Targeted drug activation

Details Targeted drug activation Targeted drug activation

2002-04-08

2003-06-10

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Capsules

C424S489000, C424S450000

Reexamination Certificate

active

06576257

ABSTRACT:

FIELD AND BACKGROUND OF THE INVENTION
The present invention relates to a targeted drug activation method and more particularly, to body region specific drug activation enabled via focused energy provided from at least two energy waves, such as, for example, ultrasound and shock waves.
The conventional methods of drug administration are the oral ingestion of tablets, capsules, liquid drug formulations, etc.; parenteral administration into the blood stream or tissues; and rectal suppository administration. Such methods are far from ideal, since they provide wide variations in plasma concentration of drugs at different times between dosages, ranging from ineffectively low concentrations to toxic levels at which harmful side effects can be experienced.
Moreover, such methods are essentially non-site specific, and deliver the drug to substantially all parts of the body and all body organs, not just the regions needing treatment by the drug. Such unfocused drug delivery subjects various body parts and organs to unneeded and oftentimes toxic substances and as such it can lead to unwanted side effects.
It has been well recognized in the medical field that one of the most effective ways to treat diseased tissues is to direct the drug treatment to the diseased area only. One particular form of drug therapy where localized action of the drug is important is cancer therapy. Drugs which are effective in attacking malignant cells, to limit their proliferation, have a tendency to attack benign cells as well, so that it is highly desirable to limit the location of their action to that of the malignancy, and to ensure that effective, but not excessive, amounts of such drugs are used, at any particular time, and further that other body-parts will not be affected by the drug.
Attempts to administer such drugs by direct injection into the location or organ having the malignancy are only partially effective. Oftentimes the malignant cells which can comprise a small fraction of a tumor mass reside deep within the tumor mass and as a result are poorly vascularized. Due to their scarcity and poor vascularization these cells are poorly targeted by a drug administered via a direct injection. Furthermore, diffusion and/or leakage of the drug from the injection site can also occur. As a result, the above limitations of direct drug injections dictate the administration of excessive quantities of the drug to effect treatment.
More effective methods for targeting drug release involve the use of prodrugs. A Prodrug constitutes a pharmaceutically inert compound or composition formed from a drug complexed with or formed within various biological carriers such as biopolymers. As such, the drug forming the prodrug can be released from the carrier by various mechanisms employed in or by selected body tissues to effect treatment.
The use of prodrugs in targeted drug therapy has been achieved to some extent by packaging or complexing the drug with biodegradable polymers or other molecules which can be placed at specific locations in the body and to effect a sustained/retarded release. In some cases slow release can be initiated by specific diseased body tissues which are characterized by distinct physiological environments typified by having a distinct pH or macromolecular content. Although some targeting of drugs via a controlled and timed release packaging can be effected, this method is still very limited in its targeting capabilities.
A more accurate and versatile method to direct and target drugs within the body is described in U.S. Pat. Nos. 4,801,459 and 5,190,761 and involves the application of directed electromagnetic radiation such as microwave or ultrasound for disrupting drug containing capsules, such as liposomes, in a specific area of the patient's body and as such to effect a localized release of the drug from the capsules.
Accordingly, other similar methods, which employ laser radiation, infrared radiation or ultrasound radiation to activate release from a drug carrying liposome have also been described (see U.S. Pat. Nos. 4,891,043; 5,470,582 and 4,898,734).
Photodynamic therapy (PDT), is another drug activation approach in which a light source, such as a laser is used for transforming an inactive photosensitive molecule into a free radical (see for example, U.S. Pat. Nos. 5,257,970; 4,649,151; 4,866,168 and 4,889,129).
Although the above described drug targeting methods improve drug targeting efficiency as compared to standard drug delivery methods, they still suffer from inherent limitations.
These prior art methods employ a single energy wave for drug activation and as such, the portion of the body through which the energy wave travels is exposed to a dose of energy sufficient for activating the drug. This exposes portions of the body which are not to be treated to the possible adverse effects of the drug. Thus, the use of such methods for targeting the release of cytotoxic drugs at small tumors is a virtual impossibility. This is especially true for liposome carrying drugs which are administered systematically. Due to the inherent instability of liposomes, an “unfocused” energy dose can activate release from a liposome carrying drug in a large portion of the patients body or in a major blood vessel, thus leading to a dispersed drug release and in the case of cytotoxic drugs, to severe side effects.
Furthermore, in cases where drug activation is effected by exposure to large doses of energy, such “unfocused” activation can lead to damage in regions of the body which are not to be treated.
There is thus a widely recognized need for, and it would be highly advantageous to have, a method for targeted drug activation devoid of the above limitation.
SUMMARY OF THE INVENTION
According to the present invention there is provided a method of providing a drug to a specific region of a patient's body, the method comprising the steps of: (a) administering to the patient a prodrug being convertible to the drug upon exposure to a predetermined dose of energy; and (b) irradiating the specific region of the body with at least two energy waves, each being provided from a different direction, thereby generating the predetermined dose of energy in the specific region of the body and converting the prodrug into the drug therein.
According to still another aspect of the present invention there is provided a method of treating a tumor in a specific region of a human body comprising the steps of: (a) administering to the patient a prodrug being convertible to a drug having cytotoxic activity upon exposure to a predetermined dose of energy; and (b) irradiating the specific region of the body with at least two energy waves, each being provided from a different direction, thereby generating the predetermined dose of energy in the specific region of the body and converting the prodrug into the drug therein.
According to further features in preferred embodiments of the invention described below, the drug is selected from the group consisting of fluorouracil, cisplatinum, vinblastin, an anthracycline analogue and doxorubicin.
According to further features in the described preferred embodiments the at least two energy waves converge upon the specific region of the body.
According to still further features in the described preferred embodiments the at least two energy waves cross one another at a location within the specific region of the body.
According to still further features in the described preferred embodiments the specific region of the body is sequentially irradiated with the at least two energy waves.
According to still further features in the described preferred embodiments the specific region of the body is simultaneously irradiated with the at least two energy waves.
According to still further features in the described preferred embodiments each of the at least two energy waves delivers an energy dose to the specific region of the body which is below the predetermined dose of energy required for converting the prodrug into the drug.
According to still further features in the described preferred embodim

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