addition of sterile water or saline.
  • the particle size after reconstitution was the same as before lyophilization.
  • the amounts, types and proportions of drug, solvents, proteins used in this example are not limiting in any way.
  • the inventive pharmaceutical composition containing albumin showed substantially lower toxicity.
  • This example demonstrates a pharmaceutical composition comprising albumin and paclitaxel having a low albumin to paclitaxel ratio.
  • paclitaxel 300 mg was dissolved in 3.0 ml methylene chloride.
  • the solution was added to 27 ml of human serum albumin solution (5% w/v). (corresponding to a ratio of albumin to paclitaxel of 4.5).
  • Deferoxamine was added as necessary.
  • the mixture was homogenized for 5 minutes at low RPM (Vitris homogenizer, model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer (Avestin).
  • the emulsification was performed at 9000-40,000 psi while recycling the emulsion for at least 5 cycles.
  • the resulting system was transferred into a rotary evaporator, and methylene chloride was rapidly removed at 40° C., at reduced pressure (30 mm Hg) for 20-30 minutes.
  • the resulting dispersion was translucent, and the typical average diameter of the resulting paclitaxel particles was in the range 50-220 nm (Z-average, Malvern Zetasizer).
  • the dispersion was further lyophilized for 48 hrs.
  • the resulting cake was easily reconstituted to the original dispersion by addition of sterile water or saline.
  • the particle size after reconstitution was the same as before lyophilization.
  • the amounts, types and proportions of drug, solvents, proteins used in this example are not limiting in any way.
  • the inventive pharmaceutical composition containing albumin showed substantially lower toxicity.
  • This example demonstrates a pharmaceutical composition comprising albumin and paclitaxel having an intermediate albumin to paclitaxel ratio.
  • paclitaxel 135 mg was dissolved in 3.0 ml methylene chloride. The solution was added to 27 ml of human serum albumin solution (5% w/v). Deferoxamine was added as necessary. The mixture was homogenized for 5 minutes at low RPM (Vitris homogenizer, model Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer (Avestin). The emulsification was performed at 9000-40,000 psi while recycling the emulsion for at least 5 cycles.
  • the resulting system was transferred into a rotary evaporator, and methylene chloride was rapidly removed at 40° C., at reduced pressure (30 mm Hg) for 20-30 minutes.
  • the resulting dispersion was translucent, and the typical average diameter of the resulting paclitaxel particles was in the range 50-220 nm (Z-average, Malvern Zetasizer).
  • the dispersion was further lyophilized for 48 hrs.
  • the resulting cake was easily reconstituted to the original dispersion by addition of sterile water or saline.
  • the particle size after reconstitution was the same as before lyophilization.
  • the calculated ratio (w/w) of albumin to paclitaxel in this invention composition is approximately 10.
  • the amounts, types and proportions of drug, solvents, proteins used in this example are not limiting in any way.
  • the inventive pharmaceutical composition containing albumin showed substantially lower toxicity.
  • This example demonstrates the treatment of rheumatoid arthritis in an animal model with an albumin-paclitaxel composition.
  • the collagen induced arthritis model in the Louvain rat was used to test the therapeutic effect of albumin-paclitaxel composition on arthritis.
  • the paw sizes of the experimental animals were monitored to evaluate the seriousness of arthritis.
  • the experimental animals were divided into different groups to receive either albumin-paclitaxel 1 mg/kg q.o.d, or albumin-paclitaxel 0.5 mg/kg+prednisone 0.2 mg/kg q.o.d. (combination treatment) intraperitoneally for 6 doses, then one dose per week for three weeks.
  • the paw sizes were measured at the beginning of treatment (day 0) and every time the drug was injected.
  • One group received only normal saline as control.
  • the group receiving albumin-paclitaxel achieved a 42% reduction of paw size
  • the combination treatment group showed a 33% reduction of the paw size
  • the control group had about 20% increase of the paw size relative to the time when the treatment was initiated.
  • albumin-paclitaxel compositions demonstrated therapeutic effect on arthritis.
  • the albumin-paclitaxel combinations are likely to localize at sites of arthritic lesions by transport through receptor-mediated mechanisms like gp60.
  • This example demonstrates the use of albumin-paclitaxel compositions to treat cardiovascular restenosis.
  • Paclitaxel eluting stents in animals cause incomplete healing and, in some instances, a lack of sustained suppression of neointimal growth in the arteries.
  • the present study tested the efficacy of a novel systemic delivery albumin-paclitaxel invention compositions for reducing in-stent restenosis.
  • albumin-paclitaxel 5.0 mg/kg was given at stenting with or without an intravenous 3.5-mg/kg repeatalbumin-paclitaxel dose at 28 days; these studies were terminated at 3 months.
  • inventive composition is suitable for treatment of cardiovascular diseases such as restenosis.
  • inventive compositions comprising pharmaceutical agents other than paclitaxel, for example rapamycin, other taxanes, epothilones etc, are all suitable for treatment of restenosis in blood vessels or artificial blood vessel grafts such as those used for arterio-venous access in patients requiring hemodialysis.

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US11/553,350 US20070129448A1 (en) 2002-12-09 2006-10-26 Compositions and methods of delivery of pharmacological agents
US12/758,413 US7923536B2 (en) 2002-12-09 2010-04-12 Compositions and methods of delivery of pharmacological agents
US12/910,693 US8138229B2 (en) 2002-12-09 2010-10-22 Compositions and methods of delivery of pharmacological agents
US13/038,287 US8314156B2 (en) 2002-12-09 2011-03-01 Compositions and methods of delivery of pharmacological agents
US13/368,250 US20120283205A1 (en) 2002-12-09 2012-02-07 Compositions and methods of delivery of pharmacological agents
US13/649,987 US8846771B2 (en) 2002-12-09 2012-10-11 Compositions and methods of delivery of pharmacological agents
US13/777,980 US9012518B2 (en) 2002-12-09 2013-02-26 Compositions and methods of delivery of pharmacological agents
US13/777,988 US9012519B2 (en) 2002-12-09 2013-02-26 Compositions and methods of delivery of pharmacological agents
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