WO2005030171A1 - Delivery of therapeutic compounds via microparticles or microbubbles - Google Patents
Delivery of therapeutic compounds via microparticles or microbubbles Download PDFInfo
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- WO2005030171A1 WO2005030171A1 PCT/US2004/031291 US2004031291W WO2005030171A1 WO 2005030171 A1 WO2005030171 A1 WO 2005030171A1 US 2004031291 W US2004031291 W US 2004031291W WO 2005030171 A1 WO2005030171 A1 WO 2005030171A1
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- therapeutic agent
- antiprouferative
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6925—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a microcapsule, nanocapsule, microbubble or nanobubble
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Definitions
- the present invention relates to methods and compositions for delivery of antiproUferative drugs to particular target sites.
- antiproUferative drugs are targeted to tumor sites.
- Drug delivery techniques are continually being developed in drug therapy to control, regulate, and target the release of drugs in the body. Goals include augmentation of drug availability, maintenance of constant and continuous therapeutic levels of a drug in the systemic circulation or at a specific target organ site, reduction of dosages and/or frequency of administration required to realize the desired therapeutic benefit, and consequent reduction of drug-induced side effects.
- Drug delivery systems currently include, for example, carriers based on proteins, polysaccharides, synthetic polymers, and liposomes. Gas filled microbubbles have been conventionally used as contrast agents for diagnostic ultrasound. They have also been described for therapeutic applications, such as enhancement of drug penetration (Tachibana et al, U.S. Patent No. 5,315,998), as thrombolytics ⁇ e.g.
- the invention is directed to the use of a composition
- a composition comprising (i) an antiproUferative therapeutic agent and (ii) a suspension of microbubbles which are encapsulated with a filmogenic protein and contain a gas selected from a perfluorocarbon and SFg for preparation of a medicament for delivering said antiproUferative therapeutic agent to the site of a tumor in a subject, wherein said composition is administered parenterally to said subject.
- the gas is a perfluorocarbon, such perfluoromethane, perfiuoroethane, perfluoropropane, perfluorobutane, or perfluoropentane
- the protein is albumin, preferably human serum albumin.
- the composition is typically formed by incubating the agent, generally in solution or suspension, with the suspension of microbubbles.
- the composition is preferably administered to the subject without appUcation of ultrasound to the composition during or following administration.
- the antiproUferative therapeutic agent is selected from the group consisting of paclitaxel, docetaxel, cisplatin, carboplatin, etoposide, tamoxifen, 5-fluorouracil, adriamycin, daunorubicin, doxorubicin, vincristine, and vinblastine.
- Preferred agents include paclitaxel and docetaxel; other preferred agents include cisplatin, carboplatin, etoposide, tamoxifen, 5-fluorouracil, vincristine, and vinblastine.
- the therapeutic agent can be selected from the group consisting of amsacrine, mitotane, topotecan, tretinoin, hydroxyurea, procarbazine, carmustine, mechlorethamine hydrochloride, cyclophosphamide, ifosfamide, chlorambucil, melphalan, busulfan, thiotepa, estramustine, dacarbazine, omustine, streptozocin, vinorelbine, vindesine, fludarabine, fluorodeoxyuridine, cytosine arabinoside, cytarabine, azidothymidine, cysteine arabinoside, azacytidine, mercaptopur
- the invention is directed to a composition
- a composition comprising (i) a suspension of microbubbles which are encapsulated with a filmogenic protein and contain a gas selected from a perfluorocarbon and SF 6 , and (ii) an antiproUferative therapeutic agent.
- the agent is selected from the group consisting of cisplatin, carboplatin, etoposide, tamoxifen, 5-fluorouracil, amsacrine, mitotane, topotecan, tretinoin, hydroxyurea, procarbazine, carmustine, mechlorethamine hydrochloride, cyclophosphamide, ifosfamide, chlorambucil, melphalan, busulfan, thiotepa, estramustine, dacarbazine, omustine, streptozocin, vincristine, vinblastine, vinorelbine, vindesine, fludarabine, fluorodeoxyuridine, cytosine arabinoside, cytarabine, azidothymidine, cysteine arabinoside, azacytidine, mercaptopurine, thioguanine, cladribine, pentostatin, arabinos
- the agent may also be an antiproUferative antisense oUgomer, preferably a morpholino oligomer having phosphoramidate or phosphorodiamidate linkages.
- the gas is preferably a perfluorocarbon, such perfluoromethane, perfiuoroethane, perfluoropropane, perfluorobutane, or perfluoropentane
- the protein is preferably albumin, more preferably human serum albumin.
- the therapeutic agent is selected from the group consisting of cisplatin, carboplatin, etoposide, tamoxifen, 5-fluorouracil, vincristine, and vinblastine.
- the therapeutic agent is selected from the group consisting of cisplatin, carboplatin, and etoposide, or it is selected from the group consisting of tamoxifen, 5-fluorouracil, vincristine, and vinblastine.
- the invention is directed to a method for delivering an antiproUferative therapeutic agent to the site of a tumor in a subject, comprising: administering parenterally to a subject having said tumor a composition comprising the therapeutic agent and a suspension of microbubbles which are encapsulated with a filmogenic protein and contain a gas selected from a perfluorocarbon and SF 6 .
- the administration is carried out without application of ultrasound to the composition during or following administration.
- the subject is preferably a mammalian subject, such as a human subject or patient.
- the composition of suspended microbubble/agent conjugate is administered internally to the subject, preferably parenterally, e.g. intravenously, percutaneously, mtraperitoneaUy, intramuscularly, or intrathecally.
- the microbubble carrier deUvers the agent or agents to the target site, where, in a preferred embodiment, the agent is released without the use of external stimulation. However, if desired, release of the agent may be modulated by appUcation of a stimulus such as radiation, heat, or ultrasound.
- the gas is preferably a perfluorocarbon, such perfiuoromethane, perfiuoroethane, perfluoropropane, perfluorobutane, or perfluoropentane
- the protein is preferably albumin, more preferably human serum albumin.
- the therapeutic agent is preferably a non-oligonucleotide agent.
- the therapeutic agent is selected from the group consisting of paclitaxel, docetaxel, cisplatin, carboplatin, etoposide, tamoxifen, 5-fluorouracil, adriamycin, daunorubicin, doxorubicin, vincristine, and vinblastine.
- it is selected from paclitaxel and docetaxel, or it is selected from the group consisting of cisplatin, carboplatin, etoposide, tamoxifen, 5-fluorouracil, vincristine, and vinblastine.
- the agent can be selected from the group consisting of amsacrine, mitotane, topotecan, tretinoin, hydroxyurea, procarbazine, carmustine, mechlorethamine hydiOchloride, cyclophosphamide, ifosfamide, ehlorambucil, melphalan, busulfan, thiotepa, estramustine, dacarbazine, omustine, streptozocin, vinorelbine, vindesine, fludarabine, fluorodeoxyuridine, cytosine arabinoside, cytarabine, azidothymidine, cysteine arabinoside, azacytidine, mercaptopurine, thioguanine, cladribine, pentostatin, arabinosyl adenine, dactinomycin, daunorubicin, doxorubicin, ams
- the present therapeutic compositions comprise a drug which is conjugated to a microparticle carrier, such as a gaseous microbubble in a fluid medium or a polymeric microparticle, with sufficient stability that the drug can be carried to and released at a target site in a subject.
- a microparticle carrier such as a gaseous microbubble in a fluid medium or a polymeric microparticle
- conjugation typicaUy refers to noncovalent binding or other association of the drug with the particle, and may be brought about by incubation with a microbubble suspension, as described further below, or intimate mixing of the drug with a polymeric microparticle carrier.
- the pharmaceutical composition comprises a Uquid suspension, preferably an aqueous suspension, of microbubbles containing a blood-insoluble gas.
- the microbubbles are preferably about 0.1 to 10 ⁇ in diameter.
- any blood- insoluble gas which is nontoxic and gaseous at body temperature can be used.
- the insoluble gas should have a diffusion coefficient and blood solubility lower than nitrogen or oxygen, which diffuse in the internal atmosphere of the blood vessel.
- useful gases are the noble gases, e.g. helium or argon, as weU as fluorocarbon gases and sulfur hexafluoride.
- perfluorocarbon gases such as perfiuoromethane, perfiuoroethane, perfluoropropane, perfluorobutane, and perfluoropentane, are preferred.
- the cell membrane fluidizing feature of the perfluorobutane gas enhances cell entry for drugs on the surface of bubbles that come into contact with denuded vessel surfaces, as described further below.
- the gaseous microbubbles are stabilized by a fluid filmogenic coating, to prevent coalescence and to provide an interface for binding of molecules to the microbubbles.
- the fluid is preferably an aqueous solution or suspension of one or more components selected from proteins, surfactants, and polysaccharides.
- the components are selected from proteins, surfactant compounds, and polysaccharides. Suitable proteins include, for example, albumin, gamma globulin, apotransferrin, hemoglobin, coUagen, and urease.
- HSA human serum albumin
- Conventional surfactants include compounds such as alkyl polyether alcohols, alkylphenol polyether alcohols, and alcohol ethoxylates, having higher alkyl (e.g. 6-20 carbon atom) groups, fatty acid alkanolamides or alkylene oxide adducts thereof, and fatty acid glycerol monoesters.
- Surfactants particularly intended for use in microbubble contrast agent compositions are disclosed, for example, in Nycomed Imaging patents US 6,274,120 (fatty acids, polyhydroxyalkyl esters such as esters of pentaerythritol, ethylene glycol or glycerol, fatty alcohols and amines, and esters or amides thereof, Upophilic aldehydes and ketones; Upophilic derivatives of sugars, etc.), US 5,990,263 (methoxy- terminated PEG acylated with e.g. 6-hexadecanoyloxyhexadecanoyl), and US 5,919,434.
- Other filmogenic synthetic polymers may also be used; see, for example, U.S. Patent Nos.
- 6,068,857 (Weitschies) and 6,143,276 (Unger), which describe microbubbles having a biodegradable polymer shell, where the polymer is selected from e.g. polylactic acid, an acrylate polymer, polyacrylamide, polycyanoacrylate, a polyester, polyether, polyamide, polysiloxane, polycarbonate, or polyphosphazene, and various combinations of copolymers thereof, such as a lactic acid-glycolic acid copolymer.
- Such compositions have been used as contrast agents for diagnostic ultrasound, and have also been described for therapeutic applications, such as enhancement of drug penetration (Tachibana et al, U.S. Patent No.
- the carrier is a suspension of perfluorocarbon-containing dextrose/albumin microbubbles known as PESDA (perfluorocarbon-exposed sonicated dextrose/albumin).
- PESDA perfluorocarbon-exposed sonicated dextrose/albumin
- Human serum albumin (HSA) is easily metabolized within the body and has been widely used as a contrast agent.
- the composition may be prepared as described in co-owned U.S. Patents 5,849,727 and 6,117,858. Briefly, a dextrose/albumin solution is sonicated while being perfused with the perfluorocarbon gas.
- the microbubbles are preferably formed in an N 2 -depleted, preferably N 2 -free, environment, typically by introducing an N 2 -depleted (in comparison to room air) or N 2 - free gas into the interface between the sonicating horn and the solution. Microbubbles formed in this way are found to be significantly smaller and stabler than those formed in the presence of room air. (See e.g. Porter et al, U.S. Patent No.
- the microbubble suspension is generally incubated, with agitation if necessary, with a liquid formulation of the agent, such that the agent non-covalently binds at the gas/fluid interface of the microbubbles.
- a liquid formulation of the agent such that the agent non-covalently binds at the gas/fluid interface of the microbubbles.
- the liquid formulation of the drug(s) is first filtered through a micropore filter and/or sterilized. The incubation may be carried out at room temperature, or at moderately higher temperatures, as long as the stability of the drug or the microbubbles is not compromised.
- the microbubble/therapeutic agent composition is thus provided in isolated form for administration to a subject.
- Drugs with limited aqueous solubility can be solubilized or intimately dispersed in pharmaceuticaUy acceptable vehicles, such as, for example, alcohol, DMSO, or an oil such as castor oil or CremophorTM, by methods known in the pharmaceutical arts.
- pharmaceuticaUy acceptable vehicles such as, for example, alcohol, DMSO, or an oil such as castor oil or CremophorTM
- solubilizing formulations are known in the art; see, for example, U.S. Patent No. 6,267,985 (Chen and Patel, 2001), which discloses formulations containing triglycerides and a combination of surfactants.
- Other microbubble-therapeutic compositions are described in, for example, U.S. Patent Nos.
- compositions are preferably admiaistered without application of external stimulation, such as ultrasound, to the composition during or after administration.
- release of the agent from the microbubbles may be modulated by application of a stimulus such as light, temperature variation, pressure, ultrasound or ionizing energy or magnetic field.
- Application of suc a stimulus may also be used to convert a prodrug to the active form of the drug, which is then released.
- other microparticles such as biocompatible polymeric particles, may be used for delivery of a conjugated drug to a target site.
- nanoparticles refers to polymeric particles in the nanometer size range (e.g.
- microparticles refers to particles in the micrometer size range (e.g. 1 to 50 ⁇ ), but may also include particles in the submicromolar range, down to about 0.1 ⁇ . For use in the methods described herein, a size range of about 0.1 to 10 ⁇ is preferred.
- polymeric particles have been described for use as drug carriers into which drugs or antigens may be incorporated in the form of solid solutions or soUd dispersions, or onto which these materials may be absorbed or chemically bound. See e.g. Kreuter 1996; Ravi Kumar 2000; Kwon 1998.
- the polymer is bioerodible in vivo.
- Biocompatible and bioerodible polymers that have been used in the art include poly(lactide-co-glycolide) copolymers, poly anhydrides, and poly(phosphoesters). Poly(orthoester) polymers designed for drug deUvery, available from A.P. Pharma, Inc., are described in Heller et al, J.
- the polymer is a diol - diol monoglycohde - orthoester copolymer.
- the polymer can be produced in powdered form, e.g. by cryogrinding or spray drying, intimately mixed in powdered form with a therapeutic compound, and fabricated into various forms, including microspheres and nanospheres.
- the antiproUferative therapeutic agent to be delivered is an antineoplastic agent.
- antrneoplastic agents include, for example, cisplatin, carboplatin, spiroplatin, iproplatin, paclitaxel, docetaxel, rapamycin, tacrolimus, asparaginase, etoposide, teniposide, methotrexate, tamoxifen, amsacrine, mitotane, topotecan, tretinoin, hydroxyurea, procarbazine, BCNU (carmustine) and other nitrosourea compounds, as well as compounds classified as alkylating agents (e.g., mechlorethamine hydrochloride, cyclophosphamide, ifosfamide, chlorambucil, melphalan, busulfan, thiotepa, carmustine, estram
- alkylating agents e.g., mechlorethamine hydrochloride
- aminoglutethimide an aromatase inhibitor
- flutamide an anti-androgen
- gemtuzumab ozogamicin a monoclonal antibody
- oprelvekin a synthetic interleukin
- Antitumor antibiotics include adriamycin, dactinomycin, daunorubicin, doxorubicin, amsacrine, idarubicin, mitoxantrone, bleomycin, plicamycin, ansamitomycin, and mitomycin.
- Antisense oligonucleotides having antiproUferative effects may also be delivered to a tumor site using the compositions described herein.
- Preferred ohgonucleotide analogs include morpholino-based oligomers having uncharged, phosphorus-containing linkages, preferably phosphoramidate or phosphorodiamidate linkages, as described, for example, in U.S. Patent Nos. 5,185,444 and 5,142,047 and in Summerton and eller, Antisense Nucleic Acid Drug Dev. 7:63-70 (1997).
- Oligomers antisense to c-myc may be used, and include those described in PCT Pubn. No. WO 00/44897 and U.S. Appn. Pubn. No.
- the ohgomer is an antiproliferatrve antisense oUgomer which is not targeted to c-myc.
- Such ohgomers include those targeted to other genes involved in cell transformation, cell survival, metastasis, and angiogenesis, such as, for example, PKC, PKA, p53, bcl-2, c-raf, ras, c-fos, MDR1, MMP-9, HER-2/neu, ⁇ 21, bcr-abl, and MDM2.
- the agent is a non-oligonucleotide agent; that is, it is not an ohgonucleotide or oUgonucleotide analog.
- the antiproUferative agent may be selected from the group consisting of pachtaxel, docetaxel, cisplatin, carboplatin, etoposide, tamoxifen, methotrexate, 5-fluorouracil, adriamycin, daunorubicin, doxorubicin, vincristine, and vinblastine.
- the agent is selected from the group consisting of paclitaxel, other taxanes, such as docetaxel, and active analogs, derivatives or prodrugs of these compounds.
- the agent is paclitaxel or docetaxel.
- the antiproUferative agent is selected from the group consisting of cisplatin, carboplatin, 5-fluorouracil, etoposide, tamoxifen, vincristine, and vinblastine.
- chemotherapeutic agents currently in widespread use include the platinum-containing agents, such as cisplatin and carboplatin, pachtaxel (Taxol®) and related drugs, such as docetaxel (Taxotere®), etoposide, and 5-fluorouracil.
- Taxol® paclitaxel
- Etoposide is currently used in therapy for a variety of cancers, including testicular cancer, lung cancer, lymphoma, neuroblastoma, non-Hodgkin's lymphoma, Kaposi's Sarcoma, Wilms' Tumor, various types of leukemia, and others.
- Fluorouracil has been used for chemotherapy for a variety of cancers, including colon cancer, rectal cancer, breast cancer, stomach cancer, pancreatic cancer, ovarian cancer, cervical cancer, and bladder cancer.
- the clinical utility of such drugs has often been limited by cost, dose-limiting adverse effects, and, in some case, such as paclitaxel, low aqueous solubility.
- Solubilizers such as Cremophor® (polyethoxylated castor oil) and alcohol have been demonstrated to improve solubility. Dose-limiting side effects of such drugs typically include reduction in white and red blood cell counts, nausea, loss of appetite, hair loss, joint and muscle pain, and diarrhea. By targeting the composition to the tumor site, systemic adverse effects can be reduced.
- Other therapeutic agents that may be used beneficially in combination with antineoplastic agents include antiinflammatory compounds, such as dexamethasone and other steroids, and immunostimulatory compounds.
- the microbubble compositions are generally prepared by incubating an antiproUferative agent of choice with a suspension of microbubbles.
- the microbubbles are coated with a filmogenic protein, such as albumin (or an albumin/dextrose mixture) and contain a perfluorocarbon gas, preferably perfluoropropane or perfluorobutane.
- a filmogenic protein such as albumin (or an albumin/dextrose mixture)
- a perfluorocarbon gas preferably perfluoropropane or perfluorobutane.
- Tumors to be targeted will generally be solid tumors, which can be located anywhere in the body.
- Tumors for which the present deUvery method is useful include, for example, solid tumors of the brain, Uver, kidney, pancreas, pituitary, colon, breast, lung, ovary, cervix, prostate, testicle, esophagus, stomach, head or neck, bone, or central nervous system.
- the method is useful to slow the growth of tumors, prevent tumor growth, induce partial regression of tumors, and induce complete regression of tumors, to the point of complete disappearance.
- the method is also useful in preventing the outgrowth of metastases derived from solid tumors.
- the compositions are typically administered parenterally, for example by intravenous injection or slow intravenous infusion. For localized lesions, the compositions can be administered by local injection. Intraperitoneal infusion can also be employed. Dosing regimens are determined by ttie physician in accordance with standard clinical procedures, taking into consideration the drug administered, the type and extent of disease, and the overaU condition of the patient.
- PESDA perfluorocarbon-exposed sonicated dextrose/albumin
- a solution or suspension of a therapeutic agent in a pharmaceutically acceptable solvent such as aqueous sahne, buffer, alcohol, DMSO, or castor oil, is incubated with agitation with the PESDA microbubble suspension at room temperature. Upon settling, the drug-conjugated microbubbles generally rise to the top of the mixture.
Abstract
Description
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Priority Applications (3)
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AU2004275792A AU2004275792A1 (en) | 2003-09-22 | 2004-09-22 | Delivery of therapeutic compounds via microparticles or microbubbles |
EP04784933A EP1675569A4 (en) | 2003-09-22 | 2004-09-22 | Delivery of therapeutic compounds via microparticles or microbubbles |
CA002539542A CA2539542A1 (en) | 2003-09-22 | 2004-09-22 | Delivery of therapeutic compounds via microparticles or microbubbles |
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US10/668,988 US20040126400A1 (en) | 2002-05-03 | 2003-09-22 | Delivery of therapeutic compounds via microparticles or microbubbles |
US10/668,988 | 2003-09-22 |
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WO2005030171A1 true WO2005030171A1 (en) | 2005-04-07 |
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EP (1) | EP1675569A4 (en) |
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US8735394B2 (en) | 2005-02-18 | 2014-05-27 | Abraxis Bioscience, Llc | Combinations and modes of administration of therapeutic agents and combination therapy |
US9101543B2 (en) | 2005-02-18 | 2015-08-11 | Abraxis Bioscience, Llc | Combinations and modes of administration of therapeutic agents and combination therapy |
US9302124B2 (en) | 2008-09-10 | 2016-04-05 | The Trustees Of Columbia University In The City Of New York | Systems and methods for opening a tissue |
US9358023B2 (en) | 2008-03-19 | 2016-06-07 | The Trustees Of Columbia University In The City Of New York | Systems and methods for opening of a tissue barrier |
US10028723B2 (en) | 2013-09-03 | 2018-07-24 | The Trustees Of Columbia University In The City Of New York | Systems and methods for real-time, transcranial monitoring of blood-brain barrier opening |
US10322178B2 (en) | 2013-08-09 | 2019-06-18 | The Trustees Of Columbia University In The City Of New York | Systems and methods for targeted drug delivery |
US10441820B2 (en) | 2011-05-26 | 2019-10-15 | The Trustees Of Columbia University In The City Of New York | Systems and methods for opening of a tissue barrier in primates |
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US9358023B2 (en) | 2008-03-19 | 2016-06-07 | The Trustees Of Columbia University In The City Of New York | Systems and methods for opening of a tissue barrier |
US10166379B2 (en) | 2008-03-19 | 2019-01-01 | The Trustees Of Columbia University In The City Of New York | Systems and methods for opening of a tissue barrier |
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US11273329B2 (en) | 2011-05-26 | 2022-03-15 | The Trustees Of Columbia University In The City Of New York | Systems and methods for opening of a tissue barrier in primates |
US10322178B2 (en) | 2013-08-09 | 2019-06-18 | The Trustees Of Columbia University In The City Of New York | Systems and methods for targeted drug delivery |
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Also Published As
Publication number | Publication date |
---|---|
AU2004275792A1 (en) | 2005-04-07 |
EP1675569A4 (en) | 2012-03-21 |
CA2539542A1 (en) | 2005-04-07 |
EP1675569A1 (en) | 2006-07-05 |
US20100074927A1 (en) | 2010-03-25 |
US20040126400A1 (en) | 2004-07-01 |
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