WO2005048988A1 - Liposomes/micelles charges a composes medicaux encapsules - Google Patents

Liposomes/micelles charges a composes medicaux encapsules Download PDF

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Publication number
WO2005048988A1
WO2005048988A1 PCT/US2003/033536 US0333536W WO2005048988A1 WO 2005048988 A1 WO2005048988 A1 WO 2005048988A1 US 0333536 W US0333536 W US 0333536W WO 2005048988 A1 WO2005048988 A1 WO 2005048988A1
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WO
WIPO (PCT)
Prior art keywords
medicament
micelle
liposome
agent
inhibitor
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Application number
PCT/US2003/033536
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English (en)
Inventor
Neal Scott
Jerome Segal
Original Assignee
Neal Scott
Jerome Segal
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
Application filed by Neal Scott, Jerome Segal filed Critical Neal Scott
Priority to PCT/US2003/033536 priority Critical patent/WO2005048988A1/fr
Priority to AU2003284327A priority patent/AU2003284327A1/en
Publication of WO2005048988A1 publication Critical patent/WO2005048988A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/325—Applying electric currents by contact electrodes alternating or intermittent currents for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/327—Applying electric currents by contact electrodes alternating or intermittent currents for enhancing the absorption properties of tissue, e.g. by electroporation

Definitions

  • Cardiovascular disease is commonly accepted as being one of the most serious health risks facing our society today.
  • Diseased and obstructed coronary arteries can restrict the flow of blood and cause tissue ischemia and necrosis.
  • tissue ischemia and necrosis After over -two decades of investigation, the exact etiology of sclerotic cardiovascular disease is still in question, the treatment of narrowed coronary arteries is more defined.
  • Surgical construction of coronary artery bypass grafts (CABG) is often the method of choice when there are several diseased segments in one or multiple arteries.
  • Open heart surgery is, of course, very traumatic for patients. In many cases, less traumatic, alternative methods are available for treating cardiovascular disease percutaneousl .
  • recurrent problem with the previous devices and PTCA procedures is their failure to maintain patency due to the growth of injured vascular tissue. This is known as "restenosis" and may be a result of the original injury to the vessel wall occurring during the angioplasty procedure.
  • Pathologically restenosis represents a neointimal proliferative response characterized by smooth muscle cell hyperplasia that results in reblockage of the vessel lumen necessitating repeat PTCA procedures up to 35-50% of all cases . It has been generally accepted that a certain therapeutic agents or medicaments may be capable of selectively inhibiting the growth of these hyperprolif rating smooth muscle cells and thereby reduce the rate of restenosis after the primary i erventional procedure .
  • Balloon angioplasty catheters have been used to place and deliver a various therapeutic agents or medicaments within human vessels.
  • U.S. Patent Nos . 5112,305, 5,746,716, 5,681,281, 5,873,852, 5,713,863 and 6,102,904 disclose and claim a balloon catheter system with various injector plates mounted on the balloon for delivering a drug into an arterial segment.
  • a standard angioplasty balloon may be coated with a substrate or polymeric material which either incorporates, or is then used to bond, certain medicaments or theraputic agents .
  • agents are then delivered to the desired therapeutic site by inflation of the balloon and diffusion of the medicatment or therpeutic agent into the vessel wall .
  • Only limited quantities of therapeutic agents can be delivered because of "wash-out" of the drug into the circulation during balloon placement and due to the limited time the inflated balloon can be left in place due to ischemia caused by the balloon.
  • iontophoretic or electrophoretic means as disclosed in Patent No. 5,499,971.
  • passive diffusion of the drug or medicament is enhanced by placing the medicament or theraputic agent in close proximity to the site of treatment and then using electrical energy to augment delivery of the drug into the tissues or cells.
  • These methods generally place the drug inside a balloon mounted distally on a catheter whereby the balloon is composed of a semi-porous material through which the drug can diffuse.
  • the balloon must be expanded and thereby restricts blood flow to the distal arterial segments while the balloon is in the expanded configuration thus limiting the time the drug delivering balloon can be clinically utilized.
  • a stent or balloon catheter to delivery a therapeutic agent or medicament to a vascular segment.
  • the therapeutic agent eluting stents once the stent is deployed, there is no means outside of invasive surgical excision, to remove the eluting stent from the vascular segment. Therefore, stents or implanted prostheses with therapeutic agent eluting properties must be precisely calibrated to deliver an exact quantity of the therapeutic agent or medicament to the vascular segment upon stent deployment.
  • Balloon catheters employed to delivery a therapeutic agent or medicament to a vascular segment have limitations including potential balloon rupture and ischemia due to balloon inflation limiting distal blood flow to the artery. This leads to tissue ischemia and potential necrosis . Even "perfusion" type angioplasty balloons used to delivery a therapeutic agent or medicament to the affected artery provide far less than physiological blood flow during balloon inflation and dwell times are limited by ischemia and tissue necrosis .
  • Another object of the invention is to provide a method to deliver high concentrations of agents that are poorly soluble or insoluble in aqueous media to selected sites in the body including arteries, veins or other tubular structures, prosthetic devices such as grafts, and tissues such as, but not limited to, brain, myocardium, colon, liver, breast and lung.
  • Another object of the invention is to provide a apparatus that can control the release or diffusion of a medicament or therapeutic agent to minimize potential systemic affects and maximize the diffusion or delivery of the medicament or therapeutic agent to the site of treatment.
  • the present invention comprises an electrically charged liposome or micelle that encapsulates a therapeutic agent or medicament.
  • the methods necessary for deployment and delivery of the charged liposomes or micelles encapsulating a therapeutic agent or medicament to an obstruction in a vessel are also disclosed and claimed.
  • the present invention not only achieves acute patency of a vessel but employs medical therapy to maintain chronic patency through the prevention of restenosis .
  • the invention also takes advantage of the prior body of knowledge that has demonstrated the enhanced solubility and delivery of agents after they have been incorporated into liposome or micelles or micelles . Since liposome or micelles and micelles possess both lipophilic and hydrophilic regions, they can be used to solubilize compounds that are insoluble in water. Electrically charging the liposome or micelles can facilitate the movement of the charged liposome or micelle in an electrical ield. This disclosure also demonstrates the delivery of charged, lipophilic medicaments or agents by incorporating them into charged liposome or micelles and then delivering them to the target site by electrophoresis .
  • the delivering of the charged present invention method also comprises the steps of advancing a catheter generally including a distal expansion member and advancin ⁇ r it to the obstruction in a vessel .
  • the clinician applies forces on the expansion member caLUsing the expansion member to become fully expanded wherein the expansion member dilates the obstruction.
  • a means is employed which actively delivers the liposome or micelle- encapsulated therapeutic agent or medicament to the obstruction or vessel wall .
  • One approach may be to 1) energize a delivery catheter to create a bond between the charged liposome or micelle encapsulating the therapeutic agent and the distal expansion means , 2) advance the system to the treatment segment, 3) expand the expansion member to dilate the segment, 4) apply electrical energy to cause iontophoresis of the therapeutic agent into the tissues and/or liposome or micelle encapsulating the therapeutic agent 5) apply electrical energy for electroporation to be applied to permeabilize the cells.
  • the catheter is able to perform steps 3, 4 and 5 sequentially without repositioning of the catheter. Even more preferably, the catheter is designed to maintain a high concentration of drug in the tissue extracellular spaces (e.g.
  • Another approach may be to 1) prepare a delivery catheter to inject charged liposomes or micelles encapsulating the therapeutic agent through the distal expansion means, 2) advance the system to the treatment segment, 3) expand the expansion member to (dilate the segment, 4) inject the charged liposomes or micelles encapsulating the therapeutic agent 5) apply electrical energy to cause iontophoresis of the therapeutic agent into the tissues and/or 6) apply electrical energy for electroporation to be applied to permeabilize the cells .
  • the catheter is able to perform steps 3, 4 and 5 and 6 sequentially without repositioning of the catheter.
  • the catheter is designed to maintain a high concentration of drug in the tissue extracellular spaces (e.g. by iontophoresis) such that the subsequent creation of transient pores in cell surface membranes by electroporation pulses results in greatly improved intracellular delivery of the medicament or therapeutic agent.
  • Figure 1 is a cross-sectional view of a charged micelle structure encapsulating a therapeutic agent.
  • Figure 2 is a cross-sectional view of a charged liposome structure encapsulating a therapeutic agent.
  • Figure 3 is a cross-sectional view taken along the line 2-2 of Figure 2.
  • Figure 4 is a representation of the present invention micelle encapsulating a therapeutic agent and having an overall positive charge.
  • Figure 5 is a representation of the present invention liposome encapsulating a therapeutic agent and having an overall positive charge.
  • Figure 6 is a representation of the present invention micelle encapsulating a therapeutic agent and having an overall negative charge.
  • Figure 7 is a representation of the present invention liposome encapsulating a therapeutic agent and having an overall negative charge.
  • the present invention relates generally to devices and methods that are used to deliver a medicament or therapeutic agent to an obstruction within a stenotic segment of a vessel.
  • the present invention is comprised of a lipsosome or micelle structure that encapsulates a medicament or therapeutic agent and has an overall electrical charge
  • the present invention micelle generally comprises a plurality of outer hydrophilic heads 10 that encapsulate a plurality of inner hydrophobia tails 20.
  • Therapeutic agents or medicaments 30 with hydrophobic characteristics can be incorporated within the inner hydrophobic tail region 25.
  • this micelle/medicament composite will include an overall negative 40 or positive charge 50.
  • present invention liposomes generally comprise a bi-layer or double structure 57. Shown more specifically in Figure 3 , the hydrophilic heads 65 of the molecules are on the outside of the bi- layer, and the hydrophobic tails 75 point toward the interior of the bi-layer.
  • the hydrophilic heads 65 of the molecules are on the outside of the bi- layer, and the hydrophobic tails 75 point toward the interior of the bi-layer.
  • there are two inner regions an first inner hydrophobic tail region 77 surrounding another inner hydrophilic tail region 76.
  • Therapeutic agents or medicaments 80 with hydrophobic characteristics can be incorporated within the inner hydrophobic region 76.
  • therapeutic agents or medicaments 82 with hydrophilic characteristics can be incorporate within the second inner hydrophilic region 77. It is not essential that the therapeutic agents or medicaments be common between the two regions, inner hydrophobic tail region 77 can contain a therapeutic agent different from that of inner hydrophobic tail region 76.
  • the liposome-encapsulated therapeutic agent, 80 or 82, or micelle encapsulated therapeutic agent 30 can be an anticoagulant selected from the group consisting of D-Phe- Pro-Arg chloromethyl ketone, an RGD peptide-containing compound, heparin, an a tithrombin compound, a platelet receptor antagonist, an anti-thrombin antibody, an anti- platelet receptor antibody, hirudin, hirulog, phe-pro-arg- chloromethyketone (Ppack) , Factor Vila, Factor Xa, aspirin, clopridogrel, ticlopidine, a prostaglandin inhibitor, a platelet inhibitor and a tick anti-platelet peptide, and combinations thereof.
  • an anticoagulant selected from the group consisting of D-Phe- Pro-Arg chloromethyl ketone, an RGD peptide-containing compound, heparin, an a tithrombin compound, a platelet receptor antagonist, an anti-thro
  • the liposome-encapsulated therapeutic agent 80 , 82 or micelle-encapsulated therapeutic agent 30, can be a promoter of vascular cell growth, such as a growth factor stimulator, a growth factor receptor agonist, a transcriptional activator , and a translational promoter .
  • the therapeutic agents can be an inhibitor of vascular cell growth, selected from the group consisting of a growth factor inhibitor, a growth factor receptor antagonist, a transcriptional represser, a translational repressor, an antisense DNA, an antisense RNA, synthetic DNA compounds, especially those with backbones that have been modified to inhibit enzymatic degradation (e.g.
  • phosphorothioate compounds and morpholino diamidate compounds a replication inhibitor, an inhibitory antibody, an antibody directed against growth factors, a bifunctional molecule consisting of a growth factor and a cytotoxin, and a bifunctional molecule consisting of an antibody and a cytotoxin, double stranded DNA, single stranded DNA, single stranded RNA and a double stranded RNA and combinations thereof.
  • the liposome-encapsulated therapeutic agent 80, 82 or micelle-encapsulated therapeutic agent 30 can be selected from the group consisting of a cholesterol-lowering agent, a vasodilating agent, and agents which interfere with endogenous vasoa ⁇ tive mechanisms, estrogen, testosterone, steroid hormones, cortisol, dexamethasone, ⁇ orticosteroids , thyroid hormones, thyroid hormones analogs, throid hormones antagonist, adrenocorticotrophic hormone, thyroid stimulating hormone, thyroid releasing factor, thyroid releasing factor analogs, thyroid releasing factor antagonists and combinations thereof.
  • the therapeutic agents 30, 80, or 82 can be smooth muscle inhibitor, such as a selected from the group consisting of an agent that modulates intracellular calcium binding proteins, a receptor blocker for contractile agonists, an inhibitor of the sodium/hydrogen antiporter, a protease inhibitor, a nitrovasodilator, a phosphodiesterase inhibitor, a phenothiazine, a growth factor receptor agonist, an anti-mitotic agent, an im unosuppressive agent, and a protein kinase inhibitor, and combinations thereof.
  • the therapeutic agents 30, 80 and 82 can be a compound that inhibits cellular proliferation, Pa ⁇ litaxel, Rapamycin, Actinomycin D, Methotrexate, Doxorubicin, cyclophosphamide, and 5-fluorouracil, 6- mer ⁇ apatopurine , 6-thioguanine, cytoxan, cytarabinoside, cis-platin, chlorambucil, busulfan, and any other drug that can inhibit cell proliferation, and combinations thereof.
  • the charged liposome-encapsulating a medicament or therapeutic agent 15 or micelle-encapsulated a medicament or therapeutic agent 5 may be disposed on or within a substrate or polymer 43, which can be biodegradable and adapted for slow release of the liposome or micelle- encapsulated therapeutic agents 30, 80, or 82.
  • a substrate or polymer 43 laden with one or more therapeutic agents 30 , 80 , or 82 can be positioned on the sur ace of a balloon or alternately injected through a delivery catheter.
  • a biodegradable substrate or polymer 43 such as polylactide, polyanhydride, polyorthoester or polyglycolide , for example can be used.
  • natural polymers can be used, such as amino acid polymers or polysaccharides .
  • the polymer or substrate 43 is selected depending on the charged liposome- encapsulating a medicament or therapeutic agent 15 or micelle-encapsulated a medicament or therapeutic agent 5 used.
  • the substrates or polymers 43 compatibility with a patient and the ultimate pharmacologic effect are desired. For example, if the effect needs to only last a short period, that a thin polymer 43.
  • the layer closest to the body fluid would contain the charged liposome-encapsulating a medicament or therapeutic agent 15 or micelle-encapsulated a medicament or therapeutic agent 5.
  • Another alternative would be to use a polymer 43 which is biodegradable over a long period of time. Naturally, the other characteristics would be selected for a desired prolonged release.
  • a plurality of charged liposomes-encapsulating a medicament or therapeutic agent 15 or micelles-encapsulated a medicament or therapeutic agent 5 can be coated on (or incorporated into a polymer or other substrate 43 and coated on the expansion means or balloon distally mounted on a catheter. Or a plurality of charged liposomes- encapsulating a medicament or therapeutic agent 15 or micelles-encapsulated a medicament or therapeutic agent 5 can be delivered to a treatment site by an injection delivery device or pressure mediated catheter.
  • the apparatuses for delivering or infusing a therapeutic agent or medicament is known to those skilled art or can be determined by reference to standard references .
  • a charge could be applied or reversed thus driving the plurality of charged liposomes-encapsulating a medicament or therapeutic agent 15 or micelles-encapsulated a medicament or therapeutic agent 5 into the target tissue.
  • the electrode placed on the skin of the patient would be used to cause active diffusion or iontophoresis of the therapeutic agent or medicament into the target tissues .
  • the present invention can benefit f om the flow of electrical current in the form of various waveforms to perform the iontophoresis and/or electroporation procedures .
  • Possible wave orms contemplated for the present invention include square waves, rectangular waves, saw-toothed waves, sinusoidal waves that do not reverse polarity, rectified sinusoidal waves, and other waveform shapes which may reverse polarity but provide a net flow of current in the desired direction.
  • Electrical current could also be coordinated with the patient' s elctrocardiogram such that electrical current is provided to the mesh only during certain phases of cardiac depolarization. This "gating" of the electrical current would avoid the potential danger of discharging electrical current to the heart during vunerable phases of depolarization which may lead to cardiac arrhythmias .
  • Iontophoreti ⁇ ally enhanced delivery requires that the therapeutic agent carry a net charge under physiological conditions whereas electroporation alone would be used for delivering treatment agents that are not sufficiently ionized to iontophorese well into tissues . Electroporation may also be the preferred strategy for enhancing localized cellular targeting of a systemically administered therapeutic agent.
  • the term "iontophoresis" means the migration of ionizable molecules through a medium driven by an applied low-level electrical potential. This electrically mediated movement of molecules into tissues is superimposed upon concentration gradient dependent di fusion processes . If the medium or tissue through which the molecules travel also carries a charge, some electro- osmotic flow occurs. However, generally, the rate of migration of molecules with a net negative charge towards the positive electrode and vice versa is determined by the net charge on the moving molecules and the applied electrical potential . The driving orce may also be considered as electrostatic repulsion. Iontophoresis usually requires relatively low constant DC current in the range of from about 2-10 mA.
  • one electrode is positioned over the treatment area and the second electrode is located at a remote site, usually somewhere else on the skin.
  • the return electrode may be similarly positioned on the skin.
  • the tip of the guide wire emerging from the distal end of the support catheter may serve as the return electrode .
  • electroporation means the temporary creation of holes or aqueous pores in the surface of a cell membrane by an applied electrical potential and through which therapeutic agents may pass into the cell.
  • Electroporation is now widely used in biology, particularly for transfection studies, where plasmids, DNA fragments and other genetic material are introduced into living cells .
  • electroporation pulsing molecules that are not normally membrane per eant are able to pass from the extracellular environment into the cells during the period of induced reversible membrane permeabilization.
  • the permeabilized state is caused by the generation of an electrical field in the cell suspension or tissue of sufficient field strength to perturb the cell surface membrane' s proteolipid structure .
  • This perturbation (sometimes referred to as dielectric breakdown) is believed to be due to both a constituent charge separation and the effect of viscoelastic compression forces within the membrane and it's sub-adjacent cytoskeletal structures.
  • the result is a localized membrane thinning.
  • pores or small domains of increased permeability are formed in the membrane proteolipid bi-layer.
  • a container having a solution of the charged liposomes or micelles encapsulating therapeutic agents 5 or 15, can be separately supplied whereby sometime prior to inserting the mechanical dilatation and medicament delivery device into the patient, the expansion member is immersed or dipped into the container in order to coat the expansion member with the present invention.
  • Appropriate time and/or temperatures will be allowed for the medicament solution to adsorb, dry and adhere to the polymer coated expansion mesh, or alternately, a charge can be applied to facilitate bonding of the medicament or therapeutic agent to the polymer coated expansion member.
  • the drug delivery device can have a means, such a series of injector plates or pores in the expansion member, to inject or infuse the present invention charged liposome or micelle with encapsulated medicaments 5, 15 into the vessel wall of the treatment site.
  • a solution of charged liposomes or micelles encapsulating therapeutic agents 5 or 15 can be supplied whereby sometime prior to inserting the medicament delivery device into the patient, the catheter is first prepared according to standard procedures . The delivery device is then inserted into a guiding catheter (not shown) typically used in such a procedure and introduced into the femoral artery and having its distal extremity in engagement with the ostium of the selected coronary artery.
  • the coated delivery catheter or means is used to deliver the present invention to a treatment site, that they have the capability to apply an electrical current with a charge opposite to that of the therapeutic agent or medicament encapsulated liposome or micelle 5 or 15.
  • liposome or micelle-encapsulated therapeutic agents or medicaments 5, 15 have an inherent charge potentials, a charge opposite that can be applied by, for example, the expansion member. This results in an electrical bond established between the surface of the expansion member and the liposome or micelle-encapsulated therapeutic agent or medicament 5, 15.
  • the continuously charged expansion member with the attached charged liposome or micelle-encapsulated therapeutic agent or medicament 5 , 15 could then be advanced through the patient' s vasculature to the site of dilatation and therapy without significant loss of the medicament in the bloodstream.
  • the medicament delivery device is then advanced in a conventional manner by the physician undertaking the procedure and into the vessel containing a stenosis .
  • the expansion member is expanded with the charged liposome or micelle-encapsulated medicament or therapeutic agent 5, 15 coated thereo .
  • expansion of the distal member provides proper orientation for injection into the vessel of the charged liposomes or micelles encapsulating a medicament or therapeutic agent 5, 15.
  • a means separate from the expansion means will than be employed to cause injection or infusion of the charged liposomes or micelles encapsulating a medicament or therapeutic agent 5, 15 into the vessel wall or obstruction.
  • an electrical charge is provided to the expansio member or other means that is in close proximity to the liposomes or micelles encapsulating the medicaments or therapeutic agents .
  • This electrical charge is opposite to the overall charge of the liposomes or micelles encapsulating the medicaments or therapeutics agents 5, 15 or alternately, the charge used to bind the liposomes or micelles encapsulating the medicament: 5, 15 to the expansion member. This charge will then tend to drive the liposomes or micelles encapsulated medicament or therapeutic agent 5, 15 into the tissue through iontophoretic means .
  • the iontophoretic process is known to facilitate or assist the transport of the liposomes or micelles with encapsulated medicaments or therapeutic agents 5, 15 across the selectively permeable membranes and enhance tissue penetration.
  • the present invention involves the use of electrical energy, there are many possible waveforms contemplated for use , square waves , rectangular waves, saw toothed waves, sinusoidal waves that do not reverse polarity, rectified sinusoidal waves, and modified rectangular or other waves, that can be employed.
  • the primary characteristic of the preferred waveforms is that they all provide a net flow of current to urge the liposomes or micelles encapsulating the medicaments or therapeutics agents into the cell membranes .
  • the waveforms with frequencies and duty cycles must be capable of delivering the desired current under varying impedances encountered by the expansion member and the surrounding vessel wall and fluids .
  • the electrical current can be altered to achieve another purpose or terminated. This makes it possible to maintain dilatation and medicament delivery of the obstruction over extended periods of time when desired.
  • the expansion member can be changed from its expanded position to a contracted position and can be removed along with the guide wire after which the guiding catheter (not shown) can be removed and the puncture site leading to the femoral artery closed in a conventional manner.
  • 7-Amino Actinomycin D is a fluorescent (emits at 610 nm, [red]) analog of Actinomycin D, a potent inhibitor of cellular proliferation. It is very lipophilic and poorly soluble in water. Liposome or micelles were prepared by mixing 3.0 g of phosphatidylcholine, 3.0 mg of cholesterol and 0.3 mg of phosphatidylserine in a test tube . Chloroform (200 microliters) was added and the solution was evaporated to dryness in a test tube. 7-Amino Actinomycin D (500 mg) was dissolved in 8 mM CaCl 2 for a final concentration of 0.5 mg/ml .
  • the 7-Amino Actinomycin D solution was added to the lipid mixture in small aliquots with constant stirring.
  • the hydrogel-coated metal mesh catheter was placed in the 7-amino Actinomycin D / liposome or micelle mixture and then used for drug delivery in the following manner:
  • the hydrogel-coated metal mesh catheter was placed in the 7-Amino Actinomycin D / liposome or micelle mixture and then removed.
  • the hydrogel-coated mesh portion of the catheter was covered with a retractable sheath to prevent loss of the compound during the transport of the catheter from the arterial access site to the target site. When the catheter was positioned at the target site the sheath was retracted and the mesh was expanded against the arterial wall .
  • lontophoersis was performed by applying an electrical current to the mesh.
  • the circuit was completed by pacing a patch on the skin that was connected to the circuit and had an opposite charge than the mesh.
  • the iontophoresis parameters were 5 mA, and 8 V, applied for 10 minutes.
  • the results also show 7-Amino Actinomycin D throughout the vessel wall and in the outer layer of the vessel. There is also evidence of localization of the 7- Amino Actinomycin D in the nuclei of the cells .
  • Paclitaxel is one of the most potent inhibitors of cellular proliferation in clinical use and has been shown to be efficacious in a large number of cancers .
  • Paclitaxel is very lipophilic and essentially insoluble in water. Liposome or micelles were prepared by mixing 0.72 mg phosphatidylcholine and 0.8 mg of phosphatidylserine in a test tube with 800 microliters of chloroform. The solution was evaporated to dryness .
  • Paclitaxel labeled with a fluorescent probe (Oregon Green) was dissolved in methanol to obtain a 20 1 mg / 1 ml solution. Twenty-five microliters of this solution was combined with 975 microliters of 8 mM CaCl 2 .
  • the paclitaxel solution was added to the dried lipid mixture in small aliquots with constant stirring.
  • the hydrogel-coated metal mesh catheter was placed in the paclitaxel / liposome or micelle mixture and then removed.
  • the hydrogel-coated mesh portion of the catheter is covered with a retractable sheath to prevent loss of the compound during the transport of the catheter from the arterial access site to the target site.
  • the sheath was retracted and the mesh was expanded against the arterial wall .
  • lontophoersis was performed y applying an electrical current to the mesh.
  • the circuit was completed by pacing a patch on the skin that was connected to the circuit and had an opposite charge than the mesh.
  • the iontophoresis parameters were 7 mA and 8 V, applied for 20 minutes. The results showed the paclitaxel throughout the vessel wall and in the outer layer of the vessel.

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Abstract

L'invention concerne un agent thérapeutique ou un médicament encapsulé à liposomes ou micelles chargés destiné au traitement de l'obstruction d'un vaisseau sanguin. Le procédé selon l'invention comprend les étapes consistant à avancer un cathéter d'administration comprenant un élément d'expansion distale dans l'obstruction d'un vaisseau, à étendre l'élément d'expansion dans une conception dans laquelle l'élément d'expansion dilate l'obstruction et administre les liposomes ou micelles chargés avec des agents thérapeutiques ou médicaments encapsulés dans l'obstruction. De l'énergie électrique est appliquée afin d'améliorer la pénétration dans les tissus et cellules.
PCT/US2003/033536 2003-10-22 2003-10-22 Liposomes/micelles charges a composes medicaux encapsules WO2005048988A1 (fr)

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AU2003284327A AU2003284327A1 (en) 2003-10-22 2003-10-22 Charged liposomes/micelles with encapsulated medical compounds

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1906923A2 (fr) * 2005-07-22 2008-04-09 The Foundry, Inc. Systemes et procedes d'administration d'un agent therapeutique
US10953170B2 (en) 2003-05-13 2021-03-23 Nuvaira, Inc. Apparatus for treating asthma using neurotoxin

Citations (3)

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Publication number Priority date Publication date Assignee Title
US3993754A (en) * 1974-10-09 1976-11-23 The United States Of America As Represented By The United States Energy Research And Development Administration Liposome-encapsulated actinomycin for cancer chemotherapy
US5264618A (en) * 1990-04-19 1993-11-23 Vical, Inc. Cationic lipids for intracellular delivery of biologically active molecules
US20030100887A1 (en) * 2001-11-29 2003-05-29 Neal Scott Mechanical apparatus and method for dilating and delivering a therapeutic agent to a site of treatment

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3993754A (en) * 1974-10-09 1976-11-23 The United States Of America As Represented By The United States Energy Research And Development Administration Liposome-encapsulated actinomycin for cancer chemotherapy
US5264618A (en) * 1990-04-19 1993-11-23 Vical, Inc. Cationic lipids for intracellular delivery of biologically active molecules
US20030100887A1 (en) * 2001-11-29 2003-05-29 Neal Scott Mechanical apparatus and method for dilating and delivering a therapeutic agent to a site of treatment

Cited By (11)

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US10729897B2 (en) 2005-07-22 2020-08-04 The Foundry, Llc Systems and methods for delivery of a therapeutic agent
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US11666526B2 (en) 2005-07-22 2023-06-06 The Foundry, Llc Systems and methods for delivery of a therapeutic agent
US11679077B2 (en) 2005-07-22 2023-06-20 The Foundry, Llc Systems and methods for delivery of a therapeutic agent

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