U.S. patent application number 11/008638 was filed with the patent office on 2005-06-16 for combination therapy including 9-nitro-20(s)-camptothecin.
Invention is credited to Rubinfeld, Joseph.
Application Number | 20050130882 11/008638 |
Document ID | / |
Family ID | 23659848 |
Filed Date | 2005-06-16 |
United States Patent
Application |
20050130882 |
Kind Code |
A1 |
Rubinfeld, Joseph |
June 16, 2005 |
Combination therapy including 9-nitro-20(S)-camptothecin
Abstract
A method for treating a patient having a disease associated with
undesirable or uncontrolled cell proliferation such as cancer and
restenosis is provided. The method comprises: delivering to the
patient a therapeutically effective amount of
9-nitro-20(S)-camptothecin in combination with an effective amount
of an antimetabolite such as 5-fluorouracil.
Inventors: |
Rubinfeld, Joseph;
(Danville, CA) |
Correspondence
Address: |
WILSON SONSINI GOODRICH & ROSATI
650 PAGE MILL ROAD
PALO ALTO
CA
943041050
|
Family ID: |
23659848 |
Appl. No.: |
11/008638 |
Filed: |
December 8, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11008638 |
Dec 8, 2004 |
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10074575 |
Feb 11, 2002 |
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10074575 |
Feb 11, 2002 |
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09709967 |
Nov 10, 2000 |
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6664233 |
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09709967 |
Nov 10, 2000 |
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09418862 |
Oct 15, 1999 |
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6191119 |
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Current U.S.
Class: |
514/283 ;
514/109; 514/19.3; 514/251; 514/27; 514/3.1; 514/34; 514/410;
514/49 |
Current CPC
Class: |
A61K 31/70 20130101;
A61K 31/4745 20130101; A61K 31/44 20130101; A61K 31/4745 20130101;
A61K 31/44 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 45/06 20130101; A61K 2300/00 20130101; A61K 31/70 20130101;
A61P 35/00 20180101 |
Class at
Publication: |
514/008 ;
514/027; 514/049; 514/034; 514/283; 514/410; 514/109; 514/251 |
International
Class: |
A61K 038/16; A61K
031/7072; A61K 031/7048; A61K 031/704; A61K 031/4745; A61K 031/407;
A61K 031/525 |
Claims
What is claimed is:
1. A pharmaceutical composition having therapeutic synergy
comprising: 20(S) camptothecin, an analog of 20(S) camptothecin, or
a derivative of 20(S) camptothecin; and at least one of an
alkylating agent, epidophyllotoxin, antimetabolite, antibiotic or
vinca alkaloid.
2. A pharmaceutical composition according to claim 1, wherein the
alkylating agent is cyclophosphamide, ifosfamide, melphalan,
hexamethylmelamine, thiotepa or dacarbazine.
3. A pharmaceutical composition according to claim 1, wherein the
antimetabolite is 5-fluorouracil, cytarabine or a folic acid
analog.
4. A pharmaceutical composition according to claim 1, wherein the
antibiotic is daunorubicine, doxorubicin, bleomycin or
mitomycin.
5. A pharmaceutical composition according to claim 1, wherein the
vinca alkaloid is vinblastine, vincristine, or their synthetic
analogues.
6. A pharmaceutical composition according to claim 1, wherein the
epidophyllotoxin is etoposide or teniposide.
7. A pharmaceutical composition according to claim 1, wherein said
composition is useful in the treatment of neoplastic diseases.
8. A pharmaceutical composition according to claim 1, wherein the
20(S) camptothecin is 9 amino 20(S) camptothecin.
9. A pharmaceutical composition according to claim 1, wherein the
20(S) camptothecin is 9 nitro 20(S) camptothecin.
10. A method for treating disease comprising: delivering to a
patient in need of treatment a therapeutically effective amount of
20(S) camptothecin, an analog of 20(S) camptothecin, or a
derivative of 20(S) camptothecin in combination with an effective
amount of at least one of an alkylating agent, epidophyllotoxin,
antimetabolite, antibiotic or vinca alkaloid.
11. A method according to claim 10, wherein the alkylating agent is
cyclophosphamide, ifosfamide, melphalan, hexamethylmelamine,
thiotepa or dacarbazine.
12. A method according to claim 10, wherein the antimetabolite is
5-fluorouracil, cytarabine or a folic acid analog.
13. A method according to claim 10, wherein the antibiotic is
daunorubicine, doxorubicin, bleomycin or mitomycin.
14. A method according to claim 10, wherein the vinca alkaloid is
vinblastine, vincristine, or their synthetic analogues.
15. A method according to claim 10, wherein the epidophyllotoxin is
etoposide or teniposide.
16. A method according to claim 10, wherein said composition is
useful in the treatment of neoplastic diseases.
17. A method according to claim 10, wherein the 20(S) camptothecin
is 9 amino 20(S) camptothecin.
18. A method according to claim 10, wherein the 20(S) camptothecin
is 9 nitro 20(S) camptothecin.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. application Ser.
No. 10/074,575, filed Feb. 11, 2002, which a continuation of U.S.
application Ser. No. 09/709,967, filed Nov. 10, 2000, which is a
continuation of U.S. patent application Ser. No. 09/418,862, filed
Oct. 15, 1999. These applications are incorporated herein by
reference in its entirety and to which application we claim
priority under 35 USC .sctn. 120.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to a method for treating disease
using a camptothecin, and more specifically a method for treating
disease using a camptothecin in combination with another drug.
[0004] 2. Description of Related Art
[0005] 20(S)-camptothecin, a plant alkaloid, was found to have
anticancer activity in the late 1950's. Wall, M. et al., Plant
antitumor agents. I. The isolation and structure of camptothecin, a
novel alkaloidal leukemia and tumor inhibitor from Camptotheca
acuminata, J. Am. Chem. Soc. 88: 3888 3890, (1966); Monroe E. Wall
et al., Camptothecin: Discovery to Clinic, 803 Annals of the New
York Academy of Sciences 1 (1996). These documents, and all
documents (articles, patents, etc.) cited to herein, are
incorporated by reference into the specification as if reproduced
fully below. The chemical formula of camptothecin was determined to
be C.sub.20H.sub.16N.sub.2O.sub.4.
[0006] 20(S)-camptothecin itself is insoluble in water. However,
during the sixties and seventies the sodium salt of
20(S)-camptothecin was derived from 20(S)-camptothecin through
opening of the lactone ring using a mild base. Clinical trials were
then conducted using this hydrosoluble, sodium salt derivative of
20(S)-camptothecin (20(S)-camptothecin Na.sup.+), which was
administered intravenously. The studies were later abandoned
because of the high toxicity and low potency of 20(S)-camptothecin
Na.sup.+. Gottlieb, J. A., et al., Preliminary pharmacological and
clinical evaluation of camptothecin sodium salt (NSC 100880),
Cancer Chemother. Rep. 54:461 470 (1979); Muggia, F. M., et al.,
Phase I clinical trials of weekly and daily treatment with
camptothecin (NSC 100880): Correlation with clinical studies,
Cancer Chemother. Rep. 56:515 521 (1972); Gottlieb, J. A. et al.,
Treatment of malignant melanoma with camptothecin (NSC 100880),
Cancer Chemother. Rep. 56:103 105 (1972); and Moertel, C. G., et
al., Phase II study of camptothecin (NSC 100880) in the treatment
of advanced gastrointestinal cancer, Cancer Chemother Rep. 56:95
101 (1972).
[0007] Despite its potential, interest in 20(S)-camptothecin as a
therapeutic remained at a low ebb until the mid 1980's. By that
time, drug therapies were being evaluated for treating human cancer
using human cancer xenograft lines. During these evaluations, human
tumors are serially heterotransplanted into immunodeficient, so
called "nude" mice, and the mice then tested for their
responsiveness to a specific drug. (Giovanella, B. C., et al.,
Cancer 52(7): 1146 (1983)). The data obtained in these studies
strongly support the validity of heterotransplanted human tumors
into immunodeficient mammals, such as nude mice, as a predictive
model for testing the effectiveness of anticancer agents.
[0008] 20(S)-camptothecin, and later some of its substituted forms,
elicited differential responses in the cell cycle of nontumorigenic
and tumorigenic human cells in vitro. Although it is not yet
understood why 20(S)-camptothecin and some of its substituted forms
are cytostatic for nontumorigenic cells and cytotoxic for
tumorigenic cells, the selective toxicity of the compounds against
tumorigenic cells in vitro and in vivo was an especially
interesting feature of these drugs.
[0009] Investigators began to experiment with various substituted
forms of 20(S)-camptothecin. Good activity was found when various
substitutions were made to the 20(S)-camptothecin scaffold. For
example, 9 Amino 20(S) Camptothecin (9AC) and 10,11 Methylendioxy
20(S) Camptothecin (10,11 MD) are capable of having high anticancer
activity against human colon cancer xenografts. Giovanella, B. C.,
et al., Highly effective topoisomerase 1 targeted chemotherapy of
human colon cancer in xenografts, Science 246:1046 1048 (1989).
[0010] Additionally, 9 nitrocamptothecin (9NC) has shown high
activity against human tumor xenograft models. 9NC has a nine
position hydrogen substituted with a nitro moiety. 9NC has
inhibited the growth of human tumor xenografts in immunodeficient
nude mice and has induced regression of human tumors established as
xenografts in nude mice with little or no appearance of any
measurable toxicity. D. Chatteijee et al., Induction of Apoptosis
in Malignant and Camptothecin resistant Human Cells, 803 Annals of
the New York Academy of Sciences 143 (1996).
[0011] U.S. Pat. No. 5,552,154 to Giovanella et al. disclosed
methods of treating specific forms of cancer with water insoluble
20(S) camptothecin and derivatives thereof, having the closed
lactone ring intact. In particular, transdermal, oral and
intramuscular methods of administration using solutions of water
insoluble 20(S) camptothecin were disclosed.
[0012] Other substituted 20(S)-camptothecin compounds that have
shown promise include 7 ethyl 10 hydroxy 20(S)-camptothecin, and
other 7, 9, 10, 11 substituted compounds.
[0013] A continuing need exists to develop new and improved ways to
exploit the useful therapeutic activities of 20(S)-camptothecin and
its various derivatives and analogs.
SUMMARY OF THE INVENTION
[0014] The present invention relates to new and improved
compositions, kits, and methods for treating diseases using a
combination therapy which includes 20(S) camptothecin, an analog or
20(S) camptothecin, or a derivative of 20(S) camptothecin,
collectively referred to herein as CPT. A therapeutic agent which
exhibits a therapeutic synergistic effect with CPT is employed in
the therapy.
[0015] A wide variety of non CPT therapeutic agents with
therapeutic synergistic effects with CPT may be employed. Examples
of such non CPT therapeutic agents include, but are not limited to
alkylating agents, epidophyllotoxins, antimetabolites, antibiotics,
and vinca alkaloids. Examples of alkylating agents include, but are
not limited to cyclophosphamide, ifosfamide, melphalan,
hexamethylmelamine, thiotepa and dacarbazine. Examples of
antimetabolites include, but are not limited to 5-fluorouracil,
cytarabine and folic acid analogs. Examples of folic acid analogs
include, but are not limited to methotrexate, idatrexate or
trimetrexate. Examples of antibiotics include, but are not limited
to daunorubicine, doxorubicin, bleomycin or mitomycin. Examples of
vinca alkaloids include, but are not limited to vinblastine,
vincristine, and their synthetic analogues. Examples of
epidophyllotoxin include, but are not limited to etoposide and
teniposide.
[0016] The method may be used to treat a wide variety of diseases
for which CPT has therapeutic activity. In one embodiment, the
combination therapy methods and compositions of the present
invention are useful in the treatment of neoplastic diseases.
DETAILED DESCRIPTION OF THE INVENTION
[0017] 1. Camptothecin Compounds (CPT)
[0018] The class of camptothecin compounds referred to herein as
CPT include various 20(S) camptothecins, analogs of 20(S)
camptothecin, and derivatives of 20(S) camptothecin. Camptothecin,
when used in the context of this invention, includes the plant
alkaloid 20(S) camptothecin, both substituted and unsubstituted
camptothecins, and analogs thereof. Examples of camptothecin
derivatives include, but are not limited to, 9 nitro 20(S)
camptothecin, 9 amino 20(S) camptothecin, 9 methyl camptothecin, 9
chloro camptothecin, 9 flouro camptothecin, 7 ethyl camptothecin,
10 methyl camptothecin, 10 chloro camptothecin, 10 bromo
camptothecin, 10 fluoro camptothecin, 9 methoxy camptothecin, 11
fluoro camptothecin, 7 ethyl 10 hydroxy camptothecin, 10,11
methylenedioxy camptothecin, and 10,11 ethylenedioxy camptothecin,
and 7 (4 methylpiperazinomethylene) 10,11 methylenedioxy
camptothecin. Prodrugs of camptothecin include, but are not limited
to, esterified camptothecin derivatives as decribed in U.S. Pat.
No. 5,731,316, such as camptothecin 20 O propionate, camptothecin
20 O butyrate, camptothecin 20 O valerate, camptothecin 20 O
heptanoate, camptothecin 20 O nonanoate, camptothecin 20 O
crotonate, camptothecin 20 O 2',3' epoxy butyrate,
nitrocamptothecin 20 O acetate, nitrocamptothecin 20 O propionate,
and nitrocamptothecin 20 O butyrate.
[0019] In particular, when substituted camptothecins are used, a
large range of substitutions may be made to the camptothecin
scaffold, while still retaining activity. In a preferable
embodiment, the camptothecin scaffold is substituted at the 7, 9,
10, 11, and/or 12 positions. Such preferable substitutions may
serve to provide differential activities over the unsubstituted
camptothecin compound. Especially preferable are 9
nitrocamptothecin, 9 aminocamptothecin, 10,11 methylendioxy 20(S)
camptothecin, topotecan, irinotecan, 7 ethyl 10 hydroxy
camptothecin, or another substituted camptothecin that is
substituted at least one of the 7, 9, 10, 11, or 12 positions.
[0020] Native, unsubstituted, camptothecin can be obtained by
purification of the natural extract, or may be obtained from the
Stehlin Foundation for Cancer Research (Houston, Tex.). Substituted
camptothecins can be obtained using methods known in the
literature, or can be obtained from commercial suppliers. For
example, 9 nitrocamptothecin may be obtained from SuperGen, Inc.
(San Ramon, Calif.), and 9 aminocamptothecin may be obtained from
Idec Pharmaceuticals (San Diego, Calif.). Camptothecin and various
of its analogs may also be obtained from standard fine chemical
supply houses, such as Sigma Chemicals.
[0021] Particular examples of 20(S) camptothecins include 9
nitrocamptothecin, 9 aminocamptothecin, 10,11 methylendioxy 20(S)
camptothecin, topotecan, irinotecan, 7 ethyl 10 hydroxy
camptothecin, or another substituted camptothecin that is
substituted at least one of the 7, 9, 10, 11, or 12 positions.
These camptothecins may optionally be substituted.
[0022] 2. Non CPT Therapeutic Agents
[0023] A wide variety non CPT therapeutic agents may have a
therapeutic synergistic effect with CPT. Examples of such non CPT
therapeutic agents include but are not limited to alkylating
agents, epidophyllotoxins, antimetabolites, and vinca alkaloids.
Examples of alkylating agents include, but are not limited to
cyclophosphamide, diethylnitroamine, ifosfamide, melphalan,
hexamethylmelamine, thiotepa and dacarbazine. Examples of
antimetabolites include, but are not limited to 5-fluorouracil,
cytarabine and folic acid analogs. Examples of folic acid analogs
include, but are not limited to methotrexate, idatrexate or
trimetrexate. Examples of antibiotics include, but are not limited
to daunorubicine, doxorubicin, bleomycin or mitomycin. Examples of
vinca alkaloids include, but are not limited to vinblastine,
vincristine, and their synthetic analogues. Examples of
epidophyllotoxin include, but are not limited to etoposide and
teniposide.
[0024] 3. Indications for Combination Therapy
[0025] Preferable indications that may be treated using the
combination therapies of the present invention include those
involving undesirable or uncontrolled cell proliferation. Such
indications include restenosis, benign tumors, a various types of
cancers such as primary tumors and tumor metastasis, abnormal
stimulation of endothelial cells (atherosclerosis), insults to body
tissue due to surgery, abnormal wound healing, abnormal
angiogenesis, diseases that produce fibrosis of tissue, repetitive
motion disorders, disorders of tissues that are not highly
vascularized, and proliferative responses associated with organ
transplants.
[0026] Specific types of restenotic lesions that can be treated
using the present invention include coronary, carotid, and cerebral
lesions. Specific types of benign tumors that can be treated using
the present invention include hemangiomas, acoustic neuromas,
neurofibroma, trachomas and pyogenic granulomas. Specific types of
cancers that can be treated using this invention include acute
myelogenous leukemia, bladder, breast, cervical,
cholangiocarcinoma, chronic myelogenous leukemia, colorectal,
gastric sarcoma, glioma, leukemia, lung, lymphoma, melanoma,
multiple myeloma, osteosarcoma, ovarian, pancreatic, prostrate,
stomach, or tumors at localized sites including inoperable tumors
or in tumors where localized treatment of tumors would be
beneficial, and solid tumors. In a more preferable embodiment, the
types of cancer include pancreatic, and/or colorectal. Treatment of
cell proliferation due to insults to body tissue during surgery may
be possible for a variety of surgical procedures, including joint
surgery, bowel surgery, and cheloid scarring. Diseases that produce
fibrotic tissue include emphysema. Repetitive motion disorders that
may be treated using the present invention include carpal tunnel
syndrome. An example of cell proliferative disorders that may be
treated using the invention is a bone tumor.
[0027] Abnormal angiogenesis that may be may be treated using this
invention include those abnormal angiogenesis accompanying
rheumatoid arthritis, psoriasis, diabetic retinopaphy, and other
ocular angiogenic diseases such as retinopathy of prematurity
(retrolental fibroplastic), macular degeneration, corneal graft
rejection, neuroscular glaucoma and Oster Webber syndrome.
[0028] The proliferative responses associated with organ
transplantation that may be treated using this invention include
those proliferative responses contributing to potential organ
rejections or associated complications. Specifically, these
proliferative responses may occur during transplantation of the
heart, lung, liver, kidney, and other body organs or organ
systems.
[0029] 4. Compositions, Formulations, and Kits
[0030] Compositions according to the present invention might
include a CPT, a non CPT therapeutic agent, together with a
pharmaceutical excipient. The composition preferably have a
therapeutic synergy in the treatment of a disease, or a synergistic
effect on the subjected being treated. As used herein, a
synergistic effect is achieved when a greater therapeutic effect
results with a combination therapy than using either drug or
monotherapy alone. One advantage of combination therapy with a
synergistic effect is that lower dosages of one or both of the
drugs or therapies may be used so that the therapeutic index is
increased and toxic side effects are reduced.
[0031] In an aspect, the invention is directed to kits comprising a
container that contains the compound. In another aspect, the
invention is directed to the kits, wherein the camptothecin is
[0032] 9 nitrocamptothecin, or 9 aminocamptothecin. In still
another aspect, the invention is directed to the kits, wherein the
lactone ring protecting moiety is a polyalkylene oxide, dextran,
polyvinyl alcohol, carbohydrate polymer, an antibody,
streptozoticin or derivatives or mixtures thereof.
[0033] In still another aspect, the invention is directed to the
kits, wherein the polyalkylene oxide is a polyethylene glycol.
[0034] In still another aspect, the invention is directed to kits
comprising a container that contains the composition. In still
another aspect, the invention is directed to the kits, wherein the
camptothecin is 9 nitrocamptothecin, or 9 aminocamptothecin. In
another aspect, the invention is directed to the kits, wherein the
lactone ring protecting moiety is a polyalkylene oxide, dextran,
polyvinyl alcohol, carbohydrate polymer, an antibody,
streptozoticin or derivatives or mixtures thereof.
[0035] In still another aspect, the invention is directed to the
kits, wherein the polyalkylene oxide is a polyethylene glycol.
[0036] 5. Delivery of Therapeutic Agents
[0037] A wide variety of delivery methods and formulations for
different delivery methods are intended to be encompassed by the
combination therapies of the present invention.
[0038] The inventive combination of therapeutic agents may be
administered as compositions that comprise the inventive
combination of therapeutic agents. Such compositions may include,
in addition to the inventive combination of therapeutic agents,
conventional pharmaceutical excipients, and other conventional,
pharmaceutically inactive agents. Additionally, the compositions
may include active agents in addition to the inventive combination
of therapeutic agents. These additional active agents may include
additional compounds according to the invention, or one or more
other pharmaceutically active agents. In preferable embodiments,
the inventive compositions will contain the active agents,
including the inventive combination of therapeutic agents, in an
amount effective to treat an indication of interest.
[0039] The inventive combination of therapeutic agents and/or
compositions may be administered or coadministered orally,
parenterally, intraperitoneally, intravenously, intraarterially,
transdermally, sublingually, intramuscularly, rectally,
transbuccally, intranasally, liposomally, via inhalation,
vaginally, intraoccularly, via local delivery (for example by
catheter or stent), subcutaneously, intraadiposally,
intraarticularly, or intrathecally. The compounds and/or
compositions according to the invention may also be administered or
coadministered in slow release dosage forms.
[0040] The inventive combination of therapeutic agents and
compositions may be administered by a variety of routes, and may be
administered or coadministered in any conventional dosage form.
Coadministration in the context of this invention is defined to
mean the administration of more than one therapeutic in the course
of a coordinated treatment to achieve an improved clinical outcome.
Such coadministration may also be coextensive, that is, occurring
during overlapping periods of time.
[0041] One therapeutically interesting route of administration or
coadministration is local delivery. Local delivery of inhibitory
amounts of inventive combination of therapeutic agents and/or
compositions can be by a variety of techniques and structures that
administer the inventive combination of therapeutic agents and/or
compositions at or near a desired site. Examples of local delivery
techniques and structures are not intended to be limiting but
rather as illustrative of the techniques and structures available.
Examples include local delivery catheters, site specific carriers,
implants, direct injection, or direct applications.
[0042] Local delivery by a catheter allows the administration of a
inventive combination of therapeutic agents and/or compositions
directly to the desired site. Examples of local delivery using a
balloon catheter are described in EP 383 492 A2 and U.S. Pat. No.
4,636,195 to Wolinsky. Additional examples of local, catheter based
techniques and structures are disclosed in U.S. Pat. No. 5,049,132
to Shaffer et al. and U.S. Pat No. 5,286,254 to Shapland et al.
[0043] Generally, the catheter must be placed such that the
inventive combination of therapeutic agents s and/or compositions
can be delivered at or near the desired site. Dosages delivered
through the catheter can vary, according to determinations made by
one of skill, but often are in amounts effective to create a
cytotoxic or cytostatic effect at the desired site. Preferably,
these total amounts are less than the total amounts for systemic
administration of the inventive combination of therapeutic agents
and/or compositions, and are less than the maximum tolerated dose.
The inventive combination of therapeutic agents s and/or
compositions delivered through catheters preferably should be
formulated to a viscosity that enables delivery through a small
treatment catheter, and may be formulated with pharmaceutically
acceptable additional ingredients (active and inactive).
[0044] Local delivery by an implant describes the placement of a
matrix that contains the inventive combination of therapeutic
agents s and/or compositions into the desired site. The implant may
be deposited by surgery or other means. The implanted matrix
releases the inventive combination of therapeutic agents s and/or
compositions by diffusion, chemical reaction, solvent activators,
or other equivalent mechanisms. Examples are set forth in Lange,
Science 249:1527 1533 (September, 1990). Often the implants may be
in a form that releases the inventive combination of therapeutic
agents s and/or compositions over time; these implants are termed
time release implants. The material of construction for the
implants will vary according to the nature of the implant and the
specific use to which it will be put. For example, biostable
implants may have a rigid or semi rigid support structure, with
inventive combination of therapeutic agents and/or composition
delivery taking place through a coating or a porous support
structure. Other implants made be made of a liquid that stiffens
after being implanted or may be made of a gel. The amounts of
inventive combination of therapeutic agents and/or composition
present in or on the implant may be in an amount effective to treat
cell proliferation generally, or a specific proliferation
indication, such as the indications discussed herein.
[0045] One example of local delivery of the inventive combination
of therapeutic agents and/or composition by an implant is use of a
biostable or bioabsorbable plug or patch or similar geometry that
can deliver the inventive combination of therapeutic agents and/or
composition once placed in or near the desired site. An example of
such implants can be found in U.S. Pat. No. 5,429,634 to Narciso,
Jr.
[0046] A particular application of use of an implant according to
the invention is treatment of cell proliferation in tissue that is
not highly vascularized, as discussed briefly above. An example of
such tissue is bone tissue. The difficulty in treating uncontrolled
proliferative cell growth in bone tissue may be exemplified by the
difficulties in treating bone tumors. Such tumors are typically
refractory to treatment, in part because bone tissue is not highly
vascularized. An implant in or near the proliferative site may
potentially have localized cytotoxic or cytostatic effects with
regard to the proliferative site. Therefore, in one embodiment, the
invention may be used to treat bone tumors.
[0047] Another example of local delivery by an implant is the use
of a stent. Stents are designed to mechanically prevent the
collapse and reocclusion of the coronary arteries. Incorporating an
inventive combination of therapeutic agents and/or composition into
the stent may deliver the agent directly to or near the
proliferative site. Certain aspects of local delivery by such
techniques and structures are described in Kohn, Pharmaceutical
Technology (October, 1990). Stents may be coated with the inventive
combination of therapeutic agents and/or composition to be
delivered. Examples of such techniques and structures may be found
in U.S. Pat. No. 5,464,650 to Berg et al., U.S. Pat. No. 5,545,208
to Wolff et al., U.S. Pat. No. 5,649,977 to Campbell, U.S. Pat. No.
5,679,400 to Tuch, EP 0 716 836 to Tartaglia et al. Alternatively,
the inventive combination of therapeutic agents and/or composition
loaded stent may be biorotable, i.e. designed to dissolve, thus
releasing the inventive combination of therapeutic agents and/or
composition in or near the desired site, as disclosed in U.S. Pat.
No. 5,527,337 to Stack et al. The present invention can be used
with a wide variety of stent configurations, including, but not
limited to shape memory alloy stents, expandable stents, and stents
formed in situ.
[0048] Amounts of the inventive combination of therapeutic agents
and/or composition delivered by the stent can vary, according to
determinations made by one of skill, but preferably are in amounts
effective to create a cytotoxic or cytostatic effect at the desired
site. Preferably, these total amounts are less than the total
amounts for systemic administration of the inventive combination of
therapeutic agents and/or composition, and are preferably less than
the maximum tolerated dose. Appropriate release times can vary, but
preferably should last from about 1 hour to about 6 months, most
preferably from about 1 week to about 4 weeks. Formulations
including the inventive combination of therapeutic agents and/or
composition for delivery of the agent via the stent can vary, as
determinable by one of skill, according to the particular
situation, and as generally taught herein.
[0049] Another example is a delivery system in which a polymer that
contains the inventive combination of therapeutic agents and/or
composition is injected into the target cells in liquid form. The
polymer then cures to form the implant in situ. One variation of
this technique and structure is described in WO 90/03768 to
Donn.
[0050] Another example is the delivery of the inventive combination
of therapeutic agents and/or composition by polymeric endoluminal
sealing. This technique and structure uses a catheter to apply a
polymeric implant to the interior surface of the lumen. The
inventive combination of therapeutic agents and/or composition
incorporated into the biodegradable polymer implant is thereby
released at the desired site. One example of this technique and
structure is described in WO 90/01969 to Schindler.
[0051] Another example of local delivery by an implant is by direct
injection of vesicles or microparticulates into the desired site.
These microparticulates may comprise substances such as proteins,
lipids, carbohydrates or synthetic polymers. These
microparticulates have the inventive combination of therapeutic
agents and/or composition incorporated throughout the microparticle
or over the microparticle as a coating. Examples of delivery
systems incorporating microparticulates are described in Lange,
Science, 249:1527 1533 (September, 1990) and Mathiowitz, et al., J.
App. Poly Sci. 26:809 (1981).
[0052] Local delivery by site specific carriers describes attaching
the inventive combination of therapeutic agents and/or composition
to a carrier which will direct the drug to the desired site.
Examples of this delivery technique and structure include the use
of carriers such as a protein ligand or a monoclonal antibody.
Certain aspects of these techniques and structures are described in
Lange, Science 249:1527 1533.
[0053] Local delivery also includes the use of topical
applications. An example of a local delivery by topical application
is applying the inventive combination of therapeutic agents and/or
composition directly to an arterial bypass graft during a surgical
procedure. Other equivalent examples will no doubt occur to one of
skill in the art.
[0054] The inventive combination of therapeutic agents s and/or
compositions may be used in the form of kits. The arrangement and
construction of such kits is conventionally known to one of skill
in the art. Such kits may include containers for containing the
inventive combination of therapeutic agents s and/or compositions,
and/or other apparatus for administering the inventive combination
of therapeutic agents and/or compositions.
[0055] It will be apparent to those skilled in the art that various
modifications and variations can be made in the compounds,
compositions, kits, and methods of the present invention without
departing from the spirit or scope of the invention. Thus, it is
intended that the present invention cover the modifications and
variations of this invention provided they come within the scope of
the appended claims and their equivalents.
* * * * *