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Publication numberUS20020054852 A1
Publication typeApplication
Application numberUS 10/022,021
Publication dateMay 9, 2002
Filing dateDec 13, 2001
Priority dateJan 19, 1995
Also published asDE19581906T0, DE19581906T1, US6352683, WO1996022111A1
Publication number022021, 10022021, US 2002/0054852 A1, US 2002/054852 A1, US 20020054852 A1, US 20020054852A1, US 2002054852 A1, US 2002054852A1, US-A1-20020054852, US-A1-2002054852, US2002/0054852A1, US2002/054852A1, US20020054852 A1, US20020054852A1, US2002054852 A1, US2002054852A1
InventorsFolkert Cate
Original AssigneeCate Folkert Jan Ten
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
A carrier material reflects or absorbs or emits electromagnetic or mechanical vibration enabling the monitoring of carrier material and a drug associated with carrier, and a targeting agent bind to the site
US 20020054852 A1
Abstract
A method of treating a specific site in a mammal with a drug comprises (a) providing a carrier material which reflects or absorbs or emits electromagnetic or mechanical vibrations enabling the monitoring of the carrier material, (b) providing a drug associated with the carrier material, (c) providing a targeting agent associated with the carrier material, the targeting agent being capable of binding to the specific site in the mammal, (d) delivering the carrier material and the drug to the specific site in the mammal, and (e) monitoring the mammal to detect arrival of the carrier material at the specific site. A local and site-specific drug delivery system for delivering a drug to a specific site within an individual comprises a carrier material which reflects or absorbs or emits electromagnetic or mechanical vibrations enabling the monitoring of the carrier material, a drug associated with the carrier material, and a targeting agent associated with the carrier material that delivers the carrier material and the drug to a specific site within the individual, the targeting agent being capable of binding to the specific site within the individual.
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Claims(33)
1. A method of treating a specific site in a mammal with a drug, said method comprising:
(a) providing a carrier material which reflects or absorbs or emits electromagnetic or mechanical vibrations enabling the monitoring of said carrier material;
(b) providing a drug associated with said carrier material, said drug being 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, valproic acid, verapamil, warfarin, protriptyline, pyrimethamine, quinidine, ranitidine, rifampin, salicylic acid, streptomycin, streptokinase, sulfadiazine, sulfamethoxazole, sulfisoxazole, ternazepam, terbutaline, tetracycline, theophylline, and tissue plasminogen activator (tpa);
(c) providing a targeting agent associated with said carrier material, said targeting agent being capable of binding to said specific site in the mammal;
(d) delivering said carrier material and said drug to said specific site in the mammal; and
(e) monitoring the mammal to detect arrival of said carrier material at said specific site.
2. A drug delivery system as defined in claim 1 wherein said targeting agent is a protein.
3. A drug delivery system as defined in claim 1 wherein said targeting agent is an antibody.
4. A drug delivery system as defined in claim 1 wherein said targeting agent is a glycogen IIa/IIB receptor antibody, Von Willebrand's factor antibody, an antitumor antibody, hepatic cellular antibody, a white blood cell antibody, or antifibrin.
5. A method as defined in claim 1 comprising generating an image of said carrier material at said specific site.
6. A method as defined in claim 1 additionally comprising (f) inducing said drug to be released from said carrier material when said carrier material and said drug are at said specific site.
7. A method as defined in claim 1 additionally comprising (f) inducing said drug to be released from said carrier material when said carrier material and said drug are at said specific site by subjecting said carrier material to ultrasonic vibrations.
8. A method of treating a specific site in a mammal with a drug, said method comprising:
(a) providing a carrier material which reflects or absorbs or emits electromagnetic or mechanical vibrations enabling the monitoring of said carrier material;
(b) providing a drug associated with said carrier material;
(c) providing a targeting agent associated with said carrier material, said targeting agent being capable of binding to said specific site in the mammal;
(d) delivering said carrier material and said drug to said specific site in the mammal; and
(e) monitoring the mammal to detect arrival of said carrier material at said specific site.
9. A method as defined in claim 8 wherein said drug is 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, valproic acid, verapamil, warfarin, protriptyline, pyrimethamine, quinidine, ranitidine, rifampin, salicylic acid, streptomycin, streptokinase, sulfadiazine, sulfamethoxazole, sulfisoxazole, ternazepam, terbutaline, tetracycline, theophylline, and tissue plasminogen activator (tpa).
10. A method as defined in claim 8 wherein said drug comprises a chemotherapy agent, a thrombolytic drug, or an anti-infection agent.
11. A method as defined in claim 8 wherein said targeting agent is a protein.
12. A method as defined in claim 8 wherein said targeting agent is an antibody.
13. A method as defined in claim 8 wherein said targeting agent is a glycogen IIa/IIB receptor antibody, Von Willebrand's factor antibody, an antitumor antibody, hepatic cellular antibody, a white blood cell antibody, or antifibrin.
14. A method as defined in claim 8 comprising generating an image of said carrier material at said specific site.
15. A method as defined in claim 8 additionally comprising (f) inducing said drug to be released from said carrier material when said carrier material and said drug are at said specific site.
16. A method as defined in claim 8 additionally comprising (f) inducing said drug to be released from said carrier material when said carrier material and said drug are at said specific site by subjecting said carrier material to ultrasonic vibrations.
17. A method of delivering a drug to a specific target site in an individual, said method comprising:
(a) administering an ultrasonic contrast agent-drug complex to a specific target site in an individual, said complex comprising an ultrasonic contrast agent, a drug, and a targeting agent capable of binding said ultrasonic contrast agent to said specific target site in the individual;
(b) monitoring the individual using ultrasound to determine arrival of said complex at said specific target site in the individual; and
(c) releasing said drug at said specific target site by applying sufficient energy to rupture said complex at said specific target site.
18. A method as defined in claim 17 wherein said drug is 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, valproic acid, verapamil, warfarin, protriptyline, pyrimethamine, quinidine, ranitidine, rifampin, salicylic acid, streptomycin, streptokinase, sulfadiazine, sulfamethoxazole, sulfisoxazole, ternazepam, terbutaline, tetracycline, theophylline, and tissue plasminogen activator (tpa).
19. A method as defined in claim 17 wherein said drug comprises a chemotherapy agent, a thrombolytic drug, or an anti-infection agent.
20. A method as defined in claim 17 wherein said targeting agent is a protein.
21. A method as defined in claim 17 wherein said targeting agent is an antibody.
22. A method as defined in claim 17 wherein said targeting agent is a glycogen IIa/IIB receptor antibody, Von Willebrand's factor antibody, an antitumor antibody, hepatic cellular antibody, a white blood cell antibody, or antifibrin.
23. A method as defined in claim 17 comprising generating an image of said carrier material at said specific site.
24. A method as defined in claim 17 comprising subjecting said carrier material to ultrasonic vibrations.
25. A method as defined in claim 17 comprising imaging said target site using ultrasound energy.
26. A local and site-specific drug delivery system for delivering a drug to a specific site within an individual, said drug delivery system comprising:
a carrier material which reflects or absorbs or emits electromagnetic or mechanical vibrations enabling the monitoring of said carrier material;
a drug associated with said carrier material; and
a targeting agent associated with said carrier material that delivers said carrier material and said drug to a specific site within the individual, said targeting agent being capable of binding to said specific site within the individual.
27. A drug delivery system as defined in claim 26 wherein said drug is 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, diphenihydramnine, disopyramide, doxorubicin, doxycycline, ceftazidime, ceftizoxime, cefliroxime, cephalexin, cephalothin, cephapirin, chloramnphenicol, 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, valproic acid, verapamil, warfarin, protriptyline, pyrimethamine, quinidine, ranitidine, rifampin, salicylic acid, streptomycin, streptokinase, sulfadiazine, sulfamethoxazole, sulfisoxazole, ternazepam, terbutaline, tetracycline, theophylline, and tissue plasminogen activator (tpa).
28. A drug delivery system as defined in claim 26 wherein said drug comprises a chemotherapy agent, a thrombolytic drug, or an anti-infection agent.
29. A drug delivery system as defined in claim 26 wherein said targeting agent is a protein.
30. A drug delivery system as defined in claim 26 wherein said targeting agent is an antibody.
31. A drug delivery system as defined in claim 26 wherein said targeting agent is a glycogen IIa/IIB receptor antibody, Von Willebrand's factor antibody, an antitumor antibody, hepatic cellular antibody, a white blood cell antibody, or antifibrin.
32. A drug delivery system as defined in claim 26 additionally comprising an apparatus that monitors delivery of said drug to said specific site.
33. A drug delivery system as defined in claim 26 additionally comprising an apparatus that induces release of said drug from said carrier material when said carrier material is at said specific site.
Description

[0001] This is a divisional of U.S. Ser. No. 08/893,206 filed Jul. 15, 1997, which is a continuation-in-part of International application PCT/NL95/00028 filed Jan. 19, 1995. Both of the above applications are incorporated by reference herein in their entirety.

BACKGROUND

[0002] This patent relates to a system and method for the delivery of a drug to a specific site in an individual, such as a mammal.

[0003] Local delivery of drugs has been previously accomplished by conjugating a drug to biocompatible or biodegradable macromolecules, e.g. biopolymers, lipids, polysaccharides, proteins including albumin and immunoglobulines, which have a particular receptor specificity. In this way the drug can be transferred to a particular part of the human body which is subject to treatment with the particular drug. For example, Oppenheim, et al. disclose in U.S. Pat. No. 4,107,288 a process for the preparation of drug containing gelatine particles having a diameter mainly below 500 μm which can be administered parenterally.

[0004] Solid serum albumin spherules having 5 to 30% by weight of an entrapped drug are disclosed by Yapel, Jr. in U.S. Pat. No. 4,147,767. The spherules are particularly suited for intravenous injection into the human body whereafter the drug is released from the spherule in a biphasic manner having an initial fast-release phase followed by a slow release phase.

[0005] A method of preparing aqueous suspensions of drug containing spherules comprising a phospholipid has been described by Suzuki, et al. in U.S. Pat. No. 4,016,100. These spherules, which are suitable for injection as well as oral administration, give controlled release of the entrapped drug after administration.

SUMMARY OF THE INVENTION

[0006] In one aspect, the invention is directed to a method of treating a specific site in a mammal with a drug which method comprises (a) providing a carrier material which reflects or absorbs or emits electromagnetic or mechanical vibrations enabling the monitoring of the carrier material, (b) providing a drug associated with the carrier material, (c) providing a targeting agent associated with the carrier material, the targeting agent being capable of binding to the specific site in the mammal, (d) delivering the carrier material and the drug to the specific site in the mammal, and (e) monitoring the mammal to detect arrival of the carrier material at the specific site.

[0007] In another aspect, the invention is directed to a local and site-specific drug delivery system for delivering a drug to a specific site within an individual that comprises a carrier material which reflects or absorbs or emits electromagnetic or mechanical vibrations enabling the monitoring of the carrier material, a drug associated with the carrier material, and a targeting agent associated with the carrier material that delivers the carrier material and the drug to a specific site within the individual, the targeting agent being capable of binding to the specific site within the individual.

[0008] Additional aspects of the invention will be apparent to those of ordinary skill in the art in view of the detailed description of various embodiments, which is made with reference to the drawings, a brief description of which is provided below.

BRIEF DESCRIPTION OF THE DRAWINGS

[0009]FIG. 1 illustrates the relation between acoustic pulse pressure and reflected backscatter when a 2.5 MHz transducer was used in connection with one example in accordance with an example described below;

[0010]FIG. 2A illustrates the unobservability of a contrast difference when no contrast agent was used in an example described below;

[0011]FIG. 2B illustrates the observability of a contrast difference when a contrast agent was used in an example described below;

[0012]FIG. 3 schematically illustrates a first embodiment of a local drug delivery system in accordance with the invention; and

[0013]FIG. 4 schematically illustrates a second embodiment of a local drug delivery system in accordance with the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Although the following text sets forth a detailed description of numerous different embodiments of the invention, it should be understood that the legal scope of the invention is defined by the words of the claims set forth at the end of this patent. The detailed description is to be construed as exemplary only and does not describe every possible embodiment of the invention since describing every possible embodiment would be impractical, if not impossible. Numerous alternative embodiments could be implemented, using either current technology or technology developed after the filing date of this patent, which would still fall within the scope of the claims defining the invention.

[0015] It should also be understood that, unless a term is expressly defined in this patent using the sentence “As used herein, the term ‘______’ is hereby defined to mean . . .” or a similar sentence, there is no intent to limit the meaning of that term, either expressly or by implication, beyond its plain or ordinary meaning, and such term should not be interpreted to be limited in scope based on any statement made in any section of this patent (other than the language of the claims). To the extent that any term recited in the claims at the end of this patent is referred to in this patent in a manner consistent with a single meaning, that is done for sake of clarity only so as to not confuse the reader, and it is not intended that such claim term by limited, by implication or otherwise, to that single meaning. Finally, it is not intended that the scope of any claim element be interpreted based on the application of 35 U.S.C. § 112, sixth paragraph.

[0016] A local and site specific drug delivery system is intended to be a system, comprising biocompatible or biodegradable materials, which is capable of transferring or carrying a drug to a specific area or site, e.g. an organ or organella, at which specific area or site the system releases the drug in an active and controlled manner enabling the interaction of the drug with the specific area or site, when—prior to or after administration of the drug delivery system to the human or animal body—the site is treated with electromagnetic and/or mechanical vibrations.

[0017] In this application electromagnetic and/or mechanical vibrations are intended to comprise vibrations or waves, which are reflected or absorbed or emitted, and propagated in the form of energy through a space or through a material medium. Examples of such vibrations or waves are cosmic rays, gamma rays, X-rays, ultraviolet-, visible and infrared waves, sound waves, microwaves and radiowaves, streams of sub-atomic particles, e.g. alpha-rays, beta-rays and photons, and the like.

[0018] Preferably, the vibrations are not harmful to the mammalian body as will be clear to one skilled in the art, although it is possible to use vibrations (or radiation) which also have therapeutic value, e.g. in cytostatic treatment.

[0019] The expression “imaging techniques” is intended to encompass techniques by which the electromagnetic and/or mechanical vibrations can be detected or monitored, and such techniques will described hereinbelow and/or will be clear to one skilled in the art. In principle, any usual imaging technique for use in medical procedures can be used to follow the drug, its concentration at specific sites of the body, and/or the release of the drug therefrom.

[0020] Although not limited to this mechanism, preferably the interaction of the vibrations with the drug delivery system will lead to or trigger the degradation of the delivery system at the specific site treated with the vibrations, or make the delivery system more susceptible to biological degradation, thereby providing for the local and site specific release of the drug. The degradation and thereby the release can then be followed by means of the above-mentioned imaging techniques.

[0021] It will furthermore be clear to one skilled in the art that the site of the release of the drug can be controlled by controlling the vibrations, i.e. by only treating those sites at which release of the drug is desired. Furthermore, in most cases—and preferably—the rate of degradation and thereby the rate of release is controlled by the amount of vibrations used, i.e. by controlling the intensity or the time of the treatment.

[0022] The local and site specific delivery system will therefore comprise a material that can interact with electromagnetic and/or mechanical vibrations, causing alteration of the release properties of the system. The interaction preferably leads to an enhancement of the release properties, so that by means of the vibrations the release of the drug contained in the system can be effected in a local and site specific manner. For instance, the interaction of the vibrations can lead to or trigger the partial destruction of the walls of the delivery system, or make it more susceptible to biological degradation as described hereinabove.

[0023] Although the preparation will usually comprise b) a material which reflects or absorbs or emits electromagnetic and/or mechanical vibrations enabling the monitoring of the material by imaging techniques, it will be clear to one skilled in the art that component b) can be omitted when component a)—i.e. the local and site specific drug delivery system—itself is made of a material that reflects or absorbs or emits electromagnetic and/or mechanical vibrations, enabling the monitoring of the system by imaging techniques.

[0024] Additionally, the release of the drug can be monitored without simultaneously altering the release properties of the drug delivery system, for instance when two types of vibrations are used, e.g. a first type for altering the release properties and a second type for the subsequent monitoring of the release of the drug. It is also possible to follow the biological release from the delivery system.

[0025] Furthermore, it is possible to alter the release properties and monitor the release of the drug at the same time, using the same or different vibrations for achieving these two objectives.

[0026] The preparation described above may be administered by a catheter-based intravascular delivery system. Local intravascular administration by means of a catheter is a common technique in medical practice. For example, catheters as double balloon, porous balloon, microporous balloon, stent in a balloon, hydrogel, dispatch and iontophoresis may be used.

[0027] For intravenous injection in mammals the preparation must be smaller than 10 μm because otherwise they can not pass the capillary circulation of various organ systems. For direct intra arterial injections, however, the preparation may be larger, although it is preferred that their size does not exceed 50 μm. Consequently, to ensure safe parenteral administration the size of the preparation is determined by their intended use (parenteral intravenous or parenteral intra arterial).

[0028] Preferably, the preparation may comprise as constituent of component a) and/or as component b) a material that can be monitored by ultrasonic imaging and/or an ultrasonic contrast agent, respectively.

[0029] In the description of this application an ultrasonic contrast agent comprises a material, which is a chemical substance or compound, either in the gaseous, liquid or solid state, or a particle comprising biocompatible or biodegradable materials such as polysaccharides, proteins, including albumin, and immunoglobulines and which may be in the form of a microparticle, microbubble, microsphere or microcapsule, or a particle comprising synthetic or natural polymers, and the like, and which is capable of reflecting vibrations, preferably ultrasonic vibrations. This description of an ultrasonic contrast agent is, however, not intended to be limited to ultrasonic vibrations reflecting materials only, but also to include materials capable of reflecting or absorbing or emitting other electromagnetic and/or mechanical vibrations. The preparation preferably reflects ultrasonic waves, which can be monitored by ultrasonic imaging.

[0030] Preferably, the preparation comprises a material, wherein the material which reflects or absorbs or emits electromagnetic and/or mechanical vibrations, preferably ultrasonic vibrations, can be monitored by clinical ultrasound imaging, including Doppler flow, color Doppler and color tissue imaging methods as well as ultrasound imaging based on techniques using the high frequency imaging (Rf signal) by reflected backscatter, color imaging, Doppler imaging or phenomena based on frequency shifts and second harmonic imaging.

[0031] The preparation can be used for inducing and monitoring local and site specific drug delivery for use in medical procedures. The preparation releases a drug upon irradiation of the preparation with electromagnetic and/or mechanical vibrations and can be imaged ultrasonically. The preparation is in particular irradiated with ultrasonic waves in a predetermined area and can be imaged ultrasonically in an area including the predetermined area. Consequently, the drug can be imaged ultrasonically in an area including the predetermined area enabling the determination of the rate of the release of the drug as function of space and time.

[0032] Preferably, the preparation comprises biodegradable particles containing a drug. The particles, when exposed to harmless ultrasonic vibrations at sufficient intensity or during a sufficient period, change their release properties, such as by degradation, thereby releasing the drug. Concurrently, the particles as well as the release can be monitored by means of ultrasonic imaging techniques, using the same harmless ultrasonic vibrations—reflected or absorbed/emitted—that are used for changing the release properties. Because of these advantageous properties, which were not known from the prior art, biodegradable particles are preferred. Suitable biodegradable particles will be clear to one skilled in the art on the basis of the present description, and are for instance described in the prior art mentioned hereinabove.

[0033] According to another preferred embodiment, the preparation comprises solid gold containing particles, such as the solid gold albumin particles described hereinabove, and at least one drug. According to this embodiment, the gold-component will serve as component b), as will be clear to one skilled in the art.

[0034] The size of the biodegradable and/or gold containing biodegradable particles will be 1-1000 μm, preferably 1-100 μm and more preferably 1-20 μm. Depending on their use, i.e. intravenous or intra arterial, the particles will most preferably have a diameter no larger than 10 μm or 50 μm, respectively.

[0035] The preparation may also comprise preparations in the form or microparticles, microbubbles, microspheres or microcapsules and at least one drug. The size of these microparticles, microbubbles, microspheres or microcapsules will preferably be 1-50 μm. Depending on their use, i.e. intravenous or intra arterial, the particles will most preferably have a diameter no larger than 10 μm or 50 μm, respectively.

[0036] These microparticles, microbubbles, microspheres or microcapsules will usually comprise as component b) a material preferably selected from the group comprising gases, aqueous solutions of a contrasting agent and optionally a drug, biocompatible and biodegradable materials.

[0037] Although in principle any drug compatible with the components a) and b) can be used as component c), the drug comprised by the above mentioned preparation is preferably elected from the group comprising oncological agents, viral vectors, growth factors, antibiotics, antihypertensive drugs, vasodilators, tissue protective agents, calcium-instream inhibitors, antithrombosis agents and corticosteroids. The preparation may also be used to administer drugs, e.g. antineoplastic drugs, which are highly toxic to health as well as malignant tissue.

[0038] Although not limited thereto, the drug will be usually be contained inside the preparation or bound thereto, such as by encapsulation or reversible chemical bonds, as will be known to one skilled in the art.

[0039] A method for treating specific sites in a mammal may be provided that comprises the steps of: 1) injecting a drug delivery system into a mammal to thereby alter the acoustic properties of a predetermined area; 2) optionally inducing the release of a drug from the drug delivery system by irradiating the system with electromagnetic and/or mechanical vibrations; and 3) imaging ultrasonically an area including the predetermined area so that an image of the predetermined area is obtained and, when a drug is released, the rate of the release can be determined as function of space and time by the ultrasonic imaging.

[0040] By using the preparation according to the method described above, drugs can be administered to greater therapeutic advantage. These drugs may be selected from the group comprising oncological agents, viral vectors, growth factors, antibiotics, antihypertensive drugs, vasodilators, tissue protective agents, calcium-instream inhibitors, anti-thrombosis agents and corticosteroids, although any drug known in the art may be selected. The preparation may also be used to administer drugs, e.g. antineoplastic drugs for the treatment of tumors, which are highly toxic to health as well as malignant tissue.

[0041] A method for monitoring the local release of a drug may also be provided that comprises changing of the release properties from an already injected drug delivery system as described hereinabove by irradiating the system with electromagnetic and/or mechanical vibrations, and then imaging ultrasonically the area where the drug is released as function of space and time.

[0042] Additionally, a method may be provided for altering the release properties of an administered local and site specific drug delivery system, in which the delivery system is treated with electromagnetic and/or mechanical vibrations, as described hereinabove. Preferably, the release properties are enhanced. Thus, the local and site specific drug delivery system containing a drug is administered to a mammal, such as by injection or another suitable method, whereafter it is transferred to the area to be treated. As soon as the local and site specific drug delivery system has arrived at the area to be treated with the vibrations, its release properties are altered through local and site specific irradiation with the electromagnetic and/or mechanical vibrations, as described hereinabove.

[0043] According to a further embodiment, this method further comprises the monitoring of the release of the drug as described herein.

[0044] A method may be provided for monitoring the delivery of a drug contained by a local and site specific drug delivery system in an area in a mammal which is subject to treatment with the drug, by using a suitable monitoring technique, e.g. NMR tomography, X-ray imaging, preferably ultrasonic imaging, enabling the determination of the effective concentration of the drug in space and time in the area which is subject to treatment with the drug.

[0045] Preferably, the electromagnetic and/or mechanical vibrations used for altering the release properties of a local and site specific drug delivery system are also used for the monitoring of the delivery of a drug contained by the local and site specific drug delivery system in an area in a mammal which is subject to treatment with the drug.

[0046] A method may be provided for monitoring the delivery of a drug contained by a local and site specific drug delivery system by forming an image of the area, which is subject to treatment with the drug and wherein the administered local and site specific drug delivery system is already present, by using a suitable imaging technique, preferably ultrasonic imaging.

[0047] The following examples will further illustrate the present invention. It is, however, to be understood that these examples do not restrict the scope of the invention.

EXAMPLE 1

[0048] Commercially available albumin microspheres having a diameter in the range of 5 to 30 μm were administered parenterally by direct intra arterial injection. In this particular example injections were conducted into the left atrium of a pig's heart. Continuous ultrasonic imaging of the heart was performed during the experiment using a commercially available ultrasonic machine (Hewlett Packard Sonos 1000).

[0049] The images were recorded on videotape. After 3 to 5 beats after injection an increased video intensity was observed in the left ventricle and thereafter in the muscle of the heart which indicated the pressure of the albumin microspheres in this myocardium. This was also confirmed by an increased video intensity. After one to two hours the video intensity gradually decreased indicating the biodegradation of the albumin microspheres.

[0050] In FIG. 1 the relation between acoustic pulse pressure and reflected backscatter is displayed when a 2.5 MHz transducer was used. Below 0.05 MPa (1 Mpa=106 Pa≈10 atm.) the backscatter intensity was linearly related to the acoustic pressure. Above 0.05 Mpa, however, the backscatter remained constant at higher acoustic pressures showing that the albumin microspheres were destroyed.

EXAMPLE 2

[0051] The experiment of Example 1 was repeated with a 3.75 MHz transducer from Hewlett Packard Sonos 1000 and a 5 Mhz transducer from Vingmed. Identical results were obtained, i.e. the microspheres were destroyed at the same pressures.

EXAMPLE 3

[0052] A closed tube containing water was placed in a water containing reservoir. A 2.5, 3.75 or a 5 Mhz transducer was placed in the container and acoustic pressure was applied. An image was visualized by using a television set and the image was subsequently videotaped. Reflections of both edges of the tube were visible which clearly showed the presence of the tube. Because both the container and the tube contained the same fluid, no contrast difference was observed, as shown in FIG. 2A.

[0053] Next, the tube was filled with water containing commercially available albumin gold particles having a diameter in the range of 10 to 20 μm and placed in the container. On applying acoustic pressure, the image showed a contrast difference between the water contained by the reservoir and that contained by the tube, as shown in FIG. 2B.

First Embodiment

[0054]FIG. 3 schematically illustrates a first embodiment of a local drug delivery system 10. Referring to FIG. 3, the drug delivery system 10 includes an intravascular catheter (shown in cross-section) in the form of a balloon-type catheter 12 having an elongate flexible tube portion 14 a and an expandable balloon portion 14 b, an ultrasonic imaging system 16, a vibration generator 18, a carrier material 20 (shown greatly enlarged in the form of a microbubble contrast agent) disposed within the interior of the catheter 12, and a drug 22 associated with the carrier material 20 (shown disposed within the center of the microbubble 20). The catheter 12 is shown disposed within a blood vessel 24, such as an artery or vein.

[0055] To use the local drug delivery system 10, the catheter 12, having the carrier material 20 and the drug 22 disposed therein, is inserted into the blood vessel 24 in a conventional manner, and then the fluid pressure within the balloon portion 14 b is increased a sufficient amount so that the balloon portion 14 b is forced against the interior wall of the blood vessel 24 and so that the carrier material 20 with the drug 22 is forced out of the balloon portion 14 b through small holes (not shown) in the balloon portion 14 b. Consequently, due to the use of relatively high pressure, the carrier material 20 and the drug 22 will become embedded in the wall of the vessel 24 at the specific site or location of the balloon portion 14 b of the catheter 12.

[0056] The presence of the carrier material 20 (and the drug 22 within the carrier material 20) at that specific site can be verified by using the ultrasonic imaging system 16. When desired, the drug 22 can be administered to that specific site (by inducing release of the drug 22 from the carrier material 20) with the vibration generator 18 that generates vibrations of sufficient magnitude to collapse the microbubbles of the carrier material 20.

[0057] Although FIG. 3 separately illustrates the imaging system 16 and the vibration generator 18, a single ultrasonic system could be used for both functions, with a relatively low power of ultrasonic energy being used to image the microbubbles 20 and a relatively high power of ultrasonic energy to collapse the microbubbles 20 to induce release of the drug 22.

Second Embodiment

[0058] The previous embodiment illustrates binding a carrier material, like an ultrasonic contrast agent, such as a gas microbubble, to a drug to form an ultrasonic contrast agent-drug complex that can be administered to an individual. The complex is administered to an individual in a manner such that the complex is trapped by mechanical or biological mechanisms at a specific site in the individual, then ultrasound or another imaging technique is used to detect the complex at a site of entrapment. The drug can be released at the site of entrapment by disrupting the complex, e.g., disintegrating the microbubble, by increasing the power, or altering the frequency, of the ultrasound energy.

[0059] The embodiment disclosed above utilizes mechanical mechanisms to trap the complex at a specific target site. In particular, an intravascular catheter system forced the complex into a vessel wall, thus trapping the complex and permitting diagnostic imaging and therapeutic release of the drug at a predetermined target site. A simpler version of the first embodiment could utilize an intravascular catheter to deliver the drug containing particles of a size greater than capillaries to the target area and allow mechanical trapping of the particles in the capillaries. However, it has been found that other mechanisms, and particularly biochemical mechanisms, also can be used to trap the ultrasonic contrast agent-drug complex at a predetermined target site. Biochemical trapping mechanisms permit administration of the complex at a site different from the target site. The complex then can travel, and is trapped, and collected, at the predetermined target site.

[0060] The second embodiment provides a therapeutic delivery system for site-specific delivery of a therapeutic drug. The delivery system preferably utilizes an ultrasonic contrast agent comprising gas microbubbles. The microbubbles have a drug and optionally, a targeting agent associated with the microbubble to provide site-specific delivery. The drug can be embedded in the microbubble shell, encapsulated in the microbubbles, or bound to the surface of the microbubbles. The targeting agent is bound to the surface of the microbubble shell and can be, for example, a monoclonal antibody bound to the outer surface of the microbubble, a chemical or electrochemical linkage, or a compound that is known to bind to specific sites in an individual, e.g., albumin microcapsules are known to bind to the reticuloendothelial system. The complexes, therefore, use biological properties to trap the microbubbles, and, therefore, the drug, at a specific target site in an individual.

[0061] An ultrasonic contrast agent-drug complex having a targeting agent for site-specific delivery (for example, a monoclonal antibody to a glycogen IIa/IIB receptor and a drug, like streptokinase, bound to a microbubble shell) is injected into the body. The microbubbles travel through the body, and because the microbubble shells of the ultrasonic contrast agent contain a targeting agent, like a specific monoclonal antibody, the microbubbles collect at a site where antibodies to the targeting agent are present.

[0062] Using low energy ultrasound imaging, movement of the complex, and positioning of the complex at the predetermined target site, is monitored. Then the drug is released at the target site by using high energy ultrasound energy, or other techniques known in the art (e.g., electromagnetic or mechanical vibrations), to disrupt or disintegrate the microbubbles. Specifically, a site-specific therapeutic delivery system may be provided that comprises a carrier material, like an ultrasonic contrast agent (e.g., a microsphere containing a gas), a drug located in or on the shell of the microsphere, and a targeting agent, like an antibody for a specific site, bound to the shell.

[0063] An ultrasonic contrast agent-drug complex in accordance with the second embodiment is illustrated in FIG. 4. A complex 30 is a sphere having a core 32 comprising a gas. A shell 34 surrounds core 32 and has a surface 36. A drug can be incorporated into core 32, into shell 34, or bound to surface 36. A targeting agent is bound to surface 36 such that complex 30 can bind to a specific receptor site in the body and remain stationary for detection and for release of the drug. In practice, a plurality of targeting agents can be bound to surface 36 of complex 30. Complex 30 can be a microparticle, a microbubble, a microsphere, or a microcapsule.

[0064] Biochemical trapping of an ultrasonic contrast agent-drug complex is accomplished by incorporating a targeting agent into the complex. The targeting is selected such that the complex binds to a specific tissue or target site in the individual. The targeting agent can be, for example, a protein having an affinity to bind at the predetermined target site. The complex containing the drug, ultrasonic contrast agent, and targeting agent can be injected intravascularly, and the complex travels to and binds to, i.e., is trapped at, the predetermined target site by biochemical mechanisms.

[0065] After the complex has been trapped at the predetermined target site, the site may be ultrasonically imaged to confirm presence of the complex at the site. After imaging, or other diagnostic procedures, additional high gain or resonant frequency ultrasound energy is applied to the target site to induce microbubble rupture, and thereby release the drug (e.g., a thrombolytic drug carried to a site of vascular disruption).

[0066] Trapping of the complex by biochemical mechanisms is similar to the trapping of platelets along the endothelial surface within a blood vessel during periods of endothelial disruption (i.e., during periods of ischemia), wherein the initial attraction and trapping of the platelets in the endothelial lining is mediated by attraction of the glycoprotein Ib/IX complex along with the Von Willebrand's factor.

[0067] This is followed by spreading of platelets on the subendothelial matrix. Activation of platelets by collagen or other mediators, such as thrombin, leads to conformational changes in the integrin glycoprotein IIb/IIIa, and results in a second wave of platelet aggregation at the site of the subendothelial vascular wall disruption. This particular activation sequence is particularly well understood for thrombosis and ischemia.

[0068] Accordingly, the ultrasonic contrast agent-drug complex can be used to treat thrombosis or the effects of ischemia, and comprises: (a) a microbubble comprising a gas and shell, for example a protein shell, like an albumin shell, having (b) a targeting agent bound to the shell, for example an antibody, either glycoprotein Ib/IX with an autoantibody to Von Willebrand's factor, or, alternatively, to glycoprotein IIb/IIIc, and (c) a drug either bound to the shell or within the shell, for example a thrombolytic agent, like streptokinase or t-pa. Such a complex can be injected intravascularly, and the complex is biochemically trapped at a predetermined target site, for example, at a disrupted subendothelial ischemic vessel, at a thrombosis, or at a plaque rupture, where activated platelets are trapped and are aggregating.

[0069] The presence and accumulation of the complex at the predetermined target site can be monitored by ultrasound imaging techniques, and the drug, e.g., a thrombolytic drug, like streptokinase or t-pa, can be released by increasing the power, or altering the frequency, of the ultrasound energy.

[0070] In addition to treating vascular disruptions, the ultrasonic contrast agent-drug complexes can be used to deliver other types of therapeutic agents, for example drugs used in oncology and against infectious diseases. In oncologic applications, the targeting agent can be an antitumor antibody (e.g., hepatic cellular antibody) which is bound to the shell of the microbubble and the drug can be a chemotherapy agent (e.g., 5FU) bound to or within the microbubble shell. The complex is injected intravascularly, and can be detected by ultrasound imaging. Then, after identifying that the complex has accumulated at the target site, the ultrasound energy or frequency is increased, thus releasing the chemotherapy agent at the specific and predetermined target site.

[0071] In infectious disease applications, antibodies to white blood cells can be bound to the microbubble shell, and the complex can be introduced into the infected zone. Following the detection of an increased signal which indicates positioning of the complex at the target site, the drug is released at the site of infection by increasing the ultrasound energy or frequency to disrupt or disintegrate the microbubbles.

[0072] It should be understood that the drug used in the ultrasonic contrast agent-drug complex is not limited to a specific type of drug, like thrombolytic drugs, but can be any drug capable of binding to, or being encapsulated in, the microbubble shell. For example, if the microbubble shell comprises albumin, the following, nonlimiting list of drugs are known to have the capability of binding to albumin, and can be used as the drug of the ultrasonic contrast agent-drug complex: acebutolol, acetylsalicylic acid, 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, meziocillin, minocycline, morphine, moxalactam, nadolol, nafcillin, naproxen, nifedipine, nitrazepam, theopental, ticarcillin, timolol, tocainide, tolbutamide, tolmetin, triamterene, triazolam, trimethoprim, tubocurarine, valproic acid, verapamil, warfarin, protriptyline, pyrimethamine, quinidine, ranitidine, rifampin, salicylic acid, streptomycin, streptokinase, sulfadiazine, sulfamethoxazole, sulfisoxazole, ternazepam, terbutaline, tetracycline, theophylline, and tissue plasminogen activator (tpa).

[0073] Persons skilled in the art are aware of other drugs that are capable of binding to albumin, and similarly are aware, or can readily determine, drugs that are capable of binding to other materials comprising the microbubble shell. Similarly, persons skilled in the art are capable of selecting the proper targeting agent such that the complex is trapped at the predetermined target site.

[0074] With further respect to a complex useful for treating a vascular disruption, the complex can be prepared by initially treating the surface of an albumin microbubble with an autoantibody to glycoprotein IIb/IIa, then treating the surface with streptokinase. The resulting complex is injected intravascularly and trapped at sites of endothelial cell disruption. After injection, ultrasound images are obtained using a sufficiently low ultrasound energy to avoid destroying the trapped bubbles. After identifying the site specific placement of the complex, a high, continuously applied acoustic energy is used to destroy the microbubbles at the target site, and release the thrombolytic agent at the site of vascular cellular disruption.

[0075] Other methods also can be used to trap the ultrasonic contrast agent-drug complex in addition to using a protein. Nonlimiting examples include molecular adhesion and pharmacologic types of binding. For example, the surface glycoprotein from a plaque may be thin, as opposed to totally disrupted, and the microbubbles can be trapped.

[0076] It should be understood that introduction of the targeting agent and the drug onto the microbubble shell can be performed in sequence or simultaneously. In addition, introduction of the targeting agent and drug onto the microbubble shell can be performed after microbubble fabrication, before fabrication, or a combination thereof in order to provide a time release complex to position the targeting agent and drug on the outside, inside, or within the shell, or a combination thereof. The targeting agent and drug are bound to the microbubble shell by methods well known in the art.

[0077] In summary, the second embodiment is directed to methods for the controlled delivery of therapeutic compounds to specific target sites in an individual. The method comprises:

[0078] 1. administering an ultrasonic contrast agent-drug complex to an individual, wherein the complex comprises an ultrasonic contrast agent, a drug, and a targeting agent.

[0079] 2. monitoring the individual using ultrasound to determine an arrival and presence of the complex at a predetermined target site in the individual;

[0080] 3. rupturing the complex at the target site using high power ultrasound or other energy forms to release the drug at the target site; and

[0081] 4. imaging the target site using ultrasound techniques before, during, and after the release of the drug to monitor release of the drug.

[0082] The method steps, therefore, include:

[0083] 1. preparing an ultrasonic contrast agent-drug complex;

[0084] 2. introduction of the complex into an individual;

[0085] 3. imaging a specific target site by low energy ultrasound imaging (e.g., Doppler or harmonics) to monitor arrival and positioning of the complex at the target site;

[0086] 4. then applying sufficient energy to the target site to destroy the complex for delivery of the drug at the target site;

[0087] 5. then performing low energy ultrasound imaging to determine whether release of the drug has occurred (i.e., no contrast effect should be observed if the complex has been disintegrated); and

[0088] 6. modifying drug delivery and dosages by repeating the process.

[0089] Predetermined targeted sites include, for example, but are not limited to:

[0090] 1. a glycogen IIA/IIB receptor, which is located in all vessel walls, and which can be blocked by a glycogen IIA/IIB receptor blocker and be detected by a monoclonal antibody to the receptor. Generally, this method of detecting specific receptor sites is performed using monoclonal antibodies;

[0091] 2. specific electric or chemoelectrical methods that use positive or negative bindings;

[0092] 3. use of known biological characteristics to predict that the microbubbles will be trapped after administration into an individual, e.g., the liver for albumin microspheres; and

[0093] 4. fibrin and antithrombin can be targeted using antifibrin. In particular, if the antifibrin is bound to an albumin shell of a microbubble containing gas, the complex can be targeted to sites of atherosclerosis (atherosclerotic plaques).

EXAMPLE 4

[0094] To a solution (10 cc) containing 500 mg of human serum albumin is added 50 mg of tissue plasminogen activator. The mixture is sonicated for 30 seconds using a Heat Systems 450 watt sonicator. The microbubbles thus formed are allowed to float to the top of the vial. The majority of the albumin solution is drawn off with a syringe and is replaced with an equal volume of albumin solution (5%). The tissue plasminogen activator loaded microspheres are infused into the left atrium of a pig heart at a flow rate of 1 cc/min. The region is continuously imaged as described in example 1. The bubbles are destroyed by acoustic pressure greater than 0.05 Mpa. The amount of reflected ultrasound as observed by the video intensity of the region decreases with continued insonation indicating that the albumin microspheres are destroyed thus releasing the tissue plasminogen activator.

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US8440168 *Dec 19, 2008May 14, 2013The Board Of Regents Of The University Of Texas SystemImage-guided therapy of myocardial disease: composition, manufacturing and applications
US20060234960 *Mar 2, 2006Oct 19, 2006Zhongmin WangMethods and compositions for increasing the safety and efficacy of albumin-binding drugs
US20080058650 *Aug 30, 2007Mar 6, 2008Voyage Medical, Inc.Coronary sinus cannulation
US20090238756 *Dec 19, 2008Sep 24, 2009Yang David JImage-guided therapy of myocardial disease: composition, manufacturing and applications
US20090297567 *Aug 12, 2009Dec 3, 2009University Of Pittsburgh - Of The Commonwealth System Of Higher EducationMethod For Ultrasound Triggered Drug Delivery Using Hollow Microbubbles With Controlled Fragility
US20100113983 *Oct 31, 2008May 6, 2010Microsoft CorporationUtilizing ultrasound to disrupt pathogens
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WO2008131217A1 *Apr 18, 2008Oct 30, 2008Oregon Healty & Science UniverUltrasound imaging with targeted microbubbles
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Classifications
U.S. Classification424/9.2, 514/56, 514/26, 424/178.1, 514/54, 514/46, 514/200, 514/192, 514/263.32, 514/171, 514/2.3, 514/19.3, 514/14.7, 514/20.9, 514/13.6
International ClassificationA61K49/22, A61K47/48, A61K41/00, A61K38/16, A61K49/00
Cooperative ClassificationA61K41/00, A61K49/223, A61K47/48853
European ClassificationA61K41/00, A61K49/22P4, A61K47/48W8