U.S. patent application number 10/270854 was filed with the patent office on 2003-05-08 for compositions and methods for delivery of poorly water soluble drugs and methods of treatment.
Invention is credited to Jonas, Jeffrey M., Rajewski, Roger A., Subramaniam, Bala, Terranova, Katherine Fern.
Application Number | 20030087837 10/270854 |
Document ID | / |
Family ID | 23284727 |
Filed Date | 2003-05-08 |
United States Patent
Application |
20030087837 |
Kind Code |
A1 |
Jonas, Jeffrey M. ; et
al. |
May 8, 2003 |
Compositions and methods for delivery of poorly water soluble drugs
and methods of treatment
Abstract
The present embodiment of the invention is generally directed to
compositions comprising suspensions of poorly water soluble
compounds recrystallized in nanoparticulate sizes ranging from 0.1
to 5 .mu.m. In addition, the embodiment of the invention is
directed to methods for preparation and administration of these
compositions to a patient for prevention and treatment of disease
states. In particular, the embodiment of the invention is directed
to compositions comprising suspensions of poorly water-soluble
compounds, such as antimitotics and antibiotics, in
nanoparticulates and methods of prevention and treatment of chronic
disease states, such as cancer, by intraperitoneal and intravenous
administration of such compositions.
Inventors: |
Jonas, Jeffrey M.; (Kansas
City, MO) ; Rajewski, Roger A.; (Lawrence, KS)
; Subramaniam, Bala; (Lawrence, KS) ; Terranova,
Katherine Fern; (Overland Park, KS) |
Correspondence
Address: |
Jean M. Dickman
SHOOK, HARDY & BACON L.L.P.
1200 Main Street
Kansas City
MO
64105-2118
US
|
Family ID: |
23284727 |
Appl. No.: |
10/270854 |
Filed: |
October 15, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60329291 |
Oct 15, 2001 |
|
|
|
Current U.S.
Class: |
514/27 ; 424/489;
514/283; 514/365; 514/449 |
Current CPC
Class: |
A61K 9/10 20130101; A61K
9/14 20130101; A61K 9/0019 20130101; A61P 31/00 20180101; A61P
35/00 20180101; A61K 47/44 20130101; A61K 9/1688 20130101 |
Class at
Publication: |
514/27 ; 514/449;
514/283; 514/365; 424/489 |
International
Class: |
A61K 031/7048; A61K
031/4745; A61K 031/427; A61K 031/337; A61K 009/14 |
Claims
What is claimed is:
1. A composition comprising: nanoparticulates of at least one
antimitotic drug, wherein the nanoparticulates have a particle size
from 0.1 micrometer to 5 micrometers.
2. The composition of claim 1, wherein the antimitotic drug is
selected from the group consisting of: paclitaxel, paclitaxel
derivatives, taxanes, epithilones, Vinca alkaloids, camptothecin
analogs, epipodophyllotoxins and combinations thereof.
3. The composition of claim 1, wherein the nanoparticulates have a
particle size from 0.4 to 2 micrometers.
4. The composition of claim 2, wherein the antimitotic drug is a
Vinca alkaloid.
5. The composition of claim 4 wherein the antimitotic drug is
selected from the group consisting of: vinblastine, vincristine,
vindesine and vinorelbine.
6. The composition of claim 2, wherein the amitotic drug is a
camptothecin analog.
7. The composition of claim 2, wherein the antimitotic drug is an
epipodophyllotoxin.
8. The composition of claim 2, wherein the antimitotic drug is a
paclitaxel derivative.
9. The composition of claim 2, wherein the antimitotic drug is a
taxane.
10. The composition of claim 7, wherein the antimitotic drug is
selected from the group consisting of: etoposide and
teniposide.
11. The composition of claim 1, further comprising: a suspension
medium.
12. A method of administering the composition of claim 11.
13. The method of claim 12, wherein the composition is administered
intravenously.
14. The method of claim 12, wherein the composition is administered
intraperitoneally.
15. The composition of claim 11, wherein the suspension is
phosphate buffered saline.
16. The composition of claim 11, further comprising anticlotting
agents.
17. The composition of claim 11, further comprising
surfactants.
18. A composition comprising: nanoparticulates of paclitaxel,
wherein the nanoparticulates have a particle size from 0.1
micrometer to 5 micrometers.
19. The composition of claim 18, wherein the nanoparticulates have
a particle size from 0.4 to 2 micrometers.
20. The composition of claim 18, further comprising: a suspension
medium.
21. A method of administering the composition of claim 20.
22. The method of claim 21, wherein the composition is administered
intravenously.
23. The method of claim 21, wherein the composition is administered
intraperitoneally.
24. A composition comprising: nanoparticulates of an antibiotic
drug, wherein the nanoparticulates have a particle size from 0.1
micrometer to 5 micrometers.
25. The composition of claim 24, wherein the nanoparticulates have
a particle size from 0.4 to 2 micrometers
26. The composition of claim 24, wherein the antibiotic is selected
from the group consisting of: actinomycin D, mitomycin,
daunorubicin, doxorubicin and idarubicin.
27. The composition of claim 24, further comprising: a suspension
medium.
28. A method of administering the composition of claim 27.
29. The method of claim 28, wherein the composition is administered
intravenously.
30. The method of claim 28, wherein the composition is administered
intraperitoneally.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority to
Provisional Application No. 60/329,291 filed on Oct. 15, 2001.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not Applicable.
BACKGROUND OF THE INVENTION
[0003] The present embodiment of the invention is directed
generally to the prevention and treatment of disease such as
neoplastic cell growth and proliferation and, more specifically, to
compositions of poorly water soluble compounds, such as,
antimitotics and antibiotics, and methods of delivering such
compositions for the prevention and treatment of cancers and
tumors.
[0004] Cancer is one of the leading causes of death in the United
States and is characterized by uncontrolled increases in abnormal
or neoplastic cells that form a tumor mass and invade adjacent
tissues. Malignant cells spread by way of the blood system, the
lymphatic system to lymph nodes, by migration of cancer cells
within the fluids of the peritoneal cavity, and to distant sites in
a process known as metastasis.
[0005] Numerous compounds are known which are useful in the
prevention and treatment of various types of cancer. In order to
effectively deliver these compounds by intravenous administration,
it is generally preferred that the compounds be in solution to
avoid or reduce the risk of blood clotting or other adverse effects
that could result if the compounds were delivered in particulate
form. Unfortunately, many of these compounds have poor solubility
in water, the preferred solvent, and must be delivered using
solvents which can cause adverse patient reactions that must in
turn be prevented or controlled through the administration of other
compounds. For example, paclitaxel is a known inhibitor of cell
division or mitosis and is widely used in the treatment of ovarian,
breast, lung, esophageal, bladder, head and neck cancers.
Paclitaxel is a natural product originally purified from the bark
of yew trees, but now obtained by semisynthesis from
10-desacetylbaccatin, a precursor purified from yew leaves.
Paclitaxel, however, is poorly water soluble and is conventionally
solubilized in Cremophor EL, a formulation comprising 50% ethyl
alcohol and 50% polyethoxylated castor oil. Cremophor EL is
believed to result in histamine release in certain individuals and
patients receiving paclitaxel in that delivery method must normally
be protected with a histamine H.sub.1-receptor antagonist, an
H.sub.2-receptor antagonist and a corticosteroid to prevent severe
hypersensitivity reactions. Other compounds cannot be effectively
administered because they are not soluble in any known solvent that
can be tolerated by patients in need of cancer prevention or
treatment. As a result, these anti-cancer agents are unavailable
for use in cancer prevention or treatment using conventional
methods of administration.
[0006] While anti-cancer compounds are commonly administered by
intravenous injection to patients in need of treatment, it is also
known to inject cisplatin and carboplatin into the peritoneal
cavity. A comparative study of intravenous versus intraperitoneal
administration of cisplatin has been published by Alberts, et al.
in the New England Journal of Medicine, 335, 1950-1955 (1996).
Dedrick, et al., have published a pharmacokinetic rationale for the
advantage of intraperitoneal versus intravenous administration of
cisplatin in Cancer Treatment Reports, 62, 1-11 (1978). Similarly,
intraperitoneal delivery of cisplatin as an infusion is discussed
in Principles of Clinical Pharmacology (Atkinson, et al., Academic
Press 2001). To date, however, there do not appear to be any
published reports of intraperitoneal delivery of suspensions of
poorly water-soluble anticancer compounds.
SUMMARY OF THE INVENTION
[0007] A composition comprising nanoparticulates of at least one
antimitotic drug, where the nanoparticulates have a particle size
from 0.1 micrometer to 5 micrometers.
[0008] A composition comprising nanoparticulates of at least one
antimitotic drug, where the nanoparticulates have a particle size
from 0.1 micrometer to 5 micrometers in a suspension medium.
[0009] A method of administering intraperitoneally a composition
comprising nanoparticulates of at least one antimitotic drug in a
suspension medium, where the nanoparticulates have a particle size
from 0.1 micrometer to 5 micrometers.
[0010] A method of administering intravenously a composition
comprising nanoparticulates of at least one antimitotic drug in a
suspension medium, where the nanoparticulates have a particle size
from 0.1 micrometer to 5 micrometers.
[0011] A composition comprising nanoparticulates of paclitaxel,
where the nanoparticulates have a particle size from 0.1 micrometer
to 5 micrometers.
[0012] A composition comprising nanoparticulates of paclitaxel,
where the nanoparticulates have a particle size from 0.1 micrometer
to 5 micrometers in a suspension medium.
[0013] A method of administering intraperitoneally a composition
comprising nanoparticulates of paclitaxel in a suspension medium,
where the nanoparticulates have a particle size from 0.1 micrometer
to 5 micrometers.
[0014] A method of administering intravenously a composition
comprising nanoparticulates of paclitaxel in a suspension medium,
where the nanoparticulates have a particle size from 0.1 micrometer
to 5 micrometers.
[0015] A composition comprising nanoparticulates of at least one
antibiotic drug, where the nanoparticulates have a particle size
from 0.1 micrometer to 5 micrometers.
[0016] A composition comprising nanoparticulates of at least one
antibiotic drug, where the nanoparticulates have a particle size
from 0.1 micrometer to 5 micrometers in a suspension medium.
[0017] A method of administering intraperitoneally a composition
comprising nanoparticulates of at least one antibiotic drug in a
suspension medium, where the nanoparticulates have a particle size
from 0.1 micrometer to 5 micrometers.
[0018] A method of administering intravenously a composition
comprising nanoparticulates of at least one antibiotic drug in a
suspension medium, where the nanoparticulates have a particle size
from 0.1 micrometer to 5 micrometers.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] The present embodiment of the invention is described in
detail below with reference to the attached drawing figures,
wherein:
[0020] FIG. 1 is a graph illustrating the results from a study of
cancer bearing mice treated with nanoparticulate paclitaxel
administered intravenously compared with controls and paclitaxel in
Cremophor solution.
[0021] FIG. 2 is a graph illustrating the results from a study of
cancer bearing mice treated with nanoparticulates of paclitaxel
administered intraperitoneally compared with controls and
paclitaxel in Cremophor solution.
[0022] FIG. 3 is a graph illustrating the results from a study of
cancer bearing mice treated with macroparticulates of paclitaxel,
20 to 60 microns in size, administered intraperitoneally compared
with controls, paclitaxel in Cremophor solution and nanoparticulate
paclitaxel administered intraperitoneally.
[0023] FIG. 4 is a photograph of the body wall of a cancer bearing
mouse treated with the saline control.
[0024] FIG. 5 is a photograph of the body wall of a cancer bearing
mouse treated with 48 mg/kg of nanoparticulates of paclitaxel in
suspension administered intraperitoneally.
[0025] FIG. 6 is a photograph of the diaphragm of a cancer bearing
mouse treated with the saline control.
[0026] FIG. 7 is a photograph of the diaphragm of a cancer bearing
mouse treated with 48 mg/kg of nanoparticulates of paclitaxel in
suspension administered intraperitoneally.
[0027] FIG. 8 is a photograph of an external view of a cancer
bearing mouse treated with the saline control.
[0028] FIG. 9 is a photograph of an external view of a cancer
bearing mouse treated with 48 mg/kg of nanoparticulates of
paclitaxel in suspension administered intraperitoneally.
[0029] FIG. 10 is a photograph of the kidneys of a cancer bearing
mouse treated with the saline control.
[0030] FIG. 11 is a photograph of the kidneys of a cancer bearing
mouse treated with 48 mg/kg of nanoparticulates of paclitaxel in
suspension administered intraperitoneally.
[0031] FIG. 12 is a photograph of the peritoneal organs of a cancer
bearing mouse treated with the saline control.
[0032] FIG. 13 is a photograph of the peritoneal organs of a cancer
bearing mouse treated with 48 mg/kg of nanoparticulates of
paclitaxel in suspension administered intraperitoneally.
DESCRIPTION OF THE PREFERRED EMBODIMENT OF THE INVENTION
[0033] The present embodiment of the invention is generally
directed to compositions comprising suspensions of poorly water
soluble compounds recrystallized in nanoparticulate sizes ranging
from 0.1 to 5 .mu.m, and more preferably from 0.4 to 2 .mu.m. In
addition, the embodiment of the invention is directed to methods
for preparation and administration of these compositions to a
patient for prevention and treatment of disease states. In
particular, the embodiment of the invention is directed to
compositions comprising suspensions of poorly water-soluble
compounds, such as antimitotics and antibiotics, in
nanoparticulates and methods of prevention and treatment of chronic
disease states, such as cancer, by intraperitoneal and intravenous
administration of such compositions.
[0034] Various processes are disclosed in U.S. Pat. Nos. 5,833,891
and 6,113,795, which are incorporated by reference herein in their
entireties, for producing particle sizes as small as 0.1 to 10
.mu.m for compounds. Because particles that are smaller than one to
two microns can pass through the smallest capillaries in the human
body, it is desirable to determine whether suspensions of small
size particles of anti-cancer compounds could be injected into the
blood stream and produce a therapeutic effect without causing blood
clotting or other undesirable side effects as a result of
aggregation of the small particles into larger particles or
aggregation of platelets on the surface of the particles.
[0035] Antimitotics as used herein, include, but are not limited
to: paclitaxel; derivatives of paclitaxel; taxanes; epithilones,
Vinca alkaloids, such as vinblastine, vincristine, vindesine,
vinorelbine; camptothecin analogs; and epipodophyllotoxins, such as
etoposide and teniposide. Poorly water-soluble antibiotics,
include, but are not limited to, actinomycin D, mitomycin,
daunorubicin, doxorubicin and idarubicin.
[0036] Poorly water soluble compounds, as used herein, are
compounds that include: insoluble compounds that have <0.01
mg/ml solubility, very slightly soluble compounds that have 0.1-1
mg/ml solubility, slightly soluble compounds that have 1-10 mg/ml
solubility and sparingly soluble compounds that have 10-33 mg/mil
solubility. The compositions of the present embodiment of the
invention may include other pharmaceutically acceptable
ingredients, excipients and adjuvants.
[0037] The nanoparticulate intraperitoneal delivery described in
this application may ameliorate some of the side effects of
administering a poorly water-soluble drug by allowing a lower dose
to be delivered over a long period of time.
EXAMPLE 1
[0038] In this example, using the process described in U.S. Pat.
Nos. 5,833,891 and 6,113,795, paclitaxel was recrystallized to an
average particle size of about 700 nanometers and a particle size
distribution such that greater than 95% of the particles were below
one micron in size as determined by aerodynamic Time-of-Flight
particle sizing. Four groups of mice that had previously been
injected with cancerous cells and had developed ovarian cancer were
treated with one of the following: 1) a phosphate buffered saline
alone, used as a control 2) a Cremophor EL solution alone, used as
a control 3) paclitaxel in Cremophor EL solution injected by
intravenous (IV) administration, or 4) nanoparticulate paclitaxel
suspended in phosphate buffered saline and injected by IV
administration. The mice were injected with the treatment,
comparative and control compositions on the fiftieth day after
inoculation with cancer cells. Four doses of the compositions were
injected every other day.
[0039] The saline control group survived for a maximum of 110 days
post cancer cell injection and the Cremophor control group survived
for a maximum of 113 days post cancer cell injection. By day 125,
the last of the nanoparticulate paclitaxel group expired and the
group injected with paclitaxel in Cremophor was 80% expired. There
appears to be no statistical difference in overall survival of mice
treated by IV with nanoparticulate paclitaxel in suspension and
paclitaxel in Cremophor solution. The results of the IV injection
study are shown in FIG. 1.
[0040] Notably, the mice survived the direct IV injection of the
suspension of nanoparticulate paclitaxel in phosphate buffered
saline without the need to add anticlotting agents such as heparin
or agents such as surfactants or emulsifiers to prevent aggregation
of the particles. While the preferred formulations would include
these additional ingredients to further reduce the opportunity for
clotting, the nanoparticulate paclitaxel did not appear to cause
blockage or infarct of fine capillaries. Surprisingly, it was
determined that IV injection of the nanoparticulate suspension of
paclitaxel was as effective as the solution of paclitaxel in
Cremophor EL in lengthening the survival time for mice inoculated
with cancer cells. As a result, it may be possible to deliver a
suspension of nanoparticulate paclitaxel intravenously with the
same therapeutic effect as a solution of paclitaxel in Cremophor,
but without the adverse effects of Cremophor.
EXAMPLE 2
[0041] In this example, using the process described in U.S. Pat.
Nos. 5,833,891 and 6,113,795, paclitaxel was recrystallized to an
average particle size of about 700 nanometers and a particle size
distribution such that greater than 95% of the particles were below
one micron in size as determined by aerodynamic Time-Of-Flight
particle sizing. Eight groups of mice that had previously been
injected with cancerous cells and had developed ovarian cancer were
treated with one of the following: 1) a phosphate buffered saline
alone, used as a control; 2) a Cremophor EL solution alone, used as
a control; 3) paclitaxel in Cremophor EL solution, 12 mg/kg
administered intraperotenel administration; 4) paclitaxel in
Cremophor EL solution, 18 mg/kg injected by IP administration; 5)
paclitaxel in Cremophor solution, 36 mg/kg injected by IP
administration; 6) nanoparticulate paclitaxel suspended in
phosphate buffered saline, 18 mg/kg administered intraperitoneally;
7) nanoparticulate paclitaxel suspended in phosphate buffered
saline, 36 mg/kg administered intraperitoneally; or 8)
nanoparticulate paclitaxel suspended in phosphate buffered saline,
48 mg/kg administered intraperitoneally. The mice were injected
with the treatment, comparative, and control compositions on the
fiftieth day after inoculation with cancer cells. Four doses of the
compositions were injected every other day.
[0042] The longest surviving Cremophor control mouse lasted until
79 days post cancer cell injection. For the phosphate buffered
saline control group, the last member of the control group expired
on day 87. For the paclitaxel in Cremophor group, the last mouse
survived up to day 99 for the 18 mg/kg dose and day 105 for the 12
mg/kg dose. The 36 mg/kg dosage group did not survive treatment.
For the nanoparticulate paclitaxel in phosphate buffer saline
group, administered intraperitoneally, the last mouse survived up
to day 162 for the 18 mg/kg dose, day 181 for the 36 mg/kg does,
and day 220 for the 48 mg/kg does. This represents a significant
increase in survival in comparison to IV administration. The
results of the intraperitoneal injection study are shown in FIG.
2.
[0043] It was determined that intraperitoneal injection of the
suspension of paclitaxel nanoparticulates significantly lengthened
the survival time of the mice in comparison to the intraperitoneal
injection of solubilized paclitaxel in Cremophor. Further, as can
be seen from FIG. 4-FIG. 13, the mouse treated with nanoparticulate
paclitaxel, administered intraperitoneally, developed fewer
cancerous tumors and spreading of the cancer was less aggressive
than the cancer in the saline control mouse. FIG. 4 is a photograph
of the body wall of a mouse treated with the saline control showing
numerous cancerous tumors. FIG. 5 shows the body wall of a mouse
treated with 48 mg/kg of nanoparticulates of paclitaxel in
suspension administered peritoneally and shows few, if any,
cancerous tumors.
[0044] The diaphragm of a mouse treated with the saline control is
depicted in FIG. 6, where numerous cancerous tumors can be seen.
The diaphragm of a mouse treated with 48 mg/kg of nanoparticulates
of paclitaxel in suspension administered peritoneally, as shown in
FIG. 7, does not show the same proliferation of cancerous tumors.
FIG. 8 is a photograph of an external view of a mouse treated with
the saline control where abdominal cavity of the mouse is distended
from the spreading of the cancer and the accumulation of ascetic
fluids. On the other hand, the external view of the mouse treated
with nanoparticulates of paclitaxel in FIG. 9 is normal. FIG. 10 is
a photograph of the kidneys with numerous cancerous tumors of a
mouse treated with the saline control. FIG. 11 is a photograph of
the healthy kidneys of a mouse treated with nanoparticulates of
paclitaxel in suspension administered peritoneally. FIG. 12 is a
photograph of the cancerous growths on the peritoneal organs of a
mouse treated with the saline control, while FIG. 13 does not show
any cancerous growths on the peritoneal organs of a mouse treated
with nanoparticulates of paclitaxel.
EXAMPLE 3
[0045] In this example, nine groups of mice that had previously
been injected with cancerous cells and had developed ovarian cancer
were treated with one of the following: 1) a phosphate buffered
saline alone, used as a control; 2) a Cremophor EL solution alone,
used as a control; 3) paclitaxel in Cremophor EL solution, 18 mg/kg
injected by IP administration; 4) macroparticulate paclitaxel, 18
mg/kg administered intraperitoneally; 5) macroparticulate
paclitaxel, suspended in phosphate buffered saline, 36 mg/kg
administered peritoneally; 6) macroparticulate paclitaxel suspended
in phosphate buffered saline, 48 mg/kg administered
intraperitoneally; 7) nanoparticulate paclitaxel suspended in
phosphate buffered saline, 18 mg/kg administered intraperitoneally;
8) nanoparticulate paclitaxel suspended in phosphate buffered
saline, 36 mg/kg administered intraperitoneally; or 9)
nanoparticulate paclitaxel suspended in phosphate buffered saline,
48 mg/kg administered intraperitoneally. The mice were injected
with the treatment, comparative, and control compositions on the
fiftieth day after inoculation with cancer cells. Four doses of the
compositions were injected every other day.
[0046] The longest surviving Cremophor control mouse lasted until
92 days post cancer cell injection. For the phosphate buffered
saline control group, the last member of the control group survived
until day 93. For the paclitaxel in Cremophor group, the maximal
survival time was to day 115. For the macroparticulate (20-60 .mu.m
particle size) paclitaxel in phosphate buffer saline group, the
maximal survival time was 137 days for the 18 mg/kg dose, 150 days
for the 36 mg/kg dose and 151 days for the 48 mg/kg dose. For the
nanoparticulate paclitaxel in phosphate buffer saline, the last
member of the group expired on day 162 for the 48 mg/kg dosage
group, day 179 for the 36 mg/kg dosage group and day 205 for the 18
mg/kg dosage group. The survival time for mice treated with
macroparticulate paclitaxel was greater than the survival time of
mice treated with paclitaxel in Cremophor. However, the mice
treated with nanoparticulate paclitaxel had the longest survival
time. The results of this intraperitoneal injection study are shown
in FIG. 3.
[0047] The present embodiment of the invention has been described
in relation to particular embodiments which are intended in all
respects to be illustrative rather than restrictive. Alternative
embodiments will become apparent to those skilled in the art to
which the present invention pertains without departing from its
scope. From the foregoing, it will be seen that this invention is
one well adapted to attain all the ends and objects hereinabove set
forth together with other advantages which are obvious and which
are inherent to the compositions and methods of making and using
such compositions herein disclosed. Since many possible embodiments
may be made of the invention without departing from the scope
thereof, it is to be understood that all matter herein set forth or
shown in the accompanying drawing is to be interpreted as
illustrative and not in a limiting sense.
* * * * *