U.S. patent number RE40,493 [Application Number 11/213,257] was granted by the patent office on 2008-09-09 for porous paclitaxel matrices and methods of manufacture thereof.
This patent grant is currently assigned to Acusphere, Inc.. Invention is credited to Howard Bernstein, Donald E. Chickering, III, Sarwat Khattak, Greg Randall, Julie A. Straub.
United States Patent |
RE40,493 |
Straub , et al. |
September 9, 2008 |
Porous paclitaxel matrices and methods of manufacture thereof
Abstract
Paclitaxel is provided in a porous matrix form, which allows the
drug to be formulated without Cremophor and administered as a
bolus. The paclitaxel matrices preferably are made using a process
that includes (i) dissolving paclitaxel in a volatile solvent to
form a paclitaxel solution, (ii) combining at least one pore
forming agent with the paclitaxel solution to form an emulsion,
suspension, or second solution, and (iii) removing the volatile
solvent and pore forming agent from the emulsion, suspension, or
second solution to yield the porous matrix of paclitaxel. The pore
forming agent can be either a volatile liquid that is immiscible
with the paclitaxel solvent or a volatile solid compound,
preferably a volatile salt. In a preferred embodiment, spray drying
is used to remove the solvents and the pore forming agent. In a
preferred embodiment, microparticles of the porous paclitaxel
matrix are reconstituted with an aqueous medium and administered
parenterally, or processed using standard techniques into tablets
or capsules for oral administration.
Inventors: |
Straub; Julie A. (Winchester,
MA), Bernstein; Howard (Cambridge, MA), Chickering, III;
Donald E. (Framingham, MA), Khattak; Sarwat (Hadley,
MA), Randall; Greg (Arlington, MA) |
Assignee: |
Acusphere, Inc. (Watertown,
MA)
|
Family
ID: |
27767912 |
Appl.
No.: |
11/213,257 |
Filed: |
August 26, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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PCT/US00/14578 |
May 25, 2000 |
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60186310 |
Mar 2, 2000 |
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60158659 |
Oct 8, 1999 |
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60136323 |
May 27, 1999 |
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Reissue of: |
09798824 |
Mar 2, 2001 |
06610317 |
Aug 26, 2003 |
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Current U.S.
Class: |
424/489; 424/422;
424/428; 424/484; 514/449; 514/951; 549/512 |
Current CPC
Class: |
A61K
9/1611 (20130101); A61K 9/1623 (20130101); A61K
9/1694 (20130101); A61K 9/1635 (20130101); Y10S
977/906 (20130101) |
Current International
Class: |
A61K
9/14 (20060101); A61F 2/00 (20060101); A61K
9/70 (20060101) |
Field of
Search: |
;424/489,484,422,426
;514/951,449 ;549/512 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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2 136 704 |
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May 1995 |
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CA |
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37 13 326 |
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Oct 1987 |
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DE |
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0 655 237 |
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May 1995 |
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EP |
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1 265 615 |
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Mar 1972 |
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GB |
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WO 91/18590 |
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Dec 1991 |
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WO |
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WO 98/31346 |
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Jul 1998 |
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WO |
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WO 98/51282 |
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Nov 1998 |
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WO |
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WO 99/56731 |
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Nov 1999 |
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WO |
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WO 00/61147 |
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Oct 2000 |
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WO |
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|
Primary Examiner: Richter; Johann R.
Assistant Examiner: Haghighatian; Mina
Attorney, Agent or Firm: Pabst Patent Group LLP
Parent Case Text
This invention claims priority U.S. Ser. No. 60/186,310 filed Mar.
2, 2000, and is a continuation to PCT/US00/14578 filed May 25,
2000, which claims priority to U.S. Ser. No. 60/136,323 filed May
27, 1999, and U.S. Ser. No. 60/158,659 filed Oct. 8, 1999.
Claims
We claim:
1. A pharmaceutical composition comprising a porous matrix formed
of a hydrophilic excipient, a wetting agent and nanoparticles and
microparticles of a taxane, wherein the nanoparticles and
microparticles have a mean diameter between about 0.01 and 5 .mu.m
and a total surface area greater than about .[.0.5 m.sup.2.].
.Iadd.0.5 m.sup.2/mL.Iaddend., wherein the porous matrix is in a
dry powder form, and wherein upon exposure to an aqueous medium,
the matrix dissolves to leave the taxane nanoparticles and
microparticles, wherein the dissolution rate of the taxane
nanoparticles and microparticles in an aqueous solution is
increased relative to unprocessed taxane.
2. The composition of claim 1, wherein the matrix is made by a
process comprising (a) dissolving a taxane in a volatile solvent to
form a taxane solution, (b) combining at least one pore forming
agent, a wetting agent, and a hydrophilic excipient with the taxane
solution to form an emulsion, suspension, or second solution, and
(c) removing the volatile solvent and the pore forming agent from
the emulsion, suspension, or second solution to yield the porous
matrix.
3. The composition of claim 2 wherein the pore forming agent is a
volatile salt.
4. The composition of claim 1 wherein the porous matrix is in a dry
powder form having a TAP density less than or equal to 1.0
g/mL.
5. The composition of claim 1, wherein the matrix comprises at
least one excipient selected from the group consisting of
hydrophilic polymers, sugars, tonicity agents, pegylated
excipients, and combination thereof.
6. The composition of claim 1 wherein the mean diameter of the
taxane microparticles is between about 0.50 and 5 .mu.m.
7. A taxane suspension comprising the composition of claim 1 added
to an aqueous solution suitable for parenteral administration.
8. The composition of claim 1 wherein the matrix is processed into
tablets or capsules suitable for oral administration.
9. The composition of claim 1 wherein the matrix is formed into
suppositories suitable for vaginal or rectal administration.
10. The composition of claim 1 wherein the matrix is in a dry
powder form suitable for pulmonary administration.
11. A method for making a porous matrix of a taxane comprising (a)
dissolving a taxane in a volatile solvent to form a taxane
solution, (b) combining at least one pore forming agent, a wetting
agent, and a hydrophilic excipient with the taxane solution to form
an emulsion, suspension, or second solution, and (c) removing the
volatile solvent and pore forming agent from the emulsion,
suspension, or second solution to yield the porous matrix
comprising nanoparticles and microparticles of taxane, wherein the
dissolution rate of the taxane nanoparticles and microparticles in
an aqueous solution is increased relative to unprocessed
taxane.
12. The method of claim 11 wherein the wetting agent is a
polyoxyethylene sorbitan fatty acid ester.
13. The method of claim 11 wherein step (c) is conducted using a
process selected from spray drying, evaporation, fluid bed drying,
lyophilization, vacuum drying, or a combination thereof.
14. The method of claim 11 wherein the taxane solution or pore
forming agent comprises excipients selected from the group
consisting of hydrophilic excipients, pegylated excipients, and
tonicity agents.
15. The method of claim 11 wherein the pore forming agent is a
volatile salt.
16. The method of claim 15 wherein the volatile salt is selected
from the group consisting of ammonium bicarbonate, ammonium
acetate, ammonium chloride, ammonium benzoate, and mixtures
thereof.
17. A method of treating a patient with a taxane, comprising
administering to a patient in need thereof a therapeutically or
prophylactically effective amount of a taxane .Iadd.to provide
anticancer or antitumor activity .Iaddend.in a formulation
comprising a porous matrix formed of a hydrophilic excipient, a
wetting agent and nanoparticles and microparticles of a taxane,
wherein the nanoparticles and microparticles have a mean diameter
between about 0.01 and 5 .mu.m and a total surface area greater
than about 0.5 m.sup.2/mL, and wherein the porous matrix is in a
dry powder form having a TAP density less than or equal to 1.0 g/mL
wherein upon exposure to an aqueous medium, the matrix dissolves to
leave the taxane nanoparticles and microparticles wherein the
dissolution .[.rare.]. .Iadd.rate .Iaddend.of the taxane
nanoparticles and microparticles in an aqueous solution is
increased relative to unprocessed taxane.
18. The method of claim 17 wherein the formulation is suitable for
administration by a route selected from the group consisting of
parenteral, mucosal, oral, and topical administration.
19. The method of claim 18 wherein the parenteral route is selected
from the group consisting of intravenous, intraarterial,
intracardiac, intrathecal, intraosseous, intraarticular,
intrasynovial, intracutaneous, subcutaneous, and intramuscular
administration.
20. The method of claim 18 wherein the mucosal route is selected
from the group consisting of pulmonary, buccal, sublingual,
intranasal, rectal, and vaginal administration.
21. The method of claim 18 wherein the formulation is suitable for
intraocular or conjunctival administration.
22. The method of claim 18 wherein the formulation is suitable for
intracranial, intralesional, or intratumoral administration.
23. The method of claim 18 wherein the formulation is in an aqueous
solution suitable for parenteral administration.
24. The method of claim 18 wherein the formulation is in a tablet
or capsule suitable for oral administration.
25. The method of claim 18 wherein the formulation is in a
suppository suitable for vaginal or rectal administration.
26. The method of claim 18 wherein the formulation is a dry powder
suitable for pulmonary administration.
27. The composition of claim 1 wherein the taxane is
paclitaxel.
28. The method of claim 11 wherein the taxane is paclitaxel.
29. The method of claim 17 wherein the taxane is paclitaxel.
30. The composition of claim 1 wherein the hydrophilic excipient is
selected from the group consisting of water soluble polymers and
sugars, and the wetting agent is a surfactant.
31. The method of claim 11 wherein the hydrophilic excipient is
selected from the group consisting of water soluble polymers and
sugars, and the wetting agent is a surfactant.
32. The method of claim 17 wherein the hydrophilic excipient is
selected from the group consisting of water soluble polymers and
sugars, and the wetting agent is a surfactant.
.Iadd.33. A method for making a porous matrix comprising
nanoparticles and microparticles of paclitaxel, the method
comprising (a) dissolving paclitaxel in a volatile solvent to form
a paclitaxel solution, (b) combining at least one pore forming
agent including ammonium bicarbonate, a polyoxyethylene sorbitan
fatty acid ester, and polyvinylpyrrolidone with the paclitaxel
solution to form an emulsion, suspension, or second solution, and
(c) removing the volatile solvent and pore forming agent from the
emulsion, suspension, or second solution to yield the porous matrix
comprising nanoparticles and microparticles of paclitaxel, wherein
the dissolution rate of the paclitaxel nanoparticles and
microparticles in an aqueous solution is increased relative to
unprocessed paclitaxel..Iaddend.
.Iadd.34. The method of claim 33, wherein the polyoxyethylene
sorbitan fatty acid ester is polysorbate 80..Iaddend.
.Iadd.35. The method of claim 33, wherein step (b) further
comprises adding a sugar to the paclitaxel solution..Iaddend.
.Iadd.36. The method of claim 35, wherein the sugar is
mannitol..Iaddend.
.Iadd.37. A pharmaceutical composition comprising a porous matrix
formed of polyvinylpyrrolidone, a polyoxyethylene sorbitan fatty
acid ester and nanoparticles and microparticles of paclitaxel,
wherein the nanoparticles and microparticles have a mean diameter
between about 0.01 and 5 .mu.m and a total surface area greater
than about 0.5 m.sup.2/mL, wherein the porous matrix is in a dry
powder form, and wherein upon exposure to an aqueous medium, the
matrix dissolves to leave the paclitaxel nanoparticles and
microparticles, wherein the dissolution rate of the paclitaxel
nanoparticles and microparticles in an aqueous solution is
increased relative to unprocessed paclitaxel..Iaddend.
.Iadd.38. The composition of claim 37, wherein the polyoxyethylene
sorbitan fatty acid ester is polysorbate 80..Iaddend.
.Iadd.39. The composition of claim 37, further comprising a
sugar..Iaddend.
.Iadd.40. The composition of claim 39, wherein the sugar is
mannitol..Iaddend.
.Iadd.41. A method of treating a patient with a paclitaxel
formulation, comprising administering to a patient in need thereof
a therapeutically or prophylactically effective amount of
paclitaxel to provide anticancer or antitumor activity in a
formulation comprising a porous matrix formed of
polyvinylpyrrolidone, a polyoxyethylene sorbitan fatty acid ester
and nanoparticles and microparticles of paclitaxel, wherein the
nanoparticles and microparticles have a mean diameter between about
0.01 and 5 .mu.m and a total surface area greater than about 0.5
m.sup.2/mL, and wherein the porous matrix is in a dry powder form
having a TAP density less than or equal to 1.0 g/mL, wherein upon
exposure to an aqueous medium, the matrix dissolves to leave the
paclitaxel nanoparticles and microparticles wherein the dissolution
rate of the paclitaxel nanoparticles and microparticles in an
aqueous solution is increased relative to unprocessed
taxane..Iaddend.
.Iadd.42. The method of claim 41, wherein the polyoxyethylene
sorbitan fatty acid ester is polysorbate 80..Iaddend.
.Iadd.43. The method of claim 41, wherein the formulation further
comprises a sugar..Iaddend.
.Iadd.44. The method of claim 43, wherein the sugar is
mannitol..Iaddend.
.Iadd.45. The composition of claim 1, wherein the hydrophilic
excipient is the wetting agent..Iaddend.
.Iadd.46. The method of claim 11, wherein the hydrophilic excipient
is the wetting agent..Iaddend.
.Iadd.47. The method of claim 17 wherein the hydrophilic excipient
is the wetting agent..Iaddend.
Description
BACKGROUND OF THE INVENTION
This invention generally relates to formulations of paclitaxel and
more particularly to methods of making formulations of
paclitaxel.
Paclitaxel is a natural product which has been shown to possess
cytotoxic and antitumor activity. Indeed, paclitaxel may be among
the most active single agent for ovarian and breast cancers. This
compound is found in small concentrations in the Taxus brevifolia
species such as the Pacific yew tree among other Taxus species.
While having an unambiguous reputation of tremendous therapeutic
potential, paclitaxel as a therapeutic agent has some patient
related drawbacks. These stem, in part, from its extremely low
solubility in water, which makes it difficult to provide in
suitable dosage form. Because of paclitaxel's poor aqueous
solubility, the current approved clinical formulation consists of a
6 mg/ml solution of paclitaxel in 50% polyoxyethylated castor oil
(CREMOPHOR EL.TM.) and 50% dehydrated alcohol. Am. J. Hosp. Pharm.
48:1520-24 (1991). In some instances, severe reactions, including
hypersensitivity, occur in conjunction with the CREMOPHOR.TM.
administered in conjunction with paclitaxel to compensate for its
low water solubility. As a result of the incidence of
hypersensitivity reactions to the commercial paclitaxel
formulations and the potential for paclitaxel precipitation in the
blood, the formulation must be infused over several hours. In
addition, patients must be pretreated with steroids and
antihistamines prior to the infusion.
In response to the hypersensitivity related to the CREMOPHOR.TM.,
the increasing recognition of paclitaxel's promise as an
antineoplastic, and the undesirability of having to infuse the
paclitaxel over several hours, there remains a need to develop
improved formulations of the paclitaxel which can be administered
as bolus injections.
It is therefore an object of the present invention to provide
compositions of the paclitaxel without the solubilizing agent,
CREMOPHOR.TM. which is present in the commercial formulation.
It is another object of the present invention to provide methods
for producing the porous dry powder formulations of paclitaxel or
docetaxol.
It is another object of the present invention to provide
compositions providing enhanced dissolution of paclitaxel or
docetaxol in a formulation suitable for administration by a variety
of routes, including, but not limited to, parenteral, mucosal,
oral, and topical administration, for local, regional, or systemic
effect.
It is further object of the present invention to provide paclitaxel
compositions for administration as a bolus injection instead of by
infusion.
SUMMARY OF THE INVENTION
Paclitaxel is provided in a porous matrix form which forms
nanoparticles and microparticles of paclitaxel when the matrix is
contacted with an aqueous medium. The porous matrix with paclitaxel
yields upon contact with an aqueous medium microparticles having a
mean diameter between about 0.01 and 5 .mu.m and a total surface
area greater than about 0.5 m.sup.2/mL. The dry porous matrix is in
a dry powder form having a TAP density less than or equal to 1.0
g/mL.
The porous matrices that contain the paclitaxel are preferably made
using a process that includes (i) dissolving a paclitaxel in a
volatile solvent to form a paclitaxel solution, (ii) combining at
least one pore forming agent with the paclitaxel solution to form
an emulsion, suspension, or second solution, and (iii) removing the
volatile solvent and pore forming agent from the emulsion,
suspension, or second solution to yield the dry porous matrix of
paclitaxel. The resulting porous matrix has a faster rate of
dissolution following administration to a patient, as compared to
non-porous matrix forms of the paclitaxel. The pore forming agent
can be either a volatile liquid that is immiscible with the
paclitaxel solvent or a volatile solid compound, preferably a
volatile salt. If the pore forming agent is a liquid, the agent is
emulsified with the paclitaxel solution. If the pore forming agent
is a solid, the agent is (i) dissolved in the paclitaxel solution,
(ii) dissolved in a solvent that is not miscible in the paclitaxel
solvent and then emulsified with the paclitaxel solution, or (iii)
suspended as solid particulates in the paclitaxel solution.
Optionally, hydrophilic excipients, wetting agents, and/or tonicity
agents may be added to the paclitaxel solvent, the pore forming
agent solvent, or both. The solution, emulsion, or suspension of
the pore forming agent in the paclitaxel solution is then processed
to remove the paclitaxel solvent and the pore forming agent, as
well as any pore forming agent solvent. In a preferred embodiment,
spray drying, optionally followed by lyophilization, fluid bed
drying, or vacuum drying, is used to remove the solvents and the
pore forming agent.
An advantage of the formulations is that they can be administered
as a bolus, when the paclitaxel normally must be infused to avoid
toxicity and to avoid precipitation of the drug. By avoiding
precipitation of paclitaxel in vivo, the formulations can also be
administered intrarterially, intravenously, locally,
intracranially, intrathecally, or directly into a tumor. An
additional advantage is the formulations can be administered in
reduced volumes.
In one embodiment, the matrix further includes a pegylated
excipient with the paclitaxel. The pegylated excipient shields the
paclitaxel from macrophage uptake, which prolong its half-life or
enhance bioavailability of the paclitaxel.
In a preferred embodiment, the porous paclitaxel matrix is
reconstituted with an aqueous medium and administered parenterally,
such as intramuscularly, subcutaneously, or intravenously.
Alternatively, the porous paclitaxel matrix can be further
processed using standard techniques into tablets or capsules for
oral administration or into rectal suppositories, delivered using a
dry powder inhaler for pulmonary administration, or mixed/processed
into a cream or ointment for topical administration.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph of the in vitro dissolution rate (percent
dissolved versus time) for non-formulated and various formulated
paclitaxel in porous matrix form.
FIG. 2 is a graph of median MDA-MB 435 breast tumor weight in
female athymic NCr-nu mice following five days of therapy with
paclitaxel in porous matrix form.
DETAILED DESCRIPTION OF THE INVENTION
Compositions of paclitaxel without the solubilizing agent,
CREMOPHOR.TM., and which can be administered as a bolus are
disclosed. The compositions are porous dry powders, which upon the
addition of an aqueous medium form a suspension of paclitaxel
nanoparticles and microparticles. Methods for producing the
formulations of paclitaxel include using pore forming agents. The
compositions may contain hydrophilic excipients, such as water
soluble polymers and sugars, and wetting agents, such as
surfactants.
I. Paclitaxel Matrix Compositions
The porous paclitaxel matrix is at least 1 to 95%, preferably at
least about 10%, and more preferably between about 10 and 70%,
paclitaxel by weight. The matrices also may contain hydrophilic
excipients such as water soluble polymers or sugars, wetting agents
such as surfactants, and tonicity agents.
The matrix must yield microparticles of paclitaxel, upon contact
with an aqueous medium which preferably have a diameter between
about 10 nm and 5 .mu.m, more preferably between about 50 nm and 5
.mu.m. The average total surface area of the microparticles
contained within the porous matrix, which typically is in the form
of a dry powder, is 0.5 m.sup.2/mL or greater. Total surface area
values of the microparticles can be determined using standard
particle sizing equipment and techniques.
The paclitaxel matrix must be sufficiently porous to yield
microparticles, upon contact with an aqueous medium, having these
parameters. Measurements useful in characterizing the porosity of
the paclitaxel matrix are the bulk density or the transaxial
pressure ("TAP") density of the dry porous matrix (dry powder) and
the total surface area (sum of internal and external surface area)
of the dry porous matrix. The TAP density preferably is less than
about 1.0 g/ml, more preferably less than 0.8 g/ml. This level of
porosity of the matrix, characterized by density, provides
sufficient surface area to enhance wetting of the dry porous matrix
and enhance paclitaxel dissolution.
The total surface area (sum of internal and external surface area)
of the porous matrix can be measured, for example, by BET surface
area analysis. In some embodiments, the total surface area of the
porous matrix preferably is greater than 0.1 m.sup.2/g, more
preferably greater than or equal to 0.2 m.sup.2/g. This level of
total surface area provides sufficient surface area to enhance
wetting of the dry porous matrix and enhance drug dissolution.
1. Paclitaxel
As generally used in the description herein, "paclitaxel" includes
taxanes and derivatives thereof, including paclitaxel and
docetaxel, which have anticancer or antiangiogenic activity.
Paclitaxel was specifically used in the examples which follow.
2. Excipients
The matrices may contain hydrophilic excipients, such as water
soluble polymers or sugars, which can serve as bulking agents or as
wetting agents, wetting agents such as surfactants or sugars, and
tonicity agents. Upon contact with an aqueous medium, water
penetrates through the highly porous matrix to dissolve the water
soluble excipients in the matrix. A suspension of paclitaxel
particles in the aqueous medium remains. The total surface area of
the resultant low aqueous solubility paclitaxel microparticles is
increased relative to the unprocessed paclitaxel and the
dissolution rate of the paclitaxel is increased.
One of skill in the art can select appropriate excipients for use
in the paclitaxel matrix compositions, considering a variety of
factors, such as the paclitaxel to be administered, the route of
administration, the dosage, and the preferred dissolution rate. For
example, the excipients can function as bulking agents,
release-modifiers, wetting agents, tonicity agents, or combinations
thereof. Preferred excipients include hydrophilic polymers, wetting
agents, and sugars. The amount of excipient in the paclitaxel
matrix is less than about 95%, more preferably less than about 80%,
by weight of the paclitaxel matrix.
The hydrophilic excipients, wetting agents, and tonicity agents may
be added to the paclitaxel solution, the pore forming agent, or
both, during production of the matrix.
(i) Hydrophilic Polymers
The polymers that can be used in the paclitaxel matrices described
herein include both synthetic and natural polymers, either
non-biodegradable or biodegradable. Representative synthetic
polymers include polyethylene glycol ("PEG"), polyvinyl
pyrrolidone, polymethacrylates, polylysine, poloxamers, polyvinyl
alcohol, polyacrylic acid, polyethylene oxide, and
polyethyoxazoline. Representative natural polymers include albumin,
alginate, gelatin, acacia, chitosan, cellulose dextran, ficoll,
starch, hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxy-propylmethyl cellulose, hyaluronic acid, carboxyethyl
cellulose, carboxymethyl cellulose, deacetylated chitosan, dextran
sulfate, and derivatives thereof. Preferred hydrophilic polymers
include PEG, polyvinyl pyrrolidone, poloxamers, hydroxypropyl
cellulose, and hydroxyethyl cellulose.
The hydrophilic polymer selected for use in a particular paclitaxel
matrix formulation is based on a variety of factors, such as the
polymer molecular weight, polymer hydrophilicity, and polymer
inherent viscosity. The hydrophilic polymer can be used as a
bulking agent or as a wetting agent.
(ii) Sugars
Representative sugars that can be used in the paclitaxel matrices
include mannitol, sorbitol, xylitol, glucitol, ducitol, inositiol,
arabinitol, arabitol, galactitol, iditol, allitol, fructose,
sorbose, glucose, xylose, trehalose, allose, dextrose, altrose,
gulose, idose, galactose, talose, ribose, arabinose, xylose,
lyxose, sucrose, maltose, lactose, lactulose, fucose, rhamnose,
melezitose, maltotriose, and raffinose. Preferred sugars include
mannitol, lactose, sucrose, sorbitol, trehalose, glucose, and are
adjusted to provide osmolality if administered parenterally or to
provide wetting of the porous paclitaxel matrix or the paclitaxel
microparticles within the matrix.
(iii) Wetting Agents
Wetting agents can be used to facilitate water ingress into the
matrix and wetting of the paclitaxel particles in order to
facilitate dissolution.
Representative examples of wetting agents include gelatin, casein,
lecithin (phosphatides), gum acacia, cholesterol, tragacanth,
stearic acid, benzalkonium chloride, calcium stearate, glycerol
monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax,
sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol
ethers such as cetomacrogol 1000), polyoxyethylene castor oil
derivatives, polyoxyethylene sorbitan fatty acid esters (e.g.,
TWEEN.TM.s), polyethylene glycols, polyoxyethylene stearates,
colloidal silicon dioxide, phosphates, sodium dodecylsulfate,
carboxymethylcellulose calcium, carboxymethylcellulose sodium,
methylcellulose, hydroxyethylcellulose, hydroxy propylcellulose,
hydroxypropylmethylcellulose phthlate, noncrystalline cellulose,
magnesium aluminum silicate, triethanolamine, polyvinyl alcohol,
and polyvinylpyrrolidone (PVP). Tyloxapol (a nonionic liquid
polymer of the alkyl aryl polyether alcohol type, also known as
superinone or triton) is another useful wetting agent. Most of
these wetting agents are known pharmaceutical excipients and are
described in detail in the Handbook of Pharmaceutical Excipients,
published jointly by the American Pharmaceutical Association and
The Pharmaceutical Society of Great Britain (The Pharmaceutical
Press, 1986).
Preferred wetting agents include polyvinylpyrrolidone, polyethylene
glycol, tyloxapol, poloxamers such as PLURONIC.TM. F68, F127, and
F108, which are block copolymers of ethylene oxide and propylene
oxide, and polyxamines such as TETRONIC.TM. 908 (also known as
POLOXAMINE.TM. 908), which is a tetrafunctional block copolymer
derived from sequential addition of propylene oxide and ethylene
oxide to ethylenediamine (available from BASF), dextran, lecithin,
dialkylesters of sodium sulfosuccinic acid such as AEROSOL.TM. OT,
which is a dioctyl ester of sodium sulfosuccinic acid (available
from American Cyanimid), DUPONOL.TM. P, which is a sodium lauryl
sulfate (available from DuPont), TRITON.TM. X-200, which is an
alkyl aryl polyether sulfonate (available from Rohm and Haas),
TWEEN.TM. 20 .Iadd.(polysorbate 20).Iaddend.and TWEEN.TM. 80
.Iadd.(polysorbate 80).Iaddend., which are polyoxyethylene sorbitan
fatty acid esters (available from ICI Specialty Chemicals),
Carbowax 3550 and 934, which are polyethylene glycols (available
from Union Carbide), CRODESTA.TM., which is a mixture of sucrose
stearate and sucrose distearate, and CRODESTA.TM. SL-40 (both
available from Croda Inc.), and SA90HCO, which is
C.sub.18H.sub.37CH.sub.2(CON(CH.sub.3)CH.sub.2(CHOH).sub.4CH.sub.2OH).sub-
.2.
Wetting agents which have been found to be particularly useful
include TETRONIC.TM. CRODESTA.TM. 908, the TWEENS.TM., PLURONIC.TM.
F-68 and polyvinylpyrrolidone. Other useful wetting agents include
decanoyl-N-methylglucamide; n-decyl-.beta.-D-glucopyranoside;
n-decyl-.beta.-D-maltopyranoside;
n-dodecyl-.beta.-D-glucopyranoside; n-dodecyl .beta.-D-maltoside;
heptanoyl-N-methylglucamide; n-heptyl-.beta.-D-glucopyranoside;
n-heptyl-.beta.-D-thioglucoside; n-hexyl-.beta.-D-glucopyranoside;
nonanoyl-N-methylglucamide; n-noyl-.beta.-D-glucopyranoside;
octanoyl-N-methylglucamide; n-octyl-.beta.-D-glucopyranoside; and
octyl-.beta.-D-thioglucopyranoside. Another preferred wetting agent
is P-isononylphenoxypoly(glycidol), also known as OLIN.TM.-10G or
Surfactant 10-G (commercially available as 10G from Olin
Chemicals). Two or more wetting agents can be used in
combination.
(iv) Tonicity or Osmolality Agents
The porous paclitaxel matrices may include one or more tonicity
agents, such as salts (e.g., as sodium chloride or potassium
chloride) or sugars (such as mannitol, dextrose, sucrose, or
trehalose) to adjust a hypotonic solution of a paclitaxel to
isotonic so that the paclitaxel, when in solution, is
physiologically compatible with the cells of the body tissue of the
patient. The type and amount of tonicity agent can be selected by
one of skill in the art using known techniques.
(v) Pegylated Excipients
In one embodiment, the matrix further includes a pegylated
excipient. Such pegylated excipients include, but are not limited
to, pegylated phospholipids, pegylated proteins, pegylated
peptides, pegylated sugars, pegylated polysaccharides, pegylated
block co-polymers with of the blocks being PEG, and pegylated
hydrophobic compounds such as pegylated cholesterol. The pegylated
excipient beneficially envelops or shields the paclitaxel from
macrophage uptake, which prolongs its half-life or enhances
bioavailability of the paclitaxel.
Representative examples of pegylated phospholipids include
1,2-diacyl-sn-glycero-3-phosphoethanolamine-N-[Poly(ethyleneglycol)
2000] ("PEG 2000 PE") and
1,2-diacyl-sn-glycero-3-phosphoethanolamine-N-[Poly (ethylene
glycol) 5000] ("PEG 5000 PE"), where the acyl group is selected,
for example, from dimyristoyl, dipalmitoyl, distearoyl, diolcoyl,
and 1-palmitoyl-2-oleoyl.
Other polyalkyleneoxides can be used in place of the polyethylene
glycol.
II. Volatile Solvents
The choice of solvent depends on the paclitaxel. In a preferred
embodiment, the solvent is an organic solvent that is volatile, has
a relatively low boiling point, or can be removed under vacuum, and
which is acceptable for administration to humans in trace amounts.
Representative solvents include acetic acid, acetaldehyde dimethyl
acetal, acetone, acetonitrile, chloroform, chlorofluorocarbons,
dichloromethane, dipropyl ethyl, diisopropyl ether,
N,N-dimethylformamide (DMF), formamide, demethyl sulfoxide (DMSO),
dioxane, ethanol, ethyl acetate, ethyl formate, ethyl vinyl ether,
methyl ethyl ketone (MEK), glycerol, heptane, hexane, isopropanol,
methanol, isopropanol, butanol, triethylamine, nitromethane,
octane, pentane, tetrahydrofuran (THF), toluene,
1,1,1-trichloroethane, 1,1,2-trichloroethylene, water, xylene, and
combinations thereof. In general, the paclitaxel is dissolved in
the volatile solvent to form a paclitaxel solution having a
concentration of between 0.01 and 80% weight to volume (w/v), more
preferably between 0.025 and 30% (w/v).
Aqueous solvents or mixtures of aqueous and organic solvents, such
as water-alcohol mixtures, can be used to dissolve the drug. In a
preferred embodiment the volatile solvent is an aqueous mixture of
an alcohol such as methanol or ethanol where the alcohol percent is
in the range 40-100% (v/v).
III. Pore Forming Agents
Pore forming agents are volatile materials that preferably are used
during the process to create porosity in the resultant matrix. The
pore forming agent can be a volatilizable solid or volatilizable
liquid.
1. Liquid Pore Forming Agent
The liquid pore forming agent must be immiscible with the
paclitaxel solvent and volatilizable under processing conditions
compatible with the paclitaxel. To effect pore formation, the pore
forming agent first is emulsified with the paclitaxel solvent.
Then, the emulsion is further processed to remove the paclitaxel
solvent and the pore forming agent simultaneously or sequentially
using evaporation, vacuum drying, spray drying, fluid bed drying,
lyophilization, or a combination of these techniques.
The selection of liquid pore forming agents will depend on the
paclitaxel solvent. Representative liquid pore forming agents
include water; dichloromethane; alcohols such as ethanol, methanol,
or isopropanol; acetone; ethyl acetate; ethyl formate;
dimethylsulfoxide; acetonitrile; toluene; xylene; dimethylforamide;
ethers such as THF, diethyl ether, or dioxane; triethylamine;
foramide; acetic acid; methyl ethyl ketone; pyridine; hexane;
pentane; furan; water; and cyclohexane.
The liquid pore forming agent typically is used in an amount that
is between 1 and 50% (v/v), preferably between 5 and 25% (v/v), of
the paclitaxel solvent emulsion.
2. Solid Pore Forming Agent
The solid pore forming agent must be volatilizable under processing
conditions which do not harm the paclitaxel compositions. The solid
pore forming agent can be (i) dissolved in the paclitaxel solution,
(ii) dissolved in a solvent which is not miscible with the
paclitaxel solvent to form a solution which is then emulsified with
the paclitaxel solution, or (iii) added as solid particulates to
the paclitaxel solution. The solution, emulsion, or suspension of
the pore forming agent in the paclitaxel solution then is further
processed to remove the paclitaxel solvent, the pore forming agent,
and, if appropriate, the solvent for the pore forming agent
simultaneously or sequentially using evaporation, spray drying,
fluid bed drying, lyophilization, vacuum drying, or a combination
of these techniques.
In a preferred embodiment, the solid pore forming agent is a
volatile salt, such as salts of volatile bases combined with
volatile acids. Volatile salts are materials that can transform
from a solid or liquid to a gaseous state using added heat and/or
vacuum. Examples of volatile bases include ammonia, methylamine,
ethylamine, dimethylamine, diethylamine, methylethylamine,
trimethylamine, triethylamine, and pyridine. Examples of volatile
acids include carbonic acid, hydrochloric acid, hydrobromic acid,
hydroiodic acid, formic acid, acetic acid, propionic acid, butyric
acid, and benzoic acid. Preferred volatile salts include ammonium
bicarbonate, ammonium acetate, ammonium chloride, ammonium benzoate
and mixtures thereof.
Other examples of solid pore forming agents include iodine, phenol,
benzoic acid (as acid not as salt), and naphthalene.
The solid pore forming agent is used in an amount between 0.5 and
1000% (w/w), preferably between 1 and 600% (w/w), and more
preferably between 1 and 100% (w/w), of the paclitaxel.
IV. Method of Making the Porous Paclitaxel Matrix
The paclitaxel matrices preferably are made by (i) dissolving
paclitaxel in a volatile solvent to form a paclitaxel solution,
(ii) combining at least one pore forming agent with the paclitaxel
solution to form an emulsion, suspension, or second solution, and
(iii) removing the volatile solvent and pore forming agent from the
emulsion, suspension, or second solution. In a preferred
embodiment, spray drying, optionally followed by lyophilization or
vacuum drying, is used to remove the solvents and the pore forming
agent. The removal of the pore forming agent can be conducted
simultaneously with or following removal of enough solvent to
solidify the droplets. Production can be carried out using
continuous, batch, or semi-continuous processes.
First, paclitaxel is dissolved in an appropriate solvent. The
concentration of the paclitaxel in the resulting paclitaxel
solution typically is between about 0.01 and 80% (w/v), preferably
between about 0.025 and 30% (w/v).
Next, the paclitaxel solution is combined, typically under mixing
conditions, with the pore forming agent or solution thereof. If a
liquid pore forming agent is used, it is first emulsified with the
paclitaxel solution to form droplets of pore forming agent
dispersed throughout the paclitaxel solution. If a solid pore
forming agent is used, it is dissolved either directly in the
paclitaxel solution to form a solution of paclitaxel/pore forming
agent, or it is first dissolved in a second solvent. If the second
solvent is immiscible with the paclitaxel solvent, the solution of
the pore forming agent is emulsified with the paclitaxel solution
to form droplets of the pore forming agent solution dispersed
throughout the paclitaxel solution. If the second solvent is
miscible with the paclitaxel solution, the two solutions are mixed
to form a single solution. A solid pore forming agent alternatively
can be added directly to the paclitaxel solution as solid
particulates, preferably between about 10 nm and 10 .mu.m in size,
to form a suspension of pore forming agent in the paclitaxel
solution. Subsequently, the solid pore forming agent particle size
can be reduced by further processing the resulting suspension, for
example, using homogenization or sonication techniques known in the
art.
Then, the solution, emulsion, or suspension is further processed to
remove the paclitaxel solvent and the pore forming agent
simultaneously or sequentially, using evaporation, spray drying,
fluid bed drying, lyophilization, vacuum drying, or a combination
of these techniques. In a preferred embodiment, the solution,
emulsion, or suspension is spray-dried. As used herein, "spray dry"
means to atomize the solution, emulsion, or suspension to form a
fine mist of droplets (of paclitaxel solution having solid or
liquid pore forming agent dispersed throughout), which immediately
enter a drying chamber (e.g., a vessel, tank, tubing, or coil)
where they contact a drying gas. The solvent and pore forming
agents evaporate from the droplets into the drying gas to solidify
the droplets, simultaneously forming pores throughout the solid.
The solid (typically in a powder, particulate form) then is
separated from the drying gas and collected.
The temperature of the inlet and outlet ports of the drying
chamber, as well as the flow rates of the feed solution,
atomization gas, and drying gas, can be controlled to produce the
desired products. In a particularly preferred embodiment, the spray
drying methods described in U.S. Pat. No. 5,853,698 to Straub et
al., which is hereby incorporated by reference, are adapted to make
the paclitaxel matrices described herein.
The paclitaxel present in the solids or powder produced may be in a
crystalline or an amorphous state, or may be mixture of such
states. The state generally depends on how the droplets are dried
and the excipients present.
Emulsion Stabilization
In embodiments in which at least one pore forming agent is combined
with the paclitaxel solution to form an emulsion, a surfactant or
emulsifying agent can be added to enhance the stability of the
emulsion. A variety of surfactants may be incorporated in this
process, preferably to an amount between 0.1 and 5% by weight.
Exemplary emulsifiers or surfactants which may be used include most
physiologically acceptable emulsifiers, for instance egg lecithin
or soya bean lecithin, or synthetic lecithins such as saturated
synthetic lecithins, for example, dimyristoyl phosphatidyl choline,
dipalmitoyl phosphatidyl choline or distearoyl phosphatidyl choline
or unsaturated synthetic lecithins, such as dioleyl phosphatidyl
choline or dilinoleyl phosphatidyl choline. Other hydrophobic or
amphipathic compounds can be used in place of the phospholipid, for
example, cholesterol. Emulsifiers also include surfactants such as
free fatty acids, esters of fatty acids with polyoxyalkylene
compounds like polyoxypropylene glycol and polyoxyethylene glycol;
ethers of fatty alcohols with polyoxyalkylene glycols; esters of
fatty acids with polyoxyalkylated sorbitan; soaps;
glycerol-polyalkylene stearate; glycerol-polyoxyethylene
ricinoleate; homo- and co-polymers of polyalkylene glycols;
polyethoxylated soya-oil and castor oil as well as hydrogenated
derivatives; ethers and esters of sucrose or other carbohydrates
with fatty acids, fatty alcohols, these being optionally
polyoxyalkylated; mono-, di- and tri-glycerides of saturated or
unsaturated fatty acids, glycerides of soya-oil and sucrose.
Other emulsifiers include natural and synthetic forms of bile salts
or bile acids, both conjugated with amino acids and unconjugated
such as taurodeoxycholate and cholic acid.
V. Paclitaxel Matrix Applications
The paclitaxel matrices described herein are useful in formulations
for administration to a patient in need of the paclitaxel. As used
herein, "patient" refers to animals, including mammals, preferably
humans. The porous matrices or formulations thereof are suitable
for administration of the paclitaxel by a variety of routes, for
example, parenteral, mucosal, oral, topical/transdermal
administration, for local, regional, or systemic effect. Examples
of parenteral routes include intravenous, intrarterial,
intracardiac, intrathecal, intraosseous, intraarticular,
intrasynovial, intracutaneous, subcutaneous, and intramuscular.
Examples of mucosal routes include pulmonary (intrarespiratory),
buccal, sublingual, intranasal, rectal, and vaginal administration.
The porous matrices can be formulated for intraocular,
conjunctival, aural, urethral, intracranial, intralesional, and
intratumoral administration.
In a preferred embodiment, the paclitaxel matrix is in the form of
powder, which can be reconstituted with an aqueous medium, such as
physiological saline, and administered parenterally, such as
intramuscularly, subcutaneously, or intravenously. An advantage of
the formulations described herein is that they can be used to
convert paclitaxel which must be infused (e.g., to avoid
precipitation of the paclitaxel following bolus injection) to a
bolus formulation, avoiding unacceptable precipitation of
paclitaxel in vivo or for local delivery.
Alternatively, the matrix can be further processed using standard
techniques into tablets or capsules for oral administration. These
techniques are described, for example, in Ansel, et al.,
"Pharmaceutical Dosage Forms and Paclitaxel Delivery Systems,"
6.sup.th Ed., (Williams & Wilkins 1995), which is incorporated
herein by reference.
The present invention will be further understood with reference to
the following non-limiting examples.
Overview
Examples 1-2 demonstrate production of paclitaxel matrices using
different wetting agents and different solvents.
Examples 3-4 describe the analyses which were used to characterize
the porous paclitaxel matrices produced in Examples 1-2. These
characteristics include density and dissolution properties.
Example 6 describes the antitumor activity of the paclitaxel
formulation produced in example 5 in female athymic NCr-nu mice in
which the MDA-MB 435 breast tumor has been implanted subcutaneously
(sc).
Materials and Equipment
The following materials and equipment were used in the examples.
PEG 3350, polyvinylpyrrolidone K-15, TWEEN.TM. 80, and ammonium
bicarbonate, were obtained from Spectrum Chemicals (Gardena,
Calif.). Paclitaxel was obtained from Hauser (Boulder, Colo.).
Methylene chloride was obtained from EM Science (Gibbstown, N.J.).
All emulsions were produced using a Virtis IQ.sup.2 homogenizer
(Virtis, Gardiner, N.Y.). Formulations were spray dried on a
benchtop spray dryer using an air atomizing nozzle.
Example 1
Production of a Porous Paclitaxel Matrix Using Ammonium Bicarbonate
as a Pore Forming Agent
A paclitaxel-loaded organic solution was prepared by dissolving 1.0
g of paclitaxel, 0.10 g of TWEEN.TM. 80, and 0.10 g of
polyvinylpyrrolidone K-15 in 160 ml of ethanol. An aqueous solution
composed of 0.42 g of ammonium bicarbonate and 1.0 g of mannitol in
40 ml of DI water was added to the ethanol solution and mixed. The
resulting 80% ethanol solution was spray dried on a benchtop spray
dryer using an air-atomizing nozzle and nitrogen as the drying gas.
Spray drying conditions were as follows: 20 ml/min solution flow
rate, 60 L/min atomization gas rate, 100 kg/hr drying gas rate, and
55.degree. C. outlet.
Example 2
Production of a Porous Paclitaxel Matrix Using Ammonium Bicarbonate
as a Pore Forming Agent
A paclitaxel-loaded organic solution was prepared by dissolving 0.4
g of paclitaxel, 0.10 g of TWEEN.TM. 80, and 0.04 g of
polyvinylpyrrolidone K-15 in 160 ml of ethanol. An aqueous solution
composed of 0.30 g of ammonium bicarbonate and 1.0 g of mannitol in
40 ml of DI water was added to the ethanol solution and mixed. The
resulting 80% ethanol solution was spray dried on a benchtop spray
dryer using an air-atomizing nozzle and nitrogen as the drying gas.
Spray drying conditions were as follows: 20 ml/min solution flow
rate, 60 L/min atomization gas rate, 100 kg/hr drying gas rate, and
55.degree. C. outlet temperature.
Example 3
In Vitro Dissolution of Porous Paclitaxel Matrices
The in vitro dissolution rates of the powders produced in Examples
1-2 were compared to the dissolution rates of the non-formulated
paclitaxel.
Analytical Methods
Studies were conducted in PBS containing 0.08% TWEEN.TM. 80
(T80/PBS). T80/PBS (10 mL) was added to an appropriate amount of
material being tested to contain 5 mg of paclitaxel in a 15 mL
polypropylene conical tube, and the suspension was vortexed for 3-4
minutes. The suspension (0.25 mL) was then added to 250 mL of
T80/PBS in a 600 mL glass beaker for dissolution analysis. All
dissolution studies were conducted using overhead mixing. The mixer
used was an IKARW16 Basic Mixer with a R1342 impeller shaft running
at stirring rate 5. Samples were removed via pipette, filtered
through 0.22 micron CA syringe filter, and then analyzed.
Dissolution curves are presented as percent of complete
dissolution.
HPLC analysis was performed directly on the filtered aqueous
solutions using High Pressure Liquid Chromatography ("HPLC")
(Hewlett Packard Series 1100 HPLC). The chromatographic conditions
included a Nucleosil column (5:m, C18, 100A, 250.times.4.6 mm), a
mobile phase of 2 mM H.sub.3PO.sub.4/Acetonitrile (2:3) at a flow
rate of 1.5 mL/min, UV detection at 227 nm, and a run time of 25
min.
Results
The in vitro dissolution rates of the porous paclitaxel matrices
produced in examples 1-2 are provided in FIG. 1. The in vitro
dissolution of the porous paclitaxel matrices are compared to the
bulk paclitaxel of interest. In all cases, the time for 80%
dissolution of the porous paclitaxel matrices is greater than 1000
times shorter than the time for 80% of the bulk paclitaxel to
dissolve. The rate of dissolution which is approximated as the
slope of the curve is greater than 1000 times greater for the
porous paclitaxel matrices of Examples 1-2 as compared to the
specific bulk paclitaxel of interest.
Example 4
Density of Porous Paclitaxel Matrices
The densities of the dry powder produced in Examples 1-2 are
summarized in Table 1. Density was measured using Transaxial
Pressure ("TAP") with a Micromeritics GeoPyc 1360 using a
consolidation force of 8 Newtons. The density of the porous
matrices is less than 1.0 g/mL for Examples 1-2.
TABLE-US-00001 TABLE 1 Particle Density Analysis Material Density
(g/mL) Example 1 0.67 Example 2 0.52
Example 5
Production of a Porous Paclitaxel Matrix For Testing in Animal
Tumor Model
A paclitaxel-loaded organic solution was prepared by dissolving 2.0
g of paclitaxel, 0.20 g of polyvinylpyrrolidone, and 0.20 g of
TWEEN.TM. 80 in 320 ml of ethanol. An aqueous solution composed of
0.85 g of ammonium bicarbonate and 2.0 g of mannitol in 80 ml of DI
water was added to the organic solution (phase ratio 1:4). Prior to
spray drying, the solution was filtered through a 0.22 .mu.m PVDF
membrane. A benchtop spray dryer using an air-atomizing nozzle and
nitrogen as the drying gas were used. Spray drying conditions were
as follows; 20 ml/min solution flow rate, 60 L/min atomization gas
rate, 100 kg/hr drying gas rate, and 54.degree. C. outlet
temperature.
Example 6
Testing of Porous Paclitaxel Matrix in Animal Efficacy Model
The antitumor activity of the paclitaxel formulation produced in
Example 5 was tested in female athymic NCr-nu mice in which the
MDA-MB 435 breast tumor has been implanted subcutaneously (sc),
using doses of 7.5, 15, 30, and 45 mg/kg. Mice were implanted
subcutaneously with 30-40 mg fragments of the MDA-MB 435 tumor on
Day 0. Treatment with the porous paclitaxel matrix began when the
tumors ranged in size from 75-150 mg. Two control groups were
included, a vehicle-treated control group and a TAXOL.TM. treated
group. The dose of the TAXOL.TM. treated group was set at the
maximum tolerated dose in this animal model. Treatment was
administered once a day intravenously for five days. Mice were
observed daily for survival. Tumor measurements were recorded twice
weekly. Tumors were measured in two dimensions using calipers and
converted to tumor mass using the volume of a prolate ellipsoid and
assuming unit density. Median tumor mass for the various groups in
shown in FIG. 2 plotted as a function of the day, with day 0 being
the first day of dosing. There was no tumor regression in the
dextrose vehicle control group. The administration of the porous
paclitaxel matrix lead to a dose dependent regression in tumor mass
with tumor masses below the limit of detection at the highest dose
by day 6. The porous paclitaxel matrix therefore allows for
elimination of Cremophor and ethanol and thus higher total doses of
paclitaxel were administered. The higher dose porous paclitaxel
matrix groups had a more rapid rate of tumor regression and smaller
tumor mass.
Modifications and various of the present invention will be obvious
to those of skill in the art from the foregoing detailed
description. Such modifications and various are intended to come
within the scope of the following claims.
* * * * *