U.S. patent application number 12/051782 was filed with the patent office on 2009-02-19 for methods and formulations for the delivery of pharmacologically active agents.
Invention is credited to Neil P. Desai, Patrick SOON-SHIONG.
Application Number | 20090048331 12/051782 |
Document ID | / |
Family ID | 26697503 |
Filed Date | 2009-02-19 |
United States Patent
Application |
20090048331 |
Kind Code |
A1 |
SOON-SHIONG; Patrick ; et
al. |
February 19, 2009 |
METHODS AND FORMULATIONS FOR THE DELIVERY OF PHARMACOLOGICALLY
ACTIVE AGENTS
Abstract
In accordance with the present invention, novel formulations
have been developed which are much more effective for the delivery
of hydrophobic drugs to patients in need thereof than are prior art
formulations. Invention formulations are capable of delivering more
drug in shorter periods of time, with reduced side effects caused
by the pharmaceutical carrier employed for delivery.
Inventors: |
SOON-SHIONG; Patrick; (Los
Angeles, CA) ; Desai; Neil P.; (Los Angeles,
CA) |
Correspondence
Address: |
MORRISON & FOERSTER LLP
755 PAGE MILL RD
PALO ALTO
CA
94304-1018
US
|
Family ID: |
26697503 |
Appl. No.: |
12/051782 |
Filed: |
March 19, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11240940 |
Sep 29, 2005 |
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12051782 |
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10146706 |
May 14, 2002 |
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11240940 |
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09628388 |
Aug 1, 2000 |
6506405 |
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10146706 |
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08926155 |
Sep 9, 1997 |
6096331 |
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09628388 |
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08720756 |
Oct 1, 1996 |
5916596 |
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08926155 |
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08485448 |
Jun 7, 1995 |
5665382 |
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08720756 |
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08200235 |
Feb 22, 1994 |
5498421 |
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08485448 |
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08023698 |
Feb 22, 1993 |
5439686 |
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08200235 |
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08035150 |
Mar 26, 1993 |
5362478 |
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08023698 |
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Current U.S.
Class: |
514/449 |
Current CPC
Class: |
A61K 49/126 20130101;
A61K 49/222 20130101; A61K 49/1863 20130101; A23L 33/40 20160801;
A61K 49/18 20130101; A61K 49/226 20130101; A61K 9/0026 20130101;
A61K 9/5052 20130101; A61K 47/6927 20170801; A61K 49/223 20130101;
A61K 9/5146 20130101; A61K 47/6925 20170801; A61K 9/5138 20130101;
A61K 49/1818 20130101; B82Y 5/00 20130101; A61K 9/5169 20130101;
A61K 9/5161 20130101 |
Class at
Publication: |
514/449 |
International
Class: |
A61K 31/337 20060101
A61K031/337 |
Claims
1. A formulation comprising a substantially water insoluble
pharmacologically active agent and a pharmaceutically acceptable
carrier which is free of micelle-forming components, wherein said
formulation is characterized by one or more of the following:
wherein said formulation provides a higher concentration of said
agent in the cellular compartment than a formulation of the same
agent with a micelle-forming component; wherein said formulation
provides increased infra-cellular availability of said agent
relative to a formulation of the same agent with a micelle-forming
component; wherein said formulation provides prolonged activity of
said agent relative to a formulation of the same agent with a
micelle-forming component; wherein said formulation facilitates
delivery of said agent to red blood cells, relative to delivery of
said agent to red blood cells by a formulation comprising the same
agent and a carrier containing micelle-forming components; wherein
said formulation releases a portion of said agent contained therein
to the lipid membrane of a cell; wherein said formulation provides
reduced levels of said agent in the bloodstream relative to a
formulation of the same agent with a micelle-forming component;
wherein said formulation delivers said agent to the bloodstream
over an extended period of time relative to a formulation of the
same agent with a micelle-forming component; wherein the rate of
metabolism of said agent in said formulation is reduced relative to
the rate of metabolism of said agent in a formulation with a
micelle-forming component; wherein said agent has a longer half
life in said formulation relative to the half life of said agent in
a formulation with a micelle-forming component; wherein said
formulation provides a higher red blood cell/plasma ratio of said
agent than does a formulation of the same agent with a
micelle-forming component; wherein said formulation provides a
higher tumor/plasma ratio of said agent than does a formulation of
the same agent with a micelle-forming component; wherein the area
under the curve for delivery of said agent to a tumor via said
formulation is higher than the area under the curve for delivery of
said agent to a tumor via a formulation of the same agent with a
micelle-forming component; wherein said formulation provides a
higher concentration maximum (C.sub.max) for said agent in tumor
cells than does a formulation of the same agent with a
micelle-forming component; wherein said formulation provides a
lower concentration maximum (C.sub.max) for said agent in plasma
than does a formulation of the same agent with a micelle-forming
component; wherein said formulation provides more rapid uptake of
said agent by tumor cells than does a formulation of the same agent
with a micelle-forming component; and wherein said formulation
enhances delivery of said agent to tissue, relative to a
formulation of the same agent with a micelle-forming component.
2. A method for the delivery of a substantially water insoluble
pharmacologically active agent to a subject in need thereof, said
method comprising administering an effective amount of a
formulation according to claim 1 to said subject.
3. A method according to claim 2 wherein said agent is
paclitaxel.
4. A method according to claim 2 wherein said pharmaceutically
acceptable carrier is albumin.
5. A method according to claim 2 wherein said formulation is
administered by oral, intravenous, subcutaneous, intraperitoneal,
intrathecal, intramuscular, intracranial, inhalational, topical,
transdermal, rectal, or pessary route of administration.
6. A method to reduce entrapment of a substantially water insoluble
pharmacologically active agent in vehicle employed for delivery
thereof, said method comprising employing a formulation according
to claim 1 for delivery of said agent, thereby reducing entrapment
of said substantially water insoluble pharmacologically active
agent relative to a formulation comprising the same agent and a
carrier containing micelle-forming components.
7. A method to prolong exposure of a subject to a substantially
water insoluble pharmacologically active agent upon administration
thereof to a subject in need thereof, said method comprising
combining said agent with a pharmaceutically acceptable carrier
which is free of micelle-forming components to produce a
formulation according to claim 1 prior to delivery thereof, thereby
prolonging exposure of said subject to said substantially water
insoluble pharmacologically active agent relative to a formulation
comprising the same agent and a carrier containing micelle-forming
components.
8. A method to facilitate transport of a substantially water
insoluble pharmacologically active agent across cell membranes
and/or into the cellular compartment upon administration thereof to
a subject in need thereof, said method comprising combining said
agent with a pharmaceutically acceptable carrier which is free of
micelle-forming components to produce a formulation according to
claim 1 prior to delivery thereof, thereby facilitating transport
of said substantially water insoluble pharmacologically active
agent across cell membranes relative to transport of a formulation
comprising the same agent and a carrier containing micelle-forming
components.
9. A formulation according to claim 1, wherein said formulation
provides a higher concentration of said agent in the cellular
compartment than a formulation of the same agent with a
micelle-forming component and/or said formulation provides
increased intra-cellular availability of said agent relative to a
formulation of the same agent with a micelle-forming component.
10. A formulation according to claim 1, wherein said formulation
provides prolonged activity of said agent relative to a formulation
of the same agent with a micelle-forming component and/or said
formulation delivers said agent to the bloodstream over an extended
period of time relative to a formulation of the same agent with a
micelle-forming component.
11. A formulation according to claim 1, wherein said formulation
facilitates delivery of said agent to red blood cells, relative to
delivery of said agent to red blood cells by a formulation
comprising the same agent and a carrier containing micelle-forming
components and/or said formulation provides reduced levels of said
agent in the bloodstream relative to a formulation of the same
agent with a micelle-forming component.
12. A formulation according to claim 1, wherein said formulation
releases a portion of said agent contained therein to the lipid
membrane of a cell.
13. A formulation according to claim 1, wherein the rate of
metabolism of said agent in said formulation is reduced relative to
the rate of metabolism of said agent in a formulation with a
micelle-forming component and/or said agent has a longer half life
in said formulation relative to the half life of said agent in a
formulation with a micelle-forming component.
14. A formulation according to claim 1, wherein said formulation
provides a higher red blood cell/plasma ratio of said agent than
does a formulation of the same agent with a micelle-forming
component and/or said formulation provides a higher tumor/plasma
ratio of said agent than does a formulation of the same agent with
a micelle-forming component.
15. A formulation according to claim 1, wherein the area under the
curve for delivery of said agent to a tumor via said formulation is
higher than the area under the curve for delivery of said agent to
a tumor via a formulation of the same agent with a micelle-forming
component.
16. A formulation according to claim 1, wherein said formulation
provides a higher concentration maximum (C.sub.max) for said agent
in tumor cells than does a formulation of the same agent with a
micelle-forming component and/or said formulation provides a lower
concentration maximum (C.sub.max) for said agent in plasma than
does a formulation of the same agent with a micelle-forming
component.
17. A formulation according to claim 1, wherein said formulation
provides more rapid uptake of said agent by tumor cells than does a
formulation of the same agent with a micelle-forming component.
18. A formulation according to claim 1, wherein said formulation
enhances delivery of said agent to tissue, relative to a
formulation of the same agent with a micelle-forming component.
19. A formulation according to claim 1 wherein said tissue is a
tumor.
20. A formulation according to claim 1 wherein said tissue is
peritoneal tissue, bladder tissue or lung tissue.
Description
RELATED APPLICATIONS
[0001] The present application is a continuation of U.S. Ser. No.
11/240,940, filed Sep. 29, 2005, now pending, which is a
continuation of U.S. Ser. No. 10/146,706, filed May 14, 2002, now
abandoned, which is a continuation-in-part of U.S. Ser. No.
09/628,388, filed Aug. 1, 2000, now issued U.S. Pat. No. 6,506,405,
which is a divisional of U.S. Ser. No. 08/926,155, filed Sep. 9,
1997, now issued as U.S. Pat. No. 6,096,331, which is a
continuation-in-part of U.S. Ser. No. 08/720,756, filed Oct. 1,
1996, now issued as U.S. Pat. No. 5,916,596, and U.S. Ser. No.
08/485,448, filed Jun. 7, 1995, now U.S. Pat. No. 5,665,382, which
is, in turn, a continuation-in-part of U.S. Ser. No. 08/200,235,
filed Feb. 22, 1994, now issued as U.S. Pat. No. 5,498,421, which
is, in turn, a continuation-in-part of U.S. Ser. No. 08/023,698,
filed Feb. 22, 1993, now issued as U.S. Pat. No. 5,439,686 and U.S.
Ser. No. 08/035,150, filed Mar. 26, 1993, now issued as U.S. Pat.
No. 5,362,478, the content of each of which are hereby incorporated
by reference therein in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to novel formulations of
pharmacologically active agents and methods for the delivery of
such agents to subjects in need thereof.
BACKGROUND OF THE INVENTION
[0003] In the quest for next generation therapies to treat cancer,
scientist often discover promising compounds only to find that the
molecule is highly insoluble in water, and hence impossible to
deliver intravenously. Such was the problem with paclitaxel, an
extremely effective anti-tumor agent discovered over a quarter
century ago by the Nation Cancer Institute. Despite almost 30 years
of effort, the only method currently approved to address this
problem of water-insolubility of paclitaxel is the use of a toxic
solvent (cremophor) to dissolve the drug, and administer this
solvent-paclitaxel mixture over many hours using specialized
intra-venous tubing sets to prevent the leaching of plasticizers.
This solvent-drug mixture, currently marketed in branded and
generic forms, has become the most widely used anti-cancer agent as
it has shown activity in breast, lung and ovarian cancer and is
undergoing multiple clinical trials exploring its application in
combination with other drugs for other solid tumors.
[0004] The cremophor formulation of paclitaxel is associated with
significant side-effects including life-threatening allergic
reactions requiring the need for steroid pre-treatment for every
patient receiving the drug, and severe infections as a result of
lowering of white blood cells requiring the need for expensive
blood cell growth factors. Ultimately these toxicities result in
dose-limitation of cremophor-based paclitaxel formulations, thus
limiting the full potential of the very effective paclitaxel
molecule.
[0005] While the above toxic side effects of cremophor paclitaxel
formulations are well known, it has not been widely recognized by
scientists in the field that the presence of cremophor creates a
more serious impediment to realizing the maximal potential of
paclitaxel by entrapping paclitaxel within the hydrophobic cores of
cremophor micelles within microdroplets in the blood-stream. The
entrapment effect of cremophor is dependent on cremophor
concentration. Thus, increasing the doses of cremophor solutions of
paclitaxel can potentially worsen the entrapment by raising the
concentration of cremophor, leading to higher toxcities but none of
the potential benefits of higher doses of paclitaxel, since much of
the active molecule is unavailable to the intra-cellular space,
where it is needed to act.
[0006] This entrapment of paclitaxel by cremophor has a profound
effect on the intra-cellular availability of the active molecule
and hence may have significant clinical implications in terms of
clinical outcome. Accordingly, there is a need in the art for new
formulations for the delivery of substantially water insoluble
pharmacologically active agents, such as paclitaxel, which do not
suffer from the drawbacks of cremophor.
BRIEF DESCRIPTION OF THE INVENTION
[0007] In accordance with the present invention, novel formulations
have been developed which are much more effective for the delivery
of hydrophobic drugs to patients in need thereof than are prior art
formulations. Invention formulations are capable of delivering more
drug in shorter periods of time, with reduced side effects caused
by the pharmaceutical carrier employed for delivery.
BRIEF DESCRIPTION OF THE FIGURES
[0008] FIG. 1 collectively compares the plasma kinetics of
radiolabelled paclitaxel when administered to a mouse model as part
of a Taxol formulation (closed squares) or as part of in invention
formulation (diamonds; ABI-007). FIG. 1A indicates plasma
radioactivity measured up to 0.5 hours after administration. FIG.
1B indicates plasma radioactivity measured up to 24 hours after
administration. Inspection of the figure reveals that 2-5 fold
higher levels of paclitaxel are retained in the plasma up to 3
hours after administration when paclitaxel is administered in a
cremophor-based formulation (Taxol). Due to the reduced rate of
metabolism for ABI-007, plasma levels of paclitaxel are higher
after 8 hours when administered in an invention formulation,
relative to a cremophor-based formulation.
[0009] FIG. 2 compares the partitioning of paclitaxel between red
blood cells and plasma when administered to a mouse model as part
of a Taxol formulation (closed squares) or as part of in invention
formulation (diamonds; ABI-007). Inspection of the figure reveals
that the blood/plasma ratio for paclitaxel administered as part of
a cremophor-based formulation (Taxol) in the first 3 hours after
administration is about 1.5-2, indicating that the majority of
paclitaxel is retained in the plasma due to micellar formation with
cremophor. In addition, it is seen that paclitaxel in a
cremophor-based formulation does not significantly partition into
the red blood cells. In contrast, paclitaxel administered as part
of an invention formulation readily partitions into the red blood
cells.
[0010] FIG. 3 summarizes tumor/plasma partitioning kinetics of
paclitaxel when administered to a mouse model as part of a Taxol
formulation (closed squares) or as part of in invention formulation
(diamonds; ABI-007). It is seen that the tumor/plasma ratio of
paclitaxel increases significantly over the first 3 hours when as
part of an invention formulation, as opposed to a Taxol
formulation.
[0011] FIG. 4 compares the response of mammary carcinoma in a mouse
model to exposure to ABI-007 or Taxol.
[0012] FIG. 5 compares the response of ovarian carcinoma in a mouse
model to exposure to ABI-007 or Taxol.
[0013] FIG. 6 compares the response of prostate tumors in a mouse
model to exposure to ABI-007 or Taxol.
[0014] FIG. 7 compares the response of colon tumors in a mouse
model to exposure to ABI-007 or Taxol.
[0015] FIG. 8 compares the response of lung tumors in a mouse model
to exposure to ABI-007 or Taxol.
DETAILED DESCRIPTION OF THE INVENTION
[0016] In accordance with the present invention, there are provided
methods for the delivery of a substantially water insoluble
pharmacologically active agent to a subject in need thereof, said
method comprising combining said agent with an effective amount of
a pharmaceutically acceptable carrier which is substantially free
of micelle-forming components, and administering an effective
amount of said combination to said subject.
[0017] As readily recognized by those of skill in the art, a wide
variety of pharmacologically active agents are contemplated for use
in the practice of the present invention. A presently preferred
agent contemplated for use herein is paclitaxel.
[0018] Pharmaceutically acceptable carriers contemplated for use in
the practice of the present invention are biocompatible materials
such as albumin.
[0019] Micelle-forming components which are preferably avoided in
the practice of the present invention are surface active materials
which are commonly used to assist in solubilizing substantially
insoluble compounds in aqueous media, such as, for example,
cremophor.
[0020] Invention combination of active agent and pharmaceutically
acceptable carrier can be administered in a variety of ways, such
as, for example, by oral, intravenous, subcutaneous,
intraperitoneal, intrathecal, intramuscular, intracranial,
inhalational, topical, transdermal, rectal, or pessary routes of
administration, and the like.
[0021] In accordance with another embodiment of the present
invention, there are provided methods to reduce entrapment of a
substantially water insoluble pharmacologically active agent in
vehicle employed for delivery thereof, said method comprising
combining said agent with a pharmaceutically acceptable carrier
which is substantially free of micelle-forming components prior to
delivery thereof.
[0022] Presently preferred pharmaceutically acceptable carriers
contemplated for use herein are those having substantially lower
affinity for said agent than does the micelle-forming component.
Thus, for example, while cremophor has the benefit of aiding in the
solubilization of agent, it has the disadvantage of having a
substantial affinity for the agent, so that release of the agent
from the carrier becomes a limitation on the bioavailability of the
agent. In contrast, carriers contemplated herein, such as, for
example, albumin, readily release the active agent to the active
site and are thus much more effective for treatment of a variety of
conditions.
[0023] In accordance with yet another embodiment of the present
invention, there are provided methods to reduce entrapment of a
substantially water insoluble pharmacologically active agent in
vehicle employed for delivery thereof, said method comprising
employing pharmaceutically acceptable carriers which are
substantially free of micelle-forming components in aqueous media
as the vehicle for delivery of said agent.
[0024] In accordance with still another embodiment of the present
invention, there are provided methods to prolong exposure of a
subject to a substantially water insoluble pharmacologically active
agent upon administration thereof to a subject in need thereof,
said method comprising combining said agent with pharmaceutically
acceptable carrier(s) which is(are) substantially free of
micelle-forming components prior to delivery thereof.
[0025] In accordance with a further embodiment of the present
invention, there are provided methods to facilitate transport of a
substantially water insoluble pharmacologically active agent across
cell membranes upon administration thereof to a subject in need
thereof, said method comprising combining said agent with
pharmaceutically acceptable carrier(s) which is(are) substantially
free of micelle-forming components prior to delivery thereof.
[0026] In accordance with a still further embodiment of the present
invention, there are provided methods to facilitate transport of a
substantially water insoluble pharmacologically active agent into
the cellular compartment upon administration thereof to a subject
in need thereof, said method comprising combining said agent with
pharmaceutically acceptable carrier(s) which is(are) substantially
free of micelle-forming components prior to delivery thereof.
[0027] In accordance with another embodiment of the present
invention, there are provided formulations comprising a
substantially water insoluble pharmacologically active agent and a
pharmaceutically acceptable carrier which is substantially free of
micelle-forming components, wherein said formulation provides a
higher concentration of said agent in the cellular compartment than
a formulation of the same agent with a micelle-forming
component.
[0028] In accordance with yet another embodiment of the present
invention, there are provided formulations comprising a
substantially water insoluble pharmacologically active agent and a
pharmaceutically acceptable carrier which is substantially free of
micelle-forming components, wherein said formulation provides
increased intra-cellular availability of said agent relative to a
formulation of the same agent with a micelle-forming component.
[0029] In accordance with still another embodiment of the present
invention, there are provided formulations comprising a
substantially water insoluble pharmacologically active agent and a
pharmaceutically acceptable carrier which is substantially free of
micelle-forming components, wherein said formulation provides
prolonged activity of said agent relative to a formulation of the
same agent with a micelle-forming component.
[0030] In accordance with a further embodiment of the present
invention, there are provided formulations comprising a
substantially water insoluble pharmacologically active agent and a
pharmaceutically acceptable carrier which is substantially free of
micelle-forming components, wherein said formulation facilitates
delivery of said agent to red blood cells.
[0031] In accordance with another embodiment of the present
invention, there are provided formulations comprising a
substantially water insoluble pharmacologically active agent and a
pharmaceutically acceptable carrier which is substantially free of
micelle-forming components, wherein said formulation releases a
portion of said agent contained therein to the lipid membrane of a
cell.
[0032] In accordance with yet another embodiment of the present
invention, there are provided formulations comprising a
substantially water insoluble pharmacologically active agent and a
pharmaceutically acceptable carrier which is substantially free of
micelle-forming components, wherein said formulation provides
reduced levels of said agent in the bloodstream relative to a
formulation of the same agent with a micelle-forming component.
[0033] In accordance with still another embodiment of the present
invention, there are provided formulations comprising a
substantially water insoluble pharmacologically active agent and a
pharmaceutically acceptable carrier which is substantially free of
micelle-forming components, wherein said formulation delivers said
agent to the bloodstream over an extended period of time relative
to a formulation of the same agent with a micelle-forming
component.
[0034] In accordance with a further embodiment of the present
invention, there are provided formulations comprising a
substantially water insoluble pharmacologically active agent and a
pharmaceutically acceptable carrier which is substantially free of
micelle-forming components, wherein the rate of metabolism of said
agent in said formulation is reduced relative to the rate of
metabolism of said agent in a formulation with a micelle-forming
component.
[0035] In accordance with another embodiment of the present
invention, there are provided formulations comprising a
substantially water insoluble pharmacologically active agent and a
pharmaceutically acceptable carrier which is substantially free of
micelle-forming components, wherein said agent has a longer half
life in said formulation relative to the half life of said agent in
a formulation with a micelle-forming component.
[0036] In accordance with yet another embodiment of the present
invention, there are provided formulations comprising a
substantially water insoluble pharmacologically active agent and a
pharmaceutically acceptable carrier which is substantially free of
micelle-forming components, wherein said formulation provides a
higher red blood cell/plasma ratio of said agent than does a
formulation of the same agent with a micelle-forming component.
[0037] In accordance with still another embodiment of the present
invention, there are provided formulations comprising a
substantially water insoluble pharmacologically active agent and a
pharmaceutically acceptable carrier which is substantially free of
micelle-forming components, wherein said formulation provides a
higher tumor/plasma ratio of said agent than does a formulation of
the same agent with a micelle-forming component.
[0038] In accordance with a further embodiment of the present
invention, there are provided formulations comprising a
substantially water insoluble pharmacologically active agent and a
pharmaceutically acceptable carrier which is substantially free of
micelle-forming components, wherein the area under the curve for
delivery of said agent to a tumor via said formulation is higher
than the area under the curve for delivery of said agent to a tumor
via a formulation of the same agent with a micelle-forming
component.
[0039] In accordance with a still further embodiment of the present
invention, there are provided formulations comprising a
substantially water insoluble pharmacologically active agent and a
pharmaceutically acceptable carrier which is substantially free of
micelle-forming components, wherein said formulation provides a
higher concentration maximum (C.sub.max) for said agent in tumor
cells than does a formulation of the same agent with a
micelle-forming component.
[0040] In accordance with another embodiment of the present
invention, there are provided formulations comprising a
substantially water insoluble pharmacologically active agent and a
pharmaceutically acceptable carrier which is substantially free of
micelle-forming components, wherein said formulation provides a
lower concentration maximum (C.sub.max) for said agent in plasma
than does a formulation of the same agent with a micelle-forming
component.
[0041] In accordance with still another embodiment of the present
invention, there are provided formulations comprising a
substantially water insoluble pharmacologically active agent and a
pharmaceutically acceptable carrier which is substantially free of
micelle-forming components, wherein said formulation provides more
rapid uptake of said agent by tumor cells than does a formulation
of the same agent with a micelle-forming component.
[0042] In accordance with yet another embodiment of the present
invention, there are provided formulations comprising a
substantially water insoluble pharmacologically active agent and a
pharmaceutically acceptable carrier which is substantially free of
micelle-forming components, wherein said formulation enhances
delivery of said agent to tissue, relative to a formulation of the
same agent with a micelle-forming component.
[0043] Tissues contemplated for treatment according to the
invention include tumors, peritoneal tissue, bladder tissue, lung
tissue, and the like. ABI-007 is a proprietary, cremophor-free,
albumin-based paclitaxel nanoparticle, 1/100.sup.th the size of a
single red blood cell. Based on several Phase I studies, it has
been shown that ABI-007 can be administered rapidly without the
need for steroid pre-treatment and without the need for G-CSF at a
maximum tolerated dose of 300 mg/m.sup.2 given every 3 weeks. This
is a significantly higher dose than is approved for cremophor-based
paclitaxel formulations (Taxol) of 175 Mg/m.sup.2.
[0044] In accordance with the present invention, it has been
discovered that ABI-007 acts as a novel biologic nano-transporter
for hydrophobic drugs such as paclitaxel, with the capabilities of
rapidly releasing paclitaxel to the cellular compartment and
increasing intra-cellular availability of the active drug, where it
is needed in order to have its chemo-therapeutic effect.
Furthermore, through the use of the red blood cell as a secondary
storage vehicle it has been discovered that in addition to the
rapid and increased availability of paclitaxel at the
intra-cellullar level, by the recruitment of circulating red blood
cells, ABI-007 further provides a significant prolonged activity of
the parent molecule with sustained in-vivo release. These novel
mechanisms for rapid and increased intra-cellular availability of
the drug at the tumor site, together with sustained trafficking of
the non-metabolized paclitaxel, has potentially significant
implications for the clinical outcome in the treatment of solid
tumors. Indeed, the pre-clinical and Phase II clinical data
presented below supports this notion.
[0045] By taking advantage of the differences in binding affinities
of albumin and the lipid bi-layer of cell membranes for hydrophobic
paclitaxel, the drug-bearing albumin nanoparticle (ABI-007) would
rapidly release a portion of its hydrophobic paclitaxel cargo to
the lipid membrane of a cell.
[0046] In the vascular compartment, the first cell encountered is
the red blood cell. In accordance with the present invention, the
red blood cell has been found to rapidly compartmentalize the
paclitaxel molecule. Since the red blood cell has no nucleus and
hence no microtubulin to which the paclitaxel molecule can bind,
nor any degradation machinery within its core, this cell serves as
an ideal secondary storage vehicle for the active paclitaxel,
accounting in part for the prolonged activity of paclitaxel noted
with ABI-007.
[0047] Following partitioning of a portion of its paclitaxel
payload to the circulating red blood cells, the nanoparticle is
carried by the blood-stream to the hypervasular tumor, where
paclitaxel is rapidly transferred to the tumor cell-membrane, again
due to the differences in binding affinity. It has been well
established by other groups that the hydrostatic pressure within
these tumor cells is abnormally higher than the surrounding
interstitium and vascular space. This abnormally high pressure,
together with the fact that the vessels associated with tumors are
also abnormally leaky, creates a barrier to the delivery of
chemotherapeutic agents to the tumor cell. Thus, under these
circumstances it is imperative that the hydrophobic paclitaxel be
released rapidly to the lipid cell membrane and be bound by the
microtubules within the nuclues before the drug is ejected from the
tumor. Evidence presented herein indicates that ABI-007 provides
that opportunity by the ability to rapidly release the hydrophobic
molecule. In contrast, cremophor-based formulations entrap the
paclitaxel, limiting the ability of the drug to partition into
cells. This difference may have important clinical implications and
may account in part for the positive data noted in the Phase II
studies of ABI-007 in metastatic breast cancer and the evidence for
responses in patients who had previously failed Taxol therapy
[0048] As the nanoparticle depeletes itself of paclitaxel into the
cellular compartment within the first 3-8 hours following infusion,
the plasma concentartion of paclitaxel diminishes. At this
juncture, paclitaxel (still in its active, non-metabolized form)
follows the concentration gradient and is now transferred to
albumin again, and is again carried to the tumor bed. Thus, a
prolonged half-life of paclitaxel has been achieved, with sustained
release and ultimately higher tumor concentration of the drug.
[0049] The invention will now be described in greater detail by
reference to the following non-limiting examples.
EXAMPLE 1
Preclinical Studies Confirm the Modulation of Paclitaxel Release by
the Protein Nanosphere and Increased Efficacy of Equi-Dose of
ABI-007 vs Taxol
[0050] Using radio labeled paclitaxel, the enhanced intra-cellular
availability of paclitaxel has been confirmed following injection
of ABI-007. In addition, the entrapment of Cremophor-bound
paclitaxel has also been confirmed. This difference in findings
correlates with in-vivo studies in mice bearing human breast
cancer, with the finding that ABI-007 at equi-dose to Taxol,
resulted in improved outcomes that these 130 nanometer size
particles distributed throughout the body.
[0051] Thus, human MX-1 mammary tumor fragments were implanted
subcutaneously in female athymic mice. Radiolabelled drug was
administered when tumors reached about 500 mm.sup.3.
Tritium-labelled ABI-007 or tritium-labelled Taxol were
administered at a dose of 20 mg/kg. Both groups received about 7-10
.mu.Ci/mouse of tritium-labelled paclitaxel. Saline was used as the
diluent for both drugs. At various time points (5 min, 15 min, 30
min, 1 hr, 3 hr, 8 hr and 24 hr), 4 animals were sacrificed, then
blood samples and tumor were recovered for radioactivity
assessment.
[0052] Radioactivity was determined as nCi/ml of whole blood and
plasma, and nCi/g of tumor tissue. Results are presented in FIGS.
1, 2 and 3, and are standardized for radioactivity and paclitaxel
dose. The data from these studies are also presented in the
following tables.
TABLE-US-00001 PHARMACOKINETIC PARAMETERS FOR WHOLE-BLOOD, PLASMA
AND TUMOR DISTRIBUTION OF .sup.3H-PACLITAXEL IN ABI-007 VS TAXOL
New AUC.sub.0-inf (nCi hr/mL or g) AUC.sub.0-24 (nCi hr/mL or g)
C.sub.max (nCi/mL or g) Blood Plasma Tumor Blood Plasma Tumor Blood
Plasma Tumor ABI-007 939 1161 5869 ABI-007 656 836 2156 ABI-007 328
473 144 Taxol 871 1438 3716 Taxol 849 1415 1804 Taxol 752 1427 117
Ratio 1.08 0.81 1.58 Ratio 0.77 0.59 1.20 Ratio 0.44 0.33 1.23
TAXOL: high Plasma AUC-paclitaxel is trapped in ABI-007:
Substantially lower Cmax in Plasma, blood cremophor micelles
implies rapid distribution into cells and tissues ABI-007: higher
Tumor AUC (exposure, pac ABI-007: higher Tumor Cmax-more effective
tumor kill distributed into cells/tissues t.sub.max (hours)
t1/2.sub.e (hours) Vdss (mL/kg) Blood Plasma Tumor Blood Plasma
Tumor Blood Plasma Tumor ABI-007 0 0 0.5 ABI-007 17.1 16.1 40.2
ABI-007 6939 5180 NA Taxol 0 0 3 Taxol 4.0 3.3 24.1 Taxol 1409 692
NA Ratio 4.28 4.88 1.67 Ratio 4.92 7.49 ABI-007: Substantially
lower tumor ABI-007: Prolonged half life relative ABI-007:
Substantially higher volume tmax indicates rapid uptake of pacli-
to Taxol in blood, plasma and tumor of distribution indicating
extrensive dis- taxel into tumor relative to taxol may result in
higher antitumor activity tribution into tissues relative to
Taxol
[0053] Further studies demonstrate that after 24 hours, the active
ingredient of the parent molecule, paclitaxel, remains present in
the bloodstream, at double the concentration of Taxol. In studies
comparing radiolabelled paclitaxel in Taxol vs ABI-007, direct
measurements reveal increased and prolonged levels of paclitaxel in
the tumors of animals receiving ABI-007.
EXAMPLE 2
Toxicity Studies
[0054] Toxicity was assessed for Taxol, cremophor and ABI-007.
ABI-007 was found to be 50-fold less toxic than Taxol, and 30-fold
less toxic than the cremophor vehicle alone, as illustrated in the
following table:
TABLE-US-00002 Agent LD.sub.50, mg/kg Taxol 9.4 Cremophor 13.7
ABI-007 448.5
EXAMPLE 3
In Vivo Tumor Xenografts
[0055] Human tumor fragments were implanted subcutaneously in
female athymic mice. Treatment was initiated when tumors reached
about 150 mm.sup.3. The mice received either CONTROL (saline),
ABI-007 (4 dose levels: 13.4, 20, 30 and 45 mg/kg) or TAXOL (3 dose
levels: 13.4, 20, and 30 mg/kg) administered I.V. daily for 5 days.
Saline was used as the diluent for both drugs.
[0056] Determination of Equitoxic dose or MTD: The Equitoxic dose
or MTD for each drug was determined by satisfying one of the
following criteria:
[0057] a) Dose for each drug that resulted in similar body weight
loss (<20%) if no deaths were seen;
[0058] b) If body weight loss could not be matched, the highest
dose at which no deaths were seen;
[0059] If neither a) nor b) could be satisfied, the lowest dose
that resulted in similar death rate. Tumor response to the drugs
was compared at the Equitoxic dose or MTD established as above.
Results for several different tumor types are presented in FIGS.
4-8.
EXAMPLE 4
Clinical Studies
[0060] i. Entrapment of Paclitaxel By Cremophor
[0061] Working independently at Rotterdam Cancer Institute, Dr Alex
Sparreboom has reported in a series of pharmacokinetic studies
involving patients receiving Taxol that cremophor "causes a
profound alteration of paclitaxel accumulation in erythrocytes in a
concentration-dependant manner by reducing the free drug fraction
available for cellular partitioning." He has further found that the
drug trapping occurs in micelles and that these micelles act as the
principal carrier of paclitaxel in the systemic circulation. Since
that publication these findings have been independently confirmed
by two other groups.
ii. Improved Clinical Activity With ABI-007
[0062] Data from Phase II shows both increased efficacy in
metastatic breast cancer patients. When compared to the published
literature of response rates to Taxol, the study results showed a
dramatic difference in both response rates and time of response as
well as evidence of reduced toxicities associated with ABI-007.
Further details can be obtained by reviewing the posters presented
at ASCO.
[0063] Although the present invention has been described in
conjunction with the embodiments above, it is to be noted that
various changes and modifications are apparent to those who are
skilled in the art. Such changes and modifications are to be
understood as included within the scope of the present invention
defined by the appended claims.
* * * * *