Title:  Apparatus and method for the local delivery of drugs

United States Patent:  6,352,683

Assignee:  Point Biomedical Corporation (San Carlos, CA)

Filed:  July 15, 1997

A local and site-specific drug delivery apparatus for delivering a drug to a specific site is characterized by the combination of a carrier material which reflects or absorbs or emits electromagnetic or mechanical (e.g. ultrasonic) vibrations enabling the monitoring of the material, a drug associated with the carrier material, and a local-delivery mechanism for delivering the carrier material and the drug to a specific site. The local-delivery mechanism may comprise a local-delivery catheter, such as a balloon-type catheter, and the drug delivery apparatus may additionally include a monitor for monitoring the delivery of the drug to the specific site, such as an ultrasonic imaging system. The drug delivery apparatus may also include a vibration generator for inducing release of the drug from the carrier material when the carrier material is at the specific site, such as a generator of ultrasonic energy. Alternatively, the local-delivery mechanism may comprise a targeting agent associated with the carrier material, the targeting agent capable of binding to the specific site within the individual. The targeting agent may be a protein or an antibody, such as a glycogen IIa/IIB receptor antibody, Von Willebrand's factor antibody, an antitumor antibody, hepatic cellular antibody, a white blood cell antibody, or antifibrin.

SUMMARY OF THE INVENTION

The present invention is directed to a local and site-specific drug delivery system for delivering a drug to a specific site. The drug delivery system is characterized by the combination of a carrier material which reflects or absorbs or emits electromagnetic or mechanical (e.g. ultrasonic) vibrations enabling the monitoring of the material, a drug associated with the carrier material, and local-delivery means for delivering the carrier material and the drug to a specific site.

The local-delivery means may comprise a local-delivery catheter, such as a balloon-type catheter, and the drug delivery system may additionally include means for monitoring the delivery of the drug to the specific site, such as an ultrasonic imaging system. The drug delivery system may also include means for inducing release of the drug from the carrier material when the carrier material is at the specific site, such as means for generating electromagnetic or mechanical vibrations.

The carrier material may comprise an ultrasonic contrast agent in the form of microparticles, microbubbles, microspheres or microcapsules. The carrier material may comprise microbubbles having a diameter of between 1-1000 .mu.m, between 1-100 .mu.m, or between 1-20 .mu.m.

Alternatively, the local-delivery means may comprise a targeting agent associated with the carrier material, the targeting agent capable of binding to the specific site within the individual. The targeting agent may be a protein or an antibody, such as a glycoprotein IIa/IIB receptor antibody, Von Willebrand's factor antibody, an antitumor antibody, hepatic cellular antibody, a white blood cell antibody, or antifibrin antibody.

The carrier material may be in the form of an ultrasonic contrast agent, such as gas microbubbles having a gas and a shell, wherein the drug is embedded in the microbubble shell, encapsulated in the microbubble, or bound to a surface of the microbubble shell. The targeting agent may be bound to a surface of the microbubble shell.

The drug, which may comprise a chemotherapy agent, a thrombolytic drug, an anti-infection agent, vasodilation agent, tissue protective agent, or a gene therapy agent, may be selected from the group consisting of acebutolol, acetylsalicylic acid, adenosine, ATP, alfentanil, alprazolam, azlocillin, betamethasone, bleomycin, captopril, carbenicillin, cefamandole, cefazolin, cefonicid, ceforanide, cefotaxime, cefoxitin, clonidine, cloxacillin, cyclophosphamide, cytarabine, dexamethasone, dicloxacillin, diazepam, diazoxide, digitoxin, digoxin, diltiazem, diphenihydramine, disopyramide, doxorubicin, doxycycline, ceftazidime, ceftizoxime, cefuroxime, cephalexin, cephalothin, cephapirin, chloramphenicol, chloroquine, chlorothiazide, chlorpropormide, chlorthalidone, cimetidine, clofibrate, ibuprofen, imipramine, indomethacin, isosorbide dinitrate, ketoprofen, labetalol, lidocaine, lorazepam, lorcainide, meperidine, mercaptopurine, methadone, methicillin, erythromycin, ethambutol, fentanyl, flucytosine, flunitrazepam, fluorouracil, flurazepam, furosemide, gold sodium thiomalate, haloperidol, heparin, hexobarbital, hydrochlorothiazide, nortriptyline, oxacillin, oxazepam, phenobarbital, phenylbutazone, phenytoin, pindolol, prazosin, prednisolone, prednisone, protenecid, procainamide, propranolol, methothexate, methyldopa, methylprednisolone, metoprolol, metronidazole, mexiletine, mezlocillin, minocycline, morphine, moxalactam, nadolol, nafcillin, naproxen, nifedipine, nitrazepam, theopental, ticarcillin, timolol, tocainide, tolbutamide, tolmetin, triamterene, triazolam, trimethoprim, tubocurarine, urokinase, valproic acid, verapamil, warfarin, protriptyline, pyrimethamine, quinidine, ranitidine, rifampin, salicylic acid, streptomycin, streptokinase, sulfadiazine, sulfamethoxazole, sulfisoxazole, ternazepam, terbutaline, tetracycline, theophylline, andtissue plasminogen activator (tpa).

The invention is also directed to a method of treating a specific site in a mammal with a drug. The method is characterized by the steps of: (a) providing a carrier material which reflects or absorbs or emits electromagnetic or mechanical vibrations enabling the monitoring of the material and a drug associated with the carrier material, and (b) delivering the carrier material and the drug to a specific site in a mammal.

The method may also include the step of generating an image of the carrier material at the specific site, such as by ultrasonically generating an image of the carrier material at the specific site, and/or the step of inducing the drug to be released from the carrier material when the carrier material and the drug are at the specific site. The method may further include the step of inducing the drug to be released from the carrier material when the carrier material and the drug are at the specific site by subjecting the carrier material to ultrasonic vibrations.

The invention is also directed to a method of delivering a drug to a specific target site in an individual having the steps of (a) administering an ultrasonic contrast agent-drug complex to an individual, wherein the complex comprises an ultrasonic contrast agent, a drug, and optionally, a targeting agent capable of binding the ultrasonic contrast agent to the target site in the individual, (b) monitoring the individual using ultrasound to determine an arrival of the complex at the target site in the individual, (c) releasing the drug at the target site by applying sufficient energy to rupture the complex at the target site, and (d) optionally, imaging the target site using ultrasound techniques to monitor release of the drug. The target site in a patient for many applications may be generalized areas of tissue or an organ of known anatomical location such as the heart or kidneys. The general area could be irradiated with sufficient energy for drug release without imaging the target site.

Claim 1 of 15 Claims

What is claimed is:

1. A system for delivering a drug to a specific site and for monitoring the drug at the specific site, said system comprising:

a carrier material which reflects or absorbs or emits electromagnetic or mechanical vibrations enabling the monitoring of said carrier material, said carrier material comprising an ultrasonic contrast agent composed of microbubbles having a diameter of between 1-1000 .mu.m;

a drug carried by said carrier material;

a local-delivery catheter having said carrier material disposed therein and said drug carried by said carrier material disposed therein, said local-delivery catheter being designed such that said carrier material and said drug may be delivered to said specific site, said local-delivery catheter being designed so as to force said carrier material and said drug into an internal blood vessel wall at said specific site so that said carrier material and said drug are trapped therein;

an ultrasonic imaging system that detects said carrier material at said specific site to confirm the presence of said carrier material at said specific site; and

vibration generator associated with said imaging system, said vibration generator generating electromagnetic or mechanical vibrations that induce release of said drug from said carrier material when said carrier material is at said specific site by causing said microbubbles to collapse.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.