NZ717615B2 - Therapeutic polymeric nanoparticles and methods of making and using same - Google Patents
Therapeutic polymeric nanoparticles and methods of making and using same Download PDFInfo
- Publication number
- NZ717615B2 NZ717615B2 NZ717615A NZ71761514A NZ717615B2 NZ 717615 B2 NZ717615 B2 NZ 717615B2 NZ 717615 A NZ717615 A NZ 717615A NZ 71761514 A NZ71761514 A NZ 71761514A NZ 717615 B2 NZ717615 B2 NZ 717615B2
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- New Zealand
- Prior art keywords
- acid
- poly
- weight percent
- ethylene
- lactic
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
Described herein are polymeric nanoparticles that include a therapeutic agent which is 2-(3-((7-(3-(ethyl(2-hydroxyethyl)amino)propoxy)quinazolin-4-yl)amino)-1H-pyrazol- -yl)-N-(3-fluorophenyl)acetamide (also known as AZD1152 hqpa) or a pharmaceutically acceptable salt thereof, and methods of making and using such therapeutic nanoparticles. and using such therapeutic nanoparticles.
Description
(12) Granted patent specificaon (19) NZ (11) 717615 (13) B2
(47) Publicaon date: 2021.12.24
(54) THERAPEUTIC POLYMERIC NANOPARTICLES AND METHODS OF MAKING AND USING SAME
(51) Internaonal Patent Classificaon(s):
A61K 47/12 A61K 9/51 A61K 31/00 B82B 1/00 B82Y 40/00 B82Y 5/00 C07D 403/12
A61P 43/00 A61P 35/02
(22) Filing date: (73) Owner(s):
2014.09.12 ASTRAZENECA AB
(23) Complete specificaon filing date: (74) Contact:
2014.09.12 AJ PARK
(30) Internaonal Priority Data: (72) Inventor(s):
US 61/878,227 2013.09.16 ASHFORD, Marianne Bernice
US 61/939,332 2014.02.13 NOLAN, James, Martin, III
SHIN, Eyoung
(86) Internaonal Applicaon No.:
SONG, Young-Ho
TROIANO, Greg
WANG, Hong
(87) Internaonal Publicaon number:
WO/2015/036792
(57) Abstract:
Described herein are polymeric nanoparcles that include a therapeuc agent which is 2-
(3-((7-(3-(ethyl(2-hydroxyethyl)amino)propoxy)quinazolinyl)amino)-1H-pyrazol- -yl)-N-(3-
fluorophenyl)acetamide (also known as AZD1152 hqpa) or a pharmaceucally acceptable salt
thereof, and methods of making and using such therapeuc nanoparcles.
NZ 717615 B2
THERAPEUTIC POLYMERIC NANOPARTICLES AND METHODS OF
MAKING AND USING SAME
BACKGROUND
Systems that deliver certain drugs to a patient (e.g., distributed preferentially to a
particular tissue or cell type or to a specific diseased tissue more than to normal tissue) or
that control release of drugs have long been recognized as beneficial.
For example, therapeutics that include an active agent distributed preferentially to a
specific diseased tissue more than to normal tissue, may increase the exposure of the drug
in those tissues over others in the body. This is particularly important when treating a
condition such as cancer where it is desirable that a cytotoxic dose of the drug is delivered
to cancer cells without killing the surrounding non-cancerous tissue. Effective drug
distribution may reduce the undesirable and sometimes life threatening side effects
common in anticancer therapy.
Nanoparticles, by virtue of their size and surface properties, should allow
prolonged circulation in the vasculature and preferential tissue accumulation through
defective architecture of diseased tissues/tumours via the Enhanced Permeation and
Retention effect.
Therapeutics that offer controlled release therapy also must be able to deliver an
effective amount of drug, which is a known limitation in some nanoparticle delivery
systems. For example, it can be a challenge to prepare nanoparticle systems that have an
appropriate amount of drug associated with each nanoparticle, while keeping the size of the
nanoparticles small enough to have advantageous delivery properties.
Accordingly, a need exists for nanoparticle therapeutics and methods of making
such nanoparticles that are capable of delivering therapeutic levels of the therapeutic agent
to treat diseases such as cancer, while also reducing patient side effects.
Cancer (and other hyperproliferative disease) is characterised by uncontrolled
cellular proliferation. This loss of the normal regulation of cell proliferation often appears
to occur as the result of genetic damage to cellular pathways that control progress through
the cell cycle.
In eukaryotes, an ordered cascade of protein phosphorylation is thought to control
the cell cycle. Several families of protein kinases that play critical roles in this cascade
have now been identified. The activity of many of these kinases is increased in human
tumours when compared to normal tissue. This can occur by either increased levels of
expression of the protein (as a result of gene amplification for example), or by changes in
expression of co activators or inhibitory proteins.
Aurora Kinases (Aurora-A, Aurora-B and Aurora-C) encode cell cycle regulated
serine-threonine protein kinases (summarised in Adams et al., 2001, Trends in Cell
Biology. 11(2): 49-54). These show a peak of expression and kinase activity through G2
and mitosis and a role for human Aurora kinases in cancer has long been implicated.
The Aurora Kinase inhibitor known as AZD1152 (2-(ethyl(3-((4-((5-(2-((3-
fluorophenyl)amino)oxoethyl)-1H-pyrazolyl)amino)quinazolin
yl)oxy)propyl)amino)ethyl dihydrogen phosphate), pictured below, also known as
barasertib, was first disclosed in International Patent Application WO2004/058781
(Example 39) and has been studied by AstraZeneca as a potential treatment for various
cancers. However there are practical challenges in the clinical administration of AZD1152
as an intravenous solution delivered continuously over multiple days.
AZD1152
It is known that AZD1152 is metabolized in vivo to a compound known as
AZD1152 hqpa (2-(3-((7-(3-(ethyl(2-hydroxyethyl)amino)propoxy)quinazolin
yl)amino)-1H-pyrazolyl)-N-(3-fluorophenyl)acetamide), also disclosed in
WO2004/058781. AZD1152 hqpa is in fact, to a large extent, the moiety exerting the
biological effect when AZD1152 itself is administered. However pharmaceutical
compositions of AZD1152 hqpa, particularly those suitable for commercial administration,
have not previously been specifically described or tested.
AZD1152 hqpa
Nanoparticulate formulations including basic therapeutic agents with a protonatable
nitrogen are described in WO2014/043625.
SUMMARY
Described herein are polymeric nanoparticles that include AZD1152 hqpa or a
pharmaceutically acceptable salt thereof as a therapeutic agent, and methods of making and
using such therapeutic nanoparticles.
References herein to “the” or “a” “therapeutic agent” should be understood to mean
AZD1152 hqpa or a pharmaceutically acceptable salt thereof, unless the context dictates
otherwise.
In particular, the therapeutic agent is AZD1152 hqpa.
In a first aspect, the invention provides a therapeutic nanoparticle comprising 2-(3-
((7-(3-(ethyl(2-hydroxyethyl)amino)propoxy)-quinazolinyl)amino)-1H-pyrazolyl)-N-
(3-fluorophenyl)acetamide (AZD1152 hqpa), further comprising:
50 to 99.75 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer,
wherein the therapeutic nanoparticle comprises 10 to 30 weight percent
poly(ethylene)glycol, and wherein the therapeutic nanoparticle comprises a substantially
hydrophobic acid.
In a second aspect, the invention provides a pharmaceutically acceptable
composition comprising a plurality of therapeutic nanoparticles of the first aspect and one
or more pharmaceutically acceptable excipients, diluents and/or carriers.
In a third aspect, the invention provides the use of the therapeutic nanoparticle of
the first aspect in the manufacture of a medicament for the treatment of cancer.
In a fourth aspect, the invention provides a combination suitable for use in the
treatment of cancer comprising a pharmaceutically acceptable composition according to
the second aspect and another anti-tumour agent.
In a fifth aspect, the invention provides a kit of parts comprising:
a) a lyophilized pharmaceutical composition comprising disclosed
nanoparticles according to the first aspect; and
b) instructions for use.
A therapeutic nanoparticle is described. The therapeutic nanoparticle comprises
about 50 to about 99.75 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol
copolymer or a diblock poly(lactic acid-co-glycolic acid)-poly(ethylene)glycol copolymer,
wherein the therapeutic nanoparticle comprises about 10 to about 30 weight percent
poly(ethylene)glycol, and about 0.2 to about 30 weight percent of AZD1152 hqpa or a
pharmaceutically acceptable salt thereof, particularly AZD1152 hqpa.
Described herein is a therapeutic nanoparticle comprising AZD1152 hqpa and a
suitable polymer.
Described herein is a therapeutic nanoparticle comprising AZD1152 hqpa, a
suitable polymer and a hydrophobic acid.
Described herein is a therapeutic nanoparticle comprising AZD1152 hqpa, a
suitable polymer and a hydrophobic acid selected from cholic acid, deoxycholic acid,
pamoic acid and dioctyl sulfosuccinic acid.
Dioctyl sulfosuccinic acid is also referred to as docusate acid herein. Dioctyl
sodium sulfosuccinate is also known as sodium docusate.
Described herein is a therapeutic nanoparticle comprising AZD1152 hqpa, a
suitable polymer and pamoic acid.
Described herein is a therapeutic nanoparticle comprising a suitable polymer and a
mixture of AZD1152 hqpa and a hydrophobic acid.
Described herein is a therapeutic nanoparticle comprising a suitable polymer and
the product obtained by interaction of AZD1152 hqpa and a hydrophobic acid.
Described herein is a therapeutic nanoparticle comprising a suitable polymer and a
hydrophobic ion pair formed between AZD1152 hqpa and a hydrophobic acid.
Described herein is a therapeutic nanoparticle comprising AZD1152 hqpa, a
diblock poly(lactic) acid-poly(ethylene)glycol copolymer and a hydrophobic acid.
Described herein is a therapeutic nanoparticle comprising a diblock poly(lactic)
acid-poly(ethylene)glycol copolymer and a mixture of AZD1152 hqpa and a hydrophobic
acid.
Described herein is a therapeutic nanoparticle comprising a diblock poly(lactic)
acid-poly(ethylene)glycol copolymer and the product obtained by interaction of AZD1152
hqpa and a hydrophobic acid.
Described herein is a therapeutic nanoparticle comprising a diblock poly(lactic)
acid-poly(ethylene)glycol copolymer and a hydrophobic ion pair formed between
AZD1152 hqpa and a hydrophobic acid.
Described herein is a therapeutic nanoparticle comprising AZD1152 hqpa, a
diblock poly(lactic) acid-poly(ethylene)glycol copolymer and a hydrophobic acid selected
from cholic acid, deoxycholic acid, pamoic acid and dioctyl sulfosuccinic acid.
Described herein is a therapeutic nanoparticle comprising AZD1152 hqpa, a
diblock poly(lactic) acid-poly(ethylene)glycol copolymer and pamoic acid.
Described herein is a therapeutic nanoparticle comprising a diblock poly(lactic)
acid-poly(ethylene)glycol copolymer and a mixture of AZD1152 hqpa and a hydrophobic
acid selected from cholic acid, deoxycholic acid, pamoic acid and dioctyl sulfosuccinic
acid.
Described herein is a therapeutic nanoparticle comprising a diblock poly(lactic)
acid-poly(ethylene)glycol copolymer and the product obtained by interaction of AZD1152
hqpa and a hydrophobic acid selected from cholic acid, deoxycholic acid, pamoic acid and
dioctyl sulfosuccinic acid.
Described herein is a therapeutic nanoparticle comprising a diblock poly(lactic)
acid-poly(ethylene)glycol copolymer and a hydrophobic ion pair formed between
AZD1152 hqpa and a hydrophobic acid selected from cholic acid, deoxycholic acid,
pamoic acid and dioctyl sulfosuccinic acid.
Described herein is a therapeutic nanoparticle comprising a diblock poly(lactic)
acid-poly(ethylene)glycol copolymer and a mixture of AZD1152 hqpa and pamoic acid.
Described herein is a therapeutic nanoparticle comprising a diblock poly(lactic)
acid-poly(ethylene)glycol copolymer and the product obtained by interaction of AZD1152
hqpa and pamoic acid.
Described herein is a therapeutic nanoparticle comprising a diblock poly(lactic)
acid-poly(ethylene)glycol copolymer and a hydrophobic ion pair formed between
AZD1152 hqpa and pamoic acid.
Described herein is a therapeutic nanoparticle comprising AZD1152 hqpa, a
diblock poly(lactic) acid-poly(ethylene)glycol copolymer (wherein the therapeutic
nanoparticle comprises about 10 to about 30 weight percent poly(ethylene)glycol and the
poly(lactic) acid-poly(ethylene)glycol copolymer has a number average molecular weight
of about 16kDa poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol) and a hydrophobic acid selected from cholic acid, deoxycholic acid,
pamoic acid and dioctyl sulfosuccinic acid.
Described herein is a therapeutic nanoparticle comprising about 50 to about 94.95
weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer or a diblock
poly(lactic acid-co-glycolic acid)-poly(ethylene)glycol copolymer, wherein the therapeutic
nanoparticle comprises about 10 to about 30 weight percent poly(ethylene)glycol, about
0.05 to about 35 weight percent of a substantially hydrophobic acid and about 5 to about
weight percent of AZD1152 hqpa or a pharmaceutically acceptable salt thereof,
particularly AZD1152 hqpa.
Described herein is a therapeutic nanoparticle comprising about 50 to about 94
weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer or a diblock
poly(lactic acid-co-glycolic acid)-poly(ethylene)glycol copolymer, wherein the therapeutic
nanoparticle comprises about 10 to about 30 weight percent poly(ethylene)glycol, about 1
to about 35 weight percent of a substantially hydrophobic acid and about 5 to about 30
weight percent of AZD1152 hqpa or a pharmaceutically acceptable salt thereof,
particularly AZD1152 hqpa.
Described herein is a therapeutic nanoparticle. The therapeutic nanoparticle
comprises about 50 to about 99.75 weight percent of a diblock poly(lactic) acid-
poly(ethylene)glycol copolymer, wherein the therapeutic nanoparticle comprises about 10
to about 30 weight percent poly(ethylene)glycol, about 0.05 to about 35 weight percent of
a substantially hydrophobic acid selected from the group consisting of deoxycholic acid,
cholic acid and dioctyl sulfosuccinic acid, and about 5 to about 30 weight percent of
AZD1152 hqpa or a pharmaceutically acceptable salt thereof. In another embodiment, a
mixture of cholic acid and deoxycholic acid are used in a total of about 0.05 to about 35
weight percent of the nanoparticle. In a further embodiment the hydrophobic acid is oleic
acid.
In another embodiment, the therapeutic nanoparticle comprises about 35 to about
94.75 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer,
wherein the therapeutic nanoparticle comprises about 10 to about 30 weight percent
poly(ethylene)glycol, about 0.05 to about 35 weight percent of a substantially hydrophobic
acid selected from the group consisting of deoxycholic acid, cholic acid, a mixture of
cholic and deoxycholic acid, dioctyl sulfosuccinic acid and pamoic acid, and about 5 to
about 30 weight percent of AZD1152 hqpa or a pharmaceutically acceptable salt thereof.
In another embodiment, the therapeutic nanoparticle comprises about 35 to about
94 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein
the therapeutic nanoparticle comprises about 10 to about 30 weight percent
poly(ethylene)glycol, about 1 to about 35 weight percent of a substantially hydrophobic
acid selected from the group consisting of deoxycholic acid, cholic acid, a mixture of
cholic and deoxycholic acid, dioctyl sulfosuccinic acid and pamoic acid, and about 5 to
about 30 weight percent of AZD1152 hqpa or a pharmaceutically acceptable salt thereof.
In another embodiment, the therapeutic nanoparticle comprises about 65 to about
90 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein
the therapeutic nanoparticle comprises about 10 to about 30 weight percent
poly(ethylene)glycol, about 5 to about 15 weight percent of a substantially hydrophobic
acid selected from the group consisting of deoxycholic acid, cholic acid, a mixture of
cholic and deoxycholic acid, dioctyl sulfosuccinic acid and pamoic acid, and about 5 to
about 20 weight percent of AZD1152 hqpa or a pharmaceutically acceptable salt thereof.
Described herein is a therapeutic nanoparticle comprising about 35 to about 94
weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the
therapeutic nanoparticle comprises about 10 to about 30 weight percent
poly(ethylene)glycol, and a mixture of:
a) about 1 to about 35 weight percent of a substantially hydrophobic acid selected
from the group consisting of deoxycholic acid, cholic acid, a mixture of cholic and
deoxycholic acid, dioctyl sulfosuccinic acid and pamoic acid; and
b) about 5 to about 30 weight percent of AZD1152 hqpa.
Described herein is a therapeutic nanoparticle comprising about 35 to about 94
weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the
therapeutic nanoparticle comprises about 10 to about 30 weight percent
poly(ethylene)glycol, and the product obtained by interaction of:
a) about 1 to about 35 weight percent of a substantially hydrophobic acid selected
from the group consisting of deoxycholic acid, cholic acid, a mixture of cholic and
deoxycholic acid, dioctyl sulfosuccinic acid and pamoic acid; and
b) about 5 to about 30 weight percent of AZD1152 hqpa.
Described herein is a therapeutic nanoparticle comprising about 35 to about 94
weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the
therapeutic nanoparticle comprises about 10 to about 30 weight percent
poly(ethylene)glycol, and a hydrophobic ion pair formed between:
a) about 1 to about 35 weight percent of a substantially hydrophobic acid selected
from the group consisting of deoxycholic acid, cholic acid, a mixture of cholic and
deoxycholic acid, dioctyl sulfosuccinic acid and pamoic acid; and
b) about 5 to about 30 weight percent of AZD1152 hqpa.
In another embodiment, the therapeutic nanoparticle comprises about 35 to about
94.75 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer,
wherein the therapeutic nanoparticle comprises about 10 to about 30 weight percent
poly(ethylene)glycol, about 0.05 to about 35 weight percent of pamoic acid and about 5 to
about 30 weight percent of AZD1152 hqpa or a pharmaceutically acceptable salt thereof.
In another embodiment, the therapeutic nanoparticle comprises about 35 to about
94 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein
the therapeutic nanoparticle comprises about 10 to about 30 weight percent
poly(ethylene)glycol, about 1 to about 35 weight percent of pamoic acid and about 5 to
about 30 weight percent of AZD1152 hqpa or a pharmaceutically acceptable salt thereof.
In another embodiment, the therapeutic nanoparticle comprises about 55 to about
80 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein
the therapeutic nanoparticle comprises about 10 to about 30 weight percent
poly(ethylene)glycol, about 10 to about 20 weight percent of pamoic acid and about 10 to
about 25 weight percent of AZD1152 hqpa or a pharmaceutically acceptable salt thereof.
In another embodiment, the therapeutic nanoparticle comprises about 35 to about
94.75 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer,
wherein the therapeutic nanoparticle comprises about 10 to about 30 weight percent
poly(ethylene)glycol, about 0.05 to about 35 weight percent of pamoic acid and about 5 to
about 30 weight percent of AZD1152 hqpa.
In another embodiment, the therapeutic nanoparticle comprises about 35 to about
94 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein
the therapeutic nanoparticle comprises about 10 to about 30 weight percent
poly(ethylene)glycol, about 1 to about 35 weight percent of pamoic acid and about 5 to
about 30 weight percent of AZD1152 hqpa.
In another embodiment, the therapeutic nanoparticle comprises about 55 to about
85 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein
the therapeutic nanoparticle comprises about 10 to about 30 weight percent
poly(ethylene)glycol, about 5 to about 20 weight percent of pamoic acid and about 10 to
about 25 weight percent of AZD1152 hqpa.
Described herein is a therapeutic nanoparticle comprising about 55 to about 85
weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the
therapeutic nanoparticle comprises about 10 to about 30 weight percent
poly(ethylene)glycol, and a mixture of about 10 to about 25 weight percent of AZD1152
hqpa and about 5 to about 20 weight percent pamoic acid.
Described herein is a therapeutic nanoparticle comprising about 55 to about 85
weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the
therapeutic nanoparticle comprises about 10 to about 30 weight percent
poly(ethylene)glycol, and the product obtained by interaction of about 10 to about 25
weight percent of AZD1152 hqpa and about 5 to about 20 weight percent of pamoic acid.
Described herein is a therapeutic nanoparticle comprising about 55 to about 85
weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the
therapeutic nanoparticle comprises about 10 to about 30 weight percent
poly(ethylene)glycol, and a hydrophobic ion pair formed between about 10 to about 25
weight percent of AZD1152 hqpa and about 5 to about 20 weight percent of pamoic acid.
In another embodiment, the therapeutic nanoparticle comprises a diblock
poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the therapeutic nanoparticle
comprises about 10 to about 30 weight percent poly(ethylene)glycol, about 7 to about 15
weight percent of pamoic acid and about 15 to about 22 weight percent of AZD1152 hqpa.
Described herein is a therapeutic nanoparticle comprising a diblock poly(lactic)
acid-poly(ethylene)glycol copolymer, wherein the therapeutic nanoparticle comprises
about 10 to about 30 weight percent poly(ethylene)glycol, and the product obtained by
interaction of about 15 to about 22 weight percent of AZD1152 hqpa and about 7 to about
weight percent of pamoic acid.
Described herein is a therapeutic nanoparticle comprising a diblock poly(lactic)
acid-poly(ethylene)glycol copolymer, wherein the therapeutic nanoparticle comprises
about 10 to about 30 weight percent poly(ethylene)glycol, and a hydrophobic ion pair
formed between about 15 to about 22 weight percent of AZD1152 hqpa and about 7 to
about 15 weight percent of pamoic acid.
In another embodiment, the therapeutic nanoparticle comprises a diblock
poly(lactic) acid-poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle
comprises about 10 to about 30 weight percent poly(ethylene)glycol and the poly(lactic)
acid-poly(ethylene)glycol copolymer has a number average molecular weight of about
16kDa poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol), about 7 to about 15 weight percent of pamoic acid and about 15 to
about 22 weight percent of AZD1152 hqpa.
Described herein is a therapeutic nanoparticle comprising a diblock poly(lactic)
acid-poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle comprises
about 10 to about 30 weight percent poly(ethylene)glycol and the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol) and the product obtained by interaction of about 15 to about 22
weight percent of AZD1152 hqpa and about 7 to about 15 weight percent of pamoic acid.
Described herein is a therapeutic nanoparticle comprising a diblock poly(lactic)
acid-poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle comprises
about 10 to about 30 weight percent poly(ethylene)glycol and the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol) and a hydrophobic ion pair formed between about 15 to about 22
weight percent of AZD1152 hqpa and about 7 to about 15 weight percent of pamoic acid.
In another embodiment, the therapeutic nanoparticle comprises about 65 to about
76 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein
the therapeutic nanoparticle comprises about 10 to about 20 weight percent
poly(ethylene)glycol, about 9 to about 15 weight percent of pamoic acid and about 15 to
about 20 weight percent of AZD1152 hqpa or a pharmaceutically acceptable salt thereof.
In some embodiments, the poly(lactic) acid-poly(ethylene)glycol copolymer has a
poly(lactic) acid number average molecular weight fraction of about 0.7 to about 0.9. In
other embodiments, the poly(lactic) acid-poly(ethylene)glycol copolymer has a poly(lactic)
acid number average molecular weight fraction of about 0.75 to about 0.85.
In certain embodiments, contemplated nanoparticles comprise about 10 to about 25
weight percent poly(ethylene)glycol. In other embodiments, contemplated nanoparticles
comprise about 20 to about 30 weight percent poly(ethylene)glycol.
In some embodiments, the poly(lactic) acid-poly(ethylene)glycol copolymer has a
number average molecular weight of about 15kDa to about 20kDa poly(lactic acid) and a
number average molecular weight of about 4kDa to about 6kDa poly(ethylene)glycol. In
other embodiments, the poly(lactic) acid-poly(ethylene)glycol copolymer has a number
average molecular weight of about 16kDa poly(lactic acid) and a number average
molecular weight of about 5kDa poly(ethylene)glycol.
In certain embodiments, contemplated nanoparticles comprise about 65 weight
percent to about 85 weight percent of the copolymer.
In some embodiments, contemplated nanoparticles have a hydrodynamic diameter
of <200 nm, such as 70-140 nm.
In some embodiments, contemplated nanoparticles comprise a substantially
hydrophobic acid, also referred to herein as “hydrophobic acid”. For example,
contemplated nanoparticles may comprise about 0.05 to about 35 weight percent of a
substantially hydrophobic acid, about 5 to about 15 weight percent of a substantially
hydrophobic acid, or about 10 to about 20 weight percent of a substantially hydrophobic
acid. Contemplated nanoparticles may, in other embodiments, comprise about 5 to about
weight percent of a substantially hydrophobic acid. In certain embodiments more than
one substantially hydrophobic acid may be used, and the contemplated nanoparticles may
comprise about 5 to about 15 weight percent, or about 10 to about 20 weight percent of the
total hydrophobic acids together. Contemplated nanoparticles may, in other embodiments,
comprise about 5 to about 15 weight percent of a substantially hydrophobic acid selected
from deoxycholic acid, cholic acid, a mixture of deoxycholic acid and cholic acid, dioctyl
sulfosuccinic acid and pamoic acid.
In certain embodiments, the molar ratio of the substantially hydrophobic acid to
the therapeutic agent is about 0.9:1 to about 1.1:1, wherein the acid is deoxycholic acid. In
other embodiments, the molar ratio of the substantially hydrophobic acid to the therapeutic
agent is about 0.9:1 to about 1.1:1, wherein the acid is dioctyl sulfosuccinic acid. In a
further embodiment, the hydrophobic acid content comprises a mixture of deoxycholic acid
and cholic acid, for example in a ratio of between 1:5 and 5:1 deoxycholic acid:cholic acid,
such as about 3:2 deoxycholic acid: cholic acid. In other embodiments the molar ratio of
the substantially hydrophobic acid to the therapeutic agent is about 0.75:1 to about 1.0:1,
wherein the acid is pamoic acid.
In some embodiments, a pK of the therapeutic agent is at least about 1.0 pK units
greater than a pK of the hydrophobic acid.
In certain embodiments, the substantially hydrophobic acid and the therapeutic
agent form a hydrophobic ion pair in a contemplated therapeutic nanoparticle. In some
embodiments, the hydrophobic acid is a bile acid. For example, in some embodiments, the
bile acid is deoxycholic acid. In other embodiments, the bile acid is cholic acid. In still
further embodiments the bile acid is a mixture of deoxycholic acid and cholic acid. In
other embodiments, the hydrophobic acid is dioctyl sulfosuccinic acid. In still further
embodiments the hydrophobic acid is oleic acid. In further embodiments, the hydrophobic
acid is pamoic acid.
In some embodiments, contemplated nanoparticles comprise about 5 to about 20
weight percent of the therapeutic agent. In other embodiments, contemplated nanoparticles
comprise about 10 to about 20 weight percent of the therapeutic agent. In other
embodiments, contemplated nanoparticles comprise about 15 to about 20 weight percent of
the therapeutic agent. In other embodiments, contemplated nanoparticles comprise about 8
to about 15 weight percent of the therapeutic agent. In other embodiments, contemplated
nanoparticles comprise about 8 to about 20 weight percent of the therapeutic agent.
It will be understood that the composition of any preferred formulation may be a
balance of several factors, including but not limited to:
a formulation with increased drug loading where possible to minimize the volume
of pharmaceutical composition which must be administered to the patient;
the formulation which can be achieved reproducibly and reliably on large scale
manufacture;
the formulation which optimizes release profile of the therapeutic agent over time;
the formulation which preferentially distributes to diseased sites.
A futher factor may be a formulation which has reduced or minimal detrimental
effect on the bone marrow of a patient after dosing, as exemplified in animal models in the
Examples hereinafter.
In any particular preferred formulation, any one or more of the above factors may
be taken into consideration.
Described herein is a nanoparticle obtainable by any process described or
exemplified herein. Described herein is a nanoparticle obtained by any process described
or exemplified herein. Described herein is a therapeutic nanoparticle substantially as
described herein.
Described herein is a pharmaceutically acceptable composition. The
pharmaceutically acceptable composition comprises a plurality of contemplated therapeutic
nanoparticles and a pharmaceutically acceptable excipient.
Described herein is a method of treating cancer (for example including, but not
limited to, haematological cancers such as Acute Myeloid Leukaemia (AML) and Diffuse
Large B-Cell Lymphoma, and solid tumour cancers such as colorectal cancer and lung
cancer) in a patient in need thereof. The method comprises administering to the patient a
therapeutically effective amount of a composition comprising therapeutic nanoparticles
contemplated herein.
The term “comprising” as used in this specification and claims means “consisting at
least in part of”. When interpreting statements in this specification and claims which
include the term “comprising”, other features besides the features prefaced by this term in
each statement can also be present. Related terms such as “comprise” and “comprises” are
to be interpreted in similar manner.
In this specification where reference has been made to patent specifications, other
external documents, or other sources of information, this is generally for the purpose of
providing a context for discussing the features of the invention. Unless specifically stated
otherwise, reference to such external documents is not to be construed as an admission that
such documents, or such sources of information, in any jurisdiction, are prior art, or form
part of the common general knowledge in the art.
The invention is defined in the claims. However, the disclosure preceding the
claims may refer to additional methods and other subject matter outside the scope of the
present claims. This disclosure is retained for technical purposes.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is flow chart for an emulsion process for forming a disclosed nanoparticle.
Figures 2A and 2B show flow diagrams for a disclosed emulsion process.
Figure 3 depicts an in vitro release profile for control therapeutic nanoparticle
formulations.
Figure 4 depicts in vitro release profiles for deoxycholic acid nanoparticle formulations
versus a control therapeutic nanoparticle formulation.
Figure 5 depicts in vitro release profiles for a docusate acid nanoparticle formulation
versus a control therapeutic nanoparticle formulation.
Figure 6 depicts the results from SW620 human colorectal xenograft model in female nude
rats.
Figure 7 depicts results from a dosing schedule study with one AZD1152 hqpa
nanoparticulate formulation.
Figure 8 depicts a comparison of plasma concentration of AZD1152 hqpa nanoparticles
against AZD1152 IV in an in-vivo exposure study.
Figure 9 depicts in vitro release profiles for a pamoic acid nanoparticle formulation versus
a control therapeutic nanoparticle formulation.
Figure 10 depicts comparative pharmacokinetic profiles for three nanoparticulate
formulations.
Figure 11 depicts a comparison of results from an SW620 study.
Figure 12 depicts a further comparison of results from an SW620 study.
Figure 13 depicts bone marrow effects of certain nanoparticulate formulations.
Figure 14 depicts bone marrow effects of certain nanoparticulate formulations.
Figure 15 depicts in vivo activity of AZD1152 and AZD1152 hqpa nanoparticle
Formulations G1 and G2.
Figure 16 depicts effects of Formulations G1 and G2 on bone marrow integrity.
Figure 17 depicts a comparison between the tumour control from Formulation G1 and that
from AZD1152 in mice bearing U2932 tumours.
Figure 18 depicts a comparison between the tumour control from Formulation G1 and that
from AZD1152 in mice bearing SC-61 primary tumours.
Figure 19 and 19a to 19e depict comparative pharmacokinetic profiles for formulations E
to G.
Figure 20 depicts in-vitro release at 37 ºC of Formulation G1 batches shown in Example
DETAILED DESCRIPTION
Described herein are polymeric nanoparticles that include AZD1152 hqpa or a
pharmaceutically acceptable salt thereof as a therapeutic agent, and methods of making and
using such therapeutic nanoparticles. In some embodiments, inclusion (doping) of a
substantially hydrophobic acid (such as a bile acid or other suitable acids as disclosed
herein) in a disclosed nanoparticle and/or included in a nanoparticle preparation process
may result in nanoparticles that include improved drug loading. Furthermore, in certain
embodiments, nanoparticles that include and/or are prepared in the presence of the
hydrophobic acid may exhibit improved controlled release properties. For example,
disclosed nanoparticles may more slowly release the therapeutic agent as compared to
nanoparticles prepared in the absence of the hydrophobic acid.
Without wishing to be bound by any theory, it is believed that the disclosed
nanoparticle formulations that include a hydrophobic acid (such as a bile acid or other
suitable acids as disclosed herein) have significantly improved formulation properties (e.g.,
drug loading and/or release profile) which may occur through formation of a hydrophobic
ion-pair (HIP), between the substantially hydrophobic acid and, e.g., an amine group of the
therapeutic agent. As used herein, a HIP is a pair of oppositely charged ions held together
by Coulombic attraction. Also without wishing to be bound by any theory, in some
embodiments, a HIP can be used to increase the hydrophobicity of the therapeutic agent.
In some embodiments, a therapeutic agent with increased hydrophobicity can be beneficial
for nanoparticle formulations and result in HIP formation that may provide higher
solubility of the therapeutic agent in organic solvents. HIP formation, as contemplated
herein, can result in nanoparticles having for example, increased drug loading. Slower
release of the therapeutic agent from the nanoparticles may also occur, for example in
some embodiments, due to a decrease in the therapeutic agent’s solubility in aqueous
solution. Furthermore, complexing the therapeutic agent with large hydrophobic counter
ions may slow diffusion of the therapeutic agent within the polymeric matrix.
Advantageously, HIP formation occurs without the need for covalent conjugation of the
hydrophobic group to the therapeutic agent.
Without wishing to be bound by any theory, it is believed that the strength of the
HIP may impact the drug load and release rate of the contemplated nanoparticles. For
example, the strength of the HIP may be increased by increasing the magnitude of the
difference between the pK of the therapeutic agent and the pK of the hydrophobic acid, as
discussed in more detail below. Also without wishing to be bound by any theory, it is
believed that the conditions for ion pair formation may impact the drug load and release
rate of the contemplated nanoparticles.
Whatever the exact nature of the interaction (as described above) between
AZD1152 hqpa and the hydrophobic acids in the disclosed formulations, preferred
formulations are those comprising a hydrophobic acid and which have high drug loading
(for example about 15 to about 25 weight percent (wt %) AZD1152 hqpa, such as about 15
to about 22wt %, or about 15 to about 20 wt% AZD1152 hqpa) and a suitable release
profile, as discussed in more detail hereinafter. Suitably, such formulations also have
reduced impact on bone marrow in comparison with other formulations which comprise
AZD1152.
Nanoparticles disclosed herein include one, two, three or more biocompatible
and/or biodegradable polymers. For example, a contemplated nanoparticle may include
about 35 to about 99.75 weight percent, in some embodiments about 50 to about 99.75
weight percent, in some embodiments about 50 to about 99.5 weight percent, in some
embodiments about 50 to about 99 weight percent, in some embodiments about 50 to about
98 weight percent, in some embodiments about 50 to about 97 weight percent, in some
embodiments about 50 to about 96 weight percent, in some embodiments about 50 to about
95 weight percent, in some embodiments about 50 to about 94 weight percent, in some
embodiments about 50 to about 93 weight percent, in some embodiments about 50 to about
92 weight percent, in some embodiments about 50 to about 91 weight percent, in some
embodiments about 50 to about 90 weight percent, in some embodiments about 50 to about
85 weight percent, in some embodiments about 50 to about 80 weight percent, and in some
embodiments about 65 to about 85 weight percent of one or more block copolymers that
include a biodegradable polymer and poly(ethylene glycol) (PEG), and about 0 to about 50
weight percent of a biodegradable homopolymer.
AZD1152 hqpa
The disclosed nanoparticles include AZD1152 hqpa (pK = 5.7; pK = 8.46) or a
a1 a2
pharmaceutically acceptable salt thereof as a therapeutic agent. Reference herein to a
therapeutic agent should be understood as referring to AZD1152 hqpa or a
pharmaceutically acceptable salt thereof, but particularly AZD1152 hqpa, unless the
context indicates otherwise.
Described herein is a nanoparticle comprising AZD1152 hqpa. Also described
herein is a therapeutic nanoparticle comprising AZD1152 hqpa and a hydrophobic acid.
Also described herein is a therapeutic nanoparticle comprising the product obtained by the
interaction of AZD1152 hqpa and a hydrophobic acid. Also described herein is a
therapeutic nanoparticle comprising the product obtained by mixing AZD1152 hqpa and a
hydrophobic acid. Also described herein is a therapeutic nanoparticle comprising a
hydrophobic ion pair between AZD1152 hqpa and a hydrophobic acid.
Described herein is a pharmaceutical composition comprising AZD1152 hqpa in a
nanoparticle. Also described herein is a therapeutic nanoparticle comprising AZD1152
hqpa and a hydrophobic acid. Also described herein is a pharmaceutical composition
comprising a therapeutic nanoparticle which comprises the product obtained by the
interaction of AZD1152 hqpa and a hydrophobic acid. Also described herein is a
pharmaceutical composition comprising a therapeutic nanoparticle which comprises the
product obtained by mixing AZD1152 hqpa and a hydrophobic acid. Also described herein
is a pharmaceutical composition comprising a therapeutic nanoparticle which comprises a
hydrophobic ion pair between AZD1152 hqpa and a hydrophobic acid.
Described herein is a pharmaceutical composition comprising a plurality of
therapeutic nanoparticles containing AZD1152 hqpa as an active ingredient. Such
nanoparticles suitably also contain a hydrophobic acid, such as pamoic acid, mixed with
the AZD1152 hqpa in the nanoparticles and further contain a suitable polymer such as a
16/5 PLA-PEG copolymer.
A suitable pharmaceutically-acceptable salt of AZD1152 hqpa may be, for
example, an acid-addition salt of AZD1152 hqpa, for example an acid-addition salt with a
strong inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric or
trifluoroacetic acid. Other suitable pharmaceutically-acceptable salts include phosphate,
acetate, fumarate, maleate, tartrate, citrate, methanesulphonate, and p-toluenesulphonate.
Still further suitable pharmaceutically-acceptable salts include salts of AZD1152 hqpa with
acids such as hydrophobic acids defined herein. It will be understood that a counterion for
a suitable salt of AZD1152 hqpa input into the manufacturing process must be chosen such
that it does not interfere with the process for formation of the nanoparticles as described
herein. Counterions which are readily washed out from the solutions or which correspond
to counterions already present in the process may conveniently be used.
In some embodiments, disclosed nanoparticles may include about 0.2 to about 35
weight percent, about 0.2 to about 20 weight percent, about 0.2 to about 10 weight percent,
about 0.2 to about 5 weight percent, about 0.5 to about 5 weight percent, about 0.75 to
about 5 weight percent, about 1 to about 5 weight percent, about 2 to about 5 weight
percent, about 3 to about 5 weight percent, about 1 to about 20 weight percent, about 2 to
about 20 weight percent, about 5 to about 20 weight percent, about 1 to about 15 weight
percent, about 2 to about 15 weight percent, about 3 to about 15 weight percent, about 4 to
about 15 weight percent, about 5 to about 15 weight percent, about 1 to about 10 weight
percent, about 2 to about 10 weight percent, about 3 to about 10 weight percent, about 4 to
about 10 weight percent, about 5 to about 10 weight percent, about 10 to about 30 weight
percent, about 15 to about 25, or about 15 to about 20 weight percent of the therapeutic
agent.
In particular embodiments, disclosed nanoparticles may include about 5 to about
, preferably about 10 to about 20, even more preferably about 15 to about 20 weight
percent of AZD1152 hqpa, or about 15 to about 22 weight percent of AZD1152 hqpa.
Hydrophobic acid
In certain embodiments, disclosed nanoparticles comprise a hydrophobic acid (e.g.,
a bile acid) and/or are prepared by a process that includes a hydrophobic acid. Such
nanoparticles may have a higher drug loading than nanoparticles prepared by a process
without a hydrophobic acid. For example, drug loading (e.g., by weight) of disclosed
nanoparticles prepared by a process comprising the hydrophobic acid may be between
about 2 times to about 10 times higher, or even more, than disclosed nanoparticles
prepared by a process without the hydrophobic acid. In some embodiments, the drug
loading (by weight) of disclosed nanoparticles prepared by a first process comprising the
hydrophobic acid may be at least about 2 times higher, at least about 3 times higher, at
least about 4 times higher, at least about 5 times higher, or at least about 10 times higher
than disclosed nanoparticles prepared by a second process, where the second process is
identical to the first process except that the second process does not include the
hydrophobic acid.
Any suitable hydrophobic acid is contemplated. In some embodiments, the
hydrophobic acid may be a carboxylic acid (e.g., a monocarboxylic acid, dicarboxylic acid,
tricarboxylic acid, or the like), a sulfinic acid, a sulfenic acid, or a sulfonic acid. In some
cases, a contemplated hydrophobic acid may include a mixture of two or more acids. In
some cases, a salt of a hydrophobic acid may be used in a formulation. Reference herein to
“the hydrophobic acid” will be understood to apply equally to a mixture of contemplated
hydrophobic acids unless the context demands otherwise.
For example, a disclosed carboxylic acid may be an aliphatic carboxylic acid (e.g.,
a carboxylic acid having a cyclic or acyclic, branched or unbranched, hydrocarbon chain).
Disclosed carboxylic acids may, in some embodiments, be substituted with one or more
functional groups including, but not limited to, halogen (F, Cl, Br, and I), sulfonyl, nitro,
and oxo. In certain embodiments, a disclosed carboxylic acid may be unsubstituted.
Exemplary carboxylic acids may include a substituted or unsubstituted fatty acid
(e.g., C -C fatty acid). In some instances, the fatty acid may be a C -C fatty acid. In
6 50 10 20
other instances, the fatty acid may be a C -C fatty acid. The fatty acid may, in some
20
cases, be saturated. In other embodiments, the fatty acid may be unsaturated. For instance,
the fatty acid may be a monounsaturated fatty acid or a polyunsaturated fatty acid. In some
embodiments, a double bond of an unsaturated fatty acid group can be in the cis
conformation. In some embodiments, a double bond of an unsaturated fatty acid can be in
the trans conformation. Unsaturated fatty acids include, but are not limited to, omega-3,
omega-6, and omega-9 fatty acids.
Non-limiting examples of saturated fatty acids include caproic acid, enanthic acid,
caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid,
myristic acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, nonadecanoic
acid, arachidic acid, heneicosanoic acid, behenic acid, tricosanoic acid, lignoceric acid,
pentacosanoic acid, cerotic acid, heptacosanoic acid, montanic acid, nonacosanoic acid,
melissic acid, henatriacontanoic acid, lacceroic acid, psyllic acid, geddic acid, ceroplastic
acid, hexatriacontanoic acid, and combinations thereof.
Non-limiting examples of unsaturated fatty acids include hexadecatrienoic acid,
alpha-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosatetraenoic acid,
eicosapentaenoic acid, heneicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic
acid, tetracosapentaenoic acid, tetracosahexaenoic acid, linoleic acid, gamma-linolenic
acid, eicosadienoic acid, dihomo-gamma-linolenic acid, arachidonic acid, docosadienoic
acid, adrenic acid, docosapentaenoic acid, tetracosatetraenoic acid, tetracosapentaenoic
acid, oleic acid (pK = ~4-5; logP = 6.78), eicosenoic acid, mead acid, erucic acid,
nervonic acid, rumenic acid, α-calendic acid, β-calendic acid, jacaric acid, α-eleostearic
acid, β-eleostearic acid, catalpic acid, punicic acid, rumelenic acid, α-parinaric acid, β-
parinaric acid, bosseopentaenoic acid, pinolenic acid, podocarpic acid, palmitoleic acid,
vaccenic acid, gadoleic acid, erucic acid, and combinations thereof.
Other non-limiting examples of hydrophobic acids include aromatic acids, such as
1-hydroxynaphthoic acid (also known as xinafoic acid) (pK = ~2-3; log P = 2.97),
naphthalene-1,5-disulfonic acid (pK = -2; logP = 1.3), naphthalenesulfonic acid (pK =
-1.8; logP = 2.1), pamoic acid (pK = 2.4), cinnamic acid, phenylacetic acid, ( ±)-camphor-
-sulfonic acid, dodecylbenzenesulfonic acid (pKa = -1.8; logP = 6.6), and combinations
thereof. Other non-limiting examples of hydrophobic acids include dodecylsulfuric acid
(pK = -0.09; logP = 4.5), dioctyl sulfosuccinic acid (pK = -0.8; logP = 5.2), dioleoyl
phosphatidic acid (pK = ~2), and Vitamin D -sulfate (pK = -1.5).
a 3 a
In some embodiments, the hydrophobic acid may be a bile acid. Non-limiting
examples of bile acids include chenodeoxycholic acid, ursodeoxycholic acid, deoxycholic
acid (pK = 4.65; logP = 3.79), hycholic acid, beta-muricholic acid, cholic acid (pK =
~4.5; logP = 2.48), taurocholic acid, cholesteryl sulfate (pK = -1.4), lithocholic acid, an
amino acid-conjugated bile acid, and combinations thereof. In some embodiments, a
mixture of cholic acid and deoxycholic acid may be used. An amino-acid conjugated bile
acid may be conjugated to any suitable amino acid. In some embodiments, the amino acid-
conjugated bile acid is a glycine-conjugated bile acid or a taurine-conjugated bile acid.
In certain instances, the hydrophobic acid may be a polyelectrolyte. For example,
the polyelectrolyte may be a polysulfonic acid (e.g., poly(styrene sulfonic acid) or dextran
sulfate) or a polycarboxylic acid (e.g., polypolyacrylic acid or polymethacrylic acid).
In one embodiment, the hydrophobic acid is selected from cholic acid, deoxycholic
acid (including a mixture of cholic acid and deoxycholic acid), dioctylsulfosuccinic acid
and pamoic acid.
In another embodiment, the hydrophobic acid is pamoic acid.
In some instances, a contemplated acid may have a molecular weight of less than
about 1000 Da, in some embodiments less than about 500 Da, in some embodiments less
than about 400 Da, in some embodiments less than about 300 Da, in some embodiments
less than about 250 Da, in some embodiments less than about 200 Da, and in some
embodiments less than about 150 Da. In some cases, the acid may have a molecular
weight of between about 100 Da and about 1000 Da, in some embodiments between about
200 Da and about 800 Da, in some embodiments between about 200 Da and about 600 Da,
in some embodiments between about 100 Da and about 300 Da, in some embodiments
between about 200 Da and about 400 Da, in some embodiments between about 300 Da and
about 500 Da, and in some embodiments between about 300 Da and about 1000 Da. In
certain embodiments, a contemplated acid may have a molecular weight of greater than
about 300 Da, in some embodiments greater than 400 Da, and in some embodiments
greater than 500 Da. In certain embodiments, the release rate of a therapeutic agent from a
nanoparticle can be slowed by increasing the molecular weight of the hydrophobic acid
used in the nanoparticle formulation.
In some embodiments, a hydrophobic acid may be chosen, at least in part, on the
basis of the strength of the acid. For example, the hydrophobic acid may have an acid
dissociation constant in water (pK ) of about -5 to about 7, in some embodiments about -3
to about 5, in some embodiments about -3 to about 4, in some embodiments about -3 to
about 3.5, in some embodiments about -3 to about 3, in some embodiments about -3 to
about 2, in some embodiments about -3 to about 1, in some embodiments about -3 to about
0.5, in some embodiments about -0.5 to about 0.5, in some embodiments about 1 to about
7, in some embodiments about 2 to about 7, in some embodiments about 3 to about 7, in
some embodiments about 4 to about 6, in some embodiments about 4 to about 5.5, in some
embodiments about 4 to about 5, and in some embodiments about 4.5 to about 5,
determined at 25 °C. In some embodiments, the acid may have a pK of less than about 7,
less than about 5, less than about 3.5, less than about 3, less than about 2, less than about 1,
or less than about 0, determined at 25 °C.
In certain embodiments, the hydrophobic acid may be chosen, at least in part, on
the basis of the difference between the pKa of the hydrophobic acid and the pKa of the
therapeutic agent. For example, in some instances, the difference between the pK of the
hydrophobic acid and the pK of the therapeutic agent may be between about 1 pK unit
and about 15 pK units, in some embodiments between about 1 pK unit and about 10 pK
a a a
units, in some embodiments between about 1 pK unit and about 5 pK units, in some
embodiments between about 1 pK unit and about 3 pK units, in some embodiments
between about 1 pK unit and about 2 pK units, in some embodiments between about 2
pK units and about 15 pK units, in some embodiments between about 2 pK units and
a a a
about 10 pK units, in some embodiments between about 2 pK units and about 5 pK units,
a a a
in some embodiments between about 2 pKa units and about 3 pKa units, in some
embodiments between about 3 pK units and about 15 pK units, in some embodiments
between about 3 pKa units and about 10 pKa units, in some embodiments between about 3
pK units and about 5 pK units, in some embodiments between about 4 pK units and
a a a
about 15 pK units, in some embodiments between about 4 pK units and about 10 pK
a a a
units, in some embodiments between about 4 pK units and about 6 pK units, in some
embodiments between about 5 pK units and about 15 pK units, in some embodiments
between about 5 pK units and about 10 pK units, in some embodiments between about 5
pK units and about 7 pK units, in some embodiments between about 7 pK units and
a a a
about 15 pK units, in some embodiments between about 7 pK units and about 9 pK units,
a a a
in some embodiments between about 9 pK units and about 15 pK units, in some
embodiments between about 9 pK units and about 11 pK units, in some embodiments
between about 11 pKa units and about 13 pKa units, and in some embodiments between
about 13 pK units and about 15 pK units, determined at 25 °C.
In some instances, the difference between the pK of the hydrophobic acid and the
pK of the therapeutic agent may be at least about 1 pK unit, in some embodiments at least
about 2 pK units, in some embodiments at least about 3 pK units, in some embodiments
at least about 4 pK units, in some embodiments at least about 5 pK units, in some
embodiments at least about 6 pK units, in some embodiments at least about 7 pK units, in
some embodiments at least about 8 pK units, in some embodiments at least about 9 pK
units, in some embodiments at least about 10 pK units, and in some embodiments at least
about 15 pK units, determined at 25 °C.
In one embodiment, the difference between the pKa of the hydrophobic acid and
the first pKa of AZD1152 hqpa is between 2 and 5 pKa units, determined at 25 °C.
For the avoidance of doubt, pamoic acid (4,4'-methylenebis[3-hydroxynaphthoic
acid]) has a molecular weight of 388.37 and is reported (SciFinder) to have pKa = 2.67,
and log P= 6.169.
In some embodiments, the hydrophobic acid may have a logP of between about 2
and about 15, in some embodiments between about 5 and about 15, in some embodiments
between about 5 and about 10, in some embodiments between about 2 and about 8, in some
embodiments between about 4 and about 8, in some embodiments between about 2 and
about 7, or in some embodiments between about 4 and about 7. In some instances, the
hydrophobic acid may have a logP greater than about 2, greater than about 4, greater than
about 5, or greater than 6.
In some embodiments, a contemplated hydrophobic acid may have a phase
transition temperature that is advantageous, for example, for improving the properties of
the therapeutic nanoparticles. For instance, the acid may have a melting point of less than
about 300 C, in some cases less than about 100 C, and in some cases less than about 50
C. In certain embodiments, the acid may have a melting point of between about 5 C and
o o o
about 25 C, in some cases between about 15 C and about 50 C, in some cases between
o o o o
about 30 C and about 100 C, in some cases between about 75 C and about 150 C, in
o o o
some cases between about 125 C and about 200 C, in some cases between about 150 C
o o o
and about 250 C, and in some cases between about 200 C and about 300 C. In some
cases, the acid may have a melting point of less than about 15 C, in some cases less than
about 10 C, or in some cases less than about 0 C. In certain embodiments, the acid may
have a melting point of between about -30 C and about 0 C or in some cases between
about -20 C and about -10 C.
For example, an acid for use in methods and nanoparticles disclosed herein may be
chosen, at least in part, on the basis of the solubility of the therapeutic agent in a solvent
comprising the acid. For example, in some embodiments, the therapeutic agent dissolved
in a solvent comprising the acid may have a solubility of between about 15 mg/mL to
about 200 mg/mL, between about 20 mg/mL to about 200 mg/mL, between about 25
mg/mL to about 200 mg/mL, between about 50 mg/mL to about 200 mg/mL, between
about 75 mg/mL to about 200 mg/mL, between about 100 mg/mL to about 200 mg/mL,
between about 125 mg/mL to about 175 mg/mL, between about 15 mg/mL to about 50
mg/mL, between about 25 mg/mL to about 75 mg/mL. In some embodiments, the
therapeutic agent dissolved in a solvent comprising the acid may have a solubility greater
than about 10 mg/mL, greater than about 50 mg/mL, or greater than about 100 mg/mL. In
some embodiments, the therapeutic agent dissolved in a solvent comprising the
hydrophobic acid (e.g., a first solution consisting of the therapeutic agent, solvent, and
hydrophobic acid) may have a solubility of at least about 2 times greater, in some
embodiments at least about 5 times greater, in some embodiments at least about 10 times
greater, in some embodiments at least about 20 times greater, in some embodiments about
2 times to about 20 times greater or in some embodiments about 10 times to about 20 times
greater than when the therapeutic agent is dissolved in a solvent that does not contain the
hydrophobic acid (e.g., a second solution consisting of the therapeutic agent and the
solvent).
In some instances, the concentration of acid in a drug solution (the solution of
therapeutic agent) may be between about 1 weight percent and about 30 weight percent, in
some embodiments between about 2 weight percent and about 30 weight percent, in some
embodiments between about 3 weight percent and about 30 weight percent, in some
embodiments between about 4 weight percent and about 30 weight percent, in some
embodiments between about 5 weight percent and about 30 weight percent, in some
embodiments between about 6 weight percent and about 30 weight percent, in some
embodiments between about 8 weight percent and about 30 weight percent, in some
embodiments between about 10 weight percent and about 30 weight percent, in some
embodiments between about 12 weight percent and about 30 weight percent, in some
embodiments between about 14 weight percent and about 30 weight percent, in some
embodiments between about 16 weight percent and about 30 weight percent, in some
embodiments between about 1 weight percent and about 5 weight percent, in some
embodiments between about 3 weight percent and about 9 weight percent, in some
embodiments between about 6 weight percent and about 12 weight percent, in some
embodiments between about 9 weight percent and about 15 weight percent, in some
embodiments between about 12 weight percent and about 18 weight percent, and in some
embodiments between about 15 weight percent and about 21 weight percent. In certain
embodiments, the concentration of hydrophobic acid in a drug solution may be at least
about 1 weight percent, in some embodiments at least about 2 weight percent, in some
embodiments at least about 3 weight percent, in some embodiments at least about 5 weight
percent, in some embodiments at least about 10 weight percent, in some embodiments at
least about 15 weight percent, and in some embodiments at least about 20 weight percent.
In certain embodiments, the molar ratio of hydrophobic acid to therapeutic agent
(e.g., initially during formulation of the nanoparticles and/or in the nanoparticles) may be
between about 0.25:1 to about 6:1, in some embodiments between about 0.25:1 to about
:1, in some embodiments between about 0.25:1 to about 4:1, in some embodiments
between about 0.25:1 to about 3:1, in some embodiments between about 0.25:1 to about
2:1, in some embodiments between about 0.25:1 to about 1.5:1, in some embodiments
between about 0.25:1 to about 1:1, in some embodiments between about 0.25:1 to about
0.5:1, in some embodiments between about 0.5:1 to about 6:1, in some embodiments
between about 0.5:1 to about 5:1, in some embodiments between about 0.5:1 to about 4:1,
in some embodiments between about 0.5:1 to about 3:1, in some embodiments between
about 0.5:1 to about 2:1, in some embodiments between about 0.5:1 to about 1.5:1, in some
embodiments between about 0.5:1 to about 1:1, in some embodiments between about 0.5:1
to about 0.75:1, in some embodiments between about 0.75:1 to about 2:1, in some
embodiments between about 0.75:1 to about 1.5:1, in some embodiments between about
0.75:1 to about 1.25:1, in some embodiments between about 0.75:1 to about 1:1, in some
embodiments between about 1:1 to about 6:1, in some embodiments between about 1:1 to
about 5:1, in some embodiments between about 1:1 to about 4:1, in some embodiments
between about 1:1 to about 3:1, in some embodiments between about 1:1 to about 2:1, in
some embodiments between about 1:1 to about 1.5:1, in some embodiments between about
1.5:1 to about 6:1, in some embodiments between about 1.5:1 to about 5:1, in some
embodiments between about 1.5:1 to about 4:1, in some embodiments between about 1.5:1
to about 3:1, in some embodiments between about 2:1 to about 6:1, in some embodiments
between about 2:1 to about 4:1, in some embodiments between about 3:1 to about 6:1, in
some embodiments between about 3:1 to about 5:1, and in some embodiments between
about 4:1 to about 6:1. In some embodiments, the ratio is about 2:1.
In other embodiments the molar ratio of hydrophobic acid to AZD1152 hqpa during
the formation of the nanoparticles (when they are first mixed together) is about 0.75:1 to
about 1:1, for example about 0.8:1 to about 1:1. In one embodiment, the hydrophobic acid
is pamoic acid and the molar ratio of pamoic acid to AZD1152 hqpa during the formation
of the nanoparticles (when they are first mixed together) is about 0.75:1 to about 1:1, for
example about 0.8:1 to about 1:1. This embodiment is illustrated in examples 7, 7a and 7b
herein. In one embodiment, the molar ratio of pamoic acid to AZD1152 hqpa when they
are first mixed together is about 0.8:1 – this is illustrated in Example 7 and 7b. In one
embodiment, the molar ratio of pamoic acid to AZD1152 hqpa when they are first mixed
together is about 1:1 – this is illustrated in Example 7a.
In some instances, the initial molar ratio of hydrophobic acid to therapeutic agent
(during formulation of the nanoparticles) may be different from the molar ratio of
hydrophobic acid to therapeutic agent in the nanoparticles (after removal of
unencapsulated hydrophobic acid and therapeutic agent). In other instances, the initial
molar ratio of hydrophobic acid to therapeutic agent (during formulation of the
nanoparticles) may be essentially the same as the molar ratio of hydrophobic acid to
therapeutic agent in the nanoparticles (after removal of unencapsulated hydrophobic acid
and therapeutic agent). For example, in the formulations referred to herein as G1,
illustrated by Examples 7 and 7b, the input molar ratio of pamoic acid to AZD1152 hqpa is
about 0.8:1 but the final molar ratio in the exemplified G1 is about 0.76:1 and typical
batches of formulations G1 are between about 0.65-0.75:1. Similarly the input ratio for G2
in Example 7a is about 1:1 and the final molar ratio as exemplified is about 0.87:1, with
typical batches being between about 0.85-0.95:1.
In some cases, a solution containing the therapeutic agent may be prepared
separately from a solution containing the polymer, and the two solutions may then be
combined prior to nanoparticle formulation. For instance, in one embodiment, a first
solution contains the therapeutic agent and the hydrophobic acid, and a second solution
contains the polymer and optionally the hydrophobic acid. Formulations where the second
solution does not contain the hydrophobic acid may be advantageous, for example, for
minimizing the amount of hydrophobic acid used in a process or, in some cases, for
minimizing contact time between the hydrophobic acid and, e.g., a polymer that can
degrade in the presence of the hydrophobic acid. In other cases, a single solution may be
prepared containing the therapeutic agent, polymer, and hydrophobic acid.
In some embodiments, a hydrophobic ion pair may be formed prior to formulation
of the nanoparticles. For example, a solution containing a hydrophobic ion pair may be
prepared prior to formulating the contemplated nanoparticles (e.g., by preparing a solution
containing suitable amounts of the therapeutic agent and the hydrophobic acid). In other
embodiments, a hydrophobic ion pair may be formed during formulation of the
nanoparticles. For example, a first solution containing the therapeutic agent and a second
solution containing the hydrophobic acid may be combined during a process step for
preparing the nanoparticles (e.g., prior to emulsion formation and/or during emulsion
formation). In certain embodiments, a hydrophobic ion pair may form prior to
encapsulation of the therapeutic agent and hydrophobic acid in a contemplated
nanoparticle. In other embodiments, a hydrophobic ion pair may form in the nanoparticle,
e.g., after encapsulation of the therapeutic agent and hydrophobic acid.
In certain embodiments, the hydrophobic acid may have a solubility of less than
about 2 g per 100 mL of water, in some embodiments less than about 1 g per 100 mL of
water, in some embodiments less than about 100 mg per 100 mL of water, in some
embodiments less than about 10 mg per 100 mL of water, and in some embodiments less
than about 1 mg per 100 mL of water, determined at 25 °C. In other embodiments, the
acid may have a solubility of between about 1 mg per 100 mL of water to about 2 g per
100 mL of water, in some embodiments between about 1 mg per 100 mL of water to about
1 g per 100 mL of water, in some embodiments between about 1 mg per 100 mL of water
to about 500 mg per 100 mL of water, and in some embodiments between about 1 mg per
100 mL of water to about 100 mg per 100 mL of water, determined at 25 °C. In some
embodiments, the hydrophobic acid may be essentially insoluble in water at 25 °C.
In some embodiments, disclosed nanoparticles may be essentially free of the
hydrophobic acid used during the preparation of the nanoparticles. In other embodiments,
disclosed nanoparticles may comprise the hydrophobic acid. For instance, in some
embodiments, the acid content in disclosed nanoparticles may be between about 0.05
weight percent to about 30 weight percent, in some embodiments between about 0.5
weight percent to about 30 weight percent, in some embodiments between about 1 weight
percent to about 30 weight percent, in some embodiments between about 2 weight percent
to about 30 weight percent, in some embodiments between about 3 weight percent to about
weight percent, in some embodiments between about 5 weight percent to about 30
weight percent, in some embodiments between about 7 weight percent to about 30 weight
percent, in some embodiments between about 10 weight percent to about 30 weight
percent, in some embodiments between about 15 weight percent to about 30 weight
percent, in some embodiments between about 20 weight percent to about 30 weight
percent, in some embodiments between about 0.05 weight percent to about 0.5 weight
percent, in some embodiments between about 0.05 weight percent to about 5 weight
percent, in some embodiments between about 1 weight percent to about 5 weight percent,
in some embodiments between about 3 weight percent to about 10 weight percent, in some
embodiments between about 5 weight percent to about 15 weight percent, and in some
embodiments between about 10 weight percent to about 20 weight percent.
Release profile
In some embodiments, disclosed nanoparticles substantially immediately release
(e.g., over about 1 minute to about 30 minutes, about 1 minute to about 25 minutes, about 5
minutes to about 30 minutes, about 5 minutes to about 1 hour, about 1 hour, or about 24
hours) less than about 2%, less than about 5%, less than about 10%, less than about 15%,
less than about 20%, less than about 25%, less than about 30%, or less than 40% of the
therapeutic agent, for example when placed in a phosphate buffer solution at room
temperature (e.g., 25 °C) and/or at 37 °C. In certain embodiments, nanoparticles
comprising the therapeutic agent may release the therapeutic agent when placed in an
aqueous solution (e.g., a phosphate buffer solution), e.g., at 25 C and/or at 37 °C, at a rate
substantially corresponding to about 0.01 to about 50%, in some embodiments about 0.01
to about 25%, in some embodiments about 0.01 to about 15%, in some embodiments about
0.01 to about 10%, in some embodiments about 1 to about 40%, in some embodiments
about 5 to about 40%, and in some embodiments about 10 to about 40% of the therapeutic
agent released over about 1 hour. In some embodiments, nanoparticles comprising the
therapeutic agent may release the therapeutic agent when placed in an aqueous solution
(e.g., a phosphate buffer solution), e.g., at 25 C and/or at 37 °C, at a rate substantially
corresponding to about 10 to about 70%, in some embodiments about 10 to about 45%, in
some embodiments about 10 to about 35%, or in some embodiments about 10 to about
%, of the therapeutic agent released over about 4 hours.
In some embodiments, disclosed nanoparticles may substantially retain the
therapeutic agent, e.g., for at least about 1 minute, at least about 1 hour, or more, when
placed in a phosphate buffer solution at 37 °C.
In some embodiments, a contemplated therapeutic nanoparticle substantially retains
the AZD1152 hqpa for at least 1 minute when placed in a phosphate buffer solution at 37
°C.
In some embodiments, a contemplated therapeutic nanoparticle substantially
immediately releases less than about 30% of the AZD1152 hqpa when placed in a
phosphate buffer solution at 37 °C.
In some embodiments, a contemplated therapeutic nanoparticle releases about 10 to
about 45% of the AZD1152 hqpa over about 1 hour when placed in a phosphate buffer
solution at 37 °C.
In-vitro release profiles for the contemplated nanoparticles may be measured as
follows:
The release was calculated by dividing the amount of AZD1152 hqpa released from
the nanoparticle into the release medium by the amount of total AZD1152 hqpa. In order to
obtain these two values, a specified amount of nanoparticle was spiked into a closed
container containing release medium (phosphate buffer solution (PBS) containing
polysorbate20 to ensure sink conditions) and incubated in a 37°C water bath. At each set
time point, two samples were taken. The first, used to give the total AZD1152 hqpa value,
was taken from the the container and prepared for HPLC. The second sample, used to give
the released AZD1152 hqpa at the time point, was taken and pelleted in an ultracentrifuge
leaving only released AZD1152 hqpa in the suspension (or supernatant) which was then
sampled and prepared for HPLC. A suitable HPLC method is given in Example 10.
Nine batches of each formulations G1 and G2 were tested, with quantitative
compositions similar to those shown in Example 7-7b, and in particular with G1
formulations having a pamoic acid: AZD1152 hqpa molar ratio in the range of about 0.65-
0.75:1, and G2 formulations having a molar ratio of about 0.85-0.95:1. The data below
show the mean release values over 72 hours.
37°C In vitro release profiles
Formulation G1 0 4 24 48 72 Time(hr)
G1 Mean release 0.808 3.182 7.708 13.808 23.075 %
One Standard
Deviation 0.327 0.696 1.259 2.436 3.390 %
Formulation G2 0 4 24 48 72 Time(hr)
G2 Mean release 1.558 13.713 32.107 50.637 67.257 %
One Standard
Deviation 0.816 9.481 12.896 9.916 7.720 %
In one embodiment, a contemplated therapeutic nanoparticle comprising 16-5 PLA-
PEG co-polymer, pamoic acid and AZD1152 hqpa releases less than 20% of AZD1152
hqpa after 30 hours in PBS and polysorbate20 at 37ºC. In another embodiment a
contemplated therapeutic nanoparticle comprising 16-5 PLA-PEG co-polymer, pamoic
acid and AZD1152 hqpa releases less than 20% of AZD1152 hqpa after 40 hours in PBS
and polysorbate20 at 37ºC. In another embodiment, a contemplated therapeutic
nanoparticle comprising 16-5 PLA-PEG co-polymer, pamoic acid and AZD1152 hqpa
releases less than 20% of AZD1152 hqpa after 50 hours in PBS and polysorbate20 at 37ºC.
In another embodiment, a contemplated therapeutic nanoparticle comprising 16-5 PLA-
PEG co-polymer, pamoic acid and AZD1152 hqpa releases about 10% of AZD1152 hqpa
after 24 hours in PBS and polysorbate20 at 37ºC. In these embodiments, conveniently the
release is measured by the above method.
In one embodiment (for example when the therapeutic nanoparticles comprise
deoxycholic acid, cholic acid (including a mixture of deoxycholic acid and cholic acid),
dioctyl sulfosuccinic acid or pamoic acid), the therapeutic nanoparticles release the
AZD1152 hqpa in vivo at a rate such that less than 40% has been released 24 hours after
dosing. In another embodiment (for example when the therapeutic nanoparticles comprise
deoxycholic acid, cholic acid (including a mixture of deoxycholic acid and cholic acid),
dioctyl sulfosuccinic acid or pamoic acid), the therapeutic nanoparticles release the
AZD1152 hqpa in vivo at a rate such that less than 30% has been released 24 hours after
dosing. In one embodiment (for example when the therapeutic nanoparticles comprise
deoxycholic acid, cholic acid (including a mixture of deoxycholic acid and cholic acid,
dioctyl sulfosuccinic acid or pamoic acid), the therapeutic nanoparticles release the
AZD1152 hqpa in vivo at a rate of such that 25-35% has been released 24 hours after
dosing. In another embodiment (for example when the therapeutic nanoparticles comprise
pamoic acid), the therapeutic nanoparticles release the AZD1152 hqpa in vivo at a rate
such that less than 15% has been released 24 hours after dosing.
In general, a “nanoparticle” refers to any particle having a diameter of less than
1000 nm, e.g., about 10 nm to about 200 nm. Disclosed therapeutic nanoparticles may
include nanoparticles having a diameter of about 60 to about 120 nm, or about 70 to about
120 nm, or about 80 to about 120 nm, or about 90 to about 120 nm, or about 100 to about
120 nm, or about 60 to about 130 nm, or about 70 to about 130 nm, or about 80 to about
130 nm, or about 90 to about 130 nm, or about 100 to about 130 nm, or about 110 to about
130 nm, or about 60 to about 140 nm, or about 70 to about 140 nm, or about 80 to about
140 nm, or about 90 to about 140 nm, or about 100 to about 140 nm, or about 110 to about
140 nm, or about 60 to about 150 nm, or about 70 to about 150 nm, or about 80 to about
150 nm, or about 90 to about 150 nm, or about 100 to about 150 nm, or about 110 to about
150 nm, or about 120 to about 150 nm.
In some embodiments, the hydrodynamic diameter of a contemplated therapeutic
nanoparticle is about 60 to about 150 nm, or about 90 to about 140 nm, or about 90 to
about 120 nm. In a further embodiment, the hydrodynamic diameter of a contemplated
therapeutic nanoparticle is about 90 to about 110 nm, for example when the therapeutic
nanoparticles comprise a substantially hydrophobic acid selected from deoxycholic acid,
cholic acid, dioctyl sulfosuccinic acid, pamoic acid, or mixtures thereof.
In one embodiment, the disclosed nanoparticles are formed with AZD1152 hqpa
and pamoic acid, and have a hydrodynamic diameter of <500 nm, such as <200 nm, for
example 70-140 nm.
In particular, the disclosed nanoparticles are formed with AZD1152 hqpa and a
hydrophobic acid selected from cholic acid, deoxycholic acid and dioctyl sulfosuccinic
acid. In another embodiment, the disclosed nanoparticles are formed with AZD1152 hqpa
and a hydrophobic acid selected from deoxycholic acid and dioctyl sulfosuccinic acid. In
one embodiment the disclosed nanoparticles are formed with AZD1152 hqpa and
deoxycholic acid. In another embodiment the disclosed nanoparticles are formed with
AZD1152 hqpa and dioctyl sulfosuccinic acid. In another embodiment the disclosed
nanoparticles are formed with AZD1152 and cholic acid. In one embodiment the disclosed
nanoparticles are formed with AZD1152 hqpa and a mixture of cholic acid and
deoxycholic acid; in this embodiment, suitably the hydrophobic acids are in a ratio of
about 3:2 deoxycholic acid: cholic acid and the ratio of total hydrophobic acid: AZD1152
hqpa is about 2:1 (wherein ratios are expressed by weight percent). In another
embodiment, the disclosed nanoparticles are formed with AZD1152 hqpa and pamoic acid.
Polymers
In some embodiments, the nanoparticles may comprise a matrix of polymers and
the therapeutic agent. In some embodiments, the therapeutic agent can be associated with
at least part of the polymeric matrix. The therapeutic agent can be associated with the
surface of, encapsulated within, surrounded by, and/or dispersed throughout the polymeric
matrix.
Any suitable polymer can be used in the disclosed nanoparticles. Polymers can be
natural or unnatural (synthetic) polymers. Polymers can be homopolymers or copolymers
comprising two or more monomers. In terms of sequence, copolymers can be random,
block, or comprise a combination of random and block sequences. Typically, polymers are
organic polymers.
The term “polymer,” as used herein, is given its ordinary meaning as used in the
art, that is, a molecular structure comprising one or more repeat units (monomers),
connected by covalent bonds. The repeat units may all be identical, or in some cases, there
may be more than one type of repeat unit present within the polymer. In some cases, the
polymer can be biologically derived (a biopolymer). Non-limiting examples include
peptides or proteins. In some cases, additional moieties may also be present in the polymer,
for example biological moieties such as those described below. If more than one type of
repeat unit is present within the polymer, then the polymer is said to be a “copolymer.” It
is to be understood that in any embodiment employing a polymer, the polymer being
employed may be a copolymer in some cases. The repeat units forming the copolymer may
be arranged in any fashion. For example, the repeat units may be arranged in a random
order, in an alternating order, or as a block copolymer, i.e., comprising one or more regions
each comprising a first repeat unit (e.g., a first block), and one or more regions each
comprising a second repeat unit (e.g., a second block), etc. Block copolymers may have
two (a diblock copolymer), three (a triblock copolymer), or more numbers of distinct
blocks.
Disclosed particles can include copolymers, which, in some embodiments,
describes two or more polymers (such as those described herein) that have been associated
with each other, usually by covalent bonding of the two or more polymers together. Thus,
a copolymer may comprise a first polymer and a second polymer, which have been
conjugated together to form a block copolymer where the first polymer can be a first block
of the block copolymer and the second polymer can be a second block of the block
copolymer. Of course, those of ordinary skill in the art will understand that a block
copolymer may, in some cases, contain multiple blocks of polymer, and that a "block
copolymer," as used herein, is not limited to only block copolymers having only a single
first block and a single second block. For instance, a block copolymer may comprise a
first block comprising a first polymer, a second block comprising a second polymer, and a
third block comprising a third polymer or the first polymer, etc. In some cases, block
copolymers can contain any number of first blocks of a first polymer and second blocks of
a second polymer (and in certain cases, third blocks, fourth blocks, etc.). In addition, it
should be noted that block copolymers can also be formed, in some instances, from other
block copolymers. For example, a first block copolymer may be conjugated to another
polymer (which may be a homopolymer, a biopolymer, another block copolymer, etc.), to
form a new block copolymer containing multiple types of blocks, and/or to other moieties
(e.g., to non-polymeric moieties).
In some embodiments, the polymer (for example a copolymer or a block
copolymer) can be amphiphilic, that is, having a hydrophilic portion and a hydrophobic
portion, or a relatively hydrophilic portion and a relatively hydrophobic portion. A
hydrophilic polymer can be one generally that attracts water and a hydrophobic polymer
can be one that generally repels water. A hydrophilic or a hydrophobic polymer can be
identified, for example, by preparing a sample of the polymer and measuring its contact
angle with water (typically, a hydrophilic polymer will have a contact angle of less than
60°, while a hydrophobic polymer will have a contact angle of greater than about 60°). In
some cases, the hydrophilicity of two or more polymers may be measured relative to each
other, i.e., a first polymer may be more hydrophilic than a second polymer. For instance,
the first polymer may have a smaller contact angle than the second polymer.
In one set of embodiments, a polymer (such as a copolymer or a block copolymer)
contemplated herein includes a biocompatible polymer, which is a polymer that does not
typically induce an adverse response when inserted or injected into a living subject, for
example, without significant inflammation and/or acute rejection of the polymer by the
immune system, for instance through a T-cell response. Accordingly, the therapeutic
particles contemplated herein can be non-immunogenic. The term non-immunogenic as
used herein refers to endogenous growth factor in its native state which normally elicits no,
or only minimal levels of, circulating antibodies, T-cells, or reactive immune cells, and
which normally does not elicit in the individual an immune response against itself.
Biocompatibility typically refers to the acute rejection of material by at least a
portion of the immune system - a nonbiocompatible material implanted into a subject
provokes an immune response in the subject that can be severe enough such that the
rejection of the material by the immune system cannot be adequately controlled, and often
is of a degree such that the material must be removed from the subject. One simple test to
determine biocompatibility can be to expose a polymer to cells in vitro; biocompatible
polymers are polymers that typically will not result in significant cell death at moderate
concentrations, e.g., at concentrations of 50 micrograms/10 cells. For instance, a
biocompatible polymer may cause less than about 20% cell death when exposed to cells
such as fibroblasts or epithelial cells, even if phagocytosed or otherwise uptaken by such
cells. Non-limiting examples of biocompatible polymers that may be useful in various
embodiments include polydioxanone (PDO), polyhydroxyalkanoate, polyhydroxybutyrate,
poly(glycerol sebacate), polyglycolide (poly(glycolic) acid) (PGA), polylactide
(poly(lactic) acid) (PLA), poly(lactic) acid-co-poly(glycolic) acid (PLGA),
polycaprolactone, or copolymers or derivatives including these and/or other polymers.
In certain embodiments, contemplated biocompatible polymers may be
biodegradable, so that the polymer is able to degrade, chemically and/or biologically,
within a physiological environment, such as within the body. As used herein,
"biodegradable" polymers are those that, when introduced into cells, are broken down by
the cellular machinery (biologically degradable) and/or by a chemical process, such as
hydrolysis, (chemically degradable) into components that the cells can either reuse or
dispose of without significant toxic effect on the cells. In one embodiment, the
biodegradable polymer and their degradation byproducts can be biocompatible.
Particles disclosed herein may or may not contain PEG. In addition, certain
embodiments can be directed towards copolymers containing poly(ester-ether)s, e.g.,
polymers having repeat units joined by ester bonds (e.g., R-C(O)-O-R' bonds) and ether
bonds (e.g., R-O-R' bonds). In some embodiments, a biodegradable polymer, such as a
hydrolyzable polymer, containing carboxylic acid groups, may be conjugated with
poly(ethylene glycol) repeat units to form a poly(ester-ether). A polymer (e.g., copolymer,
e.g., block copolymer) containing poly(ethylene glycol) repeat units can also be referred to
as a "PEGylated" polymer.
For instance, a contemplated polymer may be one that hydrolyzes spontaneously
upon exposure to water (e.g., within a subject), or the polymer may degrade upon exposure
to heat (e.g., at temperatures of about 37°C). Degradation of a polymer may occur at
varying rates, depending on the polymer or copolymer used. For example, the half-life of
the polymer (the time at which 50% of the polymer can be degraded into monomers and/or
other nonpolymeric moieties) may be on the order of days, weeks, months, or years,
depending on the polymer. The polymers may be biologically degraded, e.g., by enzymatic
activity or cellular machinery, in some cases, for example, through exposure to a lysozyme
(e.g., having relatively low pH). In some cases, the polymers may be broken down into
monomers and/or other nonpolymeric moieties that cells can either reuse or dispose of
without significant toxic effect on the cells (for example, polylactide may be hydrolyzed to
form lactic acid, polyglycolide may be hydrolyzed to form glycolic acid, etc.).
In some embodiments, polymers may be polyesters, including copolymers
comprising lactic acid and glycolic acid units, such as poly(lactic acid-co-glycolic acid)
and poly(lactide-co-glycolide), collectively referred to herein as "PLGA"; and
homopolymers comprising glycolic acid units, referred to herein as "PGA," and lactic acid
units, such as poly-L-lactic acid, poly-D-lactic acid, poly-D,L-lactic acid, poly-L-lactide,
poly-D-lactide, and poly-D,L-lactide, collectively referred to herein as "PLA." In some
embodiments, exemplary polyesters include, for example, polyhydroxyacids; PEGylated
polymers and copolymers of lactide and glycolide (e.g., PEGylated PLA, PEGylated PGA,
PEGylated PLGA, and derivatives thereof). In some embodiments, polyesters include, for
example, polyanhydrides, poly(ortho ester) PEGylated poly(ortho ester),
poly(caprolactone), PEGylated poly(caprolactone), polylysine, PEGylated polylysine,
poly(ethylene imine), PEGylated poly(ethylene imine), poly(L-lactide-co-L-lysine),
poly(serine ester), poly(4-hydroxy-L-proline ester), poly[α-(4-aminobutyl)-L-glycolic acid],
and derivatives thereof.
In some embodiments, a polymer may be PLGA. PLGA is a biocompatible and
biodegradable co-polymer of lactic acid and glycolic acid, and various forms of PLGA can
be characterized by the ratio of lactic acid:glycolic acid. Lactic acid can be L-lactic acid,
D-lactic acid, or D,L-lactic acid. The degradation rate of PLGA can be adjusted by
altering the lactic acid-glycolic acid ratio. In some embodiments, PLGA can be
characterized by a lactic acid:glycolic acid ratio of approximately 85:15, approximately
75:25, approximately 60:40, approximately 50:50, approximately 40:60, approximately
:75, or approximately 15:85. In some embodiments, the ratio of lactic acid to glycolic
acid monomers in the polymer of the particle (e.g., the PLGA block copolymer or PLGA-
PEG block copolymer), may be selected to optimize for various parameters such as water
uptake, therapeutic agent release and/or polymer degradation kinetics can be optimized.
In some embodiments, polymers may be one or more acrylic polymers. In certain
embodiments, acrylic polymers include, for example, acrylic acid and methacrylic acid
copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl
methacrylate, amino alkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic
acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate),
poly(methacrylic acid polyacrylamide, amino alkyl methacrylate copolymer, glycidyl
methacrylate copolymers, polycyanoacrylates, and combinations comprising one or more
of the foregoing polymers. The acrylic polymer may comprise fully-polymerized
copolymers of acrylic and methacrylic acid esters with a low content of quaternary
ammonium groups.
In some embodiments, polymers can be cationic polymers. In general, cationic
polymers are able to condense and/or protect negatively charged strands of nucleic acids
(e.g., DNA, RNA, or derivatives thereof). Amine-containing polymers such as
poly(lysine), polyethylene imine (PEI), and poly(amidoamine) dendrimers are
contemplated for use, in some embodiments, in a disclosed particle.
In some embodiments, polymers can be degradable polyesters bearing cationic side
chains. Examples of these polyesters include poly(L-lactide-co-L-lysine), poly(serine
ester), poly(4-hydroxy-L-proline ester).
It is contemplated that PEG may be terminated and include an end group. For
example, PEG may terminate in a hydroxyl, a methoxy or other alkoxyl group, a methyl or
other alkyl group, an aryl group, a carboxylic acid, an amine, an amide, an acetyl group, a
guanidino group, or an imidazole. Other contemplated end groups include azide, alkyne,
maleimide, aldehyde, hydrazide, hydroxylamine, alkoxyamine, or thiol moieties.
Those of ordinary skill in the art will know of methods and techniques for
PEGylating a polymer, for example, by using EDC (l-ethyl(3-dimethylaminopropyl)
carbodiimide hydrochloride) and NHS (N-hydroxysuccinimide) to react a polymer to a
PEG group terminating in an amine, by ring opening polymerization techniques (ROMP),
or the like.
In one embodiment, the molecular weight (or e.g., the ratio of molecular weights
of, e.g., different blocks of a copolymer) of the polymers can be optimized for effective
treatment as disclosed herein. For example, the molecular weight of a polymer may
influence particle degradation rate (such as when the molecular weight of a biodegradable
polymer can be adjusted), solubility, water uptake, and drug release kinetics. For example,
the molecular weight of the polymer (or e.g., the ratio of molecular weights of, e.g.,
different blocks of a copolymer) can be adjusted such that the particle biodegrades in the
subject being treated within a reasonable period of time (ranging from a few hours to 1-2
weeks, 3-4 weeks, 5-6 weeks, 7-8 weeks, etc.).
A disclosed particle can for example comprise a diblock copolymer of PEG and
PL(G)A, wherein for example, the PEG portion may have a number average molecular
weight of about 1,000-20,000, e.g., about 2,000-20,000, e.g., about 2 to about 10,000, and
the PL(G)A portion may have a number average molecular weight of about 5,000 to about
20,000, or about 5,000-100,000, e.g., about 20,000-70,000, e.g., about 15,000-50,000.
For example, disclosed here is an exemplary therapeutic nanoparticle that includes
about 10 to about 99 weight percent poly(lactic) acid-poly(ethylene)glycol copolymer or
poly(lactic)-co-poly (glycolic) acid-poly(ethylene)glycol copolymer, or about 20 to about
80 weight percent, about 40 to about 80 weight percent, or about 30 to about 50 weight
percent, or about 70 to about 90 weight percent poly(lactic) acid-poly(ethylene)glycol
copolymer or poly(lactic)-co-poly (glycolic) acid-poly(ethylene)glycol copolymer.
Exemplary poly(lactic) acid-poly(ethylene)glycol copolymers can include a number
average molecular weight of about 15 to about 20 kDa, or about 10 to about 25 kDa of
poly(lactic) acid and a number average molecular weight of about 4 kDa to about 6 kDa, or
about 2 kDa to about 10 kDa of poly(ethylene)glycol.
In some embodiments, the poly(lactic) acid-poly(ethylene)glycol copolymer may
have a poly(lactic) acid number average molecular weight fraction of about 0.6 to about
0.95, in some embodiments between about 0.7 to about 0.9, in some embodiments between
about 0.6 to about 0.8, in some embodiments between about 0.7 to about 0.8, in some
embodiments between about 0.75 to about 0.85, in some embodiments between about 0.8
to about 0.9, and in some embodiments between about 0.85 to about 0.95. It should be
understood that the poly(lactic) acid number average molecular weight fraction may be
calculated by dividing the number average molecular weight of the poly(lactic) acid
component of the copolymer by the sum of the number average molecular weight of the
poly(lactic) acid component and the number average molecular weight of the
poly(ethylene)glycol component.
Disclosed nanoparticles may optionally include about 1 to about 50 weight percent
poly(lactic) acid or poly(lactic) acid-co-poly (glycolic) acid (which does not include PEG),
or may optionally include about 1 to about 50 weight percent, or about 10 to about 50
weight percent or about 30 to about 50 weight percent poly(lactic) acid or poly(lactic) acid-
co-poly (glycolic) acid. For example, poly(lactic) or poly(lactic)-co-poly(glycolic) acid
may have a number average molecule weight of about 5 to about 15 kDa, or about 5 to
about 12 kDa. Exemplary PLA may have a number average molecular weight of about 5
to about 10 kDa. Exemplary PLGA may have a number average molecular weight of
about 8 to about 12 kDa.
A therapeutic nanoparticle may, in some embodiments, contain about 10 to about
30 weight percent, in some embodiments about 10 to about 25 weight percent, in some
embodiments about 10 to about 20 weight percent, in some embodiments about 10 to about
weight percent, in some embodiments about 15 to about 20 weight percent, in some
embodiments about 15 to about 25 weight percent, in some embodiments about 20 to about
weight percent, in some embodiments about 20 to about 30 weight percent, or in some
embodiments about 25 to about 30 weight percent of poly(ethylene)glycol, where the
poly(ethylene)glycol may be present as a poly(lactic) acid-poly(ethylene)glycol
copolymer, poly(lactic)-co-poly (glycolic) acid-poly(ethylene)glycol copolymer, or
poly(ethylene)glycol homopolymer. In certain embodiments, the polymers of the
nanoparticles can be conjugated to a lipid. The polymer can be, for example, a lipid-
terminated PEG.
In one embodiment, the therapeutic nanoparticles contain about 50 to about 99.75
weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer or a diblock
poly(lactic acid-co-glycolic acid)-poly(ethylene)glycol copolymer, wherein the therapeutic
nanoparticle comprises about 10 to about 30 weight percent poly(ethylene)glycol; and
about 0.2 to about 30 weight percent of AZD1152 hqpa. In one embodiment the
poly(lactic) acid-poly(ethylene)glycol copolymer has a number average molecular weight
of about 15kDa to about 20kDa poly(lactic acid) and a number average molecular weight
of about 4kDa to about 6kDa poly(ethylene)glycol; for example the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol.
In another embodiment, the therapeutic nanoparticles contain about 50 to about
99.75 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer
wherein the therapeutic nanoparticle comprises about 10 to about 30 weight percent
poly(ethylene)glycol; and about 0.2 to about 30 weight percent of AZD1152 hqpa. In one
embodiment the poly(lactic) acid-poly(ethylene)glycol copolymer has a number average
molecular weight of about 15kDa to about 20kDa poly(lactic acid) and a number average
molecular weight of about 4kDa to about 6kDa poly(ethylene)glycol; for example the
poly(lactic) acid-poly(ethylene)glycol copolymer has a number average molecular weight
of about 16kDa poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol.
In another embodiment, the therapeutic nanoparticles contain about 50 to about 99
weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer wherein the
therapeutic nanoparticle comprises about 10 to about 30 weight percent
poly(ethylene)glycol; and about 1 to about 30 weight percent of AZD1152 hqpa. In one
embodiment the poly(lactic) acid-poly(ethylene)glycol copolymer has a number average
molecular weight of about 15kDa to about 20kDa poly(lactic acid) and a number average
molecular weight of about 4kDa to about 6kDa poly(ethylene)glycol; for example the
poly(lactic) acid-poly(ethylene)glycol copolymer has a number average molecular weight
of about 16kDa poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol.
In one embodiment, the poly(lactic) acid-poly(ethylene)glycol copolymer has a
poly(lactic) acid number average molecular weight fraction of about 0.7 to about 0.9, such
as about 0.75 to about 0.85.
In one embodiment the therapeutic nanoparticle comprises about 10 to about 25
weight percent poly(ethylene)glycol. In a further embodiment, the therapeutic nanoparticle
comprises about 20 to about 30 weight percent poly(ethylene)glycol.
In a further embodiment, the therapeutic nanoparticle comprises about 65 weight
percent to about 85 weight percent of the copolymer, for example about 65 weight percent
to about 80 weight percent copolymer.
In a further embodiment, when the hydrophobic acid is pamoic acid, the therapeutic
nanoparticle comprises about 60 to about 80 percent copolymer (particularly PLA-PEG co-
polymer, particularly 16/5 PLA-PEG co-polymer), such as about 65 to about 75 percent
copolymer, wherein the poly(ethylene)glycol content is about 15 to about 20 percent by
weight of the nanoparticle. It will be understood by the skilled person however, that the
weight percent of polymers present in the nanoparticle will vary to some extent between
batches as the amount of hydrophobic acid (such as pamoic acid) and AZD1152 hqpa
varies.
Preparation of Nanoparticles
Another embodiment is directed to systems and methods of making disclosed
nanoparticles. In some embodiments, using two or more different polymers (e.g.,
copolymers, e.g., block copolymers) in different ratios and producing particles from the
polymers (e.g., copolymers, e.g., block copolymers), properties of the particles be
controlled. For example, a polymer (e.g., copolymer, e.g., block copolymer) may be
chosen for its biocompatibility and/or its ability to control immunogenicity of the resultant
particle.
In some embodiments, a solvent used in a nanoparticle preparation process (e.g., a
nanoprecipitation process or a nanoemulsion process as discussed below) may include a
hydrophobic acid, which may confer advantageous properties to the nanoparticles prepared
using the process. As discussed above, in some cases, the hydrophobic acid may improve
drug loading of disclosed nanoparticles. Furthermore, in some instances, the controlled
release properties of disclosed nanoparticles may be improved by the use of the
hydrophobic acid. In some cases, the hydrophobic acid may be included in, for example,
an organic solution or an aqueous solution used in the process. In one embodiment, the
hydrophobic acid is incorporated in an aqueous solution in the form of a water-soluble salt
(such as a sodium salt), for example as sodium cholate. In one embodiment, the drug is
combined with an organic solution and the hydrophobic acid and optionally one or more
polymers. The hydrophobic acid concentration in a solution used to dissolve the drug is
discussed above and may be, for example, between about 1 weight percent and about 30
weight percent, etc.
In one set of embodiments, the particles are formed by providing a solution
comprising one or more polymers, and contacting the solution with a polymer nonsolvent
to produce the particle. The solution may be miscible or immiscible with the polymer
nonsolvent. For example, a water-miscible liquid such as acetonitrile may contain the
polymers, and particles are formed as the acetonitrile is contacted with water, a polymer
nonsolvent, e.g., by pouring the acetonitrile into the water at a controlled rate. The
polymer contained within the solution, upon contact with the polymer nonsolvent, may
then precipitate to form particles such as nanoparticles. Two liquids are said to be
“immiscible” or not miscible, with each other when one is not soluble in the other to a
level of at least 10% by weight at ambient temperature and pressure. Typically, an organic
solution (e.g., dichloromethane, acetonitrile, chloroform, tetrahydrofuran, acetone,
formamide, dimethylformamide, pyridines, dioxane, dimethylsulfoxide, etc.) and an
aqueous liquid (e.g., water, or water containing dissolved salts or other species, cell or
biological media, ethanol, etc.) are immiscible with respect to each other. For example, the
first solution may be poured into the second solution (at a suitable rate or speed). In some
cases, particles such as nanoparticles may be formed as the first solution contacts the
immiscible second liquid, e.g., precipitation of the polymer upon contact causes the
polymer to form nanoparticles while the first solution is poured into the second liquid, and
in some cases, for example, when the rate of introduction is carefully controlled and kept at
a relatively slow rate, nanoparticles may form. The control of such particle formation can
be readily optimized by one of ordinary skill in the art using only routine experimentation.
Properties such as surface functionality, surface charge, size, zeta (ζ) potential,
hydrophobicity, ability to control immunogenicity, and the like, may be highly controlled
using a disclosed process. For instance, a library of particles may be synthesized, and
screened to identify the particles having a particular ratio of polymers that allows the
particles to have a specific density of moieties present on the surface of the particle. This
allows particles having one or more specific properties to be prepared, for example, a
specific size and a specific surface density of moieties, without an undue degree of effort.
Accordingly, certain embodiments are directed to screening techniques using such
libraries, as well as any particles identified using such libraries. In addition, identification
may occur by any suitable method. For instance, the identification may be direct or
indirect, or proceed quantitatively or qualitatively.
In another embodiment, a nanoemulsion process is described, such as the process
represented in Figures 1, 2A, and 2B. For example, the therapeutic agent, a hydrophobic
acid, a first polymer (for example, a diblock co-polymer such as PLA-PEG or PLGA-PEG)
and an optional second polymer (e.g., (PL(G)A-PEG or PLA), may be combined with an
organic solution to form a first organic phase. Such first phase may include about 1 to
about 50 weight % solids, about 5 to about 50 weight % solids, about 5 to about 40 weight
% solids, about 1 to about 15 weight % solids, or about 10 to about 30 weight % solids.
The first organic phase may be combined with a first aqueous solution to form a second
phase. The organic solution can include, for example, toluene, methyl ethyl ketone,
acetonitrile, tetrahydrofuran, ethyl acetate, isopropyl alcohol, isopropyl acetate,
dimethylformamide, methylene chloride, dichloromethane, chloroform, acetone, benzyl
alcohol, Tween®80, Span ®80, Brij®100 or the like, and combinations thereof. The
organic solution may also include dimethylsulfoxide (DMSO). In an embodiment, the
organic phase may include benzyl alcohol, ethyl acetate, and combinations thereof. In
another embodiment, the organic phase may include benzyl alcohol, ethyl acetate and
DMSO. The second phase can be between about 0.1 and 50 weight %, between about 1
and 50 weight %, between about 5 and 40 weight %, or between about 1 and 15 weight %
solids. The aqueous solution can be water, optionally in combination with one or more of
sodium cholate, sodium docusate, ethyl acetate, polyvinyl acetate and benzyl alcohol. The
aqueous solution may also contain DMSO and/or Brij®100 or similar. In some
embodiments, the aqueous solution comprises Brij®100, benzyl alcohol and DMSO in
water. In some embodiments, the pH of the aqueous phase may be selected based on the
pK of the protonated therapeutic agent and/or the pK of the hydrophobic acid. For
example, in certain embodiments, the therapeutic agent, when protonated, may have a first
pK , the hydrophobic acid may have a second pK , and the aqueous phase may have a pH
equal to a pK unit between the first pK and the second pK . In a particular embodiment,
a a a
the pH of the aqueous phase may be equal to a pK unit that is about equidistant between
the the first pKa and the second pKa.
For example, the oil or organic phase may use a solvent that is only partially
miscible with the nonsolvent (water). Therefore, when mixed at a low enough ratio and/or
when using water pre-saturated with the organic solvents, the organic (oil) phase remains
liquid. The organic (oil) phase may be emulsified into an aqueous solution and, as liquid
droplets, sheared into nanoparticles using, for example, high energy dispersion systems,
such as homogenizers or sonicators. The aqueous portion of the emulsion, otherwise
known as the “water phase”, may be surfactant solution consisting of sodium cholate (or
possibly sodium docusate) and pre-saturated with ethyl acetate and benzyl alcohol. In
some instances, the organic phase (e.g., first organic phase) may include the therapeutic
agent. Additionally, in certain embodiments, the aqueous solution (e.g., first aqueous
solution) may include the substantially hydrophobic acid. In other embodiments, both the
therapeutic agent and the substantially hydrophobic acid may be dissolved in the organic
phase.
Emulsifying the second phase to form an emulsion phase may be performed, for
example, in one or two emulsification steps. For example, a primary emulsion may be
prepared, and then emulsified to form a fine emulsion. The primary emulsion can be
formed, for example, using simple mixing, a high pressure homogenizer, probe sonicator,
stir bar, or a rotor stator homogenizer. The primary emulsion may be formed into a fine
emulsion through the use of e.g., probe sonicator or a high pressure homogenizerfor
example by using 1, 2, 3, or more passes through a homogenizer. For example, when a
high pressure homogenizer is used, the pressure used may be about 30 to about 60 psi,
about 40 to about 50 psi, about 1000 to about 8000 psi, about 2000 to about 4000 psi,
about 4000 to about 8000 psi, or about 4000 to about 5000 psi, e.g., about 2000, 2500,
4000 or 5000 psi. The pressure used may be about 5,000 to 20,000psi, such 5,000 to
,000psi, such as about 8,000 to 15,000 psi, for example 8,000 to about 12,000 psi. The
processes exemplified herein use about 9,000 psi (see Examples 7, 7a and 7b) and about
11,000 psi (such as Example 1).
In some cases, fine emulsion conditions, which can be characterized by a very high
surface to volume ratio of the droplets in the emulsion, can be chosen to maximize the
solubility of the therapeutic agent and hydrophobic acid and form the desired HIP. In
certain embodiments, under fine emulsion conditions, equilibration of dissolved
components can occur very quickly, and faster than solidification of the nanoparticles.
Thus, selecting a HIP based on, e.g., the pK difference between the therapeutic agent and
the hydrophobic acid, or adjusting other parameters such as the pH of the fine emulsion
and/or the pH of the quench solution, can have a significant impact on the drug loading and
release properties of the nanoparticles by dictating, for example, the formation of a HIP in
the nanoparticle as opposed to diffusion of the therapeutic agent and/or hydrophobic acid
out of the nanoparticle.
In some embodiments, the therapeutic agent and the substantially hydrophobic acid
may be combined in the second phase prior to emulsifying the second phase. In some
instances, the therapeutic agent and the substantially hydrophobic acid may form a
hydrophobic ion pair prior to emulsifying the second phase. In other embodiments, the
therapeutic agent and the substantially hydrophobic acid may form a hydrophobic ion pair
during emulsification of the second phase. For example, the therapeutic agent and the
substantially hydrophobic acid may be combined in the second phase substantially
concurrently with emulsifying the second phase, e.g., the therapeutic agent and the
substantially hydrophobic acid may be dissolved in separate solutions (e.g., two
substantially immiscible solutions), which are then combined during emulsification. In
another example, the therapeutic agent and the substantially hydrophobic acid may be
dissolved in separate miscible solutions that are then fed into second phase during
emulsification.
Either solvent evaporation or dilution may be needed to complete the extraction of
the solvent and solidify the particles. For better control over the kinetics of extraction and
a more scalable process, a solvent dilution via aqueous quench may be used. For example,
the emulsion can be diluted into cold water to a concentration sufficient to dissolve all of
the organic solvent to form a quenched phase. In some embodiments, quenching may be
performed at least partially at a temperature of about 5 °C or less. For example, water (or
other quench solution) used in the quenching may be at a temperature that is less than room
temperature (e.g., about 0 to about 10°C, or about 0 to about 5 °C). The solutions may also
be cooled during quenching. In certain embodiments, the quench may be chosen having a
pH that is advantageous for quenching the emulsion phase, e.g., by improving the
properties of the nanoparticles, such as the release profile, or improving a nanoparticle
parameter, such as the drug loading. The pH of the quench may be adjusted by acid or
base titration, for example, or by appropriate selection of a buffer.
In some embodiments, the pH of the quench may be selected based on the pK of
the protonoated therapeutic agent and/or the pK of the hydrophobic acid. For example, in
certain embodiments, the therapeutic agent, when protonated, may have a first pK , the
hydrophobic acid may have a second pK , and the emulsion phase may be quenched with
an aqueous solution having a pH equal to a pK unit between the first pK and the second
pK . In some embodiments, the resultant quenched phase may also have a pH equal to a
pK unit between the first pK and the second pK . In a particular embodiment, the pH
a a a
may be equal to a pKa unit that is about equidistant between the the first pKa and the
second pK .
In some embodiments, the quench may have a pH between about 2 and about 12, in
some embodiments between about 3 and about 10, in some embodiments between about 3
and about 9, in some embodiments between about 3 and about 8, in some embodiments
between about 3 and about 7, in some embodiments between about 4 and about 8, in some
embodiments between about 4 and about 7, in some embodiments between about 4 and
about 6, in some embodiments between about 4 and about 5, in some embodiments
between about 4.2 and about 4.8, in some embodiments between about 6 and about 10, in
some embodiments between about 6 and about 9, in some embodiments between about 6
and about 8, in some embodiments between about 6 and about 7. In certain embodiments,
the quench may have a pH of about 4.5. In further embodiments, the quench may have a
pH of about 6.5. It should be understood that the pH of a buffer solution may vary as a
function of temperature. Unless otherwise specified, the pH of a buffer solution referred to
herein is the pH at 23 C.
In some embodiments, the quench may be an aqueous solution comprising a
buffering agent (a buffer solution). Any suitable buffering agent may be used. Non-
limiting examples of buffering agents include phosphate, citrate, acetate, borate, imidazole,
MES (4-morpholineethanesulfonic acid), bis-tris (Bis(2-hydroxyethyl)amino-
tris(hydroxymethyl)methane), ADA (N-(2-Acetamido)iminodiacetic acid), ACES (N-(2-
Acetamido)aminoethanesulfonic acid), PIPES (1,4-Piperazinediethanesulfonic acid),
MOPSO (3-Morpholinohydroxypropanesulfonic acid), bis-tris propane (1,3-
Bis[tris(hydroxymethyl)methylamino]propane), BES (N,N-Bis(2-hydroxyethyl)
aminoethanesulfonic acid), MOPS (3-(N-Morpholino)propanesulfonic acid), TES (2-[(2-
Hydroxy-1,1-bis(hydroxymethyl)ethyl)amino]ethanesulfonic acid), HEPES (4-(2-
Hydroxyethyl)piperazineethanesulfonic acid), DIPSO (3-(N,N-Bis[2-hydroxyethyl]
amino)hydroxypropanesulfonic acid), MOBS (4-(N-Morpholino)butanesulfonic acid),
TAPSO (2-Hydroxy[tris(hydroxymethyl)methylamino]propanesulfonic acid), Trizma
(2-Amino(hydroxymethyl)-1,3-propanediol), HEPPSO (4-(2-Hydroxyethyl)piperazine-
1-(2-hydroxypropanesulfonic acid)), POPSO (Piperazine-N,N′-bis(2-
hydroxypropanesulfonic acid)), TEA (triethylamine), EPPS (4-(2-Hydroxyethyl)
piperazinepropanesulfonic acid), tricine (N-[Tris(hydroxymethyl)methyl]glycine), Gly-Gly
(Diglycine), bicine (N,N-Bis(2-hydroxyethyl)glycine), HEPBS (N-(2-Hydroxyethyl)
piperazine-N′-(4-butanesulfonic acid)), TAPS (N-[Tris(hydroxymethyl)methyl]
aminopropanesulfonic acid), AMPD (2-Aminomethyl-1,3-propanediol), TABS (N-
tris(Hydroxymethyl)methylaminobutanesulfonic acid), AMPSO (N-(1,1-Dimethyl
hydroxyethyl)aminohydroxypropanesulfonic acid), CHES (2-(Cyclohexylamino)
ethanesulfonic acid), CAPSO (3-(Cyclohexylamino)hydroxypropanesulfonic acid),
AMP (β-Aminoisobutyl alcohol), CAPS (3-(Cyclohexylamino)propanesulfonic acid),
CABS (4-(Cyclohexylamino)butanesulfonic acid), and combinations thereof. It should
be understood that a buffer comprises an acid and a base in equilibrium (e.g., an acid and a
conjugate base and/or a base and a conjugate acid). Thus, it should further be understood
that, for brevity, a buffer solution or buffering agent may be referred to herein by the name
of a free acid (e.g., phosphoric acid) or its conjugate base (e.g., phosphate), or the name of
a free base (e.g., imidazole) or its conjugate acid (e.g., imidazolium), but that one of
ordinary skill in the art would understand that an equilibrium exists between two or more
different protonation species of the buffering agent (e.g., H PO , H PO , HPO , and
3 4 2 4 4
PO ). In some embodiments, the quench may comprise two or more buffering agents.
For example, the quench may comprise two, three, four, or five buffering agents. In some
embodiments, the quench may comprise a mixture of phosphate and citrate. In other
embodiments, the quench may comprise a mixture of borate, phosphate, and acetate (e.g.,
Britton-Robbinson buffer, which comprises 0.04 M H BO , 0.04 M H PO , and 0.04 M
3 3 3 4
CH COOH titrated to a desired pH).
In some embodiments, a buffer solution (a quench) may have a suitable buffering
capacity within a particular pH range. Non-limiting pH ranges for exemplary buffer
solutions are provided in Table A below. In certain embodiments, a buffer solution may
have a buffering agent concentration between about 0.001M and about 1M, in some
embodiments between about 0.001M and about 0.5M, in some embodiments between
about 0.01M and about 0.5M, in some embodiments between about 0.05M and about
0.5M, in some embodiments between about 0.1M and about 0.5M, in some embodiments
between about 0.01M and about 0.2M, in some embodiments between about 0.05M and
about 0.15M, and in some embodiments between about 0.075M and about 0.125M.
Table A. Non-limiting pH ranges for exemplary buffers.
Buffering agent pH range
Phosphate 5.7-8.0
Citrate 3.0-6.2
Phosphate-Citrate 2.6-7.6
Buffering agent pH range
Acetate 3.7-5.6
Imidazole 6.2-7.8
Britton-Robbinson 2-12
ADA 6.0–7.2
ACES 6.1–7.5
PIPES 6.1–7.5
MOPSO 6.2–7.6
Bis-tris Propane 6.3–9.5
BES 6.4–7.8
MOPS 6.5–7.9
TES 6.8–8.2
HEPES 6.8–8.2
DIPSO 7.0–8.2
MOBS 6.9–8.3
In some embodiments, a quench may have a buffering agent concentration
sufficient to resist a substantial pH change. For example, a quenched phase may have a pH
that differs from the pH of the emulsion phase by less than 1 pH unit, in some
embodiments less than 0.5 pH units, in some embodiments, less than 0.2 pH units, in some
embodiments less than 0.1 pH units, and in some embodiments less than 0.05 pH units. In
some embodiments, the pH of the quenched phase may be substantially the same as the pH
of the emulsion phase (prior to quenching).
In some embodiments, the quenched phase may have a pH between about 2 and
about 12, in some embodiments between about 3 and about 10, in some embodiments
between about 3 and about 9, in some embodiments between about 3 and about 8, in some
embodiments between about 3 and about 7, in some embodiments between about 4 and
about 8, in some embodiments between about 4 and about 7, in some embodiments
between about 4 and about 6, in some embodiments between about 4 and about 5, in some
embodiments between about 4.2 and about 4.8, in some embodiments between about 6 and
about 10, in some embodiments between about 6 and about 9, in some embodiments
between about 6 and about 8, in some embodiments between about 6 and about 7. In
certain embodiments, the quenched phase may have a pH of about 4.6.
A buffering solution (e.g., a quench) at a desired pH can be readily prepared by one
of ordinary skill in the art. For example, a buffering solution at a desired pH can prepared
by titrating a solution containing a buffering agent with a strong acid (e.g., HCl) or strong
base (e.g., NaOH). Alternatively, a buffering solution at a desired pH can prepared by
combining a weak acid (e.g., citric acid) with its conjugate base (e.g., sodium citrate) or by
combining a weak base (e.g., imidazole) with its conjugate acid (e.g., imidazolium
chloride). One of ordinary skill in the art could determine the amounts of the weak acid or
weak base and corresponding conjugate to use in preparing a buffering solution by using
the Henderson–Hasselbalch equation.
In one embodiment, the quench solution is a buffer solution at pH 6.5 (such as
0.17M sodium phosphate buffer). Conveniently, the quench solution is cooled to <5 ºC
before the emulsion is added to it. Conveniently, the mixture of quench and emulsion
solutions are cooled while they are mixed together. In one embodiment, the ratio of quench
solution to emulsion is 10:1 (by weight). In another embodiment, the ratio of quench
solution to emulsion is 3:1. In this embodiment and embodiments, conveniently the
hydrophobic acid is pamoic acid.
In certain embodiments, HIP formation can occur during or after emulsification,
e.g., as a result of equilibrium conditions in the fine emulsion. Without wishing to be
bound by any theory, it is believed that organic-soluble counter ions (the hydrophobic acid)
can facilitate diffusion of the therapeutic agent into a nanoparticle of an emulsion as a
result of HIP formation. Without wishing to be bound by any theory, the HIP may remain
in the nanoparticle before solidification of the nanoparticle since the solubility of the HIP
in the nanoparticle is higher than the solubility of the HIP in the aqueous phase of the
emulsion and/or in the quench. For example, by selecting a pH for the quench that is
between the pKa of the therapeutic agent and the pKa of the hydrophobic acid, formation of
ionized therapeutic agent and hydrophobic acid can be optimized. However, selecting a
pH that is too high may tend to cause the hydrophobic acid to diffuse out of the
nanoparticle, whereas selecting a pH that is too low may tend to cause the therapeutic
agent to diffuse out of the nanoparticle.
In some embodiments, the pH of an aqueous solution used in a nanoparticle
formulation process (e.g., including, but not limited to, the aqueous phase, the emulsion
phase, the quench, and the quenched phase) may be independently selected and may be
between about 1 and about 3, in some embodiments between about 2 and about 4, in some
embodiments between about 3 and about 5, in some embodiments between about 4 and
about 6, in some embodiments between about 5 and about 7, in some embodiments
between about 6 and about 8, in some embodiments between about 7 and about 9, and in
some embodiments between about 8 and about 10. In certain embodiments, the pH of an
aqueous solution used in a nanoparticle formulation process may be between about 3 and
about 4, in some embodiments between about 4 and about 5, in some embodiments
between about 5 and about 6, in some embodiments between about 6 and about 7, in some
embodiments between about 7 and about 8, and in some embodiments between about 8 and
about 9.
The achieved encapsulation efficiency (the percentage of active ingredient in the
nanoparticle compared to the total active ingredient in the process) will vary with the exact
components of the formulation used and the detailed process parameters. A high
encapsulation efficiency is more economical. In some embodiments, not all of the
therapeutic agent is encapsulated in the particles at this stage, and a drug solubilizer is
added to the quenched phase to form a solubilized phase. The drug solubilizer may be for
example, Tween®80, Tween® 20, polyvinyl pyrrolidone, cyclodextran, sodium dodecyl
sulfate, sodium cholate, diethylnitrosamine, sodium acetate, urea, glycerin, propylene
glycol, glycofurol, poly(ethylene)glycol, bris(polyoxyethyleneglycol)dodecyl ether,
sodium benzoate, sodium salicylate, or combinations thereof. For example, Tween®80
may be added to the quenched nanoparticle suspension to solubilize the free drug and
prevent the formation of drug crystals. In some embodiments, a ratio of drug solubilizer to
the therapeutic agent is about 200:1 to about 10:1, or in some embodiments about 100:1 to
about 10:1 (by weight).
The solubilized phase may be filtered to recover the nanoparticles.
For example, ultrafiltration membranes may be used to concentrate the nanoparticle
suspension and substantially eliminate extraneous material such as organic solvent, free
drug (that is, unencapsulated therapeutic agent), drug solubilizer, and other processing aids
(surfactants).
Exemplary filtration may be performed using a cross flow or tangential flow
filtration system, in which the feed is passed across the filter membrane (tangentially) at
positive pressure relative to the permeate side. A proportion of the extraneous material
passes through the membrane as permeate or filtrate; everything else is retained on the feed
side of the membrane as retentate. For example, by using a membrane with a pore size
suitable to retain nanoparticles while allowing solutes, micelles, and organic solvent to
pass, nanoparticles can be selectively separated. Exemplary membranes with molecular
weight cut-offs of about 300-500 kDa (~5-25 nm) may be used.
In some embodiments, the concentration of the extraneous material in the retentate
can be reduced by “washing out” with water, a process called diafiltration. The amount of
the extraneous material removed is related to the filtrate volume generated, relative to the
retentate volume. The filtrate volume generated is usually referred to in terms of
“diafiltration volumes” or diavolumes. A single diavolume is the volume of retentate when
diafiltration is started.
Diafiltration may be performed using a constant volume approach, meaning the
diafiltrate (cold deionized water, e.g., about 0 to about 5 °C, or 0 to about 10 °C) may
added to the feed suspension at the same rate as the filtrate is removed from the
suspension. When the volume of filtrate collected equals the starting retentate volume, 1
diavolume has been processed.
In some embodiments, filtering may include a first filtering using a first
temperature of about 0 to about 5 °C, or 0 to about 10 °C, and a second temperature of
about 20 to about 30 °C, or 15 to about 35 °C. In some embodiments, filtering may
include processing about 1 to about 30, in some cases about 1 to about 15, or in some cases
1 to about 6 diavolumes. For example, filtering may include processing about 1 to about
, or in some cases about 1 to about 6 diavolumes, at about 0 to about 5 °C, and
processing at least one diavolume (e.g., about 1 to about 15, about 1 to about 3, or about 1
to about 2 diavolumes) at about 20 to about 30 °C. In some embodiments, filtering
comprises processing different diavolumes at different distinct temperatures.
In one embodiment, about 20 diavolumes is used of cold deionised water. In
another embodiment, about 20 diavolumes of deionised water at ambient temperature is
used.
After purifying and concentrating the nanoparticle suspension, the particles may be
passed through one, two or more sterilizing and/or depth filters, for example, using ~0.2
µm depth pre-filter. For example, a sterile filtration step may involve filtering the
therapeutic nanoparticles using a filtration train at a controlled rate. In some embodiments,
the filtration train may include a depth filter and a sterile filter.
In another embodiment of preparing nanoparticles, an organic phase is formed
composed of a mixture of the therapeutic agent (AZD1152 hqpa) and polymer
(homopolymer and co-polymer). The organic phase is mixed with an aqueous phase at
approximately a 1:5 ratio (organic phase : aqueous phase) where the aqueous phase is
composed of a surfactant and some dissolved solvent. The primary emulsion is formed by
the combination of the two phases under simple mixing or through the use of a rotor stator
homogenizer. The primary emulsion is then formed into a fine emulsion through the use of
a high pressure homogenizer. The fine emulsion is then quenched by addition to deionized
water under mixing. In some embodiments, the quench:emulsion ratio may be about 2:1 to
about 40:1, or in some embodiments about 5:1 to about 15:1. In some embodiments, the
quench:emulsion ratio is approximately 8.5:1. Then a solution of Tween® (e.g.,
Tween®80) is added to the quench to achieve approximately 2% Tween® overall. This
serves to dissolve free, unencapsulated therapeutic agent (ie AZD1152 hqpa). The
nanoparticles are then isolated through either centrifugation or ultrafiltration/diafiltration.
It will be appreciated that the amounts of polymer, therapeutic agent (ie AZD1152
hqpa), and hydrophobic acid that are used in the preparation of the formulation may differ
from a final formulation. For example, some of the AZD1152 hqpa may not become
completely incorporated in a nanoparticle and such free AZD1152 hqpa may be e.g.,
filtered away. For example, in an embodiment, a first organic solution containing about 11
weight percent theoretical loading of AZD1152 hqpa in a first organic solution containing
about 9% of a first hydrophobic acid (e.g., a fatty acid), a second organic solution
containing about 89 weight percent polymer (e.g., the polymer may include PLA-PEG),
and an aqueous solution containing about 0.12% of a second hydrophobic acid (e.g., a bile
acid) may be used in the preparation of a formulation that results in, e.g., a final
nanoparticle comprising about 2 weight percent AZD1152 hqpa, about 97.5 weight percent
polymer, and about 0.5% total hydrophobic acid. Such processes may provide final
nanoparticles suitable for administration to a patient that includes about 1 to about 20
percent by weight AZD1152 hqpa, e.g., about 1, about 2, about 3, about 4, about 5, about
8, about 10, or about 15 percent AZD1152 hqpa by weight.
Furthermore, it will be appreciated that the product formed from processes using
hydrophobic acids such as trifluoroacetic acid (see for example Example 3) may undergo
ion exchange with hydrophobic acids from salts such as sodium cholate used initially as
surfactants in the water phase. For example cholic acid may be retained as a hydrophobic
acid in the nanoparticles after the use of trifluoroacetic acid and sodium cholate in
processing, as shown in Example 3.
In some embodiments, quenching of the emulsion phase comprises mixing the
emulsion phase with a second aqueous solution having a pH between about 2 and about 8,
such as between about 4 and about 7.
Described herein is a process for preparing a therapeutic nanoparticle. The process
comprises combining a first organic phase with a first aqueous solution to form a second
phase; emulsifying the second phase to form an emulsion phase, wherein the emulsion
phase comprises a first polymer, a basic therapeutic agent which is AZD1152 hqpa, and a
substantially hydrophobic acid; quenching of the emulsion phase thereby forming a
quenched phase, wherein quenching of the emulsion phase comprises mixing the emulsion
phase with a second aqueous solution having a pH between about 4 and about 7.
In some embodiments, the process further comprises filtering the quenched phase
to recover the therapeutic nanoparticles.
In some embodiments, the process further comprises combining AZD1152 hqpa
and the acid in the second phase prior to emulsifying the second phase. For example, in
some embodiments, AZD1152 hqpa and the acid form a hydrophobic ion pair prior to
emulsifying the second phase. In other embodiments, AZD1152 hqpa and the acid form a
hydrophobic ion pair during emulsification of the second phase.
In some embodiments, the process further comprises combining AZD1152 hqpa
and the acid in the second phase substantially concurrently with emulsifying the second
phase. For example, in some embodiments, the first organic phase comprises AZD1152
hqpa and the first aqueous solution comprises the acid.
In other embodiments, the first organic phase comprises the polymer, AZD1152
hqpa and the substantially hydrophobic acid.
Described herein is a process for preparing a therapeutic nanoparticle comprising
combining a first organic phase with a first aqueous solution to form a second phase;
emulsifying the second phase to form an emulsion phase, wherein the emulsion phase
comprises a first polymer, a basic therapeutic agent which is AZD1152 hqpa, and pamoic
acid; quenching of the emulsion phase thereby forming a quenched phase. In this
embodiment, preferably, quenching of the emulsion phase comprises mixing the emulsion
phase with a second aqueous solution having a pH between about 4 and about 7.
Described herein is a process for preparing a therapeutic nanoparticle comprising
combining a first organic phase with a first aqueous solution to form a second phase;
emulsifying the second phase to form an emulsion phase, wherein the emulsion phase
comprises a first polymer, a basic therapeutic agent which is AZD1152 hqpa and a
substantially hydrophobic acid selected from deoxycholic acid and dioctylsulfosuccinic
acid; quenching of the emulsion phase thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with an aqueous
solution having a pH between about 4 and about 7.
Conveniently, the emulsion phase is held, for example by storage in ice, for a
period (such as 5 to 15 minutes) before quenching. In some embodiments, as referred to
above, the emulsion is carried out in a two stage process, with formation of a coarse
emulsion preceding formation of a fine emulsion. In some embodiments, a coarse
emulsion is formed and this may conveniently be held, for example by storage in ice, for a
period (such as 5 to 15 minutes) before the fine emulsion is formed. The fine emulsion
itself, may also be stored, for example at a temperature of 0-5 ºC, in some embodiments at
about 2 ºC, for a period of 1-15 minutes (in some embodiments about 1 minute, in other
embodiments about 2 minutes, in other embodiments, not more than 1 minutes, in still
further embodiments for at least 5 minutes) before quenching.
Conveniently the quench is carried out at reduced temperature such as at <5ºC.
Suitably, in the above embodiments and embodiment, the first aqueous phase
comprises a surfactant, such as sodium cholate or polyoxyethylene (100) stearyl ether (for
example as sold under the tradename Brij®), in water and benzyl alcohol.
Described herein is a process for preparing a therapeutic nanoparticle comprising
combining a first organic phase with a first aqueous solution to form a second phase;
emulsifying the second phase to form an emulsion phase, wherein the emulsion phase
comprises a first polymer, a basic therapeutic agent which is AZD1152 hqpa and a
substantially hydrophobic acid selected from deoxycholic acid, pamoic acid and
dioctylsulfosuccinic acid; optionally holding the emulsion phase for a hold time (such as 5
to 15 minutes, conveniently at about 0 ºC); quenching of the emulsion phase thereby
forming a quenched phase, wherein quenching of the emulsion phase comprises mixing the
emulsion phase with an aqueous solution having a pH between about 4 and about 7 (such
as about pH 6.5), preferably at <5 ºC. Suitably the first aqueous phase comprises a
surfactant, such as sodium cholate or polyoxyethylene (100) stearyl ether (for example as
sold under the tradename Brij®), in water and benzyl alcohol.
Described herein is a process for preparing a therapeutic nanoparticle comprising:
1) combining a first organic phase (which comprises a polymer, AZD1152 hqpa and a
substantially hydrophobic acid phase selected from deoxycholic acid, pamoic acid and
dioctylsulfosuccinic acid in one or more solvents) with a first aqueous solution (comprising
a surfactant in water) to form a second phase;
2) emulsifying the second phase to form an emulsion;
3) optionally holding the emulsion phase for a hold time (such as 5 to 15 minutes,
conveniently at about 0 ºC);
4 ) quenching of the emulsion phase <5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution having a pH between about 4 and about 7 (such as about pH 6.5);
) concentrating and isolating the resulting nanoparticles by filtration.
Suitably the first aqueous phase comprises a surfactant, such as sodium cholate or
polyoxyethylene (100) stearyl ether (for example as sold under the tradename Brij®), in
water and benzyl alcohol.
Described herein is a process for preparing a therapeutic nanoparticle comprising:
1) combining a first organic phase (which comprises a polymer, AZD1152 hqpa and a
substantially hydrophobic acid phase selected from deoxycholic acid, pamoic acid and
dioctylsulfosuccinic acid in one or more solvents) with a first aqueous solution (comprising
a surfactant in water) to form a second phase;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 5 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
5) optionally waiting for a delay time of at least 5 minutes;
6) quenching of the emulsion phase <5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution having a pH between about 4 and about 7 (such as about pH 6.5);
7) concentrating and isolating the resulting nanoparticles by filtration.
Suitably the first aqueous phase comprises a surfactant, such as sodium cholate or
polyoxyethylene (100) stearyl ether (for example as sold under the tradename Brij®), in
water and benzyl alcohol.
Described herein is a process for preparing a therapeutic nanoparticle comprising:
1) combining a first organic phase (which comprises a polymer in ethyl acetate, AZD1152
hqpa in a TFA/water/benzyl alcohol solvent system and a substantially hydrophobic acid
phase selected from deoxycholic acid, pamoic acid and dioctylsulfosuccinic acid in
DMSO) with a first aqueous solution (comprising a surfactant such as sodium cholate or
polyoxyethylene (100) stearyl ether (for example as sold under the tradename Brij®), in
water and benzyl alcohol) to form a second phase;
2) emulsifying the second phase to form an emulsion;
3) optionally holding the emulsion phase for a hold time (such as 5 to 15 minutes,
conveniently at about 0 ºC);
4) quenching of the emulsion phase at <5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution having a pH between about 4 and about 7 (such as about pH 6.5);
) concentrating and isolating the resulting nanoparticles by filtration.
Further surfactant such as Tween® 80 in water may be added to the quenched solution
prior to concentration and filtration.
Described herein is a process for preparing a therapeutic nanoparticle comprising:
1) combining a first organic phase (which comprises a polymer in ethyl acetate, AZD1152
hqpa in a TFA/water/benzyl alcohol solvent system and a substantially hydrophobic acid
phase selected from deoxycholic acid, pamoic acid and dioctylsulfosuccinic acid in
DMSO) with a first aqueous solution (comprising a surfactant such as sodium cholate or
polyoxyethylene (100) stearyl ether (for example as sold under the tradename Brij®), in
water and benzyl alcohol) to form a second phase;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 5 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) optionally waiting for a delay time of at least 5 minutes;
6) quenching of the emulsion phase at 0-5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution having a pH between about 4 and about 7 (such as about pH 6.5);
7) concentrating and isolating the resulting nanoparticles by filtration.
Further surfactant such as Tween® 80 in water may be added to the quenched solution
prior to concentration and filtration.
Described herein is a process for preparing a therapeutic nanoparticle comprising:
1) combining a first organic phase (which comprises a polymer in ethyl acetate, AZD1152
hqpa in a TFA/water/benzyl alcohol solvent system and pamoic acid in DMSO) with a first
aqueous solution (comprising a surfactant such as sodium cholate or polyoxyethylene
(100) stearyl ether (for example as sold under the tradename Brij®), in water, DMSO and
benzyl alcohol) to form a second phase;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 5 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
5) optionally waiting for a delay time of at least 5 minutes;
6) quenching of the emulsion phase at 0-5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution comprising a buffer having a pH between about 4 and about 7 (such as
about pH 6.5);
7) concentrating and isolating the resulting nanoparticles by filtration.
Further surfactant such as Tween® 80 in water may be added to the quenched solution
prior to concentration and filtration.
Described herein is a process for preparing a therapeutic nanoparticle comprising:
1) combining a first organic phase (which comprises a polymer, AZD1152 hqpa and
pamoic acid in a solvent mixture comprising TFA, benzyl alcohol, DMSO and ethyl
acetate such that the benzyl alcohol: ethyl acetate are present in a molar ratio of between
1:3 and 1:4) with a first aqueous solution (comprising a surfactant such polyoxyethylene
(100) stearyl ether (for example as sold under the tradename Brij®S100), in water, DMSO
and benzyl alcohol) to form a second phase;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 5 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) optionally waiting for a delay time of at least 5 minutes;
6) quenching of the emulsion phase at 0-5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution comprising a buffer having a pH between about 4 and about 7 (such as
about pH 6.5);
7) concentrating and isolating the resulting nanoparticles by filtration.
Further surfactant such as Tween® 80 in water may be added to the quenched solution
prior to concentration and filtration.
Described herein is a process for preparing a therapeutic nanoparticle comprising:
1) combining a first organic phase (which comprises a polymer in ethyl acetate, AZD1152
hqpa in a TFA/water/benzyl alcohol solvent system and pamoic acid in DMSO) with a first
aqueous solution (comprising a surfactant such as polyoxyethylene (100) stearyl ether (for
example as sold under the tradename Brij®), in water, DMSO and benzyl alcohol) to form
a second phase;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 5 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
5) optionally waiting for a delay time of at least 5 minutes;
6) quenching of the emulsion phase at 0-5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution comprising a buffer having a pH 6.5;
7) adding an aqueous surfactant solution (such as Tween®80, for example a 35 weight
percent Tween®80 solution in water) to the quench at a ratio of about 20:1 to 100:1
Tween®80 to drug by weight;
8) concentrating and isolating the resulting nanoparticles by filtration.
Described herein is a process for preparing a therapeutic nanoparticle comprising:
1) combining a first organic phase (which comprises a polymer, AZD1152 hqpa and
pamoic acid in in a solvent mixture comprising TFA, benzyl alcohol, DMSO and ethyl
acetate such that the benzyl alcohol: ethyl acetate are present in a molar ratio of between
1:3 and 1:4) with a first aqueous solution (comprising a surfactant such polyoxyethylene
(100) stearyl ether (for example as sold under the tradename Brij®S100), in water, DMSO
and benzyl alcohol) to form a second phase;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 5 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) optionally waiting for a delay time of at least 5 minutes;
6) quenching of the emulsion phase at 0-5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution comprising a buffer at pH 6.5;
7) adding an aqueous surfactant solution as a solubilizer to the quenched solution;
8) concentrating and isolating the resulting nanoparticles by filtration.
Described herein is a process for preparing a therapeutic nanoparticle comprising:
1) combining a first organic phase (which comprises a 16/5 PLA-PEG copolymer,
AZD1152 hqpa and pamoic acid in a solvent mixture comprising TFA, benzyl alcohol,
DMSO and ethyl acetate such that the benzyl alcohol: ethyl acetate are present in a molar
ratio of about 1:3.6) with a first aqueous solution (comprising a surfactant such
polyoxyethylene (100) stearyl ether (for example as sold under the tradename Brij®S100),
in water, DMSO and benzyl alcohol) to form a second phase;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 10 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) optionally waiting for a delay time of at least 5 minutes;
6) quenching of the emulsion phase at 0-5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution comprising buffer at pH 6.5;
7) adding an aqueous surfactant solution as a solubilizer;
8) concentrating and isolating the resulting nanoparticles by filtration.
Conveniently, the pamoic acid and AZD1152 hqpa are added at an initial ratio of 0.8 moles
pamoic acid: 1 mole AZD1152 hqpa.
Described herein is a process for preparing a therapeutic nanoparticle comprising:
1) combining a first organic phase (which comprises a 16/5 PLA-PEG copolymer,
AZD1152 hqpa and pamoic acid in a solvent mixture comprising TFA, benzyl alcohol,
DMSO and ethyl acetate such that the benzyl alcohol: ethyl acetate are present in a molar
ratio of about 1:3.6) with a first aqueous solution (comprising a surfactant such
polyoxyethylene (100) stearyl ether (for example as sold under the tradename Brij®S100),
in water, DMSO and benzyl alcohol) to form a second phase;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 10 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) waiting for a delay time of at least 5 minutes;
6) quenching of the emulsion phase at 0-5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution comprising buffer at pH 6.5;
7) adding an aqueous surfactant solution as a solubilizer;
8) concentrating and isolating the resulting nanoparticles by filtration.
Conveniently, the pamoic acid and AZD1152 hqpa are added at an initial ratio of 0.8 moles
pamoic acid: 1 mole AZD1152 hqpa.
Described herein is a process for preparing a therapeutic nanoparticle comprising:
1) combining a first organic phase (which comprises a 16:5 PLA-PEG co-polymer,
AZD1152 hqpa and pamoic acid in a solvent mixture comprising TFA, benzyl alcohol,
DMSO and ethyl acetate such that the benzyl alcohol: ethyl acetate are present in a molar
ratio of about 1:3.6) with a first aqueous solution (comprising a polyoxyethylene (100)
stearyl ether (for example as sold under the tradename Brij®S100), in water, DMSO and
benzyl alcohol) to form a second phase, wherein the ratio of the aqueous phase to the
organic phase is about 5.5:1;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 10 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) waiting for a delay time of at least 5 minutes, for example 10 minutes;
6) quenching of the emulsion phase at 0-5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution comprising a buffer at pH 6.5 wherein the ratio of second aqueous
solution to emulsion is between about 2:1 and about 10:1, such as about 3:1;
7) adding an aqueous surfactant solution to the quench;
8) concentrating and isolating the resulting nanoparticles by filtration.
Conveniently, the pamoic acid and AZD1152 hqpa are added at an initial ratio of 0.8 moles
pamoic acid: 1 mole AZD1152 hqpa.
Described herein is a process for preparing a therapeutic nanoparticle comprising:
1) combining a first organic phase (which comprises a 16:5 PLA-PEG co-polymer,
AZD1152 hqpa and pamoic acid in a solvent mixture comprising TFA, benzyl alcohol,
DMSO and ethyl acetate such that the benzyl alcohol: ethyl acetate are present in a molar
ratio of about 1:3.6 and the pamoic acid and AZD1152 hqpa are added at an initial ratio of
0.8 moles pamoic acid: 1 mole AZD1152 hqpa) with a first aqueous solution (comprising a
polyoxyethylene (100) stearyl ether (for example as sold under the tradename Brij®S100),
in water, DMSO and benzyl alcohol) to form a second phase, wherein the ratio of the
aqueous phase to the organic phase is about 5.5:1;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 10 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) waiting for a delay time of at least 5 minutes, for example 10 minutes;
6) quenching of the emulsion phase at 0-5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution comprising a buffer at pH 6.5 (such as a 0.17M phosphate buffer)
wherein the ratio of second aqueous solution to emulsion is between about 2:1 and about
:1, such as about 3:1;
7) adding an aqueous surfactant solution (such as Tween®80, for example a 35 weight%
Tween®80 solution in water) to the quench solution (for example at a ratio of about 20:1
Tween®80 to drug by weight);
8) concentrating and isolating the resulting nanoparticles by filtration.
Described herein is a process for preparing a therapeutic nanoparticle comprising:
1) combining a first organic phase (which comprises a 16:5 PLA-PEG co-polymer,
AZD1152 hqpa and pamoic acid in a solvent mixture comprising TFA, benzyl alcohol,
DMSO and ethyl acetate such that the benzyl alcohol: ethyl acetate are present in a molar
ratio of about 1:3) with a first aqueous solution (comprising a polyoxyethylene (100)
stearyl ether (for example as sold under the tradename Brij®S100), in water, DMSO and
benzyl alcohol) to form a second phase;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 10 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) after about 1 minute, quenching of the emulsion phase at about 2 ºC thereby forming a
quenched phase, wherein quenching of the emulsion phase comprises mixing the emulsion
phase with a second aqueous solution comprising a buffer at pH 6.5;
6) adding an aqueous surfactant solution (such as Tween®80, for example a 35 weight %
Tween®80 solution in water) to the quench solution;
7) concentrating and isolating the resulting nanoparticles by filtration.
Conveniently, the pamoic acid and AZD1152 hqpa are added at an initial ratio of about 1
mole pamoic acid: 1 mole AZD1152 hqpa.
Described herein is a process for preparing a therapeutic nanoparticle comprising:
1) combining a first organic phase (which comprises a 16:5 PLA-PEG co-polymer,
AZD1152 hqpa and pamoic acid in a solvent mixture comprising TFA, benzyl alcohol,
DMSO and ethyl acetate such that the benzyl alcohol: ethyl acetate are present in a molar
ratio of about 1:3) with a first aqueous solution (comprising a polyoxyethylene (100)
stearyl ether (for example as sold under the tradename Brij®S100), in water, DMSO and
benzyl alcohol) to form a second phase, wherein the ratio of the aqueous phase to the
organic phase is about 5:1;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 10 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) after about 1 minute, quenching of the emulsion phase at about 2 ºC, wherein quenching
of the emulsion phase comprises mixing the emulsion phase with a second aqueous
solution comprising a buffer at pH 6.5 (such as a 0.17M phosphate buffer) and wherein the
ratio of second aqueous solution to emulsion is about 10:1;
6) adding an aqueous surfactant solution (such as Tween®80, for example a 35 weight %
Tween®80 solution in water) to the quench at a ratio of about 100:1 Tween®80 to drug by
weight;
7) concentrating and isolating the resulting nanoparticles by filtration.
Conveniently, the pamoic acid and AZD1152 hqpa are added at an initial ratio of about 1
mole pamoic acid: 1 mole AZD1152 hqpa.
Described herein is a process for preparing a therapeutic nanoparticle comprising:
1) combining a first organic phase (which comprises a 16:5 PLA-PEG co-polymer,
AZD1152 hqpa and pamoic acid in a solvent mixture comprising TFA, benzyl alcohol,
DMSO and ethyl acetate such that the benzyl alcohol: ethyl acetate are present in a molar
ratio of about 1:3 and the pamoic acid and AZD1152 hqpa are added at an initial ratio of 1
mole pamoic acid: 1 mole AZD1152 hqpa) with a first aqueous solution (comprising a
polyoxyethylene (100) stearyl ether (for example as sold under the tradename Brij®S100),
in water, DMSO and benzyl alcohol) to form a second phase, wherein the ratio of the
aqueous phase to the organic phase is about 5:1;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 10 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) after about 1 minute, quenching of the emulsion phase at about 2 ºC thereby forming a
quenched phase, wherein quenching of the emulsion phase comprises mixing the emulsion
phase with a second aqueous solution comprising a buffer at pH 6.5 and wherein the ratio
of second aqueous solution to emulsion is about 10:1;
6) adding an aqueous surfactant solution (such as Tween®80, for example a 35 weight %
Tween®80 solution in water) to the quench at a ratio of about 100:1 Tween®80 to drug by
weight;
7) concentrating and isolating the resulting nanoparticles by filtration.
Described herein is a process for preparing a therapeutic nanoparticle comprising
any of the specific methods set out in the Examples herein.
In some embodiments, AZD1152 hqpa, when protonated, has a first pK , the acid
has a second pK , and the emulsion phase is quenched with an aqueous solution having a
pH equal to a pK unit between the first pK and the second pK . For example, in some
a a a
instances, the quenched phase has a pH equal to a pK unit between the first pK and the
second pKa. In some embodiments, AZD1152 hqpa, when protonated, has a first pKa, the
acid has a second pK , and the first aqueous solution has a pH equal to a pK unit between
the first pK and the second pK . In some embodiments, the pH (e.g., of the quenched
phase or first aqueous solution) is equal to a pK unit that is about equidistant between the
first pK and the second pK .
Described herein is a therapeutic nanoparticle. The therapeutic nanoparticle is
prepared by emulsification of a mixture comprising a first polymer, AZD1152 hqpa, and a
substantially hydrophobic acid, thereby forming an emulsion phase; and quenching of the
emulsion phase thereby forming a quenched phase which comprises a plurality of the
therapeutic nanoparticles.
Described herein is a therapeutic nanoparticle, wherein the therapeutic nanoparticle
is prepared by emulsification of a mixture comprising a first polymer, AZD1152 hqpa, and
a substantially hydrophobic acid selected from deoxycholic acid, cholic acid, dioctyl
sulfosuccinic acid and pamoic acid, thereby forming an emulsion phase; and quenching of
the emulsion phase thereby forming a quenched phase which comprises a plurality of the
therapeutic nanoparticles.
Described herein is a therapeutic nanoparticle, wherein the therapeutic nanoparticle
is prepared by emulsification of a mixture comprising a first polymer, AZD1152 hqpa, and
pamoic acid, thereby forming an emulsion phase; and quenching of the emulsion phase
thereby forming a quenched phase which comprises a plurality of the therapeutic
nanoparticles.
In some embodiments, quenching of the emulsion phase comprises mixing the
emulsion phase with an aqueous solution having a pH between about 2 and about 8, such
as between about pH 4 and 7. Quenching at a reduced temperature, such as <5 ºC is
preferred.
Described herein is a therapeutic nanoparticle, wherein the therapeutic nanoparticle
is prepared by emulsification of a mixture comprising a first polymer, AZD1152 hqpa, and
a substantially hydrophobic acid, thereby forming an emulsion phase; and quenching of the
emulsion phase thereby forming a quenched phase which comprises a plurality of the
therapeutic nanoparticles, wherein quenching of the emulsion phase comprises mixing the
emulsion phase with an aqueous solution having a pH between about 4 and about 7.
Described herein is a therapeutic nanoparticle, wherein the therapeutic nanoparticle
is prepared by emulsification of a mixture comprising a first polymer, AZD1152 hqpa, and
a substantially hydrophobic acid selected from deoxycholic acid, cholic acid, dioctyl
sulfosuccinic acid and pamoic acid, thereby forming an emulsion phase; and quenching of
the emulsion phase thereby forming a quenched phase which comprises a plurality of the
therapeutic nanoparticles, wherein quenching of the emulsion phase comprises mixing the
emulsion phase with an aqueous solution having a pH between about 4 and about 7.
Described herein is a therapeutic nanoparticle, wherein the therapeutic nanoparticle
is prepared by emulsification of a mixture comprising a first polymer, AZD1152 hqpa and
pamoic acid, thereby forming an emulsion phase; and quenching of the emulsion phase
thereby forming a quenched phase which comprises a plurality of the therapeutic
nanoparticles, wherein quenching of the emulsion phase comprises mixing the emulsion
phase with an aqueous solution having a pH between about 4 and about 7.
In some embodiments, the pH of a contemplated aqueous solution (e.g., first or
second aqueous solution is between about 4 and about 7, e.g., between about 4 and about 5
or between about 6 and about 7.
In some embodiments, a contemplated aqueous solution comprises phosphate,
citrate, or a mixture of phosphate and citrate. In some embodiments, the second aqueous
solution comprises a mixture of borate, phosphate, and acetate.
In some embodiments, a contemplated process for preparing a therapeutic
nanoparticle further comprises filtration of the quenched phase to recover the therapeutic
nanoparticles.
In some embodiments, the quenched phase has a pH substantially the same as the
emulsion phase. In some embodiments, the quenched phase has a pH between about 4 and
about 7, e.g., between about 4 and about 5 or between about 6 and about 7.
Described herein is a therapeutic nanoparticle, wherein the therapeutic nanoparticle
is prepared by a process of preparation comprising:
1) combining a first organic phase (which comprises a polymer, AZD1152 hqpa and a
substantially hydrophobic acid phase selected from deoxycholic acid, pamoic acid and
dioctylsulfosuccinic acid in one or more solvents) with a first aqueous solution (comprising
a surfactant in water) to form a second phase;
2) emulsifying the second phase to form an emulsion;
3) optionally holding the emulsion phase for a hold time (such as 5 to 15 minutes,
conveniently at about 0 ºC);
4) quenching of the emulsion phase at <5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution having a pH between about 4 and about 7 (such as about pH 6.5);
5) concentrating and isolating the resulting nanoparticles by filtration.
Suitably the first aqueous phase comprises a surfactant, such as sodium cholate or
polyoxyethylene (100) stearyl ether (for example as sold under the tradename Brij®), in
water and benzyl alcohol.
Described herein is a therapeutic nanoparticle, wherein the therapeutic nanoparticle
is prepared by a process of preparation comprising:
1) combining a first organic phase (which comprises a polymer, AZD1152 hqpa and a
substantially hydrophobic acid phase selected from deoxycholic acid, pamoic acid and
dioctylsulfosuccinic acid in one or more solvents) with a first aqueous solution (comprising
a surfactant in water) to form a second phase;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 5 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) optionally waiting for a delay time of at least 5 minutes;
6) quenching of the emulsion phase at 0-5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution having a pH between about 4 and about 7 (such as about pH 6.5);
7) concentrating and isolating the resulting nanoparticles by filtration.
Suitably the first aqueous phase comprises a surfactant, such as sodium cholate or
polyoxyethylene (100) stearyl ether (for example as sold under the tradename Brij®), in
water and benzyl alcohol.
Described herein is a therapeutic nanoparticle, wherein the therapeutic nanoparticle
is prepared by a process of preparation comprising:
1) combining a first organic phase (which comprises a polymer in ethyl acetate, AZD1152
hqpa in a TFA/water/benzyl alcohol solvent system and a substantially hydrophobic acid
phase selected from deoxycholic acid, pamoic acid and dioctylsulfosuccinic acid in
DMSO) with a first aqueous solution (comprising a surfactant such as sodium cholate or
polyoxyethylene (100) stearyl ether (for example as sold under the tradename Brij®), in
water and benzyl alcohol) to form a second phase;
2) emulsifying the second phase to form an emulsion;
3) optionally holding the emulsion phase for a hold time (such as 5 to 15 minutes,
conveniently at about 0 ºC);
4 ) quenching of the emulsion phase at <5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution having a pH between about 4 and about 7 (such as about pH 6.5);
) concentrating and isolating the resulting nanoparticles by filtration.
Further surfactant such as Tween® 80 in water may be added to the quenched solution
prior to concentration and filtration.
Described herein is a therapeutic nanoparticle, wherein the therapeutic nanoparticle
is prepared by a process of preparation comprising:
1) combining a first organic phase (which comprises a polymer in ethyl acetate, AZD1152
hqpa in a TFA/water/benzyl alcohol solvent system and a substantially hydrophobic acid
phase selected from deoxycholic acid, pamoic acid and dioctylsulfosuccinic acid in
DMSO) with a first aqueous solution (comprising a surfactant such as sodium cholate or
polyoxyethylene (100) stearyl ether (for example as sold under the tradename Brij®), in
water and benzyl alcohol) to form a second phase;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 5 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) optionally waiting for a delay time of at least 5 minutes;
6) quenching of the emulsion phase at 0-5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution having a pH between about 4 and about 7 (such as about pH 6.5);
7) concentrating and isolating the resulting nanoparticles by filtration.
Further surfactant such as Tween® 80 in water may be added to the quenched solution
prior to concentration and filtration.
Described herein is a therapeutic nanoparticle, wherein the therapeutic nanoparticle
is prepared by a process of preparation comprising:
1) combining a first organic phase (which comprises a polymer in ethyl acetate, AZD1152
hqpa in a TFA/water/benzyl alcohol solvent system and pamoic acid in DMSO) with a first
aqueous solution (comprising a surfactant such as sodium cholate or polyoxyethylene
(100) stearyl ether (for example as sold under the tradename Brij®), in water, DMSO and
benzyl alcohol) to form a second phase;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 5 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) optionally waiting for a delay time of at least 5 minutes;
6) quenching of the emulsion phase at 0-5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution comprising a buffer having a pH between about 4 and about 7 (such as
about pH 6.5);
7) concentrating and isolating the resulting nanoparticles by filtration.
Further surfactant such as Tween® 80 in water may be added to the quenched solution
prior to concentration and filtration.
Described herein is a therapeutic nanoparticle, wherein the therapeutic nanoparticle
is prepared by a process of preparation comprising:
1) combining a first organic phase (which comprises a polymer, AZD1152 hqpa and
pamoic acid in a solvent mixture comprising TFA, benzyl alcohol, DMSO and ethyl
acetate such that the benzyl alcohol: ethylacetate are present in a molar ratio of between
1:3 and 1:4) with a first aqueous solution (comprising a surfactant such polyoxyethylene
(100) stearyl ether (for example as sold under the tradename Brij®S100), in water, DMSO
and benzyl alcohol) to form a second phase;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 5 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
5) optionally waiting for a delay time of at least 5 minutes;
6) quenching of the emulsion phase at 0-5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution comprising a buffer having a pH between about 4 and about 7 (such as
about pH 6.5);
7) concentrating and isolating the resulting nanoparticles by filtration.
Further surfactant such as Tween® 80 in water may be added to the quenched solution
prior to concentration and filtration.
In a further embodiment, a therapeutic nanoparticle is described, wherein the
therapeutic nanoparticle is prepared by a process of preparation comprising:
1) combining a first organic phase (which comprises a polymer in ethyl acetate, AZD1152
hqpa in a TFA/water/benzyl alcohol solvent system and pamoic acid in DMSO) with a first
aqueous solution (comprising a surfactant such as polyoxyethylene (100) stearyl ether (for
example as sold under the tradename Brij®), in water, DMSO and benzyl alcohol) to form
a second phase;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 5 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) optionally waiting for a delay time of at least 5 minutes;
6) quenching of the emulsion phase at 0-5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution comprising a buffer having a pH 6.5;
7) adding an aqueous surfactant solution (such as Tween®80, for example a 35% w/w
Tween®80 solution in water) to the quench at a ratio of about 20:1 to 100:1 Tween®80 to
drug by weight;
8) concentrating and isolating the resulting nanoparticles by filtration.
In a further embodiment, a therapeutic nanoparticle is described, wherein the
therapeutic nanoparticle is prepared by a process of preparation comprising:
1) combining a first organic phase (which comprises a polymer, AZD1152 hqpa and
pamoic acid in in a solvent mixture comprising TFA, benzyl alcohol, DMSO and ethyl
acetate such that the benzyl alcohol: ethyl acetate are present in a molar ratio of between
1:3 and 1:4) with a first aqueous solution (comprising a surfactant such polyoxyethylene
(100) stearyl ether (for example as sold under the tradename Brij®S100), in water, DMSO
and benzyl alcohol) to form a second phase;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 5 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) optionally waiting for a delay time of at least 5 minutes;
6) quenching of the emulsion phase at 0-5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution comprising a buffer at pH 6.5;
7) adding an aqueous surfactant solution as a solubilizer to the quenched solution;
8) concentrating and isolating the resulting nanoparticles by filtration.
In a further embodiment, a therapeutic nanoparticle is described herein as
formulation G1, wherein the therapeutic nanoparticle is prepared by a process of
preparation comprising:
1) combining a first organic phase (which comprises a 16/5 PLA-PEG copolymer,
AZD1152 hqpa and pamoic acid in a solvent mixture comprising TFA, benzyl alcohol,
DMSO and ethyl acetate such that the benzyl alcohol: ethyl acetate are present in a molar
ratio of about 1:3.6) with a first aqueous solution (comprising a surfactant such
polyoxyethylene (100) stearyl ether (for example as sold under the tradename Brij®S100),
in water, DMSO and benzyl alcohol) to form a second phase;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 10 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) optionally waiting for a delay time of at least 5 minutes;
6) quenching of the emulsion phase at 0-5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution comprising buffer at pH 6.5;
7) adding an aqueous surfactant solution as a solubilizer;
8) concentrating and isolating the resulting nanoparticles by filtration.
Conveniently, the pamoic acid and AZD1152 hqpa are added at an initial ratio of 0.8 moles
pamoic acid: 1 mole AZD1152 hqpa.
In a further embodiment, a therapeutic nanoparticle is described herein as
formulation G1, wherein the therapeutic nanoparticle is prepared by a process of
preparation comprising:
1) combining a first organic phase (which comprises a 16/5 PLA-PEG copolymer,
AZD1152 hqpa and pamoic acid in a solvent mixture comprising TFA, benzyl alcohol,
DMSO and ethyl acetate such that the benzyl alcohol: ethyl acetate are present in a molar
ratio of about 1:3.6) with a first aqueous solution (comprising a surfactant such
polyoxyethylene (100) stearyl ether (for example as sold under the tradename Brij®S100),
in water, DMSO and benzyl alcohol) to form a second phase;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 10 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) waiting for a delay time of at least 5 minutes;
6 ) quenching of the emulsion phase at 0-5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution comprising buffer at pH 6.5;
7) adding an aqueous surfactant solution as a solubilizer;
8) concentrating and isolating the resulting nanoparticles by filtration.
Conveniently, the pamoic acid and AZD1152 hqpa are added at an initial ratio of 0.8 moles
pamoic acid: 1 mole AZD1152 hqpa.
In a further embodiment, a therapeutic nanoparticle is described herein as
formulation G1, wherein the therapeutic nanoparticle is prepared by a process of
preparation comprising:
1) combining a first organic phase (which comprises a 16:5 PLA-PEG co-polymer,
AZD1152 hqpa and pamoic acid in a solvent mixture comprising TFA, benzyl alcohol,
DMSO and ethyl acetate such that the benzyl alcohol: ethyl acetate are present in a molar
ratio of about 1:3.6) with a first aqueous solution (comprising a polyoxyethylene (100)
stearyl ether (for example as sold under the tradename Brij®S100), in water, DMSO and
benzyl alcohol) to form a second phase, wherein the ratio of the aqueous phase to the
organic phase is about 5.5:1;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 10 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) waiting for a delay time of at least 5 minutes, for example 10 minutes;
6) quenching of the emulsion phase at 0-5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution comprising a buffer at pH 6.5 wherein the ratio of second aqueous
solution to emulsion is between about 2:1 and about 10:1, such as about 3:1;
7) adding an aqueous surfactant solution to the quench;
8) concentrating and isolating the resulting nanoparticles by filtration.
Conveniently, the pamoic acid and AZD1152 hqpa are added at an initial ratio of 0.8 moles
pamoic acid: 1 mole AZD1152 hqpa.
In a further embodiment, a therapeutic nanoparticle is described herein as
formulation G1, wherein the therapeutic nanoparticle is prepared by a process of
preparation comprising:
1) combining a first organic phase (which comprises a 16:5 PLA-PEG co-polymer,
AZD1152 hqpa and pamoic acid in a solvent mixture comprising TFA, benzyl alcohol,
DMSO and ethyl acetate such that the benzyl alcohol: ethyl acetate are present in a molar
ratio of about 1:3.6 and the pamoic acid and AZD1152 hqpa are added at an initial ratio of
0.8 moles pamoic acid: 1 mole AZD1152 hqpa) with a first aqueous solution (comprising a
polyoxyethylene (100) stearyl ether (for example as sold under the tradename Brij®S100),
in water, DMSO and benzyl alcohol) to form a second phase, wherein the ratio of the
aqueous phase to the organic phase is about 5.5:1;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 10 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) waiting for a delay time of at least 5 minutes, for example 10 minutes;
6) quenching of the emulsion phase at 0-5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution comprising a buffer at pH 6.5 (such as a 0.17M phosphate buffer)
wherein the ratio of second aqueous solution to emulsion is between about 2:1 and about
:1, such as about 3:1;
7) adding an aqueous surfactant solution (such as Tween®80, for example a 35% w/w
Tween®80 solution in water) to the quench solution (for example at a ratio of about 20:1
Tween®80 to drug by weight);
8) concentrating and isolating the resulting nanoparticles by filtration.
In a further embodiment, a therapeutic nanoparticle is described herein as
formulation G2, wherein the therapeutic nanoparticle is prepared by a process of
preparation comprising:
1) combining a first organic phase (which comprises a 16:5 PLA-PEG co-polymer,
AZD1152 hqpa and pamoic acid in a solvent mixture comprising TFA, benzyl alcohol,
DMSO and ethyl acetate such that the benzyl alcohol: ethyl acetate are present in a molar
ratio of about 1:3) with a first aqueous solution (comprising a polyoxyethylene (100)
stearyl ether (for example as sold under the tradename Brij®S100), in water, DMSO and
benzyl alcohol) to form a second phase;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 10 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) after about 1 minute, quenching of the emulsion phase at about 2 ºC thereby forming a
quenched phase, wherein quenching of the emulsion phase comprises mixing the emulsion
phase with a second aqueous solution comprising a buffer at pH 6.5;
6) adding an aqueous surfactant solution (such as Tween®80, for example a 35% w/w
Tween®80 solution in water) to the quench solution;
7) concentrating and isolating the resulting nanoparticles by filtration.
Conveniently, the pamoic acid and AZD1152 hqpa are added at an initial ratio of about 1
mole pamoic acid: 1 mole AZD1152 hqpa.
In a further embodiment, a therapeutic nanoparticle is described herein as
formulation G2, wherein the therapeutic nanoparticle is prepared by a process of
preparation comprising:
1) combining a first organic phase (which comprises a 16:5 PLA-PEG co-polymer,
AZD1152 hqpa and pamoic acid in a solvent mixture comprising TFA, benzyl alcohol,
DMSO and ethyl acetate such that the benzyl alcohol: ethyl acetate are present in a molar
ratio of about 1:3) with a first aqueous solution (comprising a polyoxyethylene (100)
stearyl ether (for example as sold under the tradename Brij®S100), in water, DMSO and
benzyl alcohol) to form a second phase, wherein the ratio of the aqueous phase to the
organic phase is about 5:1;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 10 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) after about 1 minute, quenching of the emulsion phase at about 2 ºC, wherein quenching
of the emulsion phase comprises mixing the emulsion phase with a second aqueous
solution comprising a buffer at pH 6.5 (such as a 0.17M phosphate buffer) and wherein the
ratio of second aqueous solution to emulsion is about 10:1;
6) adding an aqueous surfactant solution (such as Tween®80, for example a 35% w/w
Tween®80 solution in water) to the quench at a ratio of about 100:1 Tween®80 to drug by
weight;
7) concentrating and isolating the resulting nanoparticles by filtration.
Conveniently, the pamoic acid and AZD1152 hqpa are added at an initial ratio of about 1
mole pamoic acid: 1 mole AZD1152 hqpa.
In a further embodiment, a therapeutic nanoparticle is described herein as
formulation G2, wherein the therapeutic nanoparticle is prepared by a process of
preparation comprising:
1) combining a first organic phase (which comprises a 16:5 PLA-PEG co-polymer,
AZD1152 hqpa and pamoic acid in a solvent mixture comprising TFA, benzyl alcohol,
DMSO and ethyl acetate such that the benzyl alcohol: ethyl acetate are present in a molar
ratio of about 1:3 and the pamoic acid and AZD1152 hqpa are added at an initial ratio of 1
mole pamoic acid: 1 mole AZD1152 hqpa) with a first aqueous solution (comprising a
polyoxyethylene (100) stearyl ether (for example as sold under the tradename Brij®S100),
in water, DMSO and benzyl alcohol) to form a second phase, wherein the ratio of the
aqueous phase to the organic phase is about 5:1;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 10 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) after about 1 minute, quenching of the emulsion phase at about 2 ºC thereby forming a
quenched phase, wherein quenching of the emulsion phase comprises mixing the emulsion
phase with a second aqueous solution comprising a buffer at pH 6.5 and wherein the ratio
of second aqueous solution to emulsion is about 10:1;
6) adding an aqueous surfactant solution (such as Tween®80, for example a 35% w/w
Tween®80 solution in water) to the quench at a ratio of about 100:1 Tween®80 to drug by
weight;
7) concentrating and isolating the resulting nanoparticles by filtration.
In one embodiment, the final nanoparticles include about 5 to about 20% by weight
of AZD1152 hqpa, such as about 8 to about 20% by weight such as about 10 to about 20%
by weight, such as about 10 to about 15% by weight, such as about 10 to about 16% by
weight, such as about 12 to about 16% by weight, such as about 15 to about 20% by
weight, such as about 15 to about 18% by weight. In one embodiment, the final
nanoparticles include about 10 to about 20% by weight of AZD1152 hqpa. In a further
embodiment, the final nanoparticles include about 15 to about 20% by weight of AZD1152
hqpa. In a further embodiment, the final nanoparticles include about 15 to about 22% by
weight of AZD1152 hqpa.
Described herein are final nanoparticles comprising about 10-16% by weight of
AZD1152 hqpa, about 50 to about 90 weight percent of a diblock poly(lactic) acid-
poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle comprises about 10
to about 30 weight percent poly(ethylene)glycol and the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol) and a hydrophobic acid selected from cholic acid, deoxycholic acid
and dioctyl sulfosuccinic acid. In one embodiment of this feature, the hydrophobic acid is
selected from deoxycholic acid and dioctyl sulfosuccinic acid. In another embodiment of
this feature the hydrophobic acid is deoxycholic acid. In another embodiment of this
feature the hydrophobic acid is dioctyl sulfosuccinic acid. In another embodiment of this
feature the hydrophobic acid is cholic acid. In another embodiment of this feature the
hydrophobic acid is a mixture of cholic acid and deoxycholic acid; in this embodiment,
suitably the hydrophobic acids are in a molar ratio of about 3:2 deoxycholic acid: cholic
acid and the molar ratio of total hydrophobic acid: AZD1152 hqpa is about 2:1.
Described herein are nanoparticles comprising about 10-20% by weight of
AZD1152 hqpa, about 50 to about 90 weight percent of a diblock poly(lactic) acid-
poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle comprises about 10
to about 30 weight percent poly(ethylene)glycol and the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol) and a hydrophobic acid selected from cholic acid, deoxycholic acid,
pamoic acid and dioctyl sulfosuccinic acid.
In another embodiment, the therapeutic nanoparticle comprises about 35 to about
94.75 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer having
a number average molecular weight of about 16kDa poly(lactic acid) and a number
average molecular weight of about 5kDa poly(ethylene)glycol, wherein the therapeutic
nanoparticle comprises about 10 to about 30 weight percent poly(ethylene)glycol, about
0.05 to about 35 weight percent of a substantially hydrophobic acid selected from the
group consisting of deoxycholic acid, cholic acid, a mixture of cholic and deoxycholic
acid, dioctyl sulfosuccinic acid and pamoic acid, and about 5 to about 30 weight percent of
AZD1152 hqpa or a pharmaceutically acceptable salt thereof.
In another embodiment, the therapeutic nanoparticle comprises about 35 to about
94 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer having a
number average molecular weight of about 16kDa poly(lactic acid) and a number average
molecular weight of about 5kDa poly(ethylene)glycol, wherein the therapeutic nanoparticle
comprises about 10 to about 30 weight percent poly(ethylene)glycol, about 1 to about 35
weight percent of a substantially hydrophobic acid selected from the group consisting of
deoxycholic acid, cholic acid, a mixture of cholic and deoxycholic acid, dioctyl
sulfosuccinic acid and pamoic acid, and about 5 to about 30 weight percent of AZD1152
hqpa or a pharmaceutically acceptable salt thereof.
In another embodiment, the therapeutic nanoparticle comprises about 65 to about
90 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer having a
number average molecular weight of about 16kDa poly(lactic acid) and a number average
molecular weight of about 5kDa poly(ethylene)glycol, wherein the therapeutic nanoparticle
comprises about 10 to about 30 weight percent poly(ethylene)glycol, about 5 to about 15
weight percent of a substantially hydrophobic acid selected from the group consisting of
deoxycholic acid, cholic acid, a mixture of cholic and deoxycholic acid, dioctyl
sulfosuccinic acid and pamoic acid, and about 5 to about 20 weight percent of AZD1152
hqpa or a pharmaceutically acceptable salt thereof.
In another embodiment, the therapeutic nanoparticle comprises about 35 to about
94 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer having a
number average molecular weight of about 16kDa poly(lactic acid) and a number average
molecular weight of about 5kDa poly(ethylene)glycol, wherein the therapeutic nanoparticle
comprises about 10 to about 30 weight percent poly(ethylene)glycol, about 1 to about 35
weight percent of pamoic acid and about 5 to about 30 weight percent of AZD1152 hqpa or
a pharmaceutically acceptable salt thereof.
In another embodiment, the therapeutic nanoparticle comprises about 55 to about
80 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer having a
number average molecular weight of about 16kDa poly(lactic acid) and a number average
molecular weight of about 5kDa poly(ethylene)glycol, wherein the therapeutic nanoparticle
comprises about 10 to about 30 weight percent poly(ethylene)glycol, about 10 to about 20
weight percent of pamoic acid and about 10 to about 25 weight percent of AZD1152 hqpa
or a pharmaceutically acceptable salt thereof.
In another embodiment, the therapeutic nanoparticle comprises about 65 to about
76 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer having a
number average molecular weight of about 16kDa poly(lactic acid) and a number average
molecular weight of about 5kDa poly(ethylene)glycol, wherein the therapeutic nanoparticle
comprises about 10 to about 20 weight percent poly(ethylene)glycol, about 9 to about 15
weight percent of pamoic acid and about 15 to about 20 weight percent of AZD1152 hqpa
or a pharmaceutically acceptable salt thereof.
Described herein are nanoparticles comprising about 10-20
weight percent of AZD1152 hqpa, about 50 to about 90 weight percent of a diblock
poly(lactic) acid-poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle
comprises about 10 to about 30 weight percent poly(ethylene)glycol and the poly(lactic)
acid-poly(ethylene)glycol copolymer has a number average molecular weight of about
16kDa poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol) and pamoic acid.
Further features of the invention and/or features described herein comprise each of
the formulations of the Examples referred to as formulations E, F1, F2, G1 and G2 herein.
Still further features of the invention and/or features described herein comprise each of the
formulations of the Examples referred to as formulations E, F1, F2, G1 and G2 herein,
wherein the % by weight of AZD1152 hqpa and/or the % by weight of hydrophobic acid
varies by +/-about 1% by weight (and so the amount of polymer varies accordingly). Still
further features of the invention and/or features described herein comprise each of the
formulations of the Examples referred to as formulations E, F1, F2, G1 and G2 herein,
wherein the % by weight of AZD1152 hqpa and/or the % by weight of hydrophobic acid
varies by +/-about 1.5 % by weight (and so the amount of polymer varies accordingly).
Still further features of the invention and/or features described hereincomprise each of the
formulations of the Examples referred to as formulations E, F1, F2, G1 and G2 herein,
wherein the % by weight of AZD1152 hqpa and/or the % by weight of hydrophobic acid
varies by +/-about 2% by weight (and so the amount of polymer varies accordingly).
In one embodiment, contemplated nanoparticles have a hydrodynamic diameter of
<200 nm, such as 70-140 nm.
Described herein are nanoparticles comprising about 15-25 weight percent of
AZD1152 hqpa, about 7 to 15 weight percent of pamoic acid, and a diblock poly(lactic)
acid-poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle comprises
about 10 to about 30 weight percent poly(ethylene)glycol and the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol).
Described herein are nanoparticles comprising about 15-22 weight percent of
AZD1152 hqpa, about 7 to 15 weight percent of pamoic acid, and a diblock poly(lactic)
acid-poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle comprises
about 10 to about 30 weight percent poly(ethylene)glycol and the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol).
Described herein are nanoparticles comprising about 15-22 weight percent of
AZD1152 hqpa, about 7 to 10 weight percent of pamoic acid, and a diblock poly(lactic)
acid-poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle comprises
about 10 to about 30 weight percent poly(ethylene)glycol and the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol); wherein less than 20% of the AZD1152 hqpa is released from the
nanoparticle after 30 hours in PBS and polysorbate20 at 37ºC. In another embodiment, less
than 20% of the AZD1152 hqpa is released from the nanoparticle after 40 hours in PBS
and polysorbate20 at 37ºC. In another embodiment, less than 20% of the AZD1152 hqpa is
released from the nanoparticle after 50 hours in PBS and polysorbate20 at 37 ºC.
Conveniently, the release of AZD1152 hqpa from the nanoparticle may be measured using
the method described hereinbefore.
Described herein are nanoparticles comprising about 15-22 weight percent of
AZD1152 hqpa, about 7 to 10 weight percent of pamoic acid, wherein the AZD1152 hqpa
and the pamoic acid form a hydrophobic ion pair, and a diblock poly(lactic) acid-
poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle comprises about 10
to about 30 weight percent poly(ethylene)glycol and the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol); wherein less than 20% of the AZD1152 hqpa is released from the
nanoparticle after 30 hours in PBS and polysorbate20 at 37ºC. In another embodiment, less
than 20% of the AZD1152 hqpa is released from the nanoparticle after 40 hours in PBS
and polysorbate20 at 37ºC. In another embodiment, less than 20% of the AZD1152 hqpa is
released from the nanoparticle after 50 hours in PBS and polysorbate20 at 37ºC.
Conveniently, the release of AZD1152 hqpa from the nanoparticle may be measured using
the method described hereinbefore.
Described herein are nanoparticles comprising about 15-22 weight percent of
AZD1152 hqpa, about 7 to 10 weight percent of pamoic acid, and a diblock poly(lactic)
acid-poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle comprises
about 10 to about 30 weight percent poly(ethylene)glycol and the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol); wherein less than 20% of the AZD1152 hqpa is released from the
nanoparticle after 30 hours in PBS and polysorbate20 at 37ºC, and wherein the
nanoparticles are made by a process comprising the following steps:
1) combining a first organic phase (which comprises a 16:5 PLA-PEG co-polymer,
AZD1152 hqpa and pamoic acid in a solvent mixture comprising TFA, benzyl alcohol,
DMSO and ethyl acetate such that the benzyl alcohol: ethyl acetate are present in a molar
ratio of about 1:3.6 and the pamoic acid and AZD1152 hqpa are added at an initial ratio of
0.8 moles pamoic acid: 1 mole AZD1152 hqpa) with a first aqueous solution (comprising a
polyoxyethylene (100) stearyl ether (for example as sold under the tradename Brij®S100),
in water, DMSO and benzyl alcohol) to form a second phase, wherein the ratio of the
aqueous phase to the organic phase is about 5.5:1;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 10 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) optionally waiting for a delay time of at least 5 minutes, for example 10 minutes;
6) quenching of the emulsion phase at 0-5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution comprising a buffer at pH 6.5 (such as a 0.17M phosphate buffer)
wherein the ratio of second aqueous solution to emulsion is between about 2:1 and about
:1, such as about 3:1;
7) adding an aqueous surfactant solution (such as Tween®80, for example a 35 weight
percent Tween®80 solution in water) to the quench solution (for example at a ratio of
about 20:1 Tween®80 to drug by weight);
8) concentrating and isolating the resulting nanoparticles by filtration.
Described herein are nanoparticles comprising about 15-22 weight percent of
AZD1152 hqpa, about 7 to 10 weight percent of pamoic acid, and a diblock poly(lactic)
acid-poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle comprises
about 10 to about 30 weight percent poly(ethylene)glycol and the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol); wherein the nanoparticles are made by a process comprising the
following steps:
1) combining a first organic phase (which comprises a 16:5 PLA-PEG co-polymer,
AZD1152 hqpa and pamoic acid in a solvent mixture comprising TFA, benzyl alcohol,
DMSO and ethyl acetate such that the benzyl alcohol: ethyl acetate are present in a molar
ratio of about 1:3.6 and the pamoic acid and AZD1152 hqpa are added at an initial ratio of
0.8 moles pamoic acid: 1 mole AZD1152 hqpa) with a first aqueous solution (comprising a
polyoxyethylene (100) stearyl ether (for example as sold under the tradename Brij®S100),
in water, DMSO and benzyl alcohol) to form a second phase, wherein the ratio of the
aqueous phase to the organic phase is about 5.5:1;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 10 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) optionally waiting for a delay time of at least 5 minutes, for example 10 minutes;
6) quenching of the emulsion phase at 0-5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution comprising a buffer at pH 6.5 (such as a 0.17M phosphate buffer)
wherein the ratio of second aqueous solution to emulsion is between about 2:1 and about
:1, such as about 3:1;
7) adding an aqueous surfactant solution (such as Tween®80, for example a 35 weight
percent Tween®80 solution in water) to the quench solution (for example at a ratio of
about 20:1 Tween®80 to drug by weight);
8) concentrating and isolating the resulting nanoparticles by filtration.
Described herein is formulation G1, comprising about 15-22 weight percent of
AZD1152 hqpa, about 7 to 10 weight percent of pamoic acid, and a diblock poly(lactic)
acid-poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle comprises
about 10 to about 30 weight percent poly(ethylene)glycol and the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol).
Described herein is formulation G2, comprising about 15-22 weight percent of
AZD1152 hqpa, about 9 to 13 weight percent of pamoic acid, and a diblock poly(lactic)
acid-poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle comprises
about 10 to about 30 weight percent poly(ethylene)glycol and the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol).
Pharmaceutical Formulations
Nanoparticles disclosed herein may be combined with pharmaceutically acceptable
carriers to form a pharmaceutical composition, according to another embodiment. As
would be appreciated by one of skill in this art, the carriers may be chosen based on the
route of administration as described below, the location of the target issue, the drug being
delivered, the time course of delivery of the drug, etc.
A pharmaceutically acceptable composition is described. The pharmaceutically
acceptable composition comprises a plurality of contemplated therapeutic nanoparticles
and a pharmaceutically acceptable carrier. The pharmaceutically acceptable composition
may also comprise one or more excipients and/or diluents. In one embodiment, the
pharmaceutical composition comprises a plurality of therapeutic nanoparticles, wherein the
nanoparticles comprise about 10-20% by weight of AZD1152 hqpa, about 50 to about 90
weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer (wherein the
therapeutic nanoparticle comprises about 10 to about 30 weight percent
poly(ethylene)glycol and the poly(lactic) acid-poly(ethylene)glycol copolymer has a
number average molecular weight of about 16kDa poly(lactic acid) and a number average
molecular weight of about 5kDa poly(ethylene)glycol) and a hydrophobic acid selected
from cholic acid, deoxycholic acid, pamoic acid and dioctyl sulfosuccinic acid.
Described herein is a pharmaceutical composition comprising a plurality of
therapeutic nanoparticles and one or more pharmaceutically-acceptable excipients, diluents
and/or carriers, wherein each therapeutic nanoparticle comprises AZD1152 hqpa and
optionally further comprises a hydrophobic acid.
Described herein is a pharmaceutical composition comprising a plurality of
therapeutic nanoparticles and one or more pharmaceutically-acceptable excipients, diluents
and/or carriers, wherein each therapeutic nanoparticle comprises AZD1152 hqpa, a suitable
polymer and optionally further comprises a hydrophobic acid.
Described herein is a pharmaceutical composition comprising a plurality of
therapeutic nanoparticles and one or more pharmaceutically-acceptable excipients, diluents
and/or carriers, wherein the nanoparticles comprise AZD1152 hqpa, a diblock poly(lactic)
acid-poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle comprises
about 10 to about 30 weight percent poly(ethylene)glycol and the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol) and a hydrophobic acid selected from cholic acid, deoxycholic acid,
pamoic acid and dioctyl sulfosuccinic acid.
Described herein is a pharmaceutical composition comprising a plurality of
therapeutic nanoparticles and one or more pharmaceutically-acceptable excipients, diluents
and/or carriers, wherein each therapeutic nanoparticle comprises AZD1152 hqpa and
further comprises a hydrophobic acid. In these embodiments, conveniently the
hydrophobic acid is selected from deoxycholic acid, cholic acid, dioctyl sulfosuccinic acid
and pamoic acid; conveniently the hydrophobic acid may be a mixture of deoxycholic acid
and cholic acid.
Described herein is a pharmaceutical composition comprising a plurality of
therapeutic nanoparticles and one or more pharmaceutically-acceptable excipients, diluents
and/or carriers, wherein each therapeutic nanoparticle comprises about 35 to about 94.75
weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the
therapeutic nanoparticle comprises about 10 to about 30 weight percent
poly(ethylene)glycol, about 0.05 to about 35 weight percent of a substantially hydrophobic
acid selected from the group consisting of deoxycholic acid, cholic acid, a mixture of
cholic and deoxycholic acid, dioctyl sulfosuccinic acid and pamoic acid, and about 5 to
about 30 weight percent of AZD1152 hqpa or a pharmaceutically acceptable salt thereof.
Described herein is a pharmaceutical composition comprising a plurality of
therapeutic nanoparticles and one or more pharmaceutically-acceptable excipients, diluents
and/or carriers, wherein each therapeutic nanoparticle comprises about 65 to about 90
weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the
therapeutic nanoparticle comprises about 10 to about 30 weight percent
poly(ethylene)glycol, about 5 to about 15 weight percent of a substantially hydrophobic
acid selected from the group consisting of deoxycholic acid, cholic acid, a mixture of
cholic and deoxycholic acid, dioctyl sulfosuccinic acid and pamoic acid, and about 5 to
about 20 weight percent of AZD1152 hqpa or a pharmaceutically acceptable salt thereof.
Described herein is a pharmaceutical composition comprising a plurality of
therapeutic nanoparticles and one or more pharmaceutically-acceptable excipients, diluents
and/or carriers, wherein each therapeutic nanoparticle comprises about 35 to about 94.75
weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the
therapeutic nanoparticle comprises about 10 to about 30 weight percent
poly(ethylene)glycol, about 0.05 to about 35 weight percent of pamoic acid and about 5 to
about 30 weight percent of AZD1152 hqpa or a pharmaceutically acceptable salt thereof.
Described herein is a pharmaceutical composition comprising a plurality of
therapeutic nanoparticles and one or more pharmaceutically-acceptable excipients, diluents
and/or carriers, wherein each therapeutic nanoparticle comprises about 55 to about 80
weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the
therapeutic nanoparticle comprises about 10 to about 30 weight percent
poly(ethylene)glycol, about 10 to about 20 weight percent of pamoic acid and about 10 to
about 25 weight percent of AZD1152 hqpa or a pharmaceutically acceptable salt thereof.
Described herein is a pharmaceutical composition comprising a plurality of
therapeutic nanoparticles and one or more pharmaceutically-acceptable excipients, diluents
and/or carriers, wherein each therapeutic nanoparticle comprises about 65 to about 76
weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the
therapeutic nanoparticle comprises about 10 to about 20 weight percent
poly(ethylene)glycol, about 9 to about 15 weight percent of pamoic acid and about 15 to
about 20 weight percent of AZD1152 hqpa or a pharmaceutically acceptable salt thereof.
In the pharmaceutical compositions described in the above features, conveniently
the co-polymer has a number average molecular weight of about 16kDa poly(lactic acid)
and a number average molecular weight of about 5kDa poly(ethylene)glycol.
Further features of the invention and/or features described herein comprise a
pharmaceutical composition comprising a plurality of therapeutic nanoparticles and one or
more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle corresponds to one of the formulations of the Examples referred to
as formulations E, F1, F2, G1 and G2 herein. Still further features of the invention and/or
features described herein comprise a pharmaceutical composition comprising a plurality of
therapeutic nanoparticles and one or more pharmaceutically-acceptable excipients, diluents
and/or carriers, wherein each therapeutic nanoparticle corresponds to one of the
formulations of the Examples referred to as formulations E, F1, F2, G1 and G2 herein,
wherein the % by weight of AZD1152 hqpa and/or the % by weight of hydrophobic acid
varies by +/- about 1% by weight (and so the amount of polymer varies accordingly). Still
further features of the invention and/or features described herein comprise a
pharmaceutical composition comprising a plurality of therapeutic nanoparticles and one or
more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle corresponds to one of the formulations of the Examples referred to
as formulations E, F1, F2, G1 and G2 herein, but wherein the % by weight of AZD1152
hqpa and/or the % by weight of hydrophobic acid varies by +/- about 1.5 % by weight (and
so the amount of polymer varies accordingly) from that described in the Examples. Still
further features of the invention and/or features described herein comprise a
pharmaceutical composition comprising a plurality of therapeutic nanoparticles and one or
more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle corresponds to one of the of the Examples referred to as
formulations E, F1, F2, G1 and G2 herein, but wherein the % by weight of AZD1152 hqpa
and/or the % by weight of hydrophobic acid varies by +/- about 2% by weight (and so the
amount of polymer varies accordingly) from that described in the Examples. Still further
features of the invention and/or features described herein comprise a pharmaceutical
composition comprising a plurality of therapeutic nanoparticles and one or more
pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each therapeutic
nanoparticle corresponds to one of the of the Examples referred to as formulations E, F1,
F2, G1 and G2 herein, but wherein the % by weight of AZD1152 hqpa varies by up to
about +/- 3% by weight, the amount of hydrophobic acid varies in proportion to the amount
of AZD1152 hqpa corresponding to the proportions in the Exemplified formulations herein
and so the amount of polymer varies accordingly.
Described herein is a pharmaceutical composition comprising a plurality of
therapeutic nanoparticles and one or more pharmaceutically-acceptable excipients, diluents
and/or carriers, wherein each therapeutic nanoparticle comprises about 15 to about 25% by
weight of AZD1152 hqpa, about 7 to about 15% by weight of pamoic acid, and a diblock
poly(lactic) acid-poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle
comprises about 10 to about 30 weight percent poly(ethylene)glycol and the poly(lactic)
acid-poly(ethylene)glycol copolymer has a number average molecular weight of about
16kDa poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol).
Described herein is a pharmaceutical composition comprising a plurality of
therapeutic nanoparticles and one or more pharmaceutically-acceptable excipients, diluents
and/or carriers, wherein each therapeutic nanoparticle comprises about 15 to about 22% by
weight of AZD1152 hqpa, about 7 to about15% by weight of pamoic acid, and a diblock
poly(lactic) acid-poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle
comprises about 10 to about 30 weight percent poly(ethylene)glycol and the poly(lactic)
acid-poly(ethylene)glycol copolymer has a number average molecular weight of about
16kDa poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol).
Described herein is a pharmaceutical composition comprising a plurality of
therapeutic nanoparticles and one or more pharmaceutically-acceptable excipients, diluents
and/or carriers, wherein each therapeutic nanoparticle comprises about 15 to about 22% by
weight of AZD1152 hqpa, about 7 to about 15% by weight of pamoic acid, and about 63 to
about 78 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer
(wherein the therapeutic nanoparticle comprises about 10 to about 30 weight percent
poly(ethylene)glycol and the poly(lactic) acid-poly(ethylene)glycol copolymer has a
number average molecular weight of about 16kDa poly(lactic acid) and a number average
molecular weight of about 5kDa poly(ethylene)glycol).
Described herein is a pharmaceutical composition comprising a plurality of
therapeutic nanoparticles and one or more pharmaceutically-acceptable excipients, diluents
and/or carriers, wherein each therapeutic nanoparticle comprises a diblock poly(lactic)
acid-poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle comprises
about 10 to about 30 weight percent poly(ethylene)glycol and the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol) and a mixture of about 15 to about 22% by weight of AZD1152 hqpa
and about 7 to about 15% by weight of pamoic acid.
Described herein is a pharmaceutical composition comprising a plurality of
therapeutic nanoparticles and one or more pharmaceutically-acceptable excipients, diluents
and/or carriers, wherein each therapeutic nanoparticle comprises a diblock poly(lactic)
acid-poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle comprises
about 10 to about 30 weight percent poly(ethylene)glycol and the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol) and the product obtained by interaction of about 15 to about 22% by
weight of AZD1152 hqpa and about 7 to about 15% by weight of pamoic acid.
Described herein is a pharmaceutical composition comprising a plurality of
therapeutic nanoparticles and one or more pharmaceutically-acceptable excipients, diluents
and/or carriers, wherein each therapeutic nanoparticle comprises a diblock poly(lactic)
acid-poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle comprises
about 10 to about 30 weight percent poly(ethylene)glycol and the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol) and a hydrophobic ion pair formed between about 15 to about 22%
by weight (of the nanoparticle) of AZD1152 hqpa and about 7 to about 15% by weight (of
the nanoparticle) of pamoic acid.
Described herein is a pharmaceutical composition comprising a plurality of
therapeutic nanoparticles and one or more pharmaceutically-acceptable excipients, diluents
and/or carriers, wherein each therapeutic nanoparticle comprises about 15 to about 22% by
weight of AZD1152 hqpa, about 7 to about 15% by weight of pamoic acid, and a diblock
poly(lactic) acid-poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle
comprises about 10 to about 30 weight percent poly(ethylene)glycol and the poly(lactic)
acid-poly(ethylene)glycol copolymer has a number average molecular weight of about
16kDa poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol); wherein less than 20% of the AZD1152 hqpa is released from the
nanoparticle after 30 hours in PBS and polysorbate20 at 37 ºC. In another embodiment,
less than 20% of the AZD1152 hqpa is released from the nanoparticle after 40 hours in
PBS and polysorbate20 at 37 ºC. In another embodiment, less than 20% of the AZD1152
hqpa is released from the nanoparticle after 50 hours in PBS and polysorbate20 at 37 ºC.
Conveniently, the release of AZD1152 hqpa from the nanoparticle is measured using the
method described hereinbefore.
Described herein is a pharmaceutical composition comprising a plurality of
therapeutic nanoparticles and one or more pharmaceutically-acceptable excipients, diluents
and/or carriers, wherein each therapeutic nanoparticle comprises about 15 to about 22% by
weight of AZD1152 hqpa, about 7 to about 15% by weight of pamoic acid, and a diblock
poly(lactic) acid-poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle
comprises about 10 to about 30 weight percent poly(ethylene)glycol and the poly(lactic)
acid-poly(ethylene)glycol copolymer has a number average molecular weight of about
16kDa poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol); wherein less than 20% of the AZD1152 hqpa is released from the
nanoparticle after 30 hours in PBS and polysorbate20 at 37 ºC, and wherein the
nanoparticles are made by a process comprising the following steps:
1) combining a first organic phase (which comprises a 16:5 PLA-PEG co-polymer,
AZD1152 hqpa and pamoic acid in a solvent mixture comprising TFA, benzyl alcohol,
DMSO and ethyl acetate such that the benzyl alcohol: ethyl acetate are present in a molar
ratio of about 1:3.6 and the pamoic acid and AZD1152 hqpa are added at an initial ratio of
0.8 moles pamoic acid: 1 mole AZD1152 hqpa) with a first aqueous solution (comprising a
polyoxyethylene (100) stearyl ether (for example as sold under the tradename Brij®S100),
in water, DMSO and benzyl alcohol) to form a second phase, wherein the ratio of the
aqueous phase to the organic phase is about 5.5:1;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 10 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) optionally waiting for a delay time of at least 5 minutes, for example 10 minutes;
6) quenching of the emulsion phase at 0-5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution comprising a buffer at pH 6.5 (such as a 0.17M phosphate buffer)
wherein the ratio of second aqueous solution to emulsion is between about 2:1 and about
:1, such as about 3:1;
7) adding an aqueous surfactant solution (such as Tween®80, for example a 35 weight
percent Tween®80 solution in water) to the quench solution (for example at a ratio of
about 20:1 Tween®80 to drug by weight);
8) concentrating and isolating the resulting nanoparticles by filtration.
Suitably, nanoparticles in the above pharmaceutical compositions have a
hydrodynamic diameter of <200 nm, such as 70-140 nm.
The pharmaceutical compositions can be administered to a patient by any means
known in the art including oral and parenteral routes. The term “patient,” as used herein,
refers to humans as well as non-humans, including, for example, mammals, birds, reptiles,
amphibians, and fish. For instance, the non-humans may be mammals (e.g., a rodent, a
mouse, a rat, a rabbit, a monkey, a dog, a cat, a primate, or a pig). In certain embodiments
parenteral routes are desirable since they avoid contact with the digestive enzymes that are
found in the alimentary canal. According to such embodiments, inventive compositions
may be administered by injection (e.g., intravenous, subcutaneous or intramuscular,
intraperitoneal injection), rectally, vaginally, topically (as by powders, creams, ointments,
or drops), or by inhalation (as by sprays).
In a particular embodiment, the nanoparticles are administered to a subject in need
thereof systemically, e.g., by IV (IntraVenous) infusion or injection.
Injectable preparations, for example, sterile injectable aqueous or oleaginous
suspensions may be formulated according to the known art using suitable dispersing or
wetting agents and suspending agents. The sterile injectable preparation may also be a
sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable
diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are water, Ringer's solution, U.S.P., and
isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally
employed as a solvent or suspending medium. For this purpose any bland fixed oil can be
employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic
acid are used in the preparation of injectables. In one embodiment, the inventive conjugate
is suspended in a carrier fluid comprising 1 % (w/v) sodium carboxymethyl cellulose and
0.1% (v/v) TWEEN™ 80. The injectable formulations can be sterilized, for example, by
filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the
form of sterile solid compositions which can be dissolved or dispersed in sterile water or
other sterile injectable medium prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders,
and granules. In such solid dosage forms, the encapsulated or unencapsulated conjugate is
mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as
sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches,
lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example,
carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c)
humectants such as glycerol, (d) disintegrating agents such as agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e)
solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary
ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol
monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as
talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form
may also comprise buffering agents.
It will be appreciated that the exact dosage of a nanoparticle containing the
therapeutic agent is chosen by the individual physician in view of the patient to be treated,
in general, dosage and administration are adjusted to provide an effective amount of the
therapeutic nanoparticle to the patient being treated. As used herein, the "effective
amount" of a nanoparticle containing the therapeutic agent refers to the amount necessary
to elicit the desired biological response. As will be appreciated by those of ordinary skill
in this art, the effective amount of a nanoparticle containing the therapeutic agent may vary
depending on such factors as the desired biological endpoint, the drug to be delivered, the
target tissue, the route of administration, etc. For example, the effective amount of a
nanoparticle containing the therapeutic agent might be the amount that results in a
reduction in tumor size by a desired amount over a desired period of time. Additional
factors which may be taken into account include the severity of the disease state; age,
weight and gender of the patient being treated; diet, time and frequency of administration;
drug combinations; reaction sensitivities; and tolerance/response to therapy.
The nanoparticles may be formulated in dosage unit form for ease of administration
and uniformity of dosage. The expression “dosage unit form” as used herein refers to a
physically discrete unit of nanoparticle appropriate for the patient to be treated. It will be
understood, however, that the total daily usage of the compositions will be decided by the
attending physician within the scope of sound medical judgment. For any nanoparticle, the
therapeutically effective dose can be estimated initially either in cell culture assays or in
animal models, usually mice, rabbits, dogs, or pigs. The animal model is also used to
achieve a desirable concentration range and route of administration. Such information can
then be used to determine useful doses and routes for administration in humans.
Therapeutic efficacy and toxicity of nanoparticles can be determined by standard
pharmaceutical procedures in cell cultures or experimental animals, e.g., ED (the dose is
therapeutically effective in 50% of the population) and LD (the dose is lethal to 50% of
the population). The dose ratio of toxic to therapeutic effects is the therapeutic index, and
it can be expressed as the ratio, LD /ED . Pharmaceutical compositions which exhibit
50 50
large therapeutic indices may be useful in some embodiments. The data obtained from cell
culture assays and animal studies can be used in formulating a range of dosage for human
use.
In one embodiment, the pharmaceutical formulation comprising the AZD1152
hqpa containing nanoparticles is designed such that it releases the AZD1152 hqpa slowly
over several days. For example, the pharmaceutical formulation may be such that a dose is
administered to the patient on (for example) days 1 and 3, days 1 and 5 or days 1 and 7 of a
seven day treatment cycle. The cycle may be repeated every week, two weeks or three
weeks in a monthly or bi-monthly treatment cycle. The amount of drug to be administered
at each visit is thus calculated in order to achieve a particular total drug exposure over the
treatment schedule. Advantageously, the nanoparticle containing formulations may reduce
the time required for administration of the drug to the patient at each dose and may reduce
the number of hospital visits for treatments that a patient needs to make, compared to
previously known methods of administering AZD1152.
Suitably when administering to man the dose of AZD1152 hqpa delivered by the
nanoparticulate formulation of the invention may be in the range from 100mg to 2000mg.
The exact total dose to be administered will be determined by optimal PK and safety
profile for the patient and the tumour type being treated, to be delivered, for example, in
the schedules described above.
In an embodiment, compositions disclosed herein may include less than about 10
ppm of palladium, or less than about 8 ppm, or less than about 6 ppm of palladium. For
example, described here is a composition that includes nanoparticles wherein the
composition has less than about 10 ppm of palladium.
In some embodiments, a composition suitable for freezing is contemplated,
including nanoparticles disclosed herein and a solution suitable for freezing, e.g., a sugar
such as a mono, di, or poly saccharide, e.g., sucrose and/or a trehalose, and/or a salt and/or
a cyclodextrin solution is added to the nanoparticle suspension. The sugar (e.g., sucrose or
trehalose) may act, e.g., as a cryoprotectant to prevent the particles from aggregating upon
freezing. For example, described herein is a nanoparticle formulation comprising a
plurality of disclosed nanoparticles, sucrose, an ionic halide, and water; wherein the
nanoparticles/sucrose/water/ionic halide is about 3-40%/10-40%/20-95%/0.1-10%
(w/w/w/w) or about 5-10%/10-15%/80-90%/1-10% (w/w/w/w). For example, such
solution may include nanoparticles as disclosed herein, about 5% to about 20% by weight
sucrose and an ionic halide such as sodium chloride, in a concentration of about 10 to
about 100 mM. In another example, described herein is a nanoparticle formulation
comprising a plurality of disclosed nanoparticles, trehalose, cyclodextrin, and water;
wherein the nanoparticles/trehalose/water/cyclodextrin is about 3-40%/1-25%/20-95%/1-
% (w/w/w/w) or about 5-10%/1-25%/80-90%/10-15% (w/w/w/w).
For example, a contemplated solution may include nanoparticles as disclosed
herein, about 1% to about 25% by weight of a disaccharide such as trehalose or sucrose
(e.g., about 5% to about 25% trehalose or sucrose, e.g. about 10% trehalose or sucrose, or
about 15% trehalose or sucrose, e.g. about 5% sucrose) by weight) and a cyclodextrin such
as β-cyclodextrin, in a concentration of about 1% to about 25% by weight (e.g. about 5%
to about 20%, e.g. 10% or about 20% by weight, or about 15% to about 20% by weight
cyclodextrin). Contemplated formulations may include a plurality of disclosed
nanoparticles (e.g. nanoparticles having PLA-PEG and an active agent), and about 2% to
about 15 wt% (or about 4 wt% to about 6wt%, e.g. about 5 wt%) sucrose and about 5 wt%
to about 20 wt% (e.g. about 7 wt% to about 12 wt%, e.g. about 10 wt%) of a cyclodextrin,
e.g., HPbCD).
The present disclosure relates in part to lyophilized pharmaceutical compositions
that, when reconstituted, have a minimal amount of large aggregates. Such large
aggregates may have a size greater than about 0.5 μm, greater than about 1 μm, or greater
than about 10 μm, and can be undesirable in a reconstituted solution. Aggregate sizes can
be measured using a variety of techniques including those indicated in the U.S.
Pharmacopeia at 32 <788>, hereby incorporated by reference. The tests outlined in USP
32 <788> include a light obscuration particle count test, microscopic particle count test,
laser diffraction, and single particle optical sensing. In one embodiment, the particle size
in a given sample is measured using laser diffraction and/or single particle optical sensing.
The USP 32 <788> by light obscuration particle count test sets forth guidelines for
sampling particle sizes in a suspension. For solutions with less than or equal to 100 mL,
the preparation complies with the test if the average number of particles present does not
exceed 6000 per container that are ≥10 μm and 600 per container that are ≥25 μm.
As outlined in USP 32 <788>, the microscopic particle count test sets forth
guidelines for determining particle amounts using a binocular microscope adjusted to 100
± 10x magnification having an ocular micrometer. An ocular micrometer is a circular
diameter graticule that consists of a circle divided into quadrants with black reference
circles denoting 10 μm and 25 μm when viewed at 100x magnification. A linear scale is
provided below the graticule. The number of particles with reference to 10 μm and 25 μm
are visually tallied. For solutions with less than or equal to 100 mL, the preparation
complies with the test if the average number of particles present does not exceed 3000 per
container that are ≥10 μm and 300 per container that are ≥25 μm.
In some embodiments, a 10 mL aqueous sample of a disclosed composition upon
reconstitution comprises less than 600 particles per ml having a size greater than or equal
to 10 microns; and/or less than 60 particles per ml having a size greater than or equal to 25
microns.
Dynamic light scattering (DLS) may be used to measure particle size, but it relies
on Brownian motion so the technique may not detect some larger particles. Laser
diffraction relies on differences in the index of refraction between the particle and the
suspension media. The technique is capable of detecting particles at the sub-micron to
millimeter range. Relatively small (e.g., about 1-5 weight %) amounts of larger particles
can be determined in nanoparticle suspensions. Single particle optical sensing (SPOS)
uses light obscuration of dilute suspensions to count individual particles of about 0.5 μm.
By knowing the particle concentration of the measured sample, the weight percentage of
aggregates or the aggregate concentration (particles/mL) can be calculated.
Formation of aggregates can occur during lyophilization due to the dehydration of
the surface of the particles. This dehydration can be avoided by using lyoprotectants, such
as disaccharides, in the suspension before lyophilization. Suitable disaccharides include
sucrose, lactulose, lactose, maltose, trehalose, or cellobiose, and/or mixtures thereof. Other
contemplated disaccharides include kojibiose, nigerose, isomaltose, β, β-trehalose, α, β-
trehalose, sophorose, laminaribiose, gentiobiose, turanose, maltulose, palatinose,
gentiobiulose, mannobiase, melibiose, melibiulose, rutinose, rutinulose, and xylobiose.
Reconstitution shows equivalent DLS size distributions when compared to the starting
suspension. However, laser diffraction can detect particles of >10 μm in size in some
reconstituted solutions. Further, SPOS also may detect >10 μm sized particles at a
concentration above that of the FDA guidelines (10 -10 particles/mL for >10 μm
particles).
In some embodiments, one or more ionic halide salts may be used as an additional
lyoprotectant to a sugar, such as sucrose, trehalose or mixtures thereof. Sugars may
include disaccharides, monosaccharides, trisaccharides, and/or polysaccharides, and may
include other excipients, e.g. glycerol and/or surfactants. Optionally, a cyclodextrin may
be included as an additional lyoprotectant. The cyclodextrin may be added in place of the
ionic halide salt. Alternatively, the cyclodextrin may be added in addition to the ionic
halide salt.
Suitable ionic halide salts may include sodium chloride, calcium chloride, zinc
chloride, or mixtures thereof. Additional suitable ionic halide salts include potassium
chloride, magnesium chloride, ammonium chloride, sodium bromide, calcium bromide,
zinc bromide, potassium bromide, magnesium bromide, ammonium bromide, sodium
iodide, calcium iodide, zinc iodide, potassium iodide, magnesium iodide, or ammonium
iodide, and/or mixtures thereof. In one embodiment, about 1 to about 15 weight percent
sucrose may be used with an ionic halide salt. In one embodiment, the lyophilized
pharmaceutical composition may comprise about 10 to about 100 mM sodium chloride. In
another embodiment, the lyophilized pharmaceutical composition may comprise about 100
to about 500 mM of divalent ionic chloride salt, such as calcium chloride or zinc chloride.
In yet another embodiment, the suspension to be lyophilized may further comprise a
cyclodextrin, for example, about 1 to about 25 weight percent of cyclodextrin may be used.
A suitable cyclodextrin may include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin,
or mixtures thereof. Exemplary cyclodextrins contemplated for use in the compositions
disclosed herein include hydroxypropyl- β-cyclodextrin (HPbCD), hydroxyethyl- β-
cyclodextrin, sulfobutylether- β-cyclodextrin, methyl- β-cyclodextrin, dimethyl- β-
cyclodextrin, carboxymethyl- β-cyclodextrin, carboxymethyl ethyl - β-cyclodextrin, diethyl-
β-cyclodextrin, tri-O-alkyl-- β-cyclodextrin, glocosyl- β-cyclodextrin, and maltosyl- β-
cyclodextrin. In one embodiment, about 1 to about 25 weight percent trehalose (e.g. about
% to about 15%, e.g. 5 to about 20% by weight) may be used with cyclodextrin. In one
embodiment, the lyophilized pharmaceutical composition may comprise about 1 to about
weight percent β-cyclodextrin. An exemplary composition may comprise nanoparticles
comprising PLA-PEG, an active/therapeutic agent, about 4 wt% to about 6 wt% (e.g. about
5 wt%) sucrose, and about 8 to about 12 weight percent (e.g. about 10 wt %) HPbCD.
A lyophilized pharmaceutical composition is described comprising disclosed
nanoparticles, wherein upon reconstitution of the lyophilized pharmaceutical composition
at a nanoparticle concentration of about 50 mg/mL, in less than or about 100 mL of an
aqueous medium, the reconstituted composition suitable for parenteral administration
comprises less than 6000, such as less than 3000, microparticles of greater than or equal to
microns; and/or less than 600, such as less than 300, microparticles of greater than or
equal to 25 microns.
The number of microparticles can be determined by means such as the USP 32
<788> by light obscuration particle count test, the USP 32 <788> by microscopic particle
count test, laser diffraction, and single particle optical sensing.
A pharmaceutical composition suitable for parenteral use upon reconstitution is
described comprising a plurality of therapeutic particles each comprising a copolymer
having a hydrophobic polymer segment and a hydrophilic polymer segment; an active
agent; a sugar; and a cyclodextrin.
For example, the copolymer may be poly(lactic) acid-block-poly(ethylene)glycol
copolymer. Upon reconstitution, a 100 mL aqueous sample may comprise less than 6000
particles having a size greater than or equal to 10 microns; and less than 600 particles
having a size greater than or equal to 25 microns.
The step of adding a disaccharide and an ionic halide salt may comprise adding
about 5 to about 15 weight percent sucrose or about 5 to about 20 weight percent trehalose
(e.g., about 10 to about 20 weight percent trehalose), and about 10 to about 500 mM ionic
halide salt. The ionic halide salt may be selected from sodium chloride, calcium chloride,
and zinc chloride, or mixtures thereof. In an embodiment, about 1 to about 25 weight
percent cyclodextrin is also added.
In another embodiment, the step of adding a disaccharide and a cyclodextrin may
comprise adding about 5 to about 15 weight percent sucrose or about 5 to about 20 weight
percent trehalose (e.g., about 10 to about 20 weight percent trehalose), and about 1 to about
weight percent cyclodextrin. In an embodiment, about 10 to about 15 weight percent
cyclodextrin is added. The cyclodextrin may be selected from α-cyclodextrin, β-
cyclodextrin, γ-cyclodextrin, or mixtures thereof.
A method of preventing substantial aggregation of particles in a pharmaceutical
nanoparticle composition is described comprising adding a sugar and a salt to the
lyophilized formulation to prevent aggregation of the nanoparticles upon reconstitution. In
an embodiment, a cyclodextrin is also added to the lyophilized formulation. In yet another
embodiment, a method of preventing substantial aggregation of particles in a
pharmaceutical nanoparticle composition is described comprising adding a sugar and a
cyclodextrin to the lyophilized formulation to prevent aggregation of the nanoparticles
upon reconstitution.
A contemplated lyophilized composition may have a therapeutic particle
concentration of greater than about 40 mg/mL. The formulation suitable for parenteral
administration may have less than about 600 particles having a size greater than 10
microns in a 10 mL dose. Lyophilizing may comprise freezing the composition at a
temperature of greater than about -40 °C, or e.g. less than about -30 °C, forming a frozen
composition; and drying the frozen composition to form the lyophilized composition. The
step of drying may occur at about 50 mTorr at a temperature of about -25 to about -34 °C,
or about -30 to about -34 °C.
Further features of the invention and/or features described herein comprise a
lyophilized pharmaceutical composition comprising a plurality of therapeutic nanoparticles
and one or more pharmaceutically-acceptable excipients, wherein each therapeutic
nanoparticle corresponds to one of the formulations of the Examples referred to as
formulations E, F1, F2, G1 and G2 herein. Still further features of the invention and/or
features described herein comprise a lyophilized pharmaceutical composition comprising a
plurality of therapeutic nanoparticles and one or more pharmaceutically-acceptable
excipients, wherein each therapeutic nanoparticle corresponds to one of the formulations of
the Examples referred to as formulations E, F1, F2, G1 and G2 herein, wherein the % by
weight of AZD1152 hqpa and/or the % by weight of hydrophobic acid varies by +/- about
1% by weight (and so the amount of polymer varies accordingly). Still further features of
the invention and/or features described herein comprise a lyophilized pharmaceutical
composition comprising a plurality of therapeutic nanoparticles and one or more
pharmaceutically-acceptable excipients, wherein each therapeutic nanoparticle corresponds
to one of the formulations of the Examples referred to as formulations E, F1, F2, G1 and
G2 herein, but wherein the % by weight of AZD1152 hqpa and/or the % by weight of
hydrophobic acid varies by +/- about 1.5 % by weight (and so the amount of polymer
varies accordingly) from that described in the Examples. Still further features of the
invention and/or features described herein comprise a lyophilized pharmaceutical
composition comprising a plurality of therapeutic nanoparticles and one or more
pharmaceutically-acceptable excipients, wherein each therapeutic nanoparticle corresponds
to one of the of the Examples referred to as formulations E, F1, F2, G1 and G2 herein, but
wherein the % by weight of AZD1152 hqpa and/or the % by weight of hydrophobic acid
varies by +/- about 2% by weight (and so the amount of polymer varies accordingly) from
that described in the Examples. Still further features of the invention and/or features
described herein comprise a lyophilized pharmaceutical composition comprising a plurality
of therapeutic nanoparticles and one or more pharmaceutically-acceptable excipients,
wherein each therapeutic nanoparticle corresponds to one of the of the Examples referred
to as formulations E, F1, F2, G1 and G2 herein, but wherein the % by weight of AZD1152
hqpa varies by up to about +/- 3% by weight, the amount of hydrophobic acid varies in
proportion to the amount of AZD1152 hqpa corresponding to the proportions in the
Exemplified formulations herein and so the amount of polymer varies accordingly.
Described herein is a lyophilized pharmaceutical composition comprising a
plurality of therapeutic nanoparticles and one or more pharmaceutically-acceptable
excipients, wherein each therapeutic nanoparticle comprises about 15 to about 25% by
weight of AZD1152 hqpa, about 7 to about 15% by weight of pamoic acid, and a diblock
poly(lactic) acid-poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle
comprises about 10 to about 30 weight percent poly(ethylene)glycol and the poly(lactic)
acid-poly(ethylene)glycol copolymer has a number average molecular weight of about
16kDa poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol).
Described herein is a lyophilized pharmaceutical composition comprising a
plurality of therapeutic nanoparticles and one or more pharmaceutically-acceptable
excipients, wherein each therapeutic nanoparticle comprises about 15 to about 22% by
weight of AZD1152 hqpa, about 7 to about15% by weight of pamoic acid, and a diblock
poly(lactic) acid-poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle
comprises about 10 to about 30 weight percent poly(ethylene)glycol and the poly(lactic)
acid-poly(ethylene)glycol copolymer has a number average molecular weight of about
16kDa poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol).
Described herein is a lyophilized pharmaceutical composition comprising a
plurality of therapeutic nanoparticles and one or more pharmaceutically-acceptable
excipients, wherein each therapeutic nanoparticle comprises about 15 to about 22% by
weight of AZD1152 hqpa, about 7 to about 15% by weight of pamoic acid, and about 63 to
about 78 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer
(wherein the therapeutic nanoparticle comprises about 10 to about 30 weight percent
poly(ethylene)glycol and the poly(lactic) acid-poly(ethylene)glycol copolymer has a
number average molecular weight of about 16kDa poly(lactic acid) and a number average
molecular weight of about 5kDa poly(ethylene)glycol).
Described herein is a lyophilized pharmaceutical composition comprising a
plurality of therapeutic nanoparticles and one or more pharmaceutically-acceptable
excipients, wherein each therapeutic nanoparticle comprises a diblock poly(lactic) acid-
poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle comprises about 10
to about 30 weight percent poly(ethylene)glycol and the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol) and a mixture of about 15 to about 22% by weight of AZD1152 hqpa
and about 7 to about 15% by weight of pamoic acid.
Described herein is a lyophilized pharmaceutical composition comprising a
plurality of therapeutic nanoparticles and one or more pharmaceutically-acceptable
excipients, wherein each therapeutic nanoparticle comprises a diblock poly(lactic) acid-
poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle comprises about 10
to about 30 weight percent poly(ethylene)glycol and the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol) and the product obtained by interaction of about 15 to about 22% by
weight of AZD1152 hqpa and about 7 to about 15% by weight of pamoic acid.
Described herein is a lyophilized pharmaceutical composition comprising a
plurality of therapeutic nanoparticles and one or more pharmaceutically-acceptable
excipients, wherein each therapeutic nanoparticle comprises a diblock poly(lactic) acid-
poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle comprises about 10
to about 30 weight percent poly(ethylene)glycol and the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol) and a hydrophobic ion pair formed between about 15 to about 22%
by weight (of the nanoparticle) of AZD1152 hqpa and about 7 to about 15% by weight (of
the nanoparticle) of pamoic acid.
Described herein is a lyophilized pharmaceutical composition comprising a
plurality of therapeutic nanoparticles and one or more pharmaceutically-acceptable
excipients, wherein each therapeutic nanoparticle comprises about 15 to about 22% by
weight of AZD1152 hqpa, about 7 to about 15% by weight of pamoic acid, and a diblock
poly(lactic) acid-poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle
comprises about 10 to about 30 weight percent poly(ethylene)glycol and the poly(lactic)
acid-poly(ethylene)glycol copolymer has a number average molecular weight of about
16kDa poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol); wherein less than 20% of the AZD1152 hqpa is released from the
nanoparticle after 30 hours in PBS and polysorbate20 at 37 ºC. In another embodiment,
less than 20% of the AZD1152 hqpa is released from the nanoparticle after 40 hours in
PBS and polysorbate20 at 37 ºC. In another embodiment, less than 20% of the AZD1152
hqpa is released from the nanoparticle after 50 hours in PBS and polysorbate20 at 37 ºC.
Conveniently, the release of AZD1152 hqpa from the nanoparticle is measured using the
method described hereinbefore.
Described herein is a lyophilized pharmaceutical composition comprising a
plurality of therapeutic nanoparticles and one or more pharmaceutically-acceptable
excipients, wherein each therapeutic nanoparticle comprises about 15 to about 22% by
weight of AZD1152 hqpa, about 7 to about 15% by weight of pamoic acid, and a diblock
poly(lactic) acid-poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle
comprises about 10 to about 30 weight percent poly(ethylene)glycol and the poly(lactic)
acid-poly(ethylene)glycol copolymer has a number average molecular weight of about
16kDa poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol); wherein less than 20% of the AZD1152 hqpa is released from the
nanoparticle after 30 hours in PBS and polysorbate20 at 37 ºC, and wherein the
nanoparticles are made by a process comprising the following steps:
1) combining a first organic phase (which comprises a 16:5 PLA-PEG co-polymer,
AZD1152 hqpa and pamoic acid in a solvent mixture comprising TFA, benzyl alcohol,
DMSO and ethyl acetate such that the benzyl alcohol: ethyl acetate are present in a molar
ratio of about 1:3.6 and the pamoic acid and AZD1152 hqpa are added at an initial ratio of
0.8 moles pamoic acid: 1 mole AZD1152 hqpa) with a first aqueous solution (comprising a
polyoxyethylene (100) stearyl ether (for example as sold under the tradename Brij®S100),
in water, DMSO and benzyl alcohol) to form a second phase, wherein the ratio of the
aqueous phase to the organic phase is about 5.5:1;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 10 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) optionally waiting for a delay time of at least 5 minutes, for example 10 minutes;
6) quenching of the emulsion phase at 0-5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution comprising a buffer at pH 6.5 (such as a 0.17M phosphate buffer)
wherein the ratio of second aqueous solution to emulsion is between about 2:1 and about
:1, such as about 3:1;
7) adding an aqueous surfactant solution (such as Tween®80, for example a 35 weight
percent Tween®80 solution in water) to the quench solution (for example at a ratio of
about 20:1 Tween®80 to drug by weight);
8) concentrating and isolating the resulting nanoparticles by filtration.
Suitably, nanoparticles in the above pharmaceutical compositions have a
hydrodynamic diameter of <200 nm, such as 70-140 nm.
In a further embodiment, a kit of parts is described, which kit comprises:
1) a lyophilized pharmaceutical composition comprising disclosed nanoparticles as
described hereinbefore; and
2) instructions for use.
In a further embodiment, a kit of parts is described, which kit comprises:
1) a freeze-dried pharmaceutical composition comprising disclosed nanoparticles as
described hereinbefore; and
2) instructions for use.
Methods of Treatment
In some embodiments, contemplated nanoparticles may be used to treat, alleviate,
ameliorate, relieve, delay onset of, inhibit progression of, reduce severity of, and/or reduce
incidence of one or more symptoms or features of a disease, disorder, and/or condition. In
some embodiments, contemplated nanoparticles may be used to treat solid tumors, e.g.,
cancer and/or cancer cells.
The term “cancer” includes pre-malignant as well as malignant cancers Cancers
include, but are not limited to, haematological (blood) (e.g., chronic myelogenous
leukemia, chronic myelomonocytic leukemia, Philadelphia chromosome positive acute
lymphoblastic leukemia, mantle cell lymphoma, acute myeloid leukemia, diffuse large B
cell lymphoma, myeloma, peripheral T-cell lymphoma, myelodysplastic syndrome),
prostate, gastric cancer, colorectal cancer, skin cancer, e.g., melanomas or basal cell
carcinomas, lung cancer (e.g., non-small cell lung cancer (NSCLC), small cell lung cancer
(SCLC)), breast cancer, ovarian cancer, cancers of the head and neck, bronchus cancer,
pancreatic cancer, urinary bladder cancer, brain or central nervous system cancer,
peripheral nervous system cancer, esophageal cancer, cancer of the oral cavity or pharynx,
liver cancer (e.g., hepatocellular carcinoma), kidney cancer (e.g., renal cell carcinoma),
testicular cancer, biliary tract cancer, small bowel or appendix cancer, gastrointestinal
stromal tumor, salivary gland cancer, thyroid gland cancer, adrenal gland cancer,
osteosarcoma, chondrosarcoma, cancer of hematological tissues, and the like. “Cancer
cells” can be in the form of a tumor (a solid tumor), exist alone within a subject (e.g.,
leukemia cells), or be cell lines derived from a cancer.
In one embodiment, the cancer to be treated is a leukemia. In another embodiment
the cancer to be treated is a haematological cancer. In another embodiment the cancer to be
treated is a haematological cancer such as AML. In another embodiment the cancer to be
treated is a haematological cancer such as DLBCL. In another embodiment the cancer to
be treated is a haematological cancer such as myelodysplastic syndrome.
In another embodiment the cancer to be treated is a solid tumour. In another
embodiment, the cancer to be treated is NSCLC. In another embodiment, the cancer to be
treated is SCLC. In another embodiment, the cancer to be treated is ovarian. In another
embodiment, the cancer to be treated is colorectal.
In one embodiment the nanoparticles of the invention are used to treat highly
proliferative cancer types.
Patients may be selected using biomarkers which may indicate a higher likelihood
of benefiting from this treatment. For example, because their tumour has cells with a high
rate of proliferation (for example due to high c-myc expression or amplification) or
dysregulated apoptotic function (for example due to Bcl-2 gene translocation).
Cancer can be associated with a variety of physical symptoms. Symptoms of
cancer generally depend on the type and location of the tumor. For example, lung cancer
can cause coughing, shortness of breath, and chest pain, while colon cancer often causes
diarrhea, constipation, and blood in the stool. However, to give but a few examples, the
following symptoms are often generally associated with many cancers: fever, chills, night
sweats, cough, dyspnea, weight loss, loss of appetite, anorexia, nausea, vomiting, diarrhea,
anemia, jaundice, hepatomegaly, hemoptysis, fatigue, malaise, cognitive dysfunction,
depression, hormonal disturbances, neutropenia, pain, non-healing sores, enlarged lymph
nodes, peripheral neuropathy, and sexual dysfunction.
Described herein is a method for the treatment of cancer. In some embodiments,
the treatment of cancer comprises administering a therapeutically effective amount of
inventive particles to a subject in need thereof, in such amounts and for such time as is
necessary to achieve the desired result. In certain embodiments, a “therapeutically
effective amount” of an inventive particle is that amount effective for treating, alleviating,
ameliorating, relieving, delaying onset of, inhibiting progression of, reducing severity of,
and/or reducing incidence of one or more symptoms or features of cancer.
Therefore, described herein is a method for the prevention or treatment of cancer in
a warm blooded animal, such as man in need thereof, comprising administering to the
patient a therapeutically effective amount of a composition comprising a therapeutic
nanoparticle comprising AZD1152 hqpa.
A method for administering inventive compositions to a subject suffering from
cancer is described. In some embodiments, nanoparticles may be administered to a subject
in such amounts and for such time as is necessary to achieve the desired result (treatment
of cancer). In certain embodiments, a “therapeutically effective amount” of a
contemplated nanoparticle is that amount effective for treating, alleviating, ameliorating,
relieving, delaying onset of, inhibiting progression of, reducing severity of, and/or
reducing incidence of one or more symptoms or features of cancer.
Described herein is a therapeutic nanoparticle comprising AZD1152 hqpa for use
as a medicament in a warm-blooded animal such as man.
Also described herein is a therapeutic nanoparticle comprising AZD1152 hqpa for
use in the production of an anti-proliferative effect in a warm-blooded animal such as man.
According to a further feature described herein a therapeutic nanoparticle comprising
AZD1152 hqpa for use in a warm-blooded animal such as man as an anti-invasive agent in
the containment and/or treatment of solid tumour disease.
Also described herein is the use of a therapeutic nanoparticle comprising AZD1152
hqpa in the prevention or treatment of cancer in a warm blooded animal such as man.
Also described herein is a therapeutic nanoparticle comprising AZD1152 hqpa for
use in the prevention or treatment of cancer in a warm blooded animal such as man.
Also described herein is the use of a therapeutic nanoparticle comprising AZD1152
hqpa in the manufacture of a medicament for the prevention or treatment of cancer in a
warm blooded animal such as man.
In one embodiment, the cancer is a solid tumour. In another embodiment, the
cancer is a leukemia.
Also described herein is the use of a therapeutic nanoparticle comprising AZD1152
hqpa for the production of an anti-proliferative effect in a warm-blooded animal such as
man.
Also described herein is the use of a therapeutic nanoparticle comprising AZD1152
hqpa in the manufacture of a medicament for use in the production of an anti-proliferative
effect in a warm-blooded animal such as man.
Also described herein is the use of a therapeutic nanoparticle comprising AZD1152
hqpa in the manufacture of a medicament for use in a warm-blooded animal such as man as
an anti-invasive agent in the containment and/or treatment of solid tumour disease.
Also described herein is a method for producing an anti-proliferative effect in a
warm blooded animal, such as man, in need of such treatment which comprises
administering to said animal an effective amount of a therapeutic nanoparticle comprising
AZD1152 hqpa.
Also described herein is a method for producing an anti-invasive effect by the
containment and/or treatment of solid tumour disease in a warm blooded animal, such as
man, in need of such treatment which comprises administering to said animal an effective
amount of a therapeutic nanoparticle comprising AZD1152 hqpa.
Also described herein is a therapeutic nanoparticle comprising AZD1152 hqpa for
use in the prevention or treatment of solid tumour disease in a warm blooded animal such as
man.
Also described herein is the use of a therapeutic nanoparticle comprising AZD1152
hqpa in the manufacture of a medicament for use in the prevention or treatment of solid
tumour disease in a warm blooded animal such as man.
Also described herein is a method for the prevention or treatment of solid tumour
disease in a warm blooded animal, such as man, in need of such treatment which comprises
administering to said animal an effective amount of a therapeutic nanoparticle comprising
AZD1152 hqpa.
In the above uses and methods, conveniently 100mg to 2000mg of AZD1152 hqpa is
administered on (for example) days 1 and 3, days 1 and 5 or days 1 and 7 of a seven day
treatment cycle. The cycle may be repeated every week, two weeks or three weeks in a
monthly or bi-monthly treatment cycle.
In the above uses and methods, suitably the therapeutic nanoparticle comprising
AZD1152 hqpa is administered in the form of a pharmaceutical composition, such as those
listed in 1) to 16):
1) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises AZD1152 hqpa and optionally further comprises a
hydrophobic acid;
2) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises AZD1152 hqpa, a suitable polymer and optionally
further comprises a hydrophobic acid;
3) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises AZD1152 hqpa, a suitable polymer and further
comprises a hydrophobic acid;
in these embodiments, conveniently the hydrophobic acid is selected from deoxycholic
acid, cholic acid, dioctyl sulfosuccinic acid and pamoic acid; conveniently the hydrophobic
acid may be a mixture of deoxycholic acid and cholic acid;
4) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises AZD1152 hqpa, a diblock poly(lactic) acid-
poly(ethylene)glycol copolymer and further comprises a hydrophobic acid. In these
embodiments, conveniently the hydrophobic acid is selected from deoxycholic acid, cholic
acid, dioctyl sulfosuccinic acid and pamoic acid; conveniently the hydrophobic acid may
be a mixture of deoxycholic acid and cholic acid;
5) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises about 35 to about 94.75 weight percent of a diblock
poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the therapeutic nanoparticle
comprises about 10 to about 30 weight percent poly(ethylene)glycol, about 0.05 to about
35 weight percent of a substantially hydrophobic acid selected from the group consisting of
deoxycholic acid, cholic acid, a mixture of cholic and deoxycholic acid, dioctyl
sulfosuccinic acid and pamoic acid, and about 5 to about 30 weight percent of AZD1152
hqpa or a pharmaceutically acceptable salt thereof;
6) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises about 65 to about 90 weight percent of a diblock
poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the therapeutic nanoparticle
comprises about 10 to about 30 weight percent poly(ethylene)glycol, about 5 to about 15
weight percent of a substantially hydrophobic acid selected from the group consisting of
deoxycholic acid, cholic acid, a mixture of cholic and deoxycholic acid, dioctyl
sulfosuccinic acid and pamoic acid, and about 5 to about 20 weight percent of AZD1152
hqpa or a pharmaceutically acceptable salt thereof;
7) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises about 35 to about 94 weight percent of a diblock
poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the therapeutic nanoparticle
comprises about 10 to about 30 weight percent poly(ethylene)glycol, about 1 to about 35
weight percent of pamoic acid and about 5 to about 30 weight percent of AZD1152 hqpa or
a pharmaceutically acceptable salt thereof;
8) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises about 55 to about 80 weight percent of a diblock
poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the therapeutic nanoparticle
comprises about 10 to about 30 weight percent poly(ethylene)glycol, about 10 to about 20
weight percent of pamoic acid and about 10 to about 25 weight percent of AZD1152 hqpa
or a pharmaceutically acceptable salt thereof;
9) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises about 65 to about 76 weight percent of a diblock
poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the therapeutic nanoparticle
comprises about 10 to about 20 weight percent poly(ethylene)glycol, about 9 to about 15
weight percent of pamoic acid and about 15 to about 20 weight percent of AZD1152 hqpa
or a pharmaceutically acceptable salt thereof;
) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises about 15 to about 25weight percent of AZD1152 hqpa,
about 7 to about 15 weight percent of pamoic acid, and a diblock poly(lactic) acid-
poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle comprises about 10
to about 30 weight percent poly(ethylene)glycol and the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol);
11) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises about 15 to about 22 weight percent of AZD1152 hqpa,
about 7 to about 15 weight percent of pamoic acid, and a diblock poly(lactic) acid-
poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle comprises about 10
to about 30 weight percent poly(ethylene)glycol and the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol);
12) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises a diblock poly(lactic) acid-poly(ethylene)glycol
copolymer (wherein the therapeutic nanoparticle comprises about 10 to about 30 weight
percent poly(ethylene)glycol and the poly(lactic) acid-poly(ethylene)glycol copolymer has
a number average molecular weight of about 16kDa poly(lactic acid) and a number
average molecular weight of about 5kDa poly(ethylene)glycol) and a mixture of about 15
to about 22 weight percent of AZD1152 hqpa and about 7 to about 15 weight percent of
pamoic acid;
13) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises a diblock poly(lactic) acid-poly(ethylene)glycol
copolymer (wherein the therapeutic nanoparticle comprises about 10 to about 30 weight
percent poly(ethylene)glycol and the poly(lactic) acid-poly(ethylene)glycol copolymer has
a number average molecular weight of about 16kDa poly(lactic acid) and a number
average molecular weight of about 5kDa poly(ethylene)glycol) and the product obtained
by interaction of about 15 to about 22 weight percent of AZD1152 hqpa and about 7 to
about 15 weight percent of pamoic acid;
14) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises a diblock poly(lactic) acid-poly(ethylene)glycol
copolymer (wherein the therapeutic nanoparticle comprises about 10 to about 30 weight
percent poly(ethylene)glycol and the poly(lactic) acid-poly(ethylene)glycol copolymer has
a number average molecular weight of about 16kDa poly(lactic acid) and a number
average molecular weight of about 5kDa poly(ethylene)glycol) and a hydrophobic ion pair
formed between about 15 to about 22 weight percent (of the nanoparticle) of AZD1152
hqpa and about 7 to about 15 weight percent (of the nanoparticle) of pamoic acid;
) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises about 15 to about 22 weight percent of AZD1152 hqpa,
about 7 to about 15 weight percent of pamoic acid, and a diblock poly(lactic) acid-
poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle comprises about 10
to about 30 weight percent poly(ethylene)glycol and the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol); wherein less than 20% of the AZD1152 hqpa is released from the
nanoparticle after 30 hours in PBS and polysorbate20 at 37ºC. Conveniently, the release of
AZD1152 hqpa from the nanoparticle is measured using the method described
hereinbefore.
16) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises about 15 to about 22 weight percent of AZD1152 hqpa,
about 7 to about 15 weight percent of pamoic acid, and a diblock poly(lactic) acid-
poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle comprises about 10
to about 30 weight percent poly(ethylene)glycol and the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol); wherein less than 20% of the AZD1152 hqpa is released from the
nanoparticle after 30 hours in PBS and polysorbate20 at 37ºC, and wherein the
nanoparticles are made by a process comprising the following steps:
1) combining a first organic phase (which comprises a 16:5 PLA-PEG co-polymer,
AZD1152 hqpa and pamoic acid in a solvent mixture comprising TFA, benzyl alcohol,
DMSO and ethyl acetate such that the benzyl alcohol: ethyl acetate are present in a molar
ratio of about 1:3.6 and the pamoic acid and AZD1152 hqpa are added at an initial ratio of
0.8 moles pamoic acid: 1 mole AZD1152 hqpa) with a first aqueous solution (comprising a
polyoxyethylene (100) stearyl ether (for example as sold under the tradename Brij®S100),
in water, DMSO and benzyl alcohol) to form a second phase, wherein the ratio of the
aqueous phase to the organic phase is about 5.5:1;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 10 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) optionally waiting for a delay time of at least 5 minutes, for example 10 minutes;
6) quenching of the emulsion phase at 0-5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution comprising a buffer at pH 6.5 (such as a 0.17M phosphate buffer)
wherein the ratio of second aqueous solution to emulsion is between about 2:1 and about
:1, such as about 3:1;
7) adding an aqueous surfactant solution (such as Tween®80, for example a 35 weight
percent Tween®80 solution in water) to the quench solution (for example at a ratio of
about 20:1 Tween®80 to drug by weight);
8) concentrating and isolating the resulting nanoparticles by filtration.
In the pharmaceutical compositions described above for use in the above uses and
methods, conveniently the co-polymer has a number average molecular weight of about
16kDa poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol.
In the above uses and methods suitably the therapeutic nanoparticle comprising
AZD1152 hqpa is administered in the form of a pharmaceutical composition comprising
one of the formulations of the Examples referred to as formulations E, F1, F2, G1 and G2
herein and one or more pharmaceutically-acceptable excipients, diluents and/or carriers.
Also suitable for use in the above methods and uses are therapeutic nanoparticles
comprising AZD1152 hqpa administered in the form of a pharmaceutical composition
comprising a formulation described in the Examples as formulations E, F1, F2, G1 and G2
herein, but wherein the % by weight of AZD1152 hqpa and/or the % by weight of
hydrophobic acid varies by +/-about 1% by weight (and so the amount of polymer varies
accordingly) from that described in the Examples, and one or more pharmaceutically-
acceptable excipients, diluents and/or carriers. Also suitable for use in the above methods
and uses are therapeutic nanoparticles comprising AZD1152 hqpa administered in the
form of a pharmaceutical composition comprising a formulation described in the Examples
as formulations E, F1, F2, G1 and G2 herein, but wherein the % by weight of AZD1152
hqpa and/or the % by weight of hydrophobic acid varies by +/-about 1.5% by weight (and
so the amount of polymer varies accordingly) from that described in the Examples and one
or more pharmaceutically-acceptable excipients, diluents and/or carriers. Also suitable for
use in the above methods and uses are therapeutic nanoparticles comprising AZD1152
hqpa administered in the form of a pharmaceutical composition comprising a formulation
described in the Examples as formulations E, F1, F2, G1 and G2 herein, but wherein the %
by weight of AZD1152 hqpa and/or the % by weight of hydrophobic acid varies by +/-
about 2% by weight (and so the amount of polymer varies accordingly) from that described
in the Examples and one or more pharmaceutically-acceptable excipients, diluents and/or
carriers. Still further features of the invention and/or features described herein comprise a
pharmaceutical composition comprising a plurality of therapeutic nanoparticles and one or
more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle corresponds to one of the of the Examples referred to as
formulations E, F1, F2, G1 and G2 herein, but wherein the % by weight of AZD1152 hqpa
varies by up to about +/- 3% by weight, the amount of hydrophobic acid varies in
proportion to the amount of AZD1152 hqpa corresponding to the proportions in the
Exemplified formulations herein and so the amount of polymer varies accordingly.
In some of the above embodiments, the therapeutic nanoparticles may comprise
about 50 to about 99.75 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol
copolymer or a diblock poly(lactic acid-co-glycolic acid)-poly(ethylene)glycol copolymer,
wherein the therapeutic nanoparticle comprises about 10 to about 30 weight percent
poly(ethylene)glycol, and optionally further comprise a substantially hydrophobic acid as
defined herein, such as cholic acid, deoxycholic acid or dioctyl sulfosuccinic acid
(particularly deoxycholic acid, dioctyl sulfosuccinic acid or a mixture of deoxycholic acid
and cholic acid).
Inventive therapeutic protocols involve administering a therapeutically effective
amount of a contemplated nanoparticle to a healthy individual (i.e., a subject who does not
display any symptoms of cancer and/or who has not been diagnosed with cancer). For
example, healthy individuals may be “immunized” with a contemplated nanoparticle prior
to development of cancer and/or onset of symptoms of cancer; at risk individuals (e.g.,
patients who have a family history of cancer; patients carrying one or more genetic
mutations associated with development of cancer; patients having a genetic polymorphism
associated with development of cancer; patients infected by a virus associated with
development of cancer; patients with habits and/or lifestyles associated with development
of cancer; etc.) can be treated substantially contemporaneously with (e.g., within 48 hours,
within 24 hours, or within 12 hours of) the onset of symptoms of cancer. Of course,
individuals known to have cancer may receive inventive treatment at any time.
In other embodiments, disclosed nanoparticles can be used to inhibit the growth of
cancer cells, e.g., lung cancer cells. As used herein, the term “inhibits growth of cancer
cells” or “inhibiting growth of cancer cells” refers to any slowing of the rate of cancer cell
proliferation and/or migration, arrest of cancer cell proliferation and/or migration, or
killing of cancer cells, such that the rate of cancer cell growth is reduced in comparison
with the observed or predicted rate of growth of an untreated control cancer cell. The term
“inhibits growth” can also refer to a reduction in size or disappearance of a cancer cell or
tumor, as well as to a reduction in its metastatic potential. Preferably, such an inhibition at
the cellular level may reduce the size, deter the growth, reduce the aggressiveness, or
prevent or inhibit metastasis of a cancer in a patient. Those skilled in the art can readily
determine, by any of a variety of suitable indicia, whether cancer cell growth is inhibited.
Inhibition of cancer cell growth may be evidenced, for example, by arrest of cancer
cells in a particular phase of the cell cycle, e.g., arrest at the G2/M phase of the cell cycle.
Inhibition of cancer cell growth can also be evidenced by direct or indirect measurement of
cancer cell or tumor size. In human cancer patients, such measurements generally are
made using well known imaging methods such as magnetic resonance imaging,
computerized axial tomography and X-rays. Cancer cell growth can also be determined
indirectly, such as by determining the levels of circulating carcinoembryonic antigen,
prostate specific antigen or other cancer-specific antigens that are correlated with cancer
cell growth. Inhibition of cancer growth is also generally correlated with prolonged
survival and/or increased health and well-being of the subject.
Also described herein are methods of administering to a patient a nanoparticle
disclosed herein including an active agent, wherein, upon administration to a patient, such
nanoparticles substantially reduces the volume of distribution and/or substantially reduces
free C , as compared to administration of the agent alone (i.e., not as a disclosed
nanoparticle).
The nanoparticles of the present invention may be administered to a patient as a
sole therapy or may be administered in combination (simultaneous or sequential) with
conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include
one or more of the following categories of anti-tumour agents:-
(i) other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical
oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin,
cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide
and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as
fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine
arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like
adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C,
dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like
vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and
polokinase inhibitors); topoisomerase inhibitors (for example epipodophyllotoxins like
etoposide and teniposide, amsacrine, topotecan and camptothecin); and others such as
therapeutic antibodies (for example rituximab);
(ii) antihormonal agents such as antioestrogens (for example tamoxifen, fulvestrant,
toremifene, raloxifene, droloxifene and iodoxyfene), progestogens (for example megestrol
acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and
exemestane);
(iii) inhibitors of growth factor function and their downstream signalling pathways:
included are Ab modulators of any growth factor or growth factor receptor targets,
reviewed by Stern et al. (Critical Reviews in Oncology/Haematology, 2005, 54, pp11-
29); also included are small molecule inhibitors of such targets, for example kinase
inhibitors - examples include the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-
EGFR antibody panitumumab, the anti-EGFR antibody cetuximab [Erbitux, C225] and
tyrosine kinase inhibitors including inhibitors of the erbB receptor family, such as
epidermal growth factor family receptor (EGFR/erbB1) tyrosine kinase inhibitors such as
gefitinib or erlotinib, erbB2 tyrosine kinase inhibitors such as lapatinib, and mixed erb1/2
inhibitors such as afatanib; similar strategies are available for other classes of growth
factors and their receptors, for example inhibitors of the hepatocyte growth factor family
or their receptors including c-met and ron; inhibitors of the insulin and insulin growth
factor family or their receptors (IGFR, IR) inhibitors of the platelet-derived growth factor
family or their receptors (PDGFR), and inhibitors of signalling mediated by other receptor
tyrosine kinases such as c-kit, AnLK, and CSF-1R;
also included are modulators which target signalling proteins in the PI3-kinase signaling
pathway, for example, inhibitors of PI3-kinase isoforms such as PI3K- α/β /γ and ser / thr
kinases such as AKT, mTOR, PDK, SGK, PI4K or PIP5K; also included are inhibitors of
serine/threonine kinases not listed above, for example raf inhibitors such as vemurafenib,
MEK inhibitors such as selumetinib (AZD6244), Abl inhibitors such as imatinib or
nilotinib, Btk inhibitors such as ibrutinib, Syk inhibitors such as fostamatinib, inhibitors of
other ser/thr kinases such as JAKs, STATs and IRAK4, and cyclin dependent kinase
inhibitors;
iv) modulators of DNA damage signalling pathways, for example PARP inhibitors (e.g.
Olaparib), ATR inhibitors or ATM inhibitors and modulators of the cell cycle, for example
CDK4 and CDK6 inhibitors (eg palbociclib);
v) modulators of apoptotic and cell death pathways such as Bcl family modulators (e.g.
ABT-263 / Navitoclax, ABT-199);
(vi) antiangiogenic agents such as those which inhibit the effects of vascular endothelial
growth factor, [for example the anti-vascular endothelial cell growth factor antibody
bevacizumab (Avastin™) and for example, a VEGF receptor tyrosine kinase inhibitor such
as sorafenib, axitinib, pazopanib, sunitinib and vandetanib (and compounds that work by
other mechanisms (for example linomide, inhibitors of integrin αv β3 function and
angiostatin)];
(vii) vascular damaging agents, such as Combretastatin A4;
(viii) anti-invasion agents, for example c-Src kinase family inhibitors like (dasatinib, J.
Med. Chem., 2004, 47, 6658-6661) and bosutinib (SKI-606), and metalloproteinase
inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function
or antibodies to Heparanase];
(ix) immunotherapy approaches, including for example ex-vivo and in-vivo approaches
to increase the immunogenicity of patient tumour cells, such as transfection with cytokines
such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor,
approaches to decrease T-cell anergy, approaches using transfected immune cells such as
cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell
lines and approaches using anti-idiotypic antibodies. Specific examples include
monoclonal antibodies targeting PD-1 (e.g. BMS-936558), PDL-1 (eg MEDI4736 see US
8,779,108) or CTLA4 (e.g. ipilimumab and tremelimumab);
(x) Antisense or RNAi based therapies, for example those which are directed to the targets
listed.
(xi) gene therapy approaches, including for example approaches to replace aberrant genes
such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme
pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or
a bacterial nitroreductase enzyme and approaches to increase patient tolerance to
chemotherapy or radiotherapy such as multi-drug resistance gene therapy.
In one embodiment there is provided a combination suitable for use in the treatment
of cancer comprising nanoparticles of the present invention as defined herein and another
anti-tumour agent selected from i-a), iv-a) and ix-a) as defined below, wherein i-a) is a
subset of i) above, iv-a) is a subset of iv) above and ix-a) is a subset of ix) above, and
wherein:
i-a) comprises standard-of-care chemotherapy regimens, including but not limited to
replacing or augmenting anti-mitotic chemotherapies in solid tumour and haematological
cancers, such as taxanes and vinca alkaloids;
iv-a) comprises therapies that target the DNA damage response, including but not limited
to agents that inhibit DNA damage repair and the cell cycle; and
ix-a) comprises immune-mediated therapies, including but not limited to inhibitors of the
immune checkpoint blockade such as CTLA4, PD-1 and PDL-1 targeted therapies.
According to this aspect of the invention there is provided a combination suitable
for use in the treatment of cancer comprising nanoparticles of the present invention as
defined herein and another anti-tumour agent, in particular any one of the anti tumour
agents listed under (i) – (xi) above. In particular, the anti-tumour agent listed under (i)-(xi)
above is the standard of care for the specific cancer to be treated; the person skilled in the
art will understand the meaning of “standard of care”.
Described herein are nanoparticles of the present invention as disclosed herein in
combination with another anti-tumour agent, in particular an anti-tumour agent selected
from one listed under (i) – (xi), such as i-a), iv-a) or ix-a), herein above. For example, the
nanoparticles of the invention for use in the combination with an anti-tumour agent
selected from one listed under (i) – (xi) herein above, such as i-a), iv-a) or ix-a), may be
provided as a pharmaceutical composition selected from 1) to 16) below:
1) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises AZD1152 hqpa and optionally further comprises a
hydrophobic acid;
2) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises AZD1152 hqpa, a suitable polymer and optionally
further comprises a hydrophobic acid;
3) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises AZD1152 hqpa, a suitable polymer and further
comprises a hydrophobic acid;
in these embodiments, conveniently the hydrophobic acid is selected from deoxycholic
acid, cholic acid, dioctyl sulfosuccinic acid and pamoic acid; conveniently the hydrophobic
acid may be a mixture of deoxycholic acid and cholic acid;
4) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises AZD1152 hqpa, a diblock poly(lactic) acid-
poly(ethylene)glycol copolymer and further comprises a hydrophobic acid. In these
embodiments, conveniently the hydrophobic acid is selected from deoxycholic acid, cholic
acid, dioctyl sulfosuccinic acid and pamoic acid; conveniently the hydrophobic acid may
be a mixture of deoxycholic acid and cholic acid;
) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises about 35 to about 94.75 weight percent of a diblock
poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the therapeutic nanoparticle
comprises about 10 to about 30 weight percent poly(ethylene)glycol, about 0.05 to about
weight percent of a substantially hydrophobic acid selected from the group consisting of
deoxycholic acid, cholic acid, a mixture of cholic and deoxycholic acid, dioctyl
sulfosuccinic acid and pamoic acid, and about 5 to about 30 weight percent of AZD1152
hqpa or a pharmaceutically acceptable salt thereof;
6) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises about 65 to about 90 weight percent of a diblock
poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the therapeutic nanoparticle
comprises about 10 to about 30 weight percent poly(ethylene)glycol, about 5 to about 15
weight percent of a substantially hydrophobic acid selected from the group consisting of
deoxycholic acid, cholic acid, a mixture of cholic and deoxycholic acid, dioctyl
sulfosuccinic acid and pamoic acid, and about 5 to about 20 weight percent of AZD1152
hqpa or a pharmaceutically acceptable salt thereof;
7) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises about 35 to about 94 weight percent of a diblock
poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the therapeutic nanoparticle
comprises about 10 to about 30 weight percent poly(ethylene)glycol, about 1 to about 35
weight percent of pamoic acid and about 5 to about 30 weight percent of AZD1152 hqpa or
a pharmaceutically acceptable salt thereof;
8) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises about 55 to about 80 weight percent of a diblock
poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the therapeutic nanoparticle
comprises about 10 to about 30 weight percent poly(ethylene)glycol, about 10 to about 20
weight percent of pamoic acid and about 10 to about 25 weight percent of AZD1152 hqpa
or a pharmaceutically acceptable salt thereof;
9) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises about 65 to about 76 weight percent of a diblock
poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the therapeutic nanoparticle
comprises about 10 to about 20 weight percent poly(ethylene)glycol, about 9 to about 15
weight percent of pamoic acid and about 15 to about 20 weight percent of AZD1152 hqpa
or a pharmaceutically acceptable salt thereof;
) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises about 15 to about 25 weight percent of AZD1152 hqpa,
about 7 to about 15 weight percent of pamoic acid, and a diblock poly(lactic) acid-
poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle comprises about 10
to about 30 weight percent poly(ethylene)glycol and the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol);
11) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises about 15 to about 22 weight percent of AZD1152 hqpa,
about 7 to about 15 weight percent of pamoic acid, and a diblock poly(lactic) acid-
poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle comprises about 10
to about 30 weight percent poly(ethylene)glycol and the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol);
12) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises a diblock poly(lactic) acid-poly(ethylene)glycol
copolymer (wherein the therapeutic nanoparticle comprises about 10 to about 30 weight
percent poly(ethylene)glycol and the poly(lactic) acid-poly(ethylene)glycol copolymer has
a number average molecular weight of about 16kDa poly(lactic acid) and a number
average molecular weight of about 5kDa poly(ethylene)glycol) and a mixture of about 15
to about 22 weight percent of AZD1152 hqpa and about 7 to about 15 weight percent of
pamoic acid;
13) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises a diblock poly(lactic) acid-poly(ethylene)glycol
copolymer (wherein the therapeutic nanoparticle comprises about 10 to about 30 weight
percent poly(ethylene)glycol and the poly(lactic) acid-poly(ethylene)glycol copolymer has
a number average molecular weight of about 16kDa poly(lactic acid) and a number
average molecular weight of about 5kDa poly(ethylene)glycol) and the product obtained
by interaction of about 15 to about 22 weight percent of AZD1152 hqpa and about 7 to
about 15 weight percent of pamoic acid;
14) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises a diblock poly(lactic) acid-poly(ethylene)glycol
copolymer (wherein the therapeutic nanoparticle comprises about 10 to about 30 weight
percent poly(ethylene)glycol and the poly(lactic) acid-poly(ethylene)glycol copolymer has
a number average molecular weight of about 16kDa poly(lactic acid) and a number
average molecular weight of about 5kDa poly(ethylene)glycol) and a hydrophobic ion pair
formed between about 15 to about 22 weight percent (of the nanoparticle) of AZD1152
hqpa and about 7 to about 15 weight percent (of the nanoparticle) of pamoic acid;
) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises about 15 to about 22 weight percent of AZD1152 hqpa,
about 7 to about 15% by weight of pamoic acid, and a diblock poly(lactic) acid-
poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle comprises about 10
to about 30 weight percent poly(ethylene)glycol and the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol); wherein less than 20% of the AZD1152 hqpa is released from the
nanoparticle after 30 hours in PBS and polysorbate20 at 37ºC. Conveniently, the release of
AZD1152 hqpa from the nanoparticle is measured using the method described
hereinbefore.
16) a pharmaceutical composition comprising a plurality of therapeutic nanoparticles and
one or more pharmaceutically-acceptable excipients, diluents and/or carriers, wherein each
therapeutic nanoparticle comprises about 15 to about 22 weight percent of AZD1152 hqpa,
about 7 to about 15 weight percent of pamoic acid, and a diblock poly(lactic) acid-
poly(ethylene)glycol copolymer (wherein the therapeutic nanoparticle comprises about 10
to about 30 weight percent poly(ethylene)glycol and the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about 16kDa
poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol); wherein less than 20% of the AZD1152 hqpa is released from the
nanoparticle after 30 hours in PBS and polysorbate20 at 37ºC, and wherein the
nanoparticles are made by a process comprising the following steps:
1) combining a first organic phase (which comprises a 16:5 PLA-PEG co-polymer,
AZD1152 hqpa and pamoic acid in a solvent mixture comprising TFA, benzyl alcohol,
DMSO and ethyl acetate such that the benzyl alcohol: ethyl acetate are present in a molar
ratio of about 1:3.6 and the pamoic acid and AZD1152 hqpa are added at an initial ratio of
0.8 moles pamoic acid: 1 mole AZD1152 hqpa) with a first aqueous solution (comprising a
polyoxyethylene (100) stearyl ether (for example as sold under the tradename Brij®S100),
in water, DMSO and benzyl alcohol) to form a second phase, wherein the ratio of the
aqueous phase to the organic phase is about 5.5:1;
2) emulsifying the second phase to form a coarse emulsion;
3) holding the coarse emulsion for a hold time (such as 10 to 15 minutes, conveniently at
about 0 ºC for example by immersing in an ice-bath);
4) forming a nano-emulsion using a high pressure homogenizer;
) optionally waiting for a delay time of at least 5 minutes, for example 10 minutes;
6) quenching of the emulsion phase at 0-5 ºC thereby forming a quenched phase, wherein
quenching of the emulsion phase comprises mixing the emulsion phase with a second
aqueous solution comprising a buffer at pH 6.5 (such as a 0.17M phosphate buffer)
wherein the ratio of second aqueous solution to emulsion is between about 2:1 and about
:1, such as about 3:1;
7) adding an aqueous surfactant solution (such as Tween®80, for example a 35% w/w
Tween®80 solution in water) to the quench solution (for example at a ratio of about 20:1
Tween®80 to drug by weight);
8) concentrating and isolating the resulting nanoparticles by filtration.
Other suitable pharmaceutical compositions comprising AZD1152 hqpa in a
nanoparticle described herein may also be used in the above combinations.
Further aspects of the invention and/or disclosures are set out in the following features:
1. A therapeutic nanoparticle comprising:
about 50 to about 99.75 weight percent of a diblock poly(lactic) acid-
poly(ethylene)glycol copolymer or a diblock poly(lactic acid-co-glycolic acid)-
poly(ethylene)glycol copolymer, wherein the therapeutic nanoparticle comprises
about 10 to about 30 weight percent poly(ethylene)glycol; and
about 0.2 to about 30 weight percent of AZD1152 hqpa or a pharmaceutically acceptable
salt thereof.
2. The therapeutic nanoparticle of feature 1, wherein the poly(lactic) acid-
poly(ethylene)glycol copolymer has a poly(lactic) acid number average molecular
weight fraction of about 0.7 to about 0.9.
3. The therapeutic nanoparticle of feature 1, wherein the poly(lactic) acid-
poly(ethylene)glycol copolymer has a poly(lactic) acid number average molecular
weight fraction of about 0.75 to about 0.85.
4. The therapeutic nanoparticle of feature 1, 2 or 3, wherein the therapeutic nanoparticle
comprises about 10 to about 25 weight percent poly(ethylene)glycol.
. The therapeutic nanoparticle of feature 1, 2 or 3, wherein the therapeutic nanoparticle
comprises about 20 to about 30 weight percent poly(ethylene)glycol.
6. The therapeutic nanoparticle of any preceding feature, wherein the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about
15kDa to about 20kDa poly(lactic acid) and a number average molecular weight of
about 4kDa to about 6kDa poly(ethylene)glycol.
7. The therapeutic nanoparticle of feature 6, wherein the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about
16kDa poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol.
8. The therapeutic nanoparticle of any one of features 1-6, comprising about 65 weight
percent to about 85 weight percent of the copolymer.
9. The therapeutic nanoparticle of any one of features 1-8, further comprising a
substantially hydrophobic acid.
10. The therapeutic nanoparticle of any one of features 1-8, further comprising about
0.05 to about 35 weight percent of a substantially hydrophobic acid.
11. The therapeutic nanoparticle of any one of features 1-8, further comprising about 5 to
about 15 weight percent of a substantially hydrophobic acid.
12. The therapeutic nanoparticle of any one of features 1-8, further comprising about 10
to about 20 weight percent of a substantially hydrophobic acid.
13. The therapeutic nanoparticle of any one of features 9 to 12, wherein the hydrophobic
acid is a bile acid.
14. The therapeutic nanoparticle of feature 13, wherein the bile acid is deoxycholic acid,
cholic acid or a mixture thereof.
. The therapeutic nanoparticle of any one of features 9 to 12, wherein the hydrophobic
acid is dioctyl sulfosuccinic acid.
16. The therapeutic nanoparticle of any one of features 9 to 12, wherein the hydrophobic
acid is pamoic acid.
17. The therapeutic nanoparticle of any one of features 9-12, wherein the molar ratio of
the substantially hydrophobic acid to the therapeutic agent is about 0.5:1 to about
1.6:1, wherein the acid is deoxycholic acid, cholic acid or a mixture of cholic acid
and deoxycholic acid.
18. The therapeutic nanoparticle of any one of features 9-12, wherein the molar ratio of
the substantially hydrophobic acid to AZD1152 hqpa is about 1.3:1 to about 1.6:1,
wherein the acid is a mixture of cholic acid and deoxycholic acid.
19. The therapeutic nanoparticle of any one of features 9-12, wherein the molar ratio of
the substantially hydrophobic acid to AZD1152 hqpa is about 0.9:1 to about 1.1:1,
wherein the acid is dioctyl sulfosuccinic acid.
. The therapeutic nanoparticle of any one of features 9-15, wherein a pK of AZD1152
hqpa is at least about 1.0 pK units greater than a pK of the hydrophobic acid.
21. The therapeutic nanoparticle of any one of features 9-19, wherein the substantially
hydrophobic acid and AZD1152 hqpa form a hydrophobic ion pair in the therapeutic
nanoparticle.
22. The therapeutic nanoparticle of any one of features 1-21, comprising about 5 to about
weight percent of AZD1152 hqpa.
23. The therapeutic nanoparticle of any one of features 1-21, comprising about 10 to
about 20 weight percent of AZD1152 hqpa.
24. A therapeutic nanoparticle comprising: about 50 to about 99.75 weight percent of a
diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the therapeutic
nanoparticle comprises about 10 to about 30 weight percent poly(ethylene)glycol;
about 5 to about 30 weight percent of a therapeutic agent which is AZD1152 hqpa or
a pharmaceutically acceptable salt thereof; and either about 0.05 to about 35 weight
percent of a substantially hydrophobic acid selected from the group consisting of
deoxycholic acid, cholic acid and dioctyl sulfosuccinic acid; or about 0.05 to about
weight percent of a mixture of substantially hydrophobic acids which are
deoxycholic acid and cholic acid.
25. A therapeutic nanoparticle comprising: about 50 to about 99.75 weight percent of a
diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the therapeutic
nanoparticle comprises about 10 to about 30 weight percent poly(ethylene)glycol;
about 5 to about 30 weight percent of a therapeutic agent which is AZD1152 hqpa or
a pharmaceutically acceptable salt thereof; and either about 0.05 to about 35 weight
percent of a substantially hydrophobic acid selected from the group consisting of
deoxycholic acid, cholic acid and dioctyl sulfosuccinic acid; or about 0.05 to about
weight percent of a mixture of substantially hydrophobic acids which are
deoxycholic acid and cholic acid.
26. A therapeutic nanoparticle comprising: about 35 to about 94.75 weight percent of a
diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the therapeutic
nanoparticle comprises about 10 to about 30 weight percent poly(ethylene)glycol;
about 0.05 to about 35 weight percent of a substantially hydrophobic acid selected
from the group consisting of deoxycholic acid, cholic acid, (or a mixture of cholic
and deoxycholic acid), dioctyl sulfosuccinic acid and pamoic acid; and about 5 to
about 30 weight percent of AZD1152 hqpa or a pharmaceutically acceptable salt
thereof.
27. A therapeutic nanoparticle comprising: about 65 to about 90 weight percent of a
diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the therapeutic
nanoparticle comprises about 10 to about 30 weight percent poly(ethylene)glycol;
about 5 to about 15 weight percent of a substantially hydrophobic acid selected from
the group consisting of deoxycholic acid, cholic acid, (or a mixture of cholic and
deoxycholic acid), dioctyl sulfosuccinic acid and pamoic acid; and about 5 to about
weight percent of AZD1152 hqpa or a pharmaceutically acceptable salt thereof.
28. The therapeutic nanoparticle of feature 24, feature 25, feature 26 or feature 27
wherein the poly(lactic) acid-poly(ethylene)glycol copolymer has a poly(lactic) acid
number average molecular weight fraction of about 0.7 to about 0.9.
29. The therapeutic nanoparticle of feature 24, feature 25, feature 26 or feature 27
wherein the poly(lactic) acid-poly(ethylene)glycol copolymer has a poly(lactic) acid
number average molecular weight fraction of about 0.75 to about 0.85.
. The therapeutic nanoparticle of feature 24, feature 25, feature 26 or feature 27
wherein the therapeutic nanoparticle comprises about 10 to about 25 weight percent
poly(ethylene)glycol.
31. The therapeutic nanoparticle of feature 24, feature 25, feature 26 or feature 27
wherein the therapeutic nanoparticle comprises about 20 to about 30 weight percent
poly(ethylene)glycol.
32. The therapeutic nanoparticle of any of features 24 to 31, wherein the poly(lactic)
acid-poly(ethylene)glycol copolymer has a number average molecular weight of
about 15kDa to about 20kDa poly(lactic acid) and a number average molecular
weight of about 4kDa to about 6kDa poly(ethylene)glycol.
33. The therapeutic nanoparticle of any of features 24 to 31, wherein the poly(lactic)
acid-poly(ethylene)glycol copolymer has a number average molecular weight of
about 16kDa poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol.
34. The therapeutic nanoparticle of any one of features 24-33, comprising about 65
weight percent to about 85 weight percent of the copolymer.
35. A pharmaceutically acceptable composition comprising a plurality of therapeutic
nanoparticles of any one of features 1-34 and a pharmaceutically acceptable
excipient.
36. A method of treating cancer in a patient in need thereof, comprising administering to
the patient a therapeutically effective amount of a composition comprising the
therapeutic nanoparticle of any one of features 1-34.
37. The method of feature 36, wherein the cancer is lung cancer.
38. The method of feature 36, wherein the cancer is a leukemia.
39. The method of feature 36, wherein the cancer is colorectal cancer.
Further aspects of the invention and/or disclosures are set out in the following features:
1a. A therapeutic nanoparticle comprising: about 50 to about 99.75 weight percent of a
diblock poly(lactic) acid-poly(ethylene)glycol copolymer or a diblock poly(lactic
acid-co-glycolic acid)-poly(ethylene)glycol copolymer, wherein the therapeutic
nanoparticle comprises about 10 to about 30 weight percent poly(ethylene)glycol;
and about 0.2 to about 30 weight percent of AZD1152 hqpa or a pharmaceutically
acceptable salt thereof.
2a. The therapeutic nanoparticle of feature 1a, wherein the poly(lactic) acid-
poly(ethylene)glycol copolymer has a poly(lactic) acid number average molecular
weight fraction of about 0.7 to about 0.9.
3a. The therapeutic nanoparticle of feature 1a, wherein the poly(lactic) acid-
poly(ethylene)glycol copolymer has a poly(lactic) acid number average molecular
weight fraction of about 0.75 to about 0.85.
4a. The therapeutic nanoparticle of feature 1a, wherein the therapeutic nanoparticle
comprises about 10 to about 25 weight percent poly(ethylene)glycol.
5a. The therapeutic nanoparticle of feature 1a, wherein the therapeutic nanoparticle
comprises about 20 to about 30 weight percent poly(ethylene)glycol.
6a. The therapeutic nanoparticle of feature 1a, wherein the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about
15kDa to about 20kDa poly(lactic acid) and a number average molecular weight of
about 4kDa to about 6kDa poly(ethylene)glycol.
7a. The therapeutic nanoparticle of feature 6a, wherein the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about
16kDa poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol.
8a. The therapeutic nanoparticle of any one of features 1a-6a, comprising about 65
weight percent to about 85 weight percent of the copolymer.
9a. The therapeutic nanoparticle of any one of features 1a-8a, further comprising a
substantially hydrophobic acid.
10a. The therapeutic nanoparticle of any one of features 1a-8a, further comprising about
0.05 to about 35 weight percent of a substantially hydrophobic acid.
11a. The therapeutic nanoparticle of any one of features 1a-8a, further comprising about 5
to about 15 weight percent of a substantially hydrophobic acid.
12a. The therapeutic nanoparticle of any one of features 1a-8a, further comprising about
to about 20 weight percent of a substantially hydrophobic acid.
13a. The therapeutic nanoparticle of any one of features 9a-12a, wherein the molar ratio
of the substantially hydrophobic acid to the therapeutic agent is about 0.5:1 to about
1.6:1, wherein the acid is deoxycholic acid, cholic acid or a mixture of cholic acid
and deoxycholic acid.
14a. The therapeutic nanoparticle of any one of features 9a-12a, wherein the molar ratio
of the substantially hydrophobic acid to the therapeutic agent is about 1.3:1 to about
1.6:1, wherein the acid is a mixture of cholic acid and deoxycholic acid.
15a. The therapeutic nanoparticle of any one of features 9a-12a, wherein the molar ratio
of the substantially hydrophobic acid to the therapeutic agent is about 0.9:1 to about
1.1:1, wherein the acid is dioctyl sulfosuccinic acid.
16a. The therapeutic nanoparticle of any one of features 9a-15a, wherein a pK of the
therapeutic agent is at least about 1.0 pKa units greater than a pKa of the hydrophobic
acid.
17a. The therapeutic nanoparticle of any one of features 9a-16a, wherein the substantially
hydrophobic acid and the therapeutic agent form a hydrophobic ion pair in the
therapeutic nanoparticle.
18a. The therapeutic nanoparticle of any one of features 9a-17a, wherein the hydrophobic
acid is a bile acid.
19a. The therapeutic nanoparticle of feature 18a, wherein the bile acid is deoxycholic
acid, cholic acid or a mixture thereof.
20a. The therapeutic nanoparticle of any one of features 9a-18a, wherein the hydrophobic
acid is dioctyl sulfosuccinic acid.
21a. The therapeutic nanoparticle of any one of features 1a-20a, comprising about 5 to
about 20 weight percent of the therapeutic agent.
22a. The therapeutic nanoparticle of any one of features 1a-20a, comprising about 10 to
about 20 weight percent of the therapeutic agent.
23a. A therapeutic nanoparticle comprising: about 50 to about 99.75 weight percent of a
diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the therapeutic
nanoparticle comprises about 10 to about 30 weight percent poly(ethylene)glycol;
about 5 to about 30 weight percent of a therapeutic agent which is AZD1152 hqpa or
a pharmaceutically acceptable salt thereof; and either about 0.05 to about 35 weight
percent of a substantially hydrophobic acid selected from the group consisting of
deoxycholic acid, cholic acid and dioctyl sulfosuccinic acid; or about 0.05 to about
weight percent of a mixture of substantially hydrophobic acids which are
deoxycholic acid and cholic acid.
24a. The therapeutic nanoparticle of feature 23a, wherein the poly(lactic) acid-
poly(ethylene)glycol copolymer has a poly(lactic) acid number average molecular
weight fraction of about 0.7 to about 0.9.
25a. The therapeutic nanoparticle of feature 23a, wherein the poly(lactic) acid-
poly(ethylene)glycol copolymer has a poly(lactic) acid number average molecular
weight fraction of about 0.75 to about 0.85.
26a. The therapeutic nanoparticle of feature 23a, wherein the therapeutic nanoparticle
comprises about 10 to about 25 weight percent poly(ethylene)glycol.
27a. The therapeutic nanoparticle of feature 23a, wherein the therapeutic nanoparticle
comprises about 20 to about 30 weight percent poly(ethylene)glycol.
28a. The therapeutic nanoparticle of feature 23a, wherein the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about
15kDa to about 20kDa poly(lactic acid) and a number average molecular weight of
about 4kDa to about 6kDa poly(ethylene)glycol.
29a. The therapeutic nanoparticle of feature 28a, wherein the poly(lactic) acid-
poly(ethylene)glycol copolymer has a number average molecular weight of about
16kDa poly(lactic acid) and a number average molecular weight of about 5kDa
poly(ethylene)glycol.
30a. The therapeutic nanoparticle of any one of features 23a-29a, comprising about 65
weight percent to about 85 weight percent of the copolymer.
31a. A pharmaceutically acceptable composition comprising a plurality of therapeutic
nanoparticles of any one of features 1a-30a and a pharmaceutically acceptable
excipient.
32a. A method of treating cancer in a patient in need thereof, comprising administering to
the patient a therapeutically effective amount of a composition comprising the
therapeutic nanoparticle of any one of features 1a-30a.
33a. The method of feature 32a, wherein the cancer is lung cancer.
34a. The method of feature 32a, wherein the cancer is a leukemia.
35a. The method of feature 32a, wherein the cancer is colorectal cancer.
EXAMPLES
The invention now being generally described, it will be more readily understood by
reference to the following examples which are included merely for purposes of illustration
of certain aspects and embodiments, and are not intended to limit the invention in any way.
Each of the following examples provides a separate independent embodiment of the
invention. In particular, the formulations disclosed in the following examples and the
methods disclosed for making them comprise separate independent embodiments of the
invention.
AZD1152 hqpa may be made as described in WO2004/058781 or
WO2007/132210.
Abbreviations:
The following abbreviations may be used.
EA ethyl acetate
BA benzyl alcohol
DI de-ionised
TFF tangential flow filtration
TFA trifluoroacetic acid
Lyo/oven lyophilizing oven
DMSO dimethylsulfoxide
scid severe compromised immunodeficient
Brij®100 Brij®S 100 surfactant is a commercially available polyoxyethylene (100)
stearyl ether with an average molecular weight of about 4670, chemical abstracts (CAS)
number 90059
Tween®80 A commercially available polyoxyethylene sorbitan monooleate, also
known as polysorbate 80, CAS number 90056
Span®80 A commercially available sorbitan monooleate, CAS number 13388
For the avoidance of doubt, where “polymer-PEG” is referred to in the following
examples, it means PLA-PEG co-polymer where the co-polymer has a number average
molecular weight of about 16kDa poly(lactic acid) and a number average molecular weight
of about 5kDa poly(ethylene)glycol. Such polymers are commercially available or may be
made by methods known in the art. Such polymers are used for example in
WO2010/005721.
EXAMPLE 1: Preparation of Therapeutic Nanoparticles Containing 2-(3-((7-(3-(ethyl(2-
hydroxyethyl)amino)propoxy)quinazolinyl)amino)-1H-pyrazolyl)-N-(3-
fluorophenyl)acetamide Using a Nanoemulsion Process
This example demonstrates procedures for preparing nanoparticles containing AZD1152
hqpa.
Deoxycholic acid Nanoparticle Preparation Procedure
1. Preparation of polymer solution
1.1 To 20mL glass vial add polymer-PEG, 350mg.
1.2 Add 3.15g of ethyl acetate to glass vial and vortex overnight to give a polymer-
EA solution.
2. Preparation of drug solution
2.1 To make 9% deoxycholic acid/BA, add 1.8g of deoxycholic acid into 18.2g of
BA in 20ml scintillation vial based on the recipe table.
2.2 Heat the solution at 80 C for 30 mins.
2.3 Weigh 150mg of therapeutic agent in 20ml scintillation vial.
2.4 Add above 9% deoxycholic acid to the drug and leave at 80 C for 15-30mins
to get clear drug solution.
2.5 Right before formulation, combine drug and polymer solution.
3. Preparation of Aqueous Solution:
- 0.475% Sodium Cholate, 4% Benzyl Alcohol in Water.
3.1 To 1L bottle add 4.75g sodium cholate and 955.25g of DI water and mix on stir
plate until dissolved.
3.2 Add 40g of benzyl alcohol to sodium cholate/water and mix on stir plate until
dissolved.
4. Formation of emulsion. Ratio of Aqueous phase to organic phase is 5:1
4.1 Pour organic phase into aqueous solution and homogenize using hand-held
rotor/stator homogenizer for 10 seconds at room temperature to form coarse
emulsion.
4.2 Feed solution through high pressure homogenizer (110S) with pressure set at
~11,000 psi on gauge for 1 discreet passes to form nanoemulsion.
. Formation of nanoparticles
Pour emulsion into Quench (D.I. water) at <5 C while stirring on stir plate.
Ratio of Quench to Emulsion is 10:1.
6. Add 35% (w/w) Tween® 80 in water to quench at ratio of 100:1 Tween® 80 to
drug by weight.
7. Concentrate nanoparticles through TFF
7.1 Concentrate quench on TFF with 300kDa Pall cassette (2 x 0.1 m membranes)
to ~200mL.
7.2 Diafilter ~20 diavolumes (4 liter) using cold DI water.
7.3 Bring volume down to minimal volume.
7.4 Add 100mL of cold water to vessel and pump through membrane to rinse.
7.5 Collect material in glass vial, ~100mL.
8. Determination of solids concentration of unfiltered final slurry:
8.1 To tared 20mL scintillation vial add a volume of final slurry and dry under
vacuum on lyo/oven.
8.2 Determine weight of nanoparticles in the volume of slurry dried down.
9. Determination of solids concentration of 0.45 μm filtered final slurry:
9.1 Filter about a portion of the final slurry sample before addition of sucrose
through 0.45µm syringe filter.
9.2 To tared 20mL scintillation vial add a volume of filtered sample and dry under
vacuum on lyo/oven.
. Add 1 part of sucrose to final 9 parts of slurry sample to attain 10% sucrose.
11. Freeze remaining sample of unfiltered final slurry with sucrose.
Docusate Nanoparticle Preparation Procedure
1. Preparation of polymer solution
1.1 To 20mL glass vial add polymer-PEG, 750mg.
1.2 Add 2.75g of ethyl acetate to glass vial and vortex overnight to give a polymer-
EA solution.
2. Preparation of drug solution
2.1 To make 30% docusate/benzyl alcohol (“30% docusate/BA”), use Table 1.
2.2 Weigh 250mg of therapeutic agent in 20ml scintillation vial.
2.3 Add above 690mg of 30% docusate to the drug and vortex for more than 1hr to
get clear drug solution.
2.4 Right before formulation, add drug and polymer solution.
Table 1. Preparation of docusate/BA solution.
Desired Total Docusate+ Docusate- HCl (g)
BA to Brine
Conc BA gram sodium Acid addition
Add (g) Needed (g)
(w/w) solution need (g) (5N)
docusate/ 30.00% 40.00 12.00 28.00 16.20 18.67
in BA
3. Preparation of Aqueous Solution:
- 0.475% Sodium Cholate, 4% Benzyl Alcohol in Water.
3.1 To 1L bottle add 4.75g sodium cholate and 955.25g of DI water and mix on stir
plate until dissolved.
3.2 Add 40g of benzyl alcohol to sodium cholate/water and mix on stir plate until
dissolved.
4. Formation of emulsion. Ratio of Aqueous phase to organic phase is 5:1
4.1 Pour organic phase into aqueous solution and homogenize using hand-held
rotor/stator homogenizer for 10 seconds at room temperature to form coarse
emulsion.
4.2 Feed solution through high pressure homogenizer (110S) with pressure set at
~11,000 psi on gauge for 1 discreet passes to form nanoemulsion.
. Formation of nanoparticles
Pour emulsion into Quench (D.I. water) at <5 C while stirring on stir plate.
Ratio of Quench to Emulsion is 10:1.
6. Add 35% (w/w) Tween® 80 in water to quench at ratio of 100:1 Tween® 80 to
drug by weight.
7. Concentrate nanoparticles through TFF
7.1 Concentrate quench on TFF with 300kDa Pall cassette (2 x 0.1 m membranes)
to ~200mL.
7.2 Diafilter ~20 diavolumes (4 liter) using cold DI water.
7.3 Bring volume down to minimal volume.
7.4 Add 100mL of cold water to vessel and pump through membrane to rinse.
7.5 Collect material in glass vial, ~100mL.
8. Determination of solids concentration of unfiltered final slurry:
8.1 To tared 20mL scintillation vial add a volume of final slurry and dry under
vacuum on lyo/oven.
8.2 Determine weight of nanoparticles in the volume of slurry dried down.
9. Determination of solids concentration of 0.45 μm filtered final slurry:
9.1 Filter about a portion of the final slurry sample before addition of sucrose
through 0.45µm syringe filter.
9.2 To tared 20mL scintillation vial add a volume of filtered sample and dry under
vacuum on lyo/oven.
. Add 1 part of sucrose to final 9 parts of slurry sample to attain 10% sucrose.
11. Freeze remaining sample of unfiltered final slurry with sucrose.
In a variation on the above procedure, sodium docusate may be used in place of sodium
cholate in step 3.1 above.
EXAMPLE 2: Characterization of Therapeutic Nanoparticles Containing AZD1152 hqpa
This example demonstrates that co-encapsulation with hydrophobic counter-ions such as
deoxycholic acid and docusate greatly improved drug loading (from ~3% to up to ~15%
drug loading). The release of therapeutic agent from nanoparticles was substantially
slower when formulated as a hydrophobic ion pair compared to the control formulation.
Control Formulations
Control formulations were made as plain nanoparticles (“NPs”) without any counter-ions.
NPs were prepared using PLA-PEG polymer matrix (16 kDa PLA / 5 kDa PEG) (“16/5
PLA-PEG”) with no additional excipients.
Therapeutic agent was dissolved in benzyl alcohol (“BA”) or BA/water to form the drug
solution, and polymer solution in ethyl acetate (“EA”) was poured into the drug solution
right before adding to aqueous for homogenization. This control formulation results in
nanoparticles with relatively low drug loading (~3%), high burst (~20%), and fast release
(>50% at 4 hrs). (See Table 1 and Figure 3.) These results are not unusual for APIs with
relatively low MW (<600 kDa) and/or lesser hydrophobicity (log P < 3).
Table 2. Control nanoparticle formulation.
Drug Organic
theoretical phase solids Loading
Lot # loading concentration % size (nm)
16/5 PLA-PEG, 7.5% water in BA 128.9
only 20 7% 3.17 (0.172)
Deoxycholic Acid Formulations
Deoxycholic acid formulations were made according to the procedure in Example 1 using
various amounts of deoxycholic acid in the organic phase as shown in Table 3.
Nanoparticles were prepared using 16/5 PLA-PEG.
Table 3. Deoxycholic acid nanoparticle formulations.
Deoxycholic
Acid wt % Total mass (g) BA
acid
8 20 18.4g 1.6g
8% Deoxycholic Acid in BA
9 20 18.2g 1.8g
9% Deoxycholic Acid in BA
% Deoxycholic Acid in BA 10 20 18.0g 2.0g
Table 4 below provides characterization data for deoxycholic acid formulations. As
evidenced by the data, the presence of the deoxycholic acid greatly enhances the API
loading in the final nanoparticle formulations as compared to the control nanoparticles.
Table 4. Characterization data for formulations containing deoxycholic acid.
Ethyl
Mean
Theoretical Organic Benzyl Acid:Drug acetate Actual
size
drug phase alcohol addition portion of drug
Lot # by
loading [solids] [deoxycholic ratio organic loading
(wt%) (wt%) acid] (wt%) (mol:mol) solvents (wt%)
(nm)
(wt%)
254
15% 9.0 0.99 70 10% 99.6
254
15% 9.0 0.99 70 9.90% 105.6
254
15% 8.0 1.02 65 7.30% 84.5
254
15% 8.0 1.02 65 8.20% 127.7
254
15% 13.5 0.99 70 10.00% 104.7
254
15% 8.0 0.99 70 9.40% 102.3
254
10% 7.0 0.98 70 10.50% 135.4
254
10% 7.0 0.98 70 10.00% 105.4
254
10% 9.0 1.05 70 11.70% 110.3
254
10% 9.0 1.05 70 11.20% 112.6
254
10% 10.0 0.97 75 11.40% 107.6
254
10% 10.0 0.97 75 11.20% 107.4
254
10% 9.0 1.05 70 9.60% 111.4
254
10% 8.0 1.06 60 6.40% 136.8
254
10% 8.0 1.06 60 7.90% 119.4
254
12.5% 8.0 1.03 50 7.40% 111.1
254
10% 8.0 1.06 60 7.40% 117.6
254
10% 8.0 1.06 60 7.80% 117.3
254 35 10% 8.0 1.06 60 7.70% 124.0
254
10% 8.0 1.06 60 8.70% 120.9
254
15% 10.0 0.98 60 7.60% 141.1
254
15% 10.0 0.98 60 9.10% 121.1
254
15% 10.0 0.98 60 8.30% 150.3
254
15% 10.0 0.98 60 10.40% 127.0
This value = wt% concentration of drug + polymer divided by organic solids and does
not include the deoxycholic acid for these batches.
DLS is dynamic light scattering.
Figure 4 shows in vitro therapeutic agent release showing controlled and slow/sustained
release of drugs from deoxycholic acid NPs compared to that from control NPs without
deoxycholic acid counter-ions.
The table below describes the composition (by percent weight) of each component in the
particle of a particular nanoparticle formulation, which is referred to herein as
“Formulation F1”.
Component Weight Percent of the Nanoparticle
16/5 PLA-PEG 75%
Deoxycholic acid 9%
Cholic acid 6%
AZD1152 hqpa 10%
Docusate Formulations
Docusate sodium (eg available as “Aerosol OT” or “AOT”) was converted into acid form
(i.e., dioctyl sulfosuccinic acid) using an in-situ converting method before being mixed
with drug. Docusate sodium was dissolved in BA, and concentrated HCl solution was
added at controlled HCl/docusate ratios. The mixture was vortexed to facilitate proton
exchange and conversion of the sodium salt to free acid form. Then, saturated sodium
chloride solution was added and mixed by vortexing to extract water and sodium chloride
salt formed in the BA mixture. After mixing, the sample was incubated at room
temperature for phase separation. Over time, two layers gradually developed with BA on
top and the aqueous layer on the bottom. The top layer was aspirated as drug solvent
containing docusate counter ion. Concentrations of docusate acid in BA were reported as
docusate sodium concentration in BA. Docusate nanoparticle formulations were prepared
using the procedure in Example 1 with 16/5 PLA/PEG polymer as for the deoxycholic acid
formulation. Typical docusate acid preparations are listed in Table 5.
Table 5. Typical preparations of protonated docusate sodium solution (DSS) in BA (as
drug solvent).
Calculated
Molar ratio
DSS % amount
Material Percent of
in BA
Mass
mMol HCl/docusate
BA 90% 60 - -
Docusate 10% 6.7 15
3.33
% 5N HCl - 10 50
Saturated
-
NaCl
BA 85% 60 - -
docusate 15% 10.6 23.8
4.20
% 5N HCl - 20 100
Saturated
-
NaCl
BA 80% 60 - -
docusate 20% 15 33.7
.93
5N HCl - 40 200
Saturated
-
NaCl
Table 6 below provides characterization data for representative docusate formulations.
Without wishing to be bound by any theory, it is believed that the presence of the docusate
counter ion serves to enhance drug encapsulation and loading by the hydrophobic ion
pairing (HIP) process.
Table 6. Characterization data for formulations containing docusate acid.
Drug
Organic Acid:Drug
theoretic Drug Mean
phase [Docusate] addition
Lot # al EA% Loading size
[solids] % ratio
loading wt% (nm)
(wt%) (mol:mol)
(wt%)
2505 20 18 20 1.09 80 8.89% 100.2
250
18 20 1.09 80 10.95% 96.6
250
18 20 1.09 70 13.75% 113.2
250
18 20 1.09 70 16.25% 132.1
250
22.5 30 0.99 80 13.80% 116.8
250
22.5 30 0.99 80 15.22% 135.6
250 20 18 20 1.09 80 9.92% 117.4
Drug
Organic Acid:Drug
theoretic Drug Mean
phase [Docusate] addition
Lot # al EA% Loading size
[solids] % ratio
loading wt% (nm)
(wt%) (mol:mol)
(wt%)
250
18 20 1.09 80 11.45% 139.2
250
18 20 1.09 80 10.52% 114.8
250
25 25 0.90 75 7.17% 104.8
250
25 25 0.90 75 6.01% 92.7
250
22.5 30 0.99 80 13.80% 116.8
250
22.5 30 0.99 80 8.49% 104
250
22.5 30 1.06 80 10.10% 125
250
22.5 30 1.06 70 13.39% 120.8
250
22.5 30 1.06 70 14.41% 124.7
250
22.5 30 1.06 70 4.61% 85
Figure 5 shows in vitro therapeutic agent release showing controlled and slow/sustained
release of drugs from docusate acid NPs compared to that from control NPs without
docusate counter-ions.
The table below describes the composition (by percent weight) of each component in the
particle of a particular nanoparticle formulation, which is referred to herein as
“Formulation F2”.
Component Weight Percent of the Nanoparticle
16/5 PLA-PEG 80%
Docusate 10%
AZD1152 hqpa 10%
Example 3
A formulation containing cholic acid is described below. This formulation is referred to
herein as “Formulation E”.
Percent of
COMPONENT particle mass
(nominal)
AZD1152 hqpa 5
PLA-PEG 16/5 90
Cholic acid 5
Cholic acid Nanoparticle Preparation Procedure
1. Preparation of polymer solution
1.1 To 20mL glass vial add polymer-PEG, 350mg.
1.2 Add 8.11g of ethyl acetate to glass vial and vortex overnight to give a
polymer-EA solution.
2. Preparation of drug solution
2.1 To make 3% TFA/BA, add 63 mg of TFA into 2.03g of BA in 20ml
scintillation vial based on the recipe table.
2.2 Weigh 150mg of therapeutic agent in 20ml scintillation vial.
2.3 Add above 3% TFA in BA to the drug and mix for 15-30mins to get
clear drug solution.
2.4 Right before formulation, combine drug and polymer solution.
3. Preparation of Aqueous Solution:
- 0.52% Sodium Cholate, 4% Benzyl Alcohol in Water.
3.1 To 1L bottle add 5.2g sodium cholate and 954.8g of DI water and mix
on stir plate until dissolved.
3.2 Add 40g of benzyl alcohol to sodium cholate/water and mix on stir plate
until dissolved.
4. Formation of emulsion. Ratio of Aqueous phase to Organic phase is 5:1
4.1 Pour organic phase into aqueous solution and homogenize using hand-
held rotor/stator homogenizer for 10 seconds at room temperature to
form coarse emulsion.
4.2 Feed solution through high pressure homogenizer (110S) with pressure
set at ~11,000 psi on gauge for 1 discreet passes to form nanoemulsion.
. Formation of nanoparticles
Pour emulsion into Quench (D.I. water) at <5 C while stirring on stir
plate. Ratio of Quench to Emulsion is 10:1.
6. Add 35% (w/w) Tween® 80 in water to quench at ratio of 100:1 Tween®
80 to drug by weight.
7. Concentrate nanoparticles through TFF
7.1 Concentrate quench on TFF with 300kDa Pall cassette (2 x 0.1 m
membranes) to ~200mL.
7.2 Diafilter ~20 diavolumes (4 liter) using cold DI water.
7.3 Bring volume down to minimal volume.
7.4 Add 100mL of cold water to vessel and pump through membrane to
rinse.
7.5 Collect material in glass vial, ~100mL.
8. Determination of solids concentration of unfiltered final slurry:
8.1 To tared 20mL scintillation vial add a volume of final slurry and dry
under vacuum on lyo/oven.
8.2 Determine weight of nanoparticles in the volume of slurry dried down.
9. Determination of solids concentration of 0.45µm filtered final slurry:
9.1 Filter about a portion of the final slurry sample before addition of
sucrose through 0.45µm syringe filter.
9.2 To tared 20mL scintillation vial add a volume of filtered sample and dry
under vacuum on lyo/oven.
. Add 1 part of sucrose to final 9 parts of slurry sample to attain 10% sucrose
by weight.
11. Freeze remaining sample of unfiltered final slurry with sucrose.
Example 4
A further formulation was prepared by a similar process to the dioctyl sulfosuccinic acid
formulation processes in Example 1. This further formulation is detailed in the table below
and is referred to herein as “Formulation B”.
Percent of
COMPONENT particle mass
(nominal)
AZD1152 hqpa 10
PLA-PEG 16/5 85
Oleic acid 5
Example 5 – Therapeutic Index
Data generated in the SW620 human tumour xenograft model in rat and mouse.
The SW620–bearing female nude rat model is known to be susceptible to spontaneous
tumour regressions which are more prevalent in longer duration xenograft studies and are
not shown.
Rat therapeutic index studies (SW620 in female nude rat)
Female nude rats were bred at AstraZeneca, and put into study at a minimum
weight of 150 g. Animals were inoculated in the flank with SW620 human tumour cells
and dosing started when tumours had reached 0.4 – 0.9cm . Compounds were dosed
intravenously (IV) at 5ml/kg with either control, AZD1152 or AZD1152 hqpa nanoparticle
formulation B or E. AZD1152 was dosed in tris buffer vehicle (days 1-4 IV, each dose at
25mg/kg) and AZD1152 hqpa nanoparticle formulation was dosed in physiological saline
(dosed 25mg/kg on each of days 1 and 3 IV). At the time points indicated animals were
sacrificed and tumour, blood and femur/bone marrow samples taken. Effects of the
treatments on the tumour and the bone marrow were scored by a pathologist assessment of
haematoxylin and eosin stained sections derived from the femur.
Effects of AZD1152 and AZD1152 nanoparticle formulations B and E in the
tumour are characterized by the presence of enlarged polyploidy nuclei. Figure 6 shows
representative images of the tumour following treatment with each therapy from samples
obtained at day 5. Effects of AZD1152 and AZD1152 hqpa nanoparticle formulations B
and E on the bone marrow are characterized by the loss of cells from the bone marrow.
Figure 6 show representative images of the tumour following treatment with each therapy
from samples obtained at day 5.
Figure 6 shows that Formulation E, delivered at half the dose intensity of
AZD1152, has greater efficacy (A), induces a similar spectrum of tumour pathology
changes (B) yet spares bone marrow (C).
Mouse anti-tumour study (SW620 in male nude mouse)
Male nude mice were bred at AstraZeneca. Animals were inoculated in the flank
with SW620 human tumour cells, and then randomized onto study when tumours reached
approximately 0.25 cm . AZD1152 was dosed in tris buffer vehicle at the concentration
indicated. AZD1152 hqpa nanoparticle formulation E was dosed in physiological saline.
Previous pre-clinical work and methodologies with AZD1152 are published in Wilkinson
et al, Clinical Cancer Research 2007 (13) 3682.
Data generated in the SW620 human tumour xenograft model in rat and mouse
suggested that delivery of AZD1152 IV at 25mg/kg for 4 days give maximal efficacy
(100mg/kg total dose).
In the SW620 model in mouse, the nanoparticles from Example 3 demonstrated
equivalent efficacy to AZD1152 IV at 100mg/kg and this efficacy was achieved at lower
doses of only 25mg/kg as a single dose, or even 5mg/kg at day 1 and 3 (10mg/kg
equivalent) showing that efficacy may be delivered using a variety of different schedules
and much lower doses using the nanoparticulate formulation of AZD1152 hqpa than an IV
formulation of AZD1152.
Hence the claimed AZD1152 hqpa nanoparticulate formulation showed equivalent
or improved tumour efficacy when delivered at a lower dose intensity. This may result in
fewer side effects, for example less bone marrow toxicity.
Maximum activity was achieved with a 50mg/kg dose equivalent of AZD1152
hqpa nanoparticulate formulation versus 100mg/kg IV AZD1152. By using the
formulations of the present invention, it may be possible to provide more active ingredient
to the patient for the same adverse effects as previous maximum tolerated dose of
AZD1152 dosed IV. Thus the risk/benefit profile of the formulations of the present
invention might be improved.
Fig 7 shows data from efficacy/dose scheduling studies with Formulation E in SW620
xenograft in nude mouse. In this study AZD1152 was dosed on day 0-3 at 25mg/kg (total
100mg/kg). Formulation E was dosed at a variety of different schedules as described
above.
Example 6
In-vivo exposure was examined comparing AZD1152 IV (dosed 4x25mg/kg) days
1-4 IV) with Formulations B (dosed 2x 25mg/kg on days 1& 3 IV) and E (dosed 2x
25mg/kg days 1 and 3 IV) from the study in nude rats described in Example 5. The results
are shown (averaged value from several data points) in Figure 8. The concentrations
measured following the AZD1152 IV dose are for the drug AZD1152 hqpa.
The data show the total AZD1152 hqpa extracted from the sample (within the
nanoparticles and released from them) at the sampling point and thus show how long either
drug or encapsulated drug is still present in the body over this time course, ie the longevity
of exposure to the AZD1152 hqpa after dosing. The data show that a lower dose intensity
gave higher total drug concentration in blood, sustained for a longer period if delivered as a
nanoparticulate formulation rather than as intravenous active drug.
Summary of Bioanalytical Method to Measure Total Drug from In-vivo samples
dosed with Nanoparticles.
This is a multi step process which must be carried out on ice wherever possible to halt
further release of drug from the nanoparticles.
Total Drug Extraction method:
• Dissolve solid parent drug in DMSO to 2mM concentration.
• Aliquot 50 μl of each plasma samples, using appropriate dilution factor, into 96 well
plate.
• Prepare at standard calibration curve using the Hamilton Star Robot from the 2mM
stock in DMSO (see appendix 1 for preparation details)
• Add 150 μl of acetonitrile with internal standard.
• Shake the plate to mix the samples.
• Spin in centrifuge at 4500rpm for 10 minutes.
• Transfer 50 μl of supernantant to clean 96 well plate.
• Add 300 μl of water.
• Analyse via LC-MS/MS (liquid chromatography – mass spectrometry / tandem
mass spectrometry).
Appendix 1 – Standard Curve Preparation Details
The robot will first add suitable diluent into the microplate for the dilutions before serially
diluting the stocks from right to left in the microplate, one row per compound (see table A
below):
Volume of
Column of Final Volume of conc to DMSO diluent dilution
predilution plate conc µM be diluted µL µL factor
12 2000 - - -
11 200 25µL from Col. 12 225 10
100 125µL from Col. 11 125 2
9 40 100µL from Col.10 150 2.5
8 20 125µL from Col. 9 125 2
7 10 125µL from Col. 8 125 2
6 2 50µL from Col.7 200 5
1 125µL from Col. 6 125 2
4 0.4 100µL from Col. 5 150 2.5
3 0.2 125µL from Col. 4 125 2
2 0.1 125µL from Col. 3 125 2
1 0.02 50µL from Col. 2 200 5
Table A: showing the 11 dilutions from right to left (columns 12-1) of the dilution plate
for a 2mM starting stock in column 12 of the dilution microplate. 2.5µl from columns 1-11
are then spiked left to right into wells 2-12 of a matrix plate to result in an eleven point
curve (Table B).
Final Column of
Concentration Volume of Volume DMSO Working Plasma Prep
(nM) matrix (µL) spiked (µL) Solution (µM) plate
2.5µL
0 47.5 DMSO 1
1 47.5 2.5 0.02 2
47.5 2.5 0.1 3
47.5 2.5 0.2 4
47.5 2.5 0.4 5
50 47.5 2.5 1 6
100 47.5 2.5 2 7
500 47.5 2.5 10 8
1000 47.5 2.5 20 9
2000 47.5 2.5 40 10
5000 47.5 2.5 100 11
10000 47.5 2.5 200 12
Table B: Table demonstrating the calibration curve generated following the spiking of the
robot-generated dilution series. Columns 1-11 from Table A are spiked into columns 2-12
of the matrix plate to produce the eleven-point calibration curve as above
LC-MS/MS Parameters
Mass Spec Waters Xevo TQS (serial No.-186005453)
Column Phenomenex Kinetex C18 50 x 2.1, 2.6u
Solvent A 95% Water + 0.1 % Formic acid
Solvent B 95% MeOH + 0.1 % Formic acid
Gradient Time (min) % A %B
0 95 5
0.3 95 5
1.9 5 95
2.3 5 95
2.31 95 5
2.5 95 5
Flow 0.75 ml/min
Run time 2.5 min, use a divert valve for initial 0.3 minutes
Optimisation Parameters
Cone Retention
Ionisation Parent Daughter voltage Collison Time
Compound mode Polarity ion ion (v) Energy (min)
AZD1152 ESI Positive 588.941 491.13 20 16 1.07
AZD1152
hqpa ESI Positive 509.042 129.74 40 16 0.98
Compound
A ESI Positive 405.588 173.81 80 22 1.35
Compound A: 2-ethyl{[2'-(1H-tetrazolyl)biphenylyl]methoxy}quinoline (internal
standard). See for example WO92/02508 and WO92/13853.
Example 7 (Using a nominal 1g batch)
Pamoic acid nanoparticle procedure
Nanoparticles of AZD1152 hqpa with pamoic acid were prepared according to the process
set out below.
Composition (of formulation described herein after as formulation G1):
Component Weight Percent of the Molar Percent of the
Nanoparticle Nanoparticle
16/5 PLA-PEG 73.1% 5.8%
PLA 54.8% 4.4%
18.3% 1.5%
AZD1152 hqpa 17.0% 53.5%
Pamoic acid 9.9% 40.7%
7.1 Preparation of pamoic acid solution. A 29% (w/w) solution of pamoic acid in
DMSO was prepared by mixing 2.9 g of pamoic acid with 7.1 g of DMSO in a container.
The container was heated in a heating oven at 70-80 C until all of the pamoic acid was
dissolved.
7.2 Preparation of 8% TFA/7.5% water/84.5% benzyl alcohol (wt%) solution.
Trifluoroacetic acid (TFA) (3.2 g), deionized (DI) water (3.0 g), and benzyl alcohol (BA) (33.8
g) were combined to prepare the 8% TFA/7.5% water/84.5% benzyl alcohol (wt%) solution.
7.3 Buffer preparation:
To make 1000 ml of 0.17 M Phosphate (pKa2=7.2) Buffer: pH= 6.5, Formulate two stock
buffers: A. dissolve 13.26 g of Sodium phosphate monobasic, anhydrous NaH PO H O
2 4 2
(Mr = 119.98) in 650 ml of pure water and B. dissolve 10.82 g of Sodium phosphate
dibasic, anhydrous NaH PO (Mr = 141.96) in 650 ml of pure water. Add buffer B to
buffer A while mixing until the pH = 6.50 at the lab temperature of 25°C.
Alternative:
To make 1000ml of 0.17 M sodium phosphate buffer at pH 6.5: Into ~800ml of DI water,
dissolve 16.26g of sodium phosphate monobasic, dihydrate (NaH2PO4-2H20; FW=156.01)
and 11.70g of sodium phosphate dibasic, dihydrate (Na HPO -2H 0; FW=177.99) and add
2 4 2
sufficient extra water to make 1000ml, at the lab temperature of 25°C.
7.4 Preparation of polymer solution
• To 20mL glass vial add polymer-PEG, 700mg
• Add 7078 mg of ethyl acetate to glass vial and vortex overnight to give a
polymer-EA solution.
7.5 Preparation of Aqueous Solution:
• 0.12% Brij®100, 4% Benzyl Alcohol in Water
• To 1L bottle add 1.2g Brij®100 and 958.8g of DI water and mix on stir
plate until dissolved.
• Add 40g of benzyl alcohol to Brij®/water and mix on stir plate until
dissolved.
7.6 Preparation of drug solution
• Weigh 300mg of AZD1152 hqpa in 20ml scintillation vial
• Add 2399mg of above 8% TFA/7.5% water/BA solution to AZD1152
• Add 634mg of above 29% pamoic/DMSO solution to the drug solution and
vortex to get clear drug solution
• Right before formulation, combine drug and polymer solution.
7.7 Formation of emulsion. Ratio of Aqueous phase to Organic phase is 5:1
• Pour organic phase into aqueous solution and homogenize using hand-held
rotor/stator homogenizer for 10 seconds at room temperature to form coarse
emulsion. Store in ice for 10-15 minutes.
• Feed solution through high pressure homogenizer (110S) with pressure set
at ~9000 psi on compressed air inlet gauge for 1 discreet passes to form
nanoemulsion
Formation of nanoparticles
• Pour emulsion into Quench (0.17M Sodium phosphate, pH 6.5) at <5C
while stirring on stir plate. Ensure at least 5 minutes has passed since the
beginning of collection, before quenching. Ratio of Quench to Emulsion is
10:1
• Add 35% (w/w) Tween® 80 in water to quench at ratio of 100:1 Tween®
80 to drug by weight.
• Concentrate nanoparticles through tangential flow filtration (TFF)
• Concentrate quench on TFF with 300kDa Pall cassette (3x 0.1 m
membranes) to ~200mL.
• Diafilter ~20 diavolumes (4 liter) using cold DI water.
• Bring volume down to minimal volume
• Add 100mL of cold water to vessel and pump through membrane to rinse.
• Collect material in glass vial, ~100mL
7.8 Determination of solids concentration of unfiltered final slurry:
• To tared 20mL scintillation vial add a volume of final slurry and dry under
vacuum on lyo/oven.
• Determine weight of nanoparticles in the volume of slurry dried down
7.9 Determination of solids concentration of 0.45µm filtered final slurry:
• Filter a portion of the final slurry sample before addition of sucrose through
0.45µm syringe filter
• To tared 20mL scintillation vial add a volume of filtered sample and dry
under vacuum on lyo/oven.
7.10 Add 1 part of sucrose to final 9 parts of slurry sample to attain 10% sucrose.
7.11 Freeze remaining sample of unfiltered final slurry with sucrose
Figure 9 shows representative AZD1152 hqpa in vitro release demonstrating controlled
and slow/sustained release of drugs from pamoic acid nanoparticles compared to that from
baseline nanoparticles without pamoic acid counter-ions (made as described for control
formulations in Example 2).
Another pamoic acid formulation, referred to hereinafter as formulation G2 was prepared
as follows: (Using a nominal 1g batch)
Composition:
Component Weight Percent of the Molar Percent of the
Nanoparticle Nanoparticle
16/5 PLA-PEG 67.7% 4.5%
PLA 50.7% 3.4%
16.9% 1.1%
AZD1152 hqpa 19.4% 51.1%
Pamoic acid 12.9% 44.4%
Example 7a
7a.1 Preparation of pamoic acid solution. A 29% (w/w) solution of pamoic acid in
DMSO was prepared by mixing 2.9 g of pamoic acid with 7.1 g of DMSO in a container.
The container was heated in a heating oven at 70-80 C until all of the pamoic acid was
dissolved.
7a.2 Preparation of 8% TFA/7.5% water/84.5% benzyl alcohol (wt%) solution.
Trifluoroacetic acid (TFA) (3.2 g), deionized (DI) water (3.0 g), and benzyl alcohol (BA) (33.8
g) were combined to prepare the 8% TFA/7.5% water/84.5% benzyl alcohol (wt%) solution.
7a.3 Buffer preparation:
To make 1000 ml of 0.17 M Phosphate (pKa2=7.2) Buffer: pH= 6.5, Formulate two stock
buffers: A. dissolve 13.26 g of Sodium phosphate monobasic, anhydrous NaH PO H O
2 4 2
(Mr = 119.98) in 650 ml of pure water and B. dissolve 10.82 g of Sodium phosphate
dibasic, anhydrous NaH PO (Mr = 141.96) in 650 ml of pure water. Add buffer B to
buffer A while mixing until the pH = 6.50 at the lab temperature of 25°C.
Alternative:
To make 1000ml of 0.17 M sodium phosphate buffer at pH 6.5: Into ~800ml of DI water,
dissolve 16.26g of sodium phosphate monobasic, dihydrate (NaH PO -2H 0; FW=156.01)
2 4 2
and 11.70g of sodium phosphate dibasic, dihydrate (Na HPO -2H 0; FW=177.99) and add
2 4 2
sufficient extra water to make 1000ml, at the lab temperature of 25°C.
7a.4 Preparation of polymer solution
• To 20mL glass vial add polymer-PEG, 700mg
• Add 6572 mg of ethyl acetate to glass vial and vortex overnight to give a
polymer-EA solution.
7a.5 Preparation of Aqueous Solution:
• 0.15% Brij®100, 4% Benzyl Alcohol in Water
• To 1L bottle add 1.5g Brij®100 and 958.5g of DI water and mix on stir
plate until dissolved.
• Add 40g of benzyl alcohol to Brij®/water and mix on stir plate until
dissolved.
7a.6 Preparation of drug solution
• Weigh 300mg of AZD1152 hqpa in 20ml scintillation vial
• Add 2746 mg of above 8% TFA/7.5% water/BA solution to AZD1152
• Add 792mg of above 29% pamoic/DMSO solution to the drug solution and
vortex to get clear drug solution
• Right before formulation, combine drug and polymer solution.
7a.7 Formation of emulsion. Ratio of Aqueous phase to organic phase is 5:1
• Pour organic phase into aqueous solution and homogenize using hand-held
rotor/stator homogenizer for 10 seconds at room temperature to form coarse
emulsion. Store in ice for 10 minutes.
• Feed solution through high pressure homogenizer (110S) with pressure set
at ~9000 psi on compressed air inlet gauge for 1 discreet passes to form
nanoemulsion
Formation of nanoparticles
• Immediately pour emulsion into Quench (0.17M Sodium phosphate, pH
6.5) at <5°C while stirring on stir plate. Ratio of Quench to Emulsion is
:1
• Add 35% (w/w) Tween® 80 in water to quench at ratio of 100:1 Tween®
80 to drug by weight.
• Concentrate nanoparticles through tangential flow filtration (TFF)
• Concentrate quench on TFF with 300kDa Pall cassette (3x 0.1 m
membranes) to ~200mL.
• Diafilter ~20 diavolumes (4 liter) using cold DI water.
• Bring volume down to minimal volume
• Add 100mL of cold water to vessel and pump through membrane to rinse.
• Collect material in glass vial, ~100mL
7a.8 Determination of solids concentration of unfiltered final slurry:
• To tared 20mL scintillation vial add a volume of final slurry and dry under
vacuum on lyo/oven.
• Determine weight of nanoparticles in the volume of slurry dried down
7a.9 Determination of solids concentration of 0.45µm filtered final slurry:
• Filter a portion of the final slurry sample before addition of sucrose through
0.45µm syringe filter
• To tared 20mL scintillation vial add a volume of filtered sample and dry
under vacuum on lyo/oven.
7a.10 Add 1 part of sucrose to final 9 parts of slurry sample to attain 10% sucrose by
weight.
7a.11 Freeze remaining sample of unfiltered final slurry with sucrose
Example 7b
A further process to make a formulation G1 (nominal 1g batch) is described below:
7b.1 Preparation of pamoic acid solution. A 29% (w/w) solution of pamoic acid in
DMSO was prepared by mixing 2.9 g of pamoic acid with 7.1 g of DMSO in a container.
The container was heated in a heating oven at 70-80 C until all of the pamoic acid was
dissolved.
7b.2 Preparation of 8% TFA/7.5% water/84.5% benzyl alcohol (wt%) solution.
Trifluoroacetic acid (TFA) (3.2 g), deionized (DI) water (3.0 g), and benzyl alcohol (BA) (33.8
g) were combined to prepare the 8% TFA/7.5% water/84.5% benzyl alcohol (wt%) solution.
7b.3 Buffer preparation:
To make 1000 ml of 0.17 M Phosphate (pKa2=7.2) Buffer: pH= 6.5, Formulate two stock
buffers: A. dissolve 13.26 g of Sodium phosphate monobasic, anhydrous NaH PO H O
2 4 2
(Mr = 119.98) in 650 ml of pure water and B. dissolve 10.82 g of Sodium phosphate
dibasic, anhydrous NaH PO (Mr = 141.96) in 650 ml of pure water. Add buffer B to
buffer A while mixing until the pH = 6.50 at the lab temperature of 25°C.
Alternative:
To make 1000ml of 0.17 M sodium phosphate buffer at pH 6.5: Into ~800ml of DI water,
dissolve 16.26g of sodium phosphate monobasic, dihydrate (NaH PO -2H 0; FW=156.01)
2 4 2
and 11.70g of sodium phosphate dibasic, dihydrate (Na2HPO4-2H20; FW=177.99) and add
sufficient extra water to make 1000ml, at the lab temperature of 25°C.
7b.4 Preparation of polymer solution
• To 20mL glass vial add polymer-PEG, 591.3mg
• Add 5978.6 mg of ethyl acetate to glass vial and vortex overnight to give a
polymer-EA solution.
7b.5 Preparation of Aqueous Solution:
• 0.12% Brij®100, 4% Benzyl Alcohol, 5.7% DMSO in Water
• To 1L bottle add 1.4g Brij® 100, and 901.6g of DI water and mix on stir
plate until dissolved.
• Add 40g of benzyl alcohol and 57g of DMSO to Brij®/water and mix on
stir plate until dissolved.
7b.6 Preparation of drug solution
• Weigh 253.4mg of AZD1152 hqpa in 20ml scintillation vial
• Add 2026.8mg of above 8% TFA/7.5% water/BA solution to AZD1152
• Add 535.5mg of above 29% pamoic/DMSO solution to the drug solution
and vortex to get clear drug solution
• Right before formulation, combine drug and polymer solution.
7b.7 Formation of emulsion. Ratio of Aqueous phase to organic phase is 5.5:1
• Pour organic phase into aqueous solution and homogenize using hand-held
rotor/stator homogenizer for 10 seconds at room temperature to form coarse
emulsion. Store in ice for 10-15 minutes.
• Feed solution through high pressure homogenizer (110S) with pressure set
at ~9,000 psi on compressed air inlet gauge for 1 discreet passes to form
nanoemulsion
Formation of nanoparticles
• Pour emulsion into Quench (0.17M Sodium phosphate, pH 6.5) at <5 °C
while stirring on stir plate. Ensure at least 5 minutes has passed since the
beginning of collection, before quenching. Ratio of Quench to Emulsion is
3:1 by weight.
• Add 35% (w/w) Tween® 80 in water to quench at ratio of 20:1 Tween® 80
to drug by weight.
• Concentrate nanoparticles through tangential flow filtration (TFF)
• Concentrate quench on TFF with 300kDa Pall cassette (3x 0.1 m
membranes) to ~200mL.
• Diafilter ~20 diavolumes (4 liter) using ambient temperature DI water.
• Bring volume down to minimal volume
• Add 100mL of DI water to vessel and pump through membrane to rinse.
• Collect material in glass vial, ~100mL
7b.8 Determination of solids concentration of unfiltered final slurry:
• To tared 20mL scintillation vial add a volume of final slurry and dry under
vacuum on lyo/oven.
• Determine weight of nanoparticles in the volume of slurry dried down.
7b.9 Determination of solids concentration of 0.45µm filtered final slurry:
• Filter a portion of the final slurry sample before addition of sucrose through
0.45µm syringe filter
• To tared 20mL scintillation vial add a volume of filtered sample and dry
under vacuum on lyo/oven.
7b.10 Add 1 part of sucrose to final 9 parts of unfiltered slurry sample to attain 10%
sucrose by weight.
7b.11 Freeze remaining sample of unfiltered final slurry with sucrose
Example 8: Comparison of Formulations E, F1 and F2
Formulation E was described in Example 3. Formulations F1 and F2 were described in
Example 2.
In-vivo exposure
Figure 10 shows a comparison of in-vivo exposure in rat for formulations E, F1 and F2.
The experiments were carried out as single doses of 25mg/kg in rats and analysed by an
analogous method to that described in Example 6.
In-vivo efficacy data
The data shown in Figure 11 show that Formulations E, F1 and F2 give equivalent efficacy
following short term dosing in of nude rats with established SW620 tumour xenografts.
The experiments were carried out according to the methods as described in Example 5.
Rats bearing SW620 tumours were dosed with AZD1152 at 25mg/kg daily for 4 days, or
Formulation E, F1 and F2 at 25mg/kg on days 0 and 2. Formulation E, F1 and F2 gave
equivalent efficacy. Efficacy was equivalent to AZD1152 and comparable to that seen in
previous studies with AZD1152 and Formulation E at this time point. The study was
terminated at day 9 to enable analysis of tumour pharmacodymanic markers and bone
marrow. These data demonstrate that formulations E, F1 and F2 give equivalent efficacy.
Comparison of nanoparticle Formulations E, F1 and F2 on tumour phospho-histone
H3 biomarkers
This experiment compares the effect of Formulation E, F1 and F2 on a phospho-histone H3
phosphorylation (pHH3) in SW620 tumours. AZD1152 was included as a positive control.
The activity was measured as an inhibition of histone H3 phosphorylation on Ser (pHH3
as a sensitive, highly dynamic surrogate marker of Aurora B kinase activity). Average
level of pHH3 positivity [%] was calculated for the cells in G2/M phase of the cell cycle
for each treatment group at 24 hrs and 96 hrs post 1 dose and compared to the pHH3 level
observed for the cells in G2/M cell cycle phase that were extracted from the tumours
treated with BIND Placebo (referred here as 100%). Statistical significance was calculated
using Student t-test assuming unequal variances (*p<0.05 , ** p<0.01, *** p<001, n.s.
P>0.05).
Formulations (Formulation E, F1 and F2) were dosed as described above to SW620
colon xenografts established in nude female rats. Rats were injected IV with BIND
Placebo (0mg/kg), or AZD1152 or AZD1152 hqpa Formulation E/F1/F2 at 25mg/kg on
st st
day 1, and terminated on day 2 (24 hrs post 1 dose) or on day 5 (96 hrs post 1 dose).
Frozen tumours were disaggregated using Medimachine (BD Biosystems), fixed with 80%
ethanol for a minimum of 12 hrs and prepared for DNA content (PI staining) and pHH3
analysis by flow cytometry using BD FACSCanto analyser (pHH3 primary antibody:
Millipore 06-570; secondary antibody: FITC Anti rabbit IgG fluorescein conjugated
secondary antibody Millipore AP307F) as previously described by Wilkinson, RW et al.,
Clin Cancer Res, 2007; 13(12).
Figure 12 shows that the proportion of pHH3-positive cells within the G2/M phase
of the cell cycle was maximally suppressed by AZD1152 at 24 hours. Tumours exposed to
Formulations E or F1, F2 showed less reduction in pHH3 at 24 hrs post single dose
compared with animals receiving AZD1152. At 96 hours levels of pHH3 reduction were
comparable across all groups.
These data show that Formulations E, F1 and F2 give equivalent suppression of
pHH3 and hence Aurora kinase B activity over a single dose time course.
Effects of Formulations E, F1 and F2 on bone marrow.
This example shows the effects of the Formulations on the bone marrow assessed
by two independent measures.
Rats were injected IV with BIND Placebo (0mg/kg), or AZD1152/AZD1152 hqpa
Formulation E/F1/F2 at 25mg/kg at the times indicated and sacrificed at the times
indicated.
Bone marrows samples were extracted from each animal. Firstly samples of bone
marrow were processed for pathological assessment. Femuro-tibial joints were taken to
% Buffered Formalin, decalcified using standard procedures, paraffin embedded and
stained with haemotoxylin and eosin. Pathological assessment of bone marrow hypo-
cellularity was carried out by a pathologist (Figure 13). Bone marrow integrity was scored
by the pathologist. A bone marrow hypocellularity score was generated based on a scoring
system of 0-4, with 0 representing no bone marrow effect and 4 representing maximal
effect on the bone marrow. The figures show the Median, the 95% confidence intervals
and the range for each group of animals at day 5 and 9. The data show that while
AZD1152 has a large impact on bone marrow, each of the tested nanoparticulate
formulations of AZD1152 hqpa show equivalent minimal effects on bone marrow.
Secondly bone marrow flushes taken to examine bone marrow cellularity by
FACs. At termination bone marrow from each Femur was taken into 50% FBS and 50%
PBS on ice. Cells were pelleted by centrifugation at 4°C and re-suspended in PBS. Cells
were pelleted again at 4°C and re-suspended in PBS. 50 μl of LDS-751 (0.5mg/ml in
methanol) was added and cells vortexed. Finally the cells were filtered through a
50micron filter into a FACS tube. Samples were analysed on a FACS Canto (Beckton
Dickinson). The results are shown in Figure 14. A bone marrow hypocellularity is
represented as a total of nucleated cells relative to untreated controls. The percentage
cellularity of each bone marrow sample in each individual animal are shown. The dotted
line represents the lowest percentage total nucleated cell value seen in animals receiving
only vehicle (empty nanoparticle). The results show that while AZD1152 has a large
impact on bone marrow, each of the tested nanoparticulate formulations of AZD1152 hqpa
show equivalent minimal effects on bone marrow.
Example 9: data for Formulations G
Comparison of nanoparticle Formulations G1 and G2 on tumour phospho-histone
H3 biomarkers
This experiment compares the effect of Formulation G1 and G2 on a phospho-
histone H3 phosphorylation (pHH3) in SW620 tumours. AZD1152 was included as a
positive control.
The activity was measured as an inhibition of histone H3 phosphorylation on Ser10
(pHH3 as a sensitive, highly dynamic surrogate marker of Aurora B kinase activity).
Average level of pHH3 positivity [%] was calculated for the cells in G2/M phase of the
cell cycle for each treatment group at 24, 48, 72, 96 and 120 hrs post 1 dose and compared
to the pHH3 level observed for the cells in G2/M cell cycle phase that were extracted from
the tumours treated with BIND Placebo (referred here as 100%).
Formulations (Formulation G1 and G2) were dosed as described above to SW620
colon xenografts established in nude female rats. Rats were injected IV with BIND
Placebo (0mg/kg), or AZD1152 or AZD1152 hqpa Formulation G1 or G2 at 25mg/kg on
st st
day 1, and terminated on day 2 (24 hrs post 1 dose), day 3 (48 hrs post 1 dose), day 4 (72
st st st
hrs after 1 dose), day 5 (96 hrs post 1 dose) and day 6 (120 hrs post 1 dose). Frozen
tumours were disaggregated using Medimachine (BD Biosystems), fixed with 80% ethanol
for a minimum of 12 hrs and prepared for DNA content (PI staining) and pHH3 analysis by
flow cytometry using BD FACSCanto analyser (pHH3 primary antibody: Millipore 06-
570; secondary antibody: FITC Anti rabbit IgG fluorescein conjugated secondary antibody
Millipore AP307F) as previously described by Wilkinson, RW et al., Clin Cancer
Res,2007; 13(12).
Figure 15 shows that the proportion of pHH3-positive cells within the G2/M phase
of the cell cycle was maximally suppressed by AZD1152 at 24 hours. Tumours exposed to
Formulations G1 or G2 showed less reduction in pHH3 at 24 hrs post single dose
compared with animals receiving AZD1152. Maximum reduction in pHH3 activity occurs
between 72 and 120 hrs after the 1 dose of formulations G1 or G2. These data show that
Formulations G1 and G2 suppression pHH3 and hence Aurora kinase B activity over a
single dose time course.
Effects of Formulations G1 and G2 on bone marrow.
This example shows the effects of the Formulations on the bone marrow.
Rats were injected IV with BIND Placebo (0mg/kg), or AZD1152 hqpa
Formulation G1 or G2 at 25mg/kg on days 1 and day 3 and sacrificed at the times
indicated.
Bone marrow samples were extracted from each animal and processed for
pathological assessment. Femuro-tibial joints were taken to 10% Buffered Formalin,
decalcified using standard procedures, paraffin embedded and stained with haemotoxylin
and eosin. Pathological assessment of bone marrow hypo-cellularity was carried out by a
pathologist (Figure 16). Bone marrow integrity was scored by the pathologist. A bone
marrow hypocellularity score was generated based on a scoring system of 0-4, with 0
representing no bone marrow effect and 4 representing maximal effect on the bone
marrow. The figures show the scores for individual animals in each group of animals at
day 5 and 9. The data show that each of the tested nanoparticulate formulations of
AZD1152 hqpa show minimal to mild hypocellularity of the bone marrow at day 5 which
has returned to similar levels as the BIND placebo by day 9.
U2932 diffuse large B cell xenograft efficacy study
Female scid mice were bred at Charles River. Animals were inoculated in the flank
with U2932 human tumour cells, and then randomized onto study when tumours reached
approximately 0.25 cm . AZD1152 was dosed in tris buffer vehicle at the concentration
indicated. AZD1152 hqpa nanoparticle formulation G1 was dosed in physiological saline.
In the U2932 model in mouse, the nanoparticle formulation G1 demonstrated equivalent
efficacy to AZD1152 IV at a total dose of 100mg/kg and this efficacy was achieved at the
lower total dose of only 50mg/kg showing that lower doses of the nanoparticulate
formulation of AZD1152 hqpa are equivalent to an IV formulation of AZD1152.
Figure 17 shows data from an efficacy study with Formulation G1 in U2932
xenograft in the scid mouse. Mice bearing U2932 tumours were dosed intravenously with
AZD1152 at 25mg/kg daily on days 26-30 post tumour implant (total dose 100mg/kg), or
Formulation G1 25mg/kg on days 26 and 28 post tumour implant (total dose 50mg/kg).
This data demonstrate that formulation G1 gives equivalent efficacy to AZD1152 at only
half the dose.
SC-61 SCLC patient derived explant efficacy study
Female nude mice were bred at Harlan. Animals were inoculated in the flank with
SC-61 human tumour fragments, and then randomized onto study when tumours reached
approximately 0.2 cm . AZD1152 was dosed in tris buffer vehicle at the concentration
indicated. AZD1152 hqpa nanoparticle formulation G1 was dosed in physiological saline.
In the SC-61 model in mouse, the nanoparticle formulation G1, at a total dose of 50mg/kg
demonstrated equivalent efficacy to AZD1152 IV at a total dose of 100mg/kg.
Figure 18 shows data from an efficacy study with Formulation G1 in SC-61
patient-derived explant in the nude mouse. Mice bearing SC-61 tumours were dosed
intravenously with AZD1152 at 25mg/kg daily on days 0-3 post randomization (total dose
100mg/kg), or Formulation G1 25mg/kg on days 0 and 2 post tumour randomisation (total
dose 50mg/kg).
This data demonstrate that formulation G1, at only half the dose, gives longer
tumour control than AZD1152 in this model.
In-vivo exposure of Formulations G1 and G2
Figure 19 shows in-vivo exposure data for Formulations G1 and G2, superimposed
on those for Formulations E and F from Figure 10. All data were generated from a single
dose of the relevant formulation at 25mg/kg in rat and analysed by an analogous method to
that decribed in Example 6. Figures 19a-19e show each of the individual data lines
separately.
Example 10: Suitable HPLC conditions for measuring in-vitro release
Instrument parameters
Flow rate 0.300 mL/min
Sample loop 20 µL
Injection volume 5 µL
Autosampler Temperature 5°C
Column Temperature 30°C
Detector wavelength 240 nm
Sampling rate 20 points/second
Run time 8 min
Pump Gradient Program
Time Mobile Mobile Gradient
Phase A (%) Phase B (%) Slope
0.0 85 15 6
4.0 80 20 6
.0 50 50 6
6.0 15 85 6
6.1 85 15 6
8 85 15 6
Mobile Phase-A: 0.10% TFA in water: Fill a 2-L glass media bottle with 2 L purified
water. Add 2.0 ± 0.1 mL of TFA and mix.
Mobile Phase-B: 0.08% TFA in acetonitrile: Fill a 2L glass media bottle with 2L
acetonitrile. Add 1.6 ± 0.1 mL of TFA and mix.
HPLC Column: Waters Acquity CSH C18, 2.1 x 150 mm, 3µm (P/N 186005298)
Example 11
Batch data for 3 batches of Formulations G1 containing pamoic acid are shown below.
Particle size was measured by dynamic light scattering.
Lot AZD1152 hqpa Load Mean Particle size
Pamoic: AZD1152
(%) (nm)
hqpa ratio
A 17.0 87.9 0.76
B 19.9 98.4 0.60
C 19.0 85.1 0.73
Mean 18.6 90.5 0.70
Std 1.5 7.0 0.09
+3 STD 23.1 111.5 0.95
-3 STD 14.2 69.4 0.44
In-vitro release profiles at 37 ºC for these batches are shown in Figure 20.
EQUIVALENTS
Those skilled in the art will recognize, or be able to ascertain using no more than routine
experimentation, many equivalents to the specific embodiments of the invention described
herein. Such equivalents are intended to be encompassed by the following claims.
INCORPORATION BY REFERENCE
The entire contents of all patents, published patent applications, websites, and other
references cited herein are hereby expressly incorporated herein in their entireties by
reference.
Claims (31)
1. A therapeutic nanoparticle comprising 2-(3-((7-(3-(ethyl(2- hydroxyethyl)amino)propoxy)-quinazolinyl)amino)-1H-pyrazolyl)-N-(3- fluorophenyl)acetamide (AZD1152 hqpa), further comprising: 5 50 to 99.75 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the therapeutic nanoparticle comprises 10 to 30 weight percent poly(ethylene)glycol, and wherein the therapeutic nanoparticle comprises a substantially hydrophobic acid. 10
2. The therapeutic nanoparticle of claim 1, wherein the poly(lactic) acid- poly(ethylene)glycol copolymer has a number average molecular weight of 15kDa to 20kDa poly(lactic acid) and a number average molecular weight of 4kDa to 6kDa poly(ethylene)glycol. 15
3. The therapeutic nanoparticle of claim 1 or 2, wherein the poly(lactic) acid- poly(ethylene)glycol copolymer has a number average molecular weight of 16kDa poly(lactic acid) and a number average molecular weight of 5kDa poly(ethylene)glycol.
4. The therapeutic nanoparticle of any one of claims 1-3, comprising 60 weight 20 percent to 85 weight percent of the copolymer.
5. The therapeutic nanoparticle of any one of claims 1-4, further comprising 5 to 15 weight percent of a substantially hydrophobic acid. 25
6. The therapeutic nanoparticle of any one of claims 1-5, wherein the hydrophobic acid is deoxycholic acid, cholic acid or a mixture thereof.
7. The therapeutic nanoparticle of any one of claims 1-5, wherein the hydrophobic acid is dioctyl sulfosuccinic acid.
8. The therapeutic nanoparticle of any one of claims 1-5, wherein the hydrophobic acid is pamoic acid.
9. The therapeutic nanoparticle of any one of claims 1-8, wherein the molar ratio of the substantially hydrophobic acid to AZD1152 hqpa is 0.5:1 to 1.6:1. 5
10. The therapeutic nanoparticle of any one of claims 1-9, comprising 5 to 30 weight percent of AZD1152 hqpa.
11. The therapeutic nanoparticle of any one of claims 1-10, comprising 15 to 22 weight percent of AZD1152 hqpa.
12. The therapeutic nanoparticle of any one of claims 1-11 which has a hydrodynamic diameter of 70-140 nm.
13. A therapeutic nanoparticle of claim 1 comprising 55 to 85 weight percent of 15 diblock poly(lactic)acid-poly(ethylene)glycol copolymer, wherein the therapeutic nanoparticle comprises 10 to 30 weight percent poly(ethylene)glycol, 5 to 20 weight percent of the hydrophobic acid and the hydrophobic acid is pamoic acid, and 10 to 25 weight percent of AZD1152 hqpa. 20
14. The therapeutic nanoparticle as claimed in claim 13, wherein the poly(lactic) acid- poly(ethylene)glycol copolymer has a number average molecular weight of 15kDa to 20kDa poly(lactic acid) and a number average molecular weight of 4kDa to 6kDa poly(ethylene)glycol. 25
15. The therapeutic nanoparticle of claim 14, wherein the poly(lactic) acid- poly(ethylene)-glycol copolymer has a number average molecular weight of 16kDa poly(lactic acid) and a number average molecular weight of 5kDa poly(ethylene)glycol.
16. The therapeutic nanoparticle of any one of claims 13-15, comprising 15 to 22 30 weight percent of AZD1152 hqpa.
17. A therapeutic nanoparticle as claimed in claim 13 comprising 15 to 25 weight percent of AZD1152 hqpa, 7 to 15 weight percent of pamoic acid, and a diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the therapeutic nanoparticle comprises 10 to 30 weight percent poly(ethylene)glycol and the poly(lactic) acid- 5 poly(ethylene)glycol copolymer has a number average molecular weight of 16kDa poly(lactic acid) and a number average molecular weight of 5kDa poly(ethylene)glycol).
18. A therapeutic nanoparticle as claimed in claim 13 comprising 15 to 22 weight percent of AZD1152 hqpa, 7 to 10 weight percent of pamoic acid, and a diblock 10 poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the therapeutic nanoparticle comprises 10 to 30 weight percent poly(ethylene)glycol and the poly(lactic) acid- poly(ethylene)glycol copolymer has a number average molecular weight of 16kDa poly(lactic acid) and a number average molecular weight of 5kDa poly(ethylene)glycol); wherein less than 20% of the AZD1152 hqpa is released from the nanoparticle after 30 15 hours in PBS and polysorbate20 at 37ºC.
19. A therapeutic nanoparticle as claimed in claim 13 comprising 15 to 22 weight percent of AZD1152 hqpa, 7 to 10 weight percent of pamoic acid, and a diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the therapeutic nanoparticle 20 comprises 10 to 30 weight percent poly(ethylene)glycol and the poly(lactic) acid- poly(ethylene)glycol copolymer has a number average molecular weight of 16kDa poly(lactic acid) and a number average molecular weight of 5kDa poly(ethylene)glycol); wherein less than 20% of the AZD1152 hqpa is released from the nanoparticle after 30 hours in PBS and polysorbate20 at 37ºC, and wherein the nanoparticles are made by a 25 process comprising the following steps: 1) combining a first organic phase which comprises a 16:5 PLA-PEG co-polymer, AZD1152 hqpa and pamoic acid in a solvent mixture comprising TFA, benzyl alcohol, DMSO and ethyl acetate such that the benzyl alcohol: ethyl acetate are present in a molar ratio of 1:3.6 and the pamoic acid and AZD1152 hqpa are added at an initial ratio of 0.8 30 moles pamoic acid: 1 mole AZD1152 hqpa; with a first aqueous solution comprising a polyoxyethylene (100) stearyl ether in water, DMSO and benzyl alcohol to form a second phase, wherein the ratio of the aqueous phase to the organic phase is 5.5:1; 2) emulsifying the second phase to form a coarse emulsion; 3) holding the coarse emulsion for a hold time (such as 10 to 15 minutes, conveniently at 0 ºC for example by immersing in an ice-bath); 4) forming a nano-emulsion using a high pressure homogenizer; 5 5) optionally waiting for a delay time of at least 5 minutes, for example 10 minutes; 6) quenching of the emulsion phase at 0-5 ºC thereby forming a quenched phase, wherein quenching of the emulsion phase comprises mixing the emulsion phase with a second aqueous solution comprising a buffer at pH 6.5, wherein the ratio of second aqueous solution to emulsion is between 2:1 and 10:1, such as 3:1; 10 7) adding an aqueous surfactant solution to the quench solution; 8) concentrating and isolating the resulting nanoparticles by filtration.
20. A therapeutic nanoparticle as claimed in claim 13 comprising 15-19 wt% of AZD1152 hqpa, pamoic acid in a molar ratio of 0.76 relative to the AZD1152 hqpa, and a 15 di-block poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the poly(lactic) acid- poly(ethylene)glycol copolymer has a number average molecular weight of 16kDa poly(lactic acid) and a number average molecular weight of 5kDa poly(ethylene)glycol.
21. A therapeutic nanoparticle as claimed in claim 15, wherein the therapeutic 20 nanoparticle releases less than 20% of AZD1152 hqpa after 30 hours in phosphate buffer solution and polysorbate20 at 37ºC.
22. The therapeutic nanoparticle of any one of claims 13-21 which has a hydrodynamic diameter of 70-140 nm.
23. A pharmaceutically acceptable composition comprising a plurality of therapeutic nanoparticles of any one of claims 1-22 and one or more pharmaceutically acceptable excipients, diluents and/or carriers. 30
24. The use of the therapeutic nanoparticle of any one of claims 13-22 in the manufacture of a medicament for the treatment of cancer.
25. The use of claim 24, wherein the cancer is lung cancer, colorectal cancer or a haematological cancer.
26. The use of claim 25 wherein the haematological cancer is selected from acute 5 myeloid leukemia or diffuse large B-cell leukemia.
27. A combination suitable for use in the treatment of cancer comprising a pharmaceutically acceptable composition as claimed in claim 23 and another anti-tumour agent.
28. A combination as claimed in claim 27 wherein the other anti-tumour agent is selected from: a) standard-of-care chemotherapy regimens including replacing or augmenting anti- mitotic chemotherapies in solid tumour and haematological cancers; 15 b) therapies that target the DNA damage response; and c) immune mediated therapies.
29. A combination as claimed in claim 28 wherein the other anti-tumour agent is selected from: 20 a) taxeanes and vinca alkaloids; b) agents that inhibit DNA damage repair and the cell cycle; and c) inhibitors of the immune checkpoint blockade.
30. A combination as claimed in claim 29 wherein c) the inhibitor of the immune 25 checkpoint blockade is selected from CTLA4, PD-1 and PDL-1 targeted therapies.
31. A kit of parts comprising: a) a lyophilized pharmaceutical composition comprising disclosed nanoparticles as claimed in any one of claims 13 to 22; and 30 b) instructions for use.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361878227P | 2013-09-16 | 2013-09-16 | |
US61/878,227 | 2013-09-16 | ||
US201461939332P | 2014-02-13 | 2014-02-13 | |
US61/939,332 | 2014-02-13 | ||
PCT/GB2014/052787 WO2015036792A1 (en) | 2013-09-16 | 2014-09-12 | Therapeutic polymeric nanoparticles and methods of making and using same |
Publications (2)
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NZ717615A NZ717615A (en) | 2021-08-27 |
NZ717615B2 true NZ717615B2 (en) | 2021-11-30 |
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