U.S. patent application number 15/153807 was filed with the patent office on 2016-09-01 for novel methods.
This patent application is currently assigned to XSPRAY MICROPARTICLES AB. The applicant listed for this patent is XSPRAY MICROPARTICLES AB. Invention is credited to Magnus BRISANDER, Mustafa DEMIRBUKER, Helene DERAND, Gerald JESSON, Martin MALMSTEN.
Application Number | 20160250153 15/153807 |
Document ID | / |
Family ID | 48781736 |
Filed Date | 2016-09-01 |
United States Patent
Application |
20160250153 |
Kind Code |
A1 |
BRISANDER; Magnus ; et
al. |
September 1, 2016 |
NOVEL METHODS
Abstract
The present invention relates to the field of methods for
providing components of pharmaceutical compositions comprising
poorly water-soluble drugs. In particular the present invention
relates to methods for providing stable, amorphous hybrid
nanoparticles, comprising at least one protein kinase inhibitor and
at least one polymeric stabilizing and matrix-forming component,
useful in pharmaceutical compositions.
Inventors: |
BRISANDER; Magnus; (Ekero,
SE) ; DEMIRBUKER; Mustafa; (Jarfalla, SE) ;
JESSON; Gerald; (Knivsta, SE) ; MALMSTEN; Martin;
(Hollviken, SE) ; DERAND; Helene; (Hollviken,
SE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
XSPRAY MICROPARTICLES AB |
Solna |
|
SE |
|
|
Assignee: |
XSPRAY MICROPARTICLES AB
Solna
SE
|
Family ID: |
48781736 |
Appl. No.: |
15/153807 |
Filed: |
May 13, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14371843 |
Jul 11, 2014 |
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PCT/SE2013/050015 |
Jan 11, 2013 |
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15153807 |
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61713120 |
Oct 12, 2012 |
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61586187 |
Jan 13, 2012 |
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Current U.S.
Class: |
424/501 |
Current CPC
Class: |
A61K 9/1652 20130101;
A61K 31/517 20130101; A61K 31/437 20130101; A61K 9/1641 20130101;
A61P 27/02 20180101; A61K 31/4439 20130101; A61K 47/32 20130101;
A61P 43/00 20180101; A61K 9/5192 20130101; A61P 35/00 20180101;
A61P 35/02 20180101; A61K 9/0053 20130101; A61P 9/10 20180101; A61K
9/14 20130101; A61K 9/5146 20130101; A61P 9/00 20180101; A61K 31/44
20130101; A61K 47/38 20130101; A61K 31/4545 20130101; A61K 9/5161
20130101; A61K 31/506 20130101; A61K 31/5377 20130101; A61K 31/444
20130101; A61K 9/5138 20130101 |
International
Class: |
A61K 9/51 20060101
A61K009/51; A61K 31/517 20060101 A61K031/517; A61K 31/437 20060101
A61K031/437; A61K 31/44 20060101 A61K031/44; A61K 31/444 20060101
A61K031/444; A61K 31/506 20060101 A61K031/506; A61K 31/5377
20060101 A61K031/5377 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 13, 2012 |
SE |
1250015-3 |
Oct 12, 2012 |
SE |
1251160-6 |
Claims
1. A method of producing stable, amorphous hybrid nanoparticles
comprising at least one protein kinase inhibitor and at least one
polymeric stabilizing and matrix-forming component, comprising a)
providing a first pressurized stream of said protein kinase
inhibitor dissolved in a solvent; b) providing a second pressurized
stream of antisolvent; wherein said at least one polymeric
stabilizing and matrix-forming component is present in either said
first or second stream; and c) mixing said first and second
streams, and spraying the mixed stream at the outlet of a nozzle,
whereby said hybrid nanoparticles are formed; followed by
collecting said hybrid nanoparticles.
2. The method of claim 1, wherein said polymeric stabilizing and
matrix-forming component is present in said solvent.
3. The method of claim 1, wherein said polymeric stabilizing and
matrix-forming component is present in said antisolvent.
4. The method according to claim 1, wherein at least one of said
fluid streams is a supercritical fluid stream, preferably a super-
or subcritical CO.sub.2 fluid stream.
5. The method according to claim 1, wherein said stream of
antisolvent is a super- or subcritical CO.sub.2 fluid stream.
6. The method according to claim 1, wherein said stream of solvent
is a super- or subcritical CO.sub.2 fluid stream.
7. The method according to claim 1, wherein said at least one
polymeric stabilizing and matrix-forming component is present in a
super- or subcritical CO.sub.2 fluid stream.
8. The method according to claim 1, wherein said first stream or
said second stream is comprised of a super- or subcritical CO.sub.2
fluid stream is provided at a temperature of about 25.degree. C. or
lower, at a pressure of from about 100 to about 150 bar.
9. The method according to claim 1, wherein said at least one
polymeric stabilizing and matrix-forming component is selected from
methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, hydroxypropyl methylcellulose
acetate succinate, hydroxypropyl methylcellulose phthalate,
polyvinylpyrrolidone, polyvinyl acetate phthalate, copolyvidone,
crospovidon, methacrylic acid and ethylacrylate copolymer,
methacrylate acid and methyl methacrylate copolymer, polyethylene
glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol
copolymer, DL lactide/glycolide copolymer, poly DL-lactide,
cellulose acetate phthalate, carbomer homopolymer Type A, carbomer
homopolymer Type B, aminoalkyl methacrylate copolymers and
polaxamers.
10. The method according to claim 1, wherein said at least one
polymeric stabilizing and matrix-forming component is selected from
hydroxypropyl methylcellulose phthalate, hydroxypropyl cellulose,
copolyvidone, hydroxypropyl methylcellulose acetate succinate,
polyvinyl acetate phthalate, cellulose acetate phthalate and
polyvinylpyrrolidone.
11. The method according to claim 1, wherein a solubilizer is added
to the hybrid nanoparticles obtained in step c.
12. The method of claim 11, wherein said solubilizer is selected
from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol
copolymer, d-.alpha.-tocopherol acid polyethylene glycol 1000
succinate and a hydrogenated castor oil.
13. The method according to claim 1, wherein said hybrid
nanoparticles comprising said protein kinase inhibitor provide an
increased dissolution rate, compared to the dissolution rate of
said protein kinase inhibitor in raw, crystalline form.
14. The method of claim 13, wherein said dissolution rate is
measured by a flow through cell system.
15. The method of claim 13, claim 13, wherein said dissolution rate
is measured within the initial 0 to 10 minutes of dissolution.
16. The method according to claim 13, wherein said increased
dissolution rate is measured in a solution as a dissolution rate
ratio of said hybrid nanoparticles comprising said protein kinase
inhibitor and said protein kinase inhibitor in raw, crystalline
form.
17. The method of claim 16, wherein said ratio is from about 1.5:1
to about 500:1.
18. The method according to claim 13, wherein said dissolution rate
is measured in a solution with a gastric pH.
19. The method according to claim 13, wherein said dissolution rate
is measured in a solution with an intestinal pH.
20. The method according to claim 1, which produces hybrid
nanoparticles that provide a solubility increase of said protein
kinase inhibitor in a solution, said increase measured as the area
under the curve (AUC) during about from 40 minutes to about 90
minutes, in said solution as compared with the AUC of said protein
kinase inhibitor in raw, crystalline form.
21. The method of claim 20, wherein said increase is from about 2:1
to about 10 000:1, wherein 1 represents the AUC of said protein
kinase inhibitor in raw, crystalline form.
22. The method of claim 20, wherein said increase is measured in a
solution with gastric pH.
23. The method according to claim 20, wherein said increase is
measured in a solution with an intestinal pH.
24. The method according to claim 1, wherein said amorphous hybrid
nanoparticles are characterized by providing an amorphous powder
X-ray diffraction pattern.
25. The method according to claim 1, wherein the dissolution rate
of said stable, amorphous hybrid nanoparticles remain stable to at
least about 90%, after 9 months of storage or more, at room
temperature.
26. The method according to claim 1, wherein said protein kinase
inhibitor is a tyrosine kinase inhibitor selected from the group
consisting of lapatinib, pazopanib, nilotinib, erlotinib,
dasatinib, gefitinib, sorafenib, crizotinib, axitinib, vemurafenib
salts thereof, hydrates thereof, solvates thereof, and combinations
thereof.
27. The method according to claim 1, wherein said hybrid
nanoparticles have an average particle diameter size of less than
about 1000 nm.
28. The method according to claim 1, wherein said hybrid
nanoparticles have an average diameter size is less than about 500
nm.
29. The method according to claim 1, wherein said solvent is an
organic solvent selected from DMSO and trifluoroethanol, or a
mixture thereof.
30. The method according to claim 1, wherein said hybrid
nanoparticles further comprise a solubilizer.
31. The method of claim 30, wherein said solubilizer is polyvinyl
caprolactam-polyvinyl acetate-polyethylene glycol copolymer,
d-.alpha.-tocopherol acid polyethylene glycol 1000 succinate or a
hydrogenated castor oil.
32. (canceled)
33. The method according to claim 1, further comprising formulating
said hybrid nanoparticles obtained from step (c) as a
pharmaceutical composition, wherein said pharmaceutical composition
optionally further comprises a pharmaceutically acceptable
excipient.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to the field of methods for
providing components of pharmaceutical compositions comprising
poorly water-soluble drugs. In particular the present invention
relates to methods for providing hybrid nanoparticles of protein
kinase inhibitors (PKIs), in order to increase the dissolution rate
and resulting bioavailability of said PKIs, useful in
pharmaceutical compositions.
BACKGROUND OF THE AND INVENTION
[0002] Components of cellular signal transduction pathways that
regulate the growth and differentiation of normal cells can, when
dysregulated, lead to the development of cellular proliferative
disorders and cancer. Mutations in cellular signaling proteins may
cause such proteins to become expressed or activated at
inappropriate levels or at inappropriate times during the cell
cycle, which in turn may lead to uncontrolled cellular growth or
changes in cell-cell attachment properties.
[0003] Many proliferative disorders, such as tumors and cancers,
have been shown to involve overexpression or upregulation of
protein kinase activity. Protein kinases are kinase enzymes that
modify proteins by chemically adding phosphate groups
(phosphorylation). Phosphorylation usually results in a functional
change of the target protein by changing enzyme activity, cellular
location, or association with other proteins. Protein kinases can
be subdivided or characterised by the amino acids of the target
protein whose phosphorylation they control: most kinases act on
both serine and threonine, the tyrosine kinases act on tyrosine,
and a number (dual-specificity kinases) act on all three. There are
also protein kinases that phosphorylate other amino acids,
including histidine kinases that phosphorylate histidine residues.
The human genome contains about 500 protein kinase genes and up to
30% of all human proteins may be modified by protein kinases.
Kinases are known to regulate the majority of cellular pathways,
especially those involved in signal transduction. Dysregulation of
protein kinases by mutation, gene rearrangement, gene
amplification, and overexpression of both receptor and ligand has
been implicated in the development and progression of human
cancers. Protein kinase inhibiting compounds or protein kinase
inhibitors (PKIs) are therefore useful for treating diseases caused
by or exacerbated by overexpression or upregulation of protein
kinases. For example, tyrosine kinase inhibitors (TKIs also known
as tyrphostins) have been shown be effective anti-tumor agents and
anti-leukemic agents (Lowery A et. al., Front Biosci. 2011 Jun. 1;
17:1996-2007).
[0004] A major objective of formulation chemistry is to improve
drug efficiency and safety, by e.g. improving bioavailability and
stability as well as convenience to the patient. Bioavailability
means the rate and extent to which an active substance or
therapeutic is absorbed from a pharmaceutical form and becomes
available at the site of action. The most common and preferred
method of delivery due to convenience, ease of ingestion, and high
patient compliance to treatment is the oral route of drug delivery.
However, for certain drugs, drug absorption from the
gastrointestinal tract is limited by poor aqueous solubility and/or
poor membrane permeability of the drug molecules.
[0005] PKIs are generally weak bases that dissolve only slightly at
low pH (e.g. 100-1000 mg/L) and are practically insoluble at
neutral pH (e.g. 0.1-10 mg/L). Therefore, enhancing the solubility
and dissolution rate of PKI-based drugs is important for improving
the bioavailability and efficacy of most of these drugs. Typical
PKIs exhibit non-polypeptide structure and have relatively low
molecular weights, such as 10000 dalton or 5000 dalton.
[0006] Several methods to improve the dissolution characteristics
of poorly water soluble drugs have been reported, including
micronisation, formation of salts or solvates, complexes and
microspheres. Additionally, attempts have been made to improve
bioavailability provided by solid dosage forms by forming particles
comprising the drug or by mixing the poorly water soluble drug with
hydrophilic excipients. Traditionally, however, these methods carry
inherent limitations concerning physical stabilities of the
particles on storage, problems with grinding or difficulty of
removal of the frequently toxic solvent. Furthermore, it is
important that the drug released from the solid phase does not
precitipitate in the gastrointestinal tract, or precipitates as
little as possible, but remains water-soluble in the aqueous fluids
of the gastrointestinal tract, since such precipitation results in
low bioavailability (see e.g. Herve J. et al. Pharm Dev Technol.
2011 June; 16(3):278-86).
[0007] pH-dependent solubility is a well-known issue for many oral
formulations of poorly water-soluble substances, such as PKIs,
since most of the absorption of the drug occurs in the small and
large intestine, where pH is close to neutral. There is thus a
continuing need to develop and improve the dissolution
characteristics of oral solid dosage forms of PKI-based drugs.
(Budha N R, Frymoyer A, Smelick G S, Jin J Y, Yago M R, Dresser M
J, Holden S N, Benet L Z, Ware J A. Clin Pharmacol Ther. 2012
August; 92(2):203-13). Therefore, methods for improving dissolution
of PKI-based drugs, as well as of other poorly water-soluble drugs,
at neutral (intestinal) pH are highly desirable.
[0008] US20090203709 discloses a pharmaceutical dosage form
comprising a solid dispersion product of at least one tyrosine
kinase inhibitor, at least one pharmaceutically acceptable polymer
and at least one pharmaceutically acceptable solubilizer. Further
the reference discloses methods for preparing the above-mentioned
pharmaceutical dosage form, comprising preparing the homogenous
melt of at least one tyrosine kinase inhibitor, at least one
pharmaceutically acceptable polymer and at least one
pharmaceutically acceptable solubilizer, and allowing the melt to
solidify to obtain a solid dispersion product.
[0009] EP2105130 discloses pharmaceutical formulations comprising a
solid dispersion or solid solution, containing a polymer and an
active agent in amorphous form. Further, the formulation comprises
an external polymer to stabilize the solution, such that the % by
weight of the external polymer is less than 20% of the total weight
of the pharmaceutical formulation. Additionally, the reference
discloses a hot melt extrusion method for production of the
above-mentioned formulation.
SUMMARY OF THE INVENTION
[0010] The present invention relates to methods of producing
stable, amorphous hybrid nanoparticles, comprising at least one
protein kinase inhibitor and at least one polymeric stabilizing and
matrix-forming component. Optionally, one or more solubilizers may
be added to the particles, present separately from the particles,
or within the particles.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1 provides a graph showing the apparent solubility for
stable, amorphous hybrid nanoparticles comprising nilotinib HCl
produced by the methods of the invention. Further experimentation
with both nilotinib base and nilotinib HCl is found in Example 1.
The details of the particles are described in Example 1, Table 1,
for experiment 3, 30 and 37, respectively. Briefly, experiment 30
represents hybrid nanoparticles comprising nilotinib HCl and HPMCP
HP55 and wherein the solubilizer polyvinyl caprolactam-polyvinyl
acetate-polyethylene glycol copolymer is present separately from
the hybrid nanoparticles. Experiment 3 represents raw, crystalline
nilotinib HCl and experiment 37 represents hybrid nanoparticles of
nilotinib HCl, HPMCP HP55 and the solubilizer polyvinyl
caprolactam-polyvinyl acetate-polyethylene glycol copolymer,
present within the hybrid nanoparticles. The experiments
illustrated in the graphs were carried out at pH 6.5, in
FaSSIF.
[0012] FIG. 2 provides a graph showing the apparent solubility for
stable, amorphous hybrid nanoparticles comprising erlotinib
produced by the methods of the invention. Further experimentation
with erlotinib is found in Example 2. The details of the hybrid
nanoparticles are described in Example 2, Table 7, for experiment
58, 65 and 67, respectively. Briefly, experiment 65 represents
hybrid nanoparticles with erlotinib HCl and HPMC-AS, wherein the
solubilizer polyvinyl caprolactam-polyvinyl acetate-polyethylene
glycol copolymer is present separately from the hybrid
nanoparticles. Experiment 58 represents raw, crystalline erlotinib
HCl and experiment 67 represents hybrid nanoparticles of erlotinib
HCl, HPMC-AS and the solubilizer polyvinyl caprolactam-polyvinyl
acetate-polyethylene glycol copolymer present within the hybrid
nanoparticles. The experiments illustrated in the graphs were
carried out at pH 6.5 in FaSSIF.
[0013] FIG. 3 provides a graph showing the apparent solubility for
stable, amorphous hybrid nanoparticles comprising pazopanib
produced by the methods of the invention. Further experimentation
with pazopanib is found in Example 3. The details of the hybrid
nanoparticles are described in Example 3, Table 13, for experiment
84, 91 and 93, respectively. Briefly, experiment 91 represents
hybrid nanoparticles comprising pazopanib and PVP 90K and wherein
the solubilizer polyvinyl caprolactam-polyvinyl
acetate-polyethylene glycol copolymer is present separately from
the hybrid nanoparticles, experiment 93 represents hybrid
nanoparticles comprising pazopanib, PVP 90K and the solubilizer
polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol
copolymer, present within the hybrid nanoparticles. Experiment 84
represents raw, crystalline pazopanib. The experiments illustrated
in the graphs were carried out at pH 6.5, in FaSSIF.
[0014] FIG. 4 provides a graph showing the apparent solubility for
stable, amorphous hybrid nanoparticles comprising lapatinib base
produced by the methods of the invention. Further experimentation
with both lapatinib base and lapatinib ditosylate salt is found in
Example 4. The details of the hybrid nanoparticles are described in
Example 4, Table 19, for experiment 110, 122 and 126, respectively.
Briefly, experiment 122 represents hybrid nanoparticles comprising
lapatinib base and HPC EF, wherein the solubilizer polyvinyl
caprolactam-polyvinyl acetate-polyethylene glycol copolymer is
present separately from the hybrid nanoparticles. Experiment 110
represents raw, lapatinib base and experiment 126 represents hybrid
nanoparticles of lapatinib base, HPC LF and the solubilizer
polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol
copolymer present within the hybrid nanoparticles. The experiments
illustrated in the graphs were carried out at pH 6.5 in FaSSIF.
[0015] FIG. 5 provides a graph showing the apparent solubility for
stable, amorphous hybrid nanoparticles particles comprising
nilotinib produced by the methods of the invention. The details of
the hybrid nanoparticles are described in Example 5, Table 21, for
experiment 127, 128 and 129, respectively. Briefly, experiment 129
represents a physical mixture of raw, crystalline nilotinib HCl,
HPMCP HP55 and the solubilizer polyvinyl caprolactam-polyvinyl
acetate-polyethylene glycol copolymer. Experiment 128 represents
hybrid nanoparticles comprising nilotinib HCl and HPMCP HP55,
wherein the solubilizer polyvinyl caprolactam-polyvinyl
acetate-polyethylene glycol copolymer is present separately from
the hybrid nanoparticles. Experiment 127 represents hybrid
nanoparticles of nilotinib HCl and HPMCP HP55. The experiments
illustrated in the graphs were carried out at pH 1.4 in SGF.
[0016] FIG. 6 provides a graph showing the apparent solubility for
stable, amorphous hybrid nanoparticles comprising gefitinib
produced by the methods of the invention. Further experimentation
with gefitinib is found in Example 6 The details of the
compositions are described in Example 6, Table 22, for experiment
131, 133, 135 and 137, respectively. Briefly, experiment 131
represents raw, crystalline gefitinib. Experiment 133 represents a
mixture of raw, crystalline gefitinib, HPMCP HP55 and the
solubilizer polyvinyl caprolactam-polyvinyl acetate-polyethylene
glycol copolymer. Experiment 135 represents hybrid nanoparticles of
gefitinib and HPMCP HP55. Experiment 137 represents hybrid
nanoparticles of gefitinib and HPMCP HP55 wherein the solubilizer
polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol
copolymer is present separately from the hybrid nanoparticles. The
experiments illustrated in the graphs were carried out at pH 6.5 in
FaSSIF.
[0017] FIG. 7 provides a graph showing the apparent solubility for
stable, amorphous hybrid nanoparticles comprising dasatinib
produced by the methods of the invention. The details of the hybrid
nanoparticles are described in Example 7, Table 24, for experiments
138-141. Briefly, experiment 138 represents raw, crystalline
dasatinib. Experiment 139 represents a mixture of raw, crystalline
dasatinib, Kollidon VA64 and the solubilizer polyvinyl
caprolactam-polyvinyl acetate-polyethylene glycol copolymer.
Experiment 140 represents hybrid nanoparticles of dasatinib and
Kollidon VA64. Experiment 141 represents hybrid nanoparticles of
dasatinib and Kollidon VA64 wherein the solubilizer polyvinyl
caprolactam-polyvinyl acetate-polyethylene glycol copolymer is
present separately from the hybrid nanoparticles. The experiments
illustrated in the graphs were carried out at pH 6.5 in FaSSIF.
[0018] FIG. 8 provides a graph showing the apparent solubility for
stable, amorphous hybrid nanoparticles comprising sorafenib
produced by the methods of the invention. The details of the hybrid
nanoparticles are described in Example 8, Table 26, for experiments
142-145. Briefly, experiment 142 represents raw, crystalline
sorafenib tosylate. Experiment 143 represents a mixture of raw,
crystalline sorafenib tosylate, HPMCP HP55 and the solubilizer
polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol
copolymer. Experiment 144 represents hybrid nanoparticles of
sorafenib tosylate and HPMCP HP55. Experiment 145 represents hybrid
nanoparticles of sorafenib tosylate and HPMCP HP55 wherein the
solubilizer polyvinyl caprolactam-polyvinyl acetate-polyethylene
glycol copolymer is present separately from the hybrid
nanoparticles. The experiments illustrated in the graphs were
carried out at pH 6.5 in FaSSIF.
[0019] FIG. 9 provides a graph showing the apparent solubility for
stable, amorphous hybrid nanoparticles comprising crizotinib
produced by the methods of the invention. Further experimentation
with crizotinib is found in Example 10. The details of the
compositions are described in Example 10, Table 30, for experiment
150, 152, 153 and 156, respectively. Briefly, experiment 150
represents raw, crystalline crizotinib. Experiment 152 represents a
mixture of raw, crystalline crizotinib, PVP 30K and the solubilizer
Cremophor RH40. Experiment 153 represents hybrid nanoparticles of
crizotinib and PVP 30K. Experiment 156 represents hybrid
nanoparticles of crizotinib and PVP 30K wherein the solubilizer
Cremophor RH40 is present separately from the hybrid nanoparticles.
The experiments illustrated in the graphs were carried out at pH
6.5 in FaSSIF.
[0020] FIG. 10 provides a graph showing the apparent solubility for
stable, amorphous hybrid nanoparticles comprising axitinib produced
by the methods of the invention. Further experimentation with
axitinib is found in Example 11 The details of the compositions are
described in Example 11, Table 32, for experiment 157, 158, 160 and
162, respectively. Briefly, experiment 157 represents raw,
crystalline axitinib. Experiment 158 represents a mixture of raw,
crystalline axitinib, Kollidon VA64 and the solubilizer polyvinyl
caprolactam-polyvinyl acetate-polyethylene glycol copolymer.
Experiment 160 represents hybrid nanoparticles of axitinib and
Kollidon VA64. Experiment 162 represents hybrid nanoparticles of
axitinib and Kollidon VA64 wherein the solubilizer polyvinyl
caprolactam-polyvinyl acetate-polyethylene glycol copolymer is
present separately from the hybrid nanoparticles. The experiments
illustrated in the graphs were carried out at pH 6.5 in FaSSIF.
[0021] FIG. 11 provides a graph showing the apparent solubility for
stable, amorphous hybrid nanoparticles comprising vemurafenib
produced by the methods of the invention. Further experimentation
with vemurafenib is found in Example 12. The details of the
compositions are described in Example 12, Table 34, for experiment
164, 166, 168 and 170, respectively. Briefly, experiment 164
represents raw, crystalline vemurafenib. Experiment 166 represents
a mixture of raw, crystalline vemurafenib, CAP and the solubilizer
polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol
copolymer. Experiment 168 represents hybrid nanoparticles of
vemurafenib and CAP. Experiment 170 represents hybrid nanoparticles
of vemurafenib and CAP wherein the solubilizer polyvinyl
caprolactam-polyvinyl acetate-polyethylene glycol copolymer is
present separately from the hybrid nanoparticles. The experiments
illustrated in the graphs were carried out at pH 6.5 in FaSSIF.
[0022] FIG. 12 provides a graph showing the dissolution rate for
stable, amorphous hybrid nanoparticles comprising nilotinib base
produced by the methods of the invention, measured under sink
conditions. Details are found in Examples 13 and 13.1, and Table 36
for experiments 500 and 501. Briefly, experiment 500 represents
raw, nilotinib HCl. Experiment 501 represents hybrid nanoparticles
of nilotinib base and HPMCP HP55. The experiments illustrated in
the graphs were carried out at pH 6.5 in FaSSIF.
[0023] FIG. 13 provides a graph showing the dissolution rate for
stable, amorphous hybrid nanoparticles comprising erlotinib HCl
produced by the methods of the invention, measured under sink
conditions. Details are found in Examples 13 and 13.2, Table 37 for
experiments 510 and 511. Briefly, experiment 510 represents raw,
erlotinib HCl. Experiment 511 represents hybrid nanoparticles of
erlotinib HCl and HPMC AS.
[0024] FIG. 14 provides a graph showing the dissolution rate for
stable, amorphous hybrid nanoparticles comprising pazopanib HCl
produced by the methods of the invention, measured under sink
conditions. Details are found in Examples 13 and 13.3, Table 38 for
experiments 520 and 521. Briefly, experiment 520 represents raw,
pazopanib HCl. Experiment 521 represents hybrid nanoparticles of
pazopanib HCl and PVP90K.
[0025] FIG. 15 provides a graph showing the dissolution rate for
stable, amorphous hybrid nanoparticles comprising lapatinib base
produced by the methods of the invention, measured under sink
conditions. Details are found in Examples 13 and 13.4, Table 39 for
experiments 530 and 531. Briefly, experiment 530 represents raw,
lapatinib ditosylate. Experiment 531 represents hybrid
nanoparticles of lapatinib base and HPC If.
[0026] FIG. 16 provides a graph showing the dissolution rate for
stable, amorphous hybrid nanoparticles comprising gefitinib
produced by the methods of the invention, measured under sink
conditions. Details are found in Examples 13 and 13.5., Table 40
for experiments 540 and 541. Briefly, experiment 540 represents
raw, gefitinib. Experiment 541 represents hybrid nanoparticles of
gefitinib and HPMCP HP55.
[0027] FIG. 17 provides a graph showing the dissolution rate for
stable, amorphous hybrid nanoparticles comprising dasatinib
produced by the methods of the invention, measured under sink
conditions. Details are found in Examples 13 and 13.6., Table 41
for experiments 550 and 551. Briefly, experiment 550 represents
raw, dasatinib. Experiment 551 represents hybrid nanoparticles of
dasatinib and Kollidon VA64.
[0028] FIG. 18 provides a graph showing the dissolution rate for
stable, amorphous hybrid nanoparticles comprising sorafenib
tosylate produced by the methods of the invention, measured under
sink conditions. Details are found in Examples 13 and 13.7., Table
42 for experiments 560 and 561. Briefly, experiment 560 represents
raw, sorafenib tosylate. Experiment 561 represents hybrid
nanoparticles of sorafenib tosylate and HPMCP HP55.
[0029] FIG. 19 provides a graph showing the dissolution rate for
stable, amorphous hybrid nanoparticles comprising crizotinib
produced by the methods of the invention, measured under sink
conditions. Details are found in Examples 13 and 13.8., Table 43
for experiments 570 and 571. Briefly, experiment 570 represents
raw, crizotinib. Experiment 571 represents hybrid nanoparticles of
crizotinib and PVP 30K.
[0030] FIG. 20 provides a graph showing the dissolution rate for
stable, amorphous hybrid nanoparticles comprising axitinib produced
by the methods of the invention, measured under sink conditions.
Details are found in Examples 13 and 13. 9., Table 44 for
experiments 580, 581 and 582. Briefly, experiment 580 represents
raw, axitinib. Experiment 581 represents hybrid nanoparticles of
axitinib and Kollidon VA64 and experiment 582 represents hybrid
nanoparticles of axitinib and HPMC AS.
[0031] FIG. 21 provides a graph showing the dissolution rate for
stable, amorphous hybrid nanoparticles comprising vemurafenib
produced by the methods of the invention, measured under sink
conditions. Details are found in Examples 13 and 13.10., Table 45
for experiments 590, 591 and 592. Briefly, experiment 590
represents raw, vemurafenib. Experiment 591 represents hybrid
nanoparticles of vemurafenib and Kollidon VA64 and experiment 592
represents hybrid nanoparticles of vemurafenib and CAP.
[0032] FIG. 22 provides graphs showing in vivo measurement of
plasma levels after oral administration to beagle dogs of
compositions, represented by formulations comprising stable,
amorphous hybrid nanoparticles of nilotinib base and the polymeric
stabilizing and matrix-forming components PVAP and HPMCP HP55,
respectively (I/P), denoted PVAP and HP55, as well as wherein the
solubilizer polyvinyl caprolactam-polyvinyl acetate-polyethylene
glycol copolymer was added (I/P+S), denoted HP55s and PVAPs,
respectively. The experiments were carried out in beagle dogs
pre-treated to have neutral stomach content. The hybrid
nanoparticles are further described in experiments 146 and 147
(Example 9) and details of the in vivo experiments are set out in
Example 14. The experiments used a marketed formulation comprising
nilotinib HCl ("Tasigna") as reference.
[0033] FIG. 23 provides graphs showing in vivo measurement of
plasma levels after oral administration to beagle dogs of
compositions, represented by formulations comprising stable,
amorphous hybrid nanoparticles of nilotinib base and the polymeric
stabilizing and matrix-forming components PVAP and HPMCP HP55,
respectively (I/P), denoted PVAP and HP55, produced by the methods
of the invention as well as wherein the solubilizer polyvinyl
caprolactam-polyvinyl acetate-polyethylene glycol copolymer was
added (I/P+S), denoted PVAPs and HP55s, respectively. The
experiments were carried out in beagle dogs pre-treated to have
acidic stomach content. The hybrid nanoparticles are further
described in experiments 146 and 147 (Example 9) and details of the
in vivo experiments are set out in Example 14. The experiments used
a marketed formulation comprising nilotinib HCl ("Tasigna") as
reference.
[0034] FIG. 24 provides graphs showing in vivo measurement of
plasma levels after oral administration to beagle dogs of
compositions, represented by formulations comprising stable,
amorphous hybrid nanoparticles of nilotinib base and the polymeric
stabilizing and matrix-forming components PVAP and HPMCP HP55,
respectively (I/P) produced by the methods of the invention,
denoted PVAP and HP55, as well as wherein the solubilizer polyvinyl
caprolactam-polyvinyl acetate-polyethylene glycol copolymer was
added after hybrid nanoparticle formation (I/P+S), denoted PVAPs
and HP55s, respectively. The experiments were carried out in beagle
dogs pre-treated to have acidic or neutral stomach content. The
hybrid nanoparticles are further described in experiments 146 and
147 (Example 9) and details of the in vivo experiments are set out
in Example 14.
[0035] FIG. 25 provides graphs showing in vivo measurement of
plasma levels after oral administration to beagle dogs of
compositions, represented by formulations comprising stable,
amorphous hybrid nanoparticles of nilotinib base and the polymeric
stabilizing and matrix-forming components PVAP and HPMCP HP55,
respectively (I/P) produced by the methods of the invention,
denoted PVAP and HP55. The experiments were carried out in beagle
dogs pre-treated to have acidic or neutral stomach content. The
hybrid nanoparticles are further described in experiments 146 and
147 (Example 9) and details of the in vivo experiments are set out
in Example 14.
[0036] FIG. 26 provides a graph showing the apparent solubility for
stable, amorphous hybrid nanoparticles produced by the methods of
the invention, before and after 11 months of storage at room
temperature. The experiment provides stable, amorphous hybrid
nanoparticles comprising nilotinib base, HPMCP HP55 and the
addition of the solubilizer polyvinyl caprolactam-polyvinyl
acetate-polyethylene glycol copolymer (I/P+S) as Exp 171 & Exp
172 with further details set out in Example 15.
[0037] FIG. 27 provides overlayed X-ray powder diffraction (XRPD)
patterns of stable hybrid nanoparticles at 40% drug load, I/P
nilotinib base/HPMCP HP55. Initial (top) and after 12 months
storage at ambient temperature (bottom). The XRPD patterns are
offset in order improve the visual comparison. Further details are
set out in Example 15.
DETAILED DESCRIPTION OF THE INVENTION
[0038] All patents, patent applications, and publications cited
herein are hereby incorporated by reference in their entirety.
[0039] As used herein, the phrase "hybrid nanoparticles" refers to
a group of particles, typically in the average size range of from 1
to 1000 nm, composed of at least two components, one of which is
the PKI and the other a polymeric stabilizing and matrix-forming
component. The particles can be either crystalline or amorphous, or
a mixture thereof. Typically, in the sense of the present
disclosure, the particles are "amorphous", or "essentially
amorphous". This means that almost all, if not all, content of the
particles comprise amorphous protein kinase inhibitor and polymeric
stabilizing and matrix-forming component. The level or degree of
amorphicity is at least 60%, such as 70%, such as 80% or 85%,
preferably at least 90% and more preferably >95%, wherein 100%
represents that all material is amorphous in the particles.
Quantification of crystalline PKI or absence of crystalline PKI may
be measured by X-ray powder diffraction methods as described in
Saleki-Gerhardt A et al. Int J Pharm. 1994; 101:237-247) or by
water vapor sorption as described in Dash A K et al. J Pharm Sci.
2002 April; 91(4):983-90.
[0040] The term "solid dispersion particles" relates to "hybrid
nanoparticles" as defined above, however, solid dispersion
particles are typically larger or much larger in size (typically
.mu.m-mm, as described in Wu K. et al. J Pharm Sci. 2009 July;
98(7):2422-3). The smaller size of hybrid nanoparticles contributes
to further stabilizing the PKI against crystallization. Typically,
hybrid nanoparticles is in the average size range of from 1 to 1000
nm, such as below 500 nm, preferably below 250 nm.
[0041] The phrase "stable" refers to the level of stability of
produced particles by the methods of the present invention and may
be measured as the capability of the hybrid nanoparticles to remain
in their physical state for 6-12 months storage at ambient
temperature (e.g. 20-25.degree. C.). The level of stability may be
measured by AUC measurements of dissolution rate over for instance
80 minutes of the particles, after such storage.
[0042] By the phrase "protein kinase inhibitor" or "PKI" is meant a
type of enzyme inhibitor that specifically blocks the action of one
or more protein kinases. PKIs include, but are not limited, to
protein kinase inhibitors and tyrosine kinase inhibitors, such as
axitinib, afatinib, bosutinib, crizotinib, cediranib, dasatinib,
erlotinib, fostamatinib, gefitinib, imatinib, lapatinib,
lenvatinib, lestaurtinib, motesanib, mubritinib, nilotinib,
pazopanib, pegaptanib, ruxolitinib, sorafenib, semaxanib,
sunitinib, tandunitib, tipifamib, vandetanib and vemurafenib; or
salts or hydrates or solvates thereof, or combinations thereof.
[0043] By the phrase "polymeric stabilizing and matrix-forming
component" is meant the component present in the hybrid
nanoparticles together with the PKI. Typically, said polymeric
stabilizing and matrix-forming component exhibits a polymeric
structure, such as, but not limited to, methyl cellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. HPC ef, HPC
If and HPC jf), hydroxypropyl methylcellulose (e.g. Methocel E3 and
E15 and Pharmacoat), hydroxypropyl methylcellulose acetate
succinate (HPMC AS), hydroxypropyl methylcellulose phthalate (e.g.
HPMCP-HP55), polyvinylpyrrolidone (e.g. PVP 30K and PVP 90K),
polyvinyl acetate phthalate (PVAP), copolyvidone (e.g. Kollidon VA
64), crospovidon (e.g. Kollidon CL), methacrylic acid and
ethylacrylate copolymer (e.g. Kollicoat ME), methacrylate acid and
methyl methacrylate copolymer (e.g. Eudragit L100), polyethylene
glycol (PEG), DL lactide/glycolide copolymer, poly DL-lactide,
cellulose acetate phthalate (CAP), aminoalkyl methacrylate
copolymers (e.g. Eudragit RL100, RL PO or RS PO), carbomer
homopolymer Type A (e.g. Carbopol 971P), carbomer homopolymer Type
B (e.g. Carbopol 974P) and Poloxamers (e.g. Pluronics,
Kolliphor).
[0044] The term "polymer" or "polymeric" is here used to mean a
compound that is made of monomers connected together to form a
larger molecule. A polymer generally consists of 20 or more
monomers connected together, however less than 20 monomers
connected together are here also referred to as polymers.
[0045] The term "solubilizer" is here used to mean a compound that
increases the solubility of a substance, such as, but not limited
to, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol
copolymer (Soluplus), d-.alpha.-tocopherol acid polyethylene glycol
1000 succinate (TPGS), PEG-40 hydrogenated castor oil (Cremophor
RH40), PEG-35 castor oil (Cremophor EL), PEG-40 stearate (MYRJ
540), hard fat (e.g. Gelucire 33/01), polyoxylglycerides (e.g.
Gelucire 44/14), stearoyl polyoxylglycerides (e.g. Gelucire 50/13),
PEG-8 caprylic/capric glycerides (e.g. Labrasol) and Poloxamers
(e.g. Pluronics, Kolliphor).
[0046] As used herein, the phrase "primary particles" refers to the
smallest particulate entities formed during the precipitation
process. The boundaries of the particles are analyzed by SEM
microscopy. Depending on process parameters, the primary particles
may build together a more or less dense and porous network forming
larger, agglomerated or bridging particles. Parameters affecting
the agglomeration are e.g. temperature that may modify the softness
of the primary particles; ratio solvent/antisolvent affecting
precipitation time, concentration of the PKI solution; and the
nature of the polymeric stabilizing and matrix-forming agent(s).
The average size of the primary particles is typically between 1 to
1000 nm, preferably below 500 nm, more preferably below 250 nm.
[0047] As used herein, the phrases "supercritical" and
"supercritical fluid" refer to that a chemical substance that is
set to both a temperature higher or equal than its critical
temperature (Tc) and a pressure higher or equal than its critical
pressure (Pc).
[0048] As used herein, the phrases "subcritical" and "subcritical
fluid" refer here to that one of critical temperature (Tc) or
critical pressure (Pc) is set to a temperature or pressure higher
than its critical temperature (Tc) or critical pressure (Pc),
respectively, and the other of critical temperature (Tc) or
critical pressure (Pc) is set to a temperature or pressure lower
than its critical temperature (Tc) or critical pressure (Pc),
respectively.
[0049] By the phrase "area under the curve (AUC)" is meant the area
under the concentration-time curve, where the x-axis represents
time and the y-axis represents solubilized drug concentration.
[0050] By the phrase "apparent solubility" is meant the
concentration of material at apparent equilibrium. See further in
the Examples section.
[0051] The term "supersaturation" is here used to mean that a
solution contains more of the dissolved substance than could be
dissolved by the solvent or media under normal circumstances.
[0052] As used herein, the term "Soluplus" or "soluplus" refers to
polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol
copolymer.
[0053] As used herein, the term "TPGS" refers to
d-.alpha.-tocopherol acid polyethylene glycol 1000 succinate.
[0054] As used herein, the term "Chremophor RH40" refers to PEG-40
hydrogenated castor oil.
[0055] As used herein, the term "PVAP" refers to polyvinyl acetate
phthalate.
[0056] As used herein, the term "PVP 90K" refers to
polyvinylpyrrolidone K-90.
[0057] As used herein, the term "PVP 30K" refers to
polyvinylpyrrolidone K-30.
[0058] As used herein, the term "HPMC-AS" refers to hydroxypropyl
methylcellulose acetate succinate.
[0059] As used herein, the term "HPMCP HP55" refers to
hydroxypropyl methyl cellulose phthalate.
[0060] As used herein, the term "HPC" refers to hydroxypropyl
cellulose, such as HPC EF and HPC LF.
[0061] As used herein, the term "Kollidon VA64" refers to
copolyvidone.
[0062] As used herein, the term "CAP" refers to cellulose acetate
phthalate.
[0063] The dissolution mediums used for purposes of testing hybrid
nanoparticles produced by the methods of the present invention,
includes Fasted State Stimulated Intestinal Fluid, referred to as
FaSSIF, Fed State Stimulated Intestinal Fluid, referred to as
FeSSIF, and Simulated Gastric Fluid, referred to as SGF. FaSSIF
media is tailored to represent a fasting state and has a pH of
about 6.5 as well as particular osmolaric properties. FeSSIF media
is tailored to represent a fed state and has a pH of about 5 as
well as specific osmolaric properties. SGF is tailored to represent
gastric fluid and has a pH of about 1.4 as well as particular
osmolaric properties. FaSSIF, FeSSIF and SGF media are generally
used in in vitro models for dissolution of poorly water-soluble
drugs. The choice of medium will be dependent of the where in the
intestinal tract and under what conditions (fasted or fed)
particles are desired to dissolve and be taken up. Further details
regarding these fluids are described in e.g. Herve J. et al. Pharm
Dev Technol. 2011 June; 16(3):278-86 and Jantratid, E., and
Dressman, J. Dissolut. Technol. 2009 8, 21-25.
[0064] By the phrase "amorphous form" is meant non-crystalline
solid form. The ease of dissolution may at least in part be
attributed to the amount of energy required for dissolution of the
components from a crystalline or amorphous solid phase. Amorphous
particles require less energy for dissolution as compared to
crystalline particles of the same compound.
[0065] The inventive methods produce hybrid nanoparticles
comprising a PKI or a combination of two or more PKIs. However, the
particles may comprise a combination of one or more PKIs and at
least one further active ingredient, such as one or more drugs.
Various kinds of PKIs can be effectively utilized.
[0066] The term PKIs (protein kinase inhibitors) as used herein, is
intended to include also the hydrates, solvates (alcoholates)
pharmaceutically acceptable acid salts, base salts or co-crystals
of such protein kinase inhibiting compounds.
[0067] As used herein, the term water-insoluble or poorly water
soluble (or hydrophobic) compounds, refers to compounds whose
solubility in water at 25.degree. C. is less than 1 g/100 ml,
especially less than 0.1 g/100 ml in pure water at neutral pH.
[0068] The hybrid nanoparticles generated by the methods of the
present invention are typically in the form of particles as
described elsewhere in this specification. There are a number of
different methods for the formation of larger particles, e.g.
granulation, melt extrusion, spray drying, precipitation etc. all
of which typically encompass starting with formation of a mixture
between the Active Pharmaceutical Ingredient (API) and the
polymeric stabilizing and matrix-forming component. The inventive
methods of the present invention are continuos processes for
generating hybrid nanoparticles. Continuous processes in this
context means that particle formation is continuously ongoing while
at the same time continuously withdrawing/collecting/retaining
hybrid nanoparticles from the mixture after their formation. In the
preferred methods, i.e. precipitation methods, this means that a
fluid which is a solution of the PKI, preferably in the form of a
fluid stream, is mixed with an antisolvent fluid, preferably in the
form of an antisolvent fluid stream. The polymeric stabilizing and
matrix-forming component may be present in either one or both of
the two fluids depending on its solubility characteristics. The
mixing of the two fluids is taking place in a mixing function, e.g.
a mixing chamber. In the case the process is continuous, i.e. the
two fluids are fluid streams, the mixing function typically is
associated with a particle formation and separation function
wherein the mixed fluid stream may pass through while retaining the
hybrid nanoparticles. Agents modifying the particle characteristics
without being incorporated into the particles may be added to
either one or both of the two fluids before the mixing step. The
fluids typically are conventional liquids or supercritical fluids,
where supercritical fluids also include subcritical fluids (i.e.
fluids for which only one of pressure and temperature is above its
supercritical value). Typical combinations are, a) conventional
(i.e., non-supercritical) liquids for both the API solution and the
antisolvent, b) supercritical solution of the API combined with
conventional liquid for the antisolvent, c) conventional liquid for
the API solution combined with supercritical fluid for the
antisolvent, and d) supercritical fluids for both of the two
fluids. In certain variants the antisolvent may be omitted. A fluid
stream, preferably supercritical, containing both the API and the
polymeric stabilizing and matrix-forming component is then allowed
to expand into the particle formation function. It is preferred
that at least one of the fluids is in a supercritical state in the
precipitation methods described above. These kinds of precipitation
methods are discussed in WO 2005061090 (Censdelivery AB), WO
2009072950 (XSpray Microparticles AB), WO 2009072953 (XSpray
Microparticles AB), WO 2011159218 (XSpray Microparticles AB) and
references cited in these publications.
[0069] The term "solution" encompasses that the solute is either a
true solute or minute particles of colloidial dimensions (typically
1-1000 nm) and less than the particles to be produced.
[0070] A preferred particle formation system is the "Right Size
system" developed by XSpray Microparticles AB, Sweden. A detailed
description of the technology can be found in the WO-publications
given in the preceding paragraph. An important characteristic of
the system is that the two fluid streams should merge within a
nozzle at an angle in the interval 45.degree.-135.degree., with
preference for about 90.degree. and sprayed into a particle
formation/separation function. In principle the system allows for
producing particles of predetermined size and/or morphology. Here
the Right Size system and apparatus will be described using the
non-limiting example of a PKI as the drug and CO.sub.2 as a
supercritical fluid antisolvent.
[0071] The system consists of one pumping set-up for the PKI
dissolved in a liquid solvent, referred to as the API solution, and
one pumping set-up for an antisolvent, for example CO.sub.2,
however also other antisolvents may be used when suitable. Each
pumping set-up includes instruments such as a flow meter and a
pressure meter that are used to control the process conditions.
These two pumping set-ups are fluidically connected at a spray
nozzle.
[0072] A stream of liquid API solution is mixed with a stream of
CO.sub.2 under flow conditions within the spray nozzle. The
polymeric stabilizing and matrix-forming component is present in
either the API solution or in the stream of CO.sub.2. These streams
are sprayed at the outlet of the nozzle into a precipitation vessel
under controlled conditions (typically pressure and temperature).
CO.sub.2 acts as an antisolvent and makes the API to precipitate
together with the polymeric stabilizing and matrix-forming
component into fine particles. Particles are retained in the vessel
by a filtering set-up. A back pressure regulator is typically used
to control the pressure inside the precipitation vessel.
[0073] For preparing hybrid nanoparticles of certain drugs, for
example but not limited to Pazopanib and Erlotinib, it may be
advantageous to have an extra pumping set-up for injecting an
additional solvent, referred to as a modifier, into the CO.sub.2.
Here a pumping set-up control is set up for the modifier and the
modifier is mixed with the CO.sub.2 in a mixer before entering the
nozzle.
[0074] When using the system, the system operator typically starts
by equilibrating the system by pumping CO.sub.2, an "PKI like
solution" (a solution similar in composition to the PKI solution
but containing no PKI and no excipient) and the modifier (if used)
through the system until flow rates, pressure and temperature have
reached a desired steady state. Critical parameters for setting up
the system are PKI solution composition, PKI solution flow rate,
CO.sub.2 flow rate, CO.sub.2 pressure and temperature, nature of
the modifier and modifier flow rate, if such is used.
[0075] Next, the "PKI like solution" is exchanged for the PKI
solution and particles are produced and retained downstream of the
mixing, e.g. downstream of the outlet of the nozzle. Afterwards,
the system is typically cleaned by pumping the "PKI like solution"
through the system. The particles are dried by flushing CO.sub.2
through the retained particles in order to extract any remaining
solvent. The precipitation vessel is then depressurized and the
particles can be collected.
[0076] The solution/solvent and the antisolvent are typically
miscible with each other. The pressure and temperature in the
particle formation function, and/or upstream of this function, such
as in the mixing function, provide supercritical or subcritical
conditions in relation to the antisolvent.
[0077] The concentration of the PKI in the solution is typically
below its saturation concentration, such as .ltoreq.50%, such as
.ltoreq.60%, such as .ltoreq.75%, such as .ltoreq.85% or such as
.ltoreq.95% of the saturation concentration. Suitable
concentrations are typically found in the interval .ltoreq.20%,
such as .ltoreq.10% or .ltoreq.5% or .ltoreq.3% with lower limits
being .ltoreq.005% or 0.1% (all in w/v-%). The term "volatile" for
solvents typically means boiling points of .ltoreq.200.degree. C.,
such as .ltoreq.150.degree. C. or .ltoreq.100.degree. C., at
atmospheric pressure. Examples are inorganic solvents and organic
solvents with particular emphasis of dimethyl sulfoxide and
trifluoroethanol and mixtures thereof. The term solvent includes
mixtures of liquids which are miscible with each other. The
solutions may contain agents that enhance or diminish the
solubility of the PKI, e.g. acidic, alkaline, buffer components
and/or other organic solvents.
[0078] Illustrative fluids which can be used as an antisolvent are
[0079] a) gaseous at room temperature and atmospheric pressures, or
[0080] b) liquid at room temperature and atmospheric pressure.
[0081] The antisolvent is typically selected for its ability to be
readily dispersed into small droplets and for its ability to act as
an atomizing agent and antisolvent against the PKI present in the
solution.
[0082] Compounds/elements according to group (a) may be selected
from carbon dioxide (Pc=74 bar and Tc=31.degree. C.) (preferred),
nitrous oxide (Pc=72 bar and Tc=36.degree. C.), sulphur
hexafluoride (Pc=37 bar and Tc=45.degree. C.), ethane (Pc=48 bar
and Tc=32.degree. C.), ethylene (Pc=51 bar and Tc=10.degree. C.),
xenon (Pc=58 bar and Tc=16.degree. C.), trifluoromethane (Pc=47 bar
and Tc=26.degree. C.), chlorotrifluoromethane (Pc=39 bar and
Tc=29.degree. C.) and nitrogen (Pc=34 bar and Tc=-147.degree. C.)
and mixtures containing these compounds/elements. Pc stands for
critical pressure and Tc for critical temperature. Compounds
according to group (b) are typically selected amongst conventional
liquids of the same general types as discussed for solvents above
but with the difference that the PKI present in the solution must
be poorly soluble in the antisolvent. Particular liquids of group
(b) comprise methanol, ethanol, acetone water and mixtures
containing one or more of these fluids.
[0083] The antisolvents of group (a) above are typically used at
pressures and temperatures providing i) supercritical conditions
(supercritical fluid) or ii) a subcritical conditions (subcritical
fluid) in the particle formation function and/or upstream of this
function, such as in the mixing function and upstream of this
latter function.
[0084] Variant (i) means pressures and temperatures which are
typically above the critical pressure Pc and critical temperature
Tc of the antisolvent used. For the pressure this typically means
pressures in the interval (1.0-7.0).times.Pc or in the interval
.gtoreq.10 bar, suitably .gtoreq.20 bar with preference for
.gtoreq.30 bar, higher than Pc with illustrative upper limits being
100 bar, 200 bar and 300 bar higher than Pc. For the temperature
this typically means temperatures within (1.0-4.0).times.Tc or in
the interval of .gtoreq.5.degree. C., suitably .gtoreq.10.degree.
C. with preference for .gtoreq.15.degree. C. above Tc with
illustrative upper limits being 10.degree. C., 40.degree. C. and
50.degree. C. above Tc.
[0085] Variant (ii) means that at least one of temperature and
pressure, with preference for only the temperature, is/are below
the critical value. (Tc and Pc, respectively). Thus the temperature
may be in the interval of (0.1-1).times.Tc, such as
(0.5-1).times.Tc, or lower. Further, the temperature may be low,
such as -10.degree. C. or -30.degree. C. These temperatures may be
combined with pressures as defined in the preceding paragraph or
with pressures lower than the Pc of the used antisolvent. For
carbon dioxide this means that the temperature in the particle
formation function is <+31.degree. C., such as about +25.degree.
C. or lower combined with a pressure above or below 74 bar.
[0086] The antisolvents of group (b) above are typically used in
the subcritical state, i.e. as a subcritical fluid.
[0087] For methods of the invention utilizing subcritical
conditions in the particle formation chamber. This include that the
pressure in the mixing function and in the antisolvent fluid always
is higher than in the particle formation function.
[0088] In one aspect of the invention, there is provided a method
of producing stable, amorphous hybrid nanoparticles comprising at
least one protein kinase inhibitor and at least one polymeric
stabilizing and matrix-forming component, comprising [0089] a)
providing a first, preferably pressurized stream of said protein
kinase inhibitor dissolved in a solvent; [0090] b) providing a
second, preferably pressurized stream of antisolvent; wherein said
at least one polymeric stabilizing and matrix-forming component is
present in either said first or second stream; and [0091] c) mixing
said first and second streams, and spraying the mixed stream at the
outlet of a nozzle, whereby said hybrid nanoparticles are formed;
followed by collecting said hybrid nanoparticles.
[0092] In one embodiment of this aspect, said polymeric stabilizing
and matrix-forming component is present in said solvent.
[0093] In another embodiment of this aspect, said polymeric
stabilizing and matrix-forming component is present in said
antisolvent.
[0094] In another embodiment of this aspect, at least one of said
fluid streams is a supercritical fluid stream, preferably a super-
or subcritical CO.sub.2 fluid stream.
[0095] In another embodiment of this aspect, said stream of
antisolvent is a super- or subcritical CO.sub.2 fluid stream.
[0096] In another embodiment of this aspect, said stream of solvent
is a super- or subcritical CO.sub.2 fluid stream.
[0097] In another embodiment of this aspect, said at least one
polymeric stabilizing and matrix-forming component is present in
said super- or subcritical CO.sub.2 fluid stream.
[0098] In another embodiment of this aspect, said stream of solvent
is a subcritical CO.sub.2 fluid stream. Said super- or subcritical
CO.sub.2 fluid stream is preferably provided at about 25.degree. C.
or lower, at a pressure of from about 100 to about 150 bar. Said
stream of solvent may, however, comprise e.g. nitrogen, methane,
ethane, propane, ethylene, methanol, ethanol, acetone, water or a
mixture of these compounds such as a mixture of CO.sub.2 and
nitrogen. Moreover a further solvent, such as an organic solvent
(e.g. methanol, acetone) or aqueous solution (e.g. water) may be
added as modifier into a super-/sub-critical solvent.
[0099] In another embodiment of this aspect, said stream of
antisolvent is a super- or subcritical CO.sub.2 fluid stream. Said
super- or subcritical CO.sub.2 fluid stream is preferably provided
at about 25.degree. C. or lower, at a pressure of from about 100 to
about 150 bar. Said stream of antisolvent may, however, comprise
e.g. nitrogen, methane, ethane, propane, ethylene, methanol,
ethanol, acetone, water or a mixture of these compounds such as a
mixture of CO.sub.2 and nitrogen. Moreover a solvent, such as an
organic solvent (e.g. methanol, acetone) or aqueous solution (e.g.
water) may be added as modifier into a super- or subcritical
antisolvent.
[0100] The polymeric stabilizing and matrix-forming component of
the present in the methods of the invention includes, but not
limited to, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose (e.g. HPC ef, HPC If and HPC jf), hydroxypropyl
methylcellulose (e.g. Methocel E3 and E15 and Pharmacoat),
hydroxypropyl methylcellulose acetate succinate (HPMC AS),
hydroxypropyl methylcellulose phthalate (e.g. HPMCP HP55),
polyvinylpyrrolidone (e.g. PVP 30K and PVP 90K), polyvinyl acetate
phthalate (PVAP), copolyvidone (e.g. Kollidon VA 64), crospovidon
(e.g. Kollidon CL), methacrylic acid and ethylacrylate copolymer
(e.g. Kollicoat ME), methacrylate acid and methyl methacrylate
copolymer (e.g. Eudragit L100), polyethylene glycol (PEG), DL
lactide/glycolide copolymer, poly DL-lactide, cellulose acetate
phthalate (CAP), carbomer homopolymer Type A (Carbopol 971P),
carbomer homopolymer Type B (Carbopol 974P), aminoalkyl
methacrylate copolymers (e.g. Eudragit RL100, RL PO or RS PO) and
Poloxamers (e.g. Pluronics, Kolliphor).
[0101] Consequently, in another embodiment of this aspect, said
polymeric stabilizing and matrix-forming component is selected from
methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, hydroxypropyl methylcellulose
acetate succinate, hydroxypropyl methylcellulose phthalate,
polyvinylpyrrolidone, polyvinyl acetate phthalate, copolyvidone,
crospovidon, methacrylic acid and ethylacrylate copolymer,
methacrylate acid and methyl methacrylate copolymer, polyethylene
glycol, DL lactide/glycolide copolymer, poly DL-lactide, cellulose
acetate phthalate, carbomer homopolymer Type A, carbomer
homopolymer Type B, aminoalkyl methacrylate copolymers, and
Poloxamers. Preferably, said polymeric stabilizing and
matrix-forming component is selected from hydroxypropyl
methylcellulose phthalate, hydroxypropyl cellulose, copolyvidon,
hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate
phthalate, cellulose acetate phthalate and
polyvinylpyrrolidone.
[0102] In another embodiment of this aspect, a solubilizer is added
to the hybrid nanoparticles obtained in step c. In this context,
the solubilizer will be present separately from the particles. Said
solubilizer may be selected from polyvinyl caprolactam-polyvinyl
acetate-polyethylene glycol copolymer, d-.alpha.-tocopherol acid
polyethylene glycol 1000 succinate and a hydrogenated castor oil,
such as PEG-40 hydrogenated castor oil or PEG-35 hydrogenated
castor oil. Furthermore, said solubilizer may be a poloxamer.
[0103] The methods of the invention provide stable, amorphous
hybrid nanoparticles comprising at least one protein kinase
inhibitor and at least one polymeric stabilizing and matrix-forming
component, which display increased dissolution rate.
[0104] Consequently, in another embodiment of this aspect, there is
provided method of producing stable, amorphous hybrid
nanoparticles, comprising at least one protein kinase inhibitor and
at least one polymeric stabilizing and matrix-forming component,
wherein said hybrid nanoparticles display an increased dissolution
rate of said protein kinase inhibitor, compared to the dissolution
rate of said protein kinase inhibitor in raw, crystalline form.
[0105] Typically, said dissolution rate is measured by a flow
through cell system in sink conditions, e.g., according to the US
Pharmacopea (USP4). Dissolution measurement in sink conditions of
hybrid nanoparticles may be measured in a method consisting of
adding the wished amount of powder into a flow through cell system
(SOTAX, Allschwill, Switzerland), mounting the cell onto its
apparatus and then pumping the appropriate medium (typically
FaSSIF, FeSSIF, SGF) through the powder. The temperature of the
apparatus is typically set to 37.degree. C. The amount of powder
added into the cell depends on drug load of the powder: The exact
amount of powder can be calculated from results obtained from drug
load analysis of the powders. The PKI may be added into the flow
through cell and a flow rate between 5 and 25 ml medium/min is
pumped through the powder. One ml samples of the medium passing
through the cell is collected at predetermined times and
subsequently analyzed by HPLC (e.g. C18 column Eclipse, 4.6
mm.times.15 cm, 1 ml/min, detection 254 to 400 nm). Samples are
typically taken after 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10,
15, 20, 25, 30, 35 and 40 min from the moment the medium comes out
from the flow through cell. The accumulated % solubilized of the
amount of active substance added into the flow through cell can be
calculated and plotted against time (min). The initial slope
("initial dissolution rate", representing 0-10 minutes) of the
graph may be estimated and taken as the dissolution rate of the
material in sink condition at 37.degree. C. in the given
dissolution medium.
[0106] Preferably, the dissolution rate is measured within the
initial 0 to 10 minutes of dissolution.
[0107] The increased dissolution rate is preferably measured in a
solution as a dissolution rate ratio of said hybrid nanoparticles
and said protein kinase inhibitor in raw, crystalline form.
Preferably said ratio is from about 1.5:1 to about 500:1, such as
from about 10:1 to about 30:1.
[0108] Preferably, the dissolution rate is measured in a solution
with intestinal pH, such as FaSSIF or FeSSIF or in a solution with
gastric pH, such as SGF.
[0109] Typically, said dissolution rate is measured by a flow
through cell system, for instance in sink conditions. Dissolution
measurement in sink conditions of hybrid nanoparticles may be
measured in a method consisting of adding the wished amount of
powder into a flow through cell system (SOTAX, Allschwill,
Switzerland), mounting the cell onto its apparatus and then pumping
the appropriate medium (typically FaSSIF, FeSSIF, SGF) through the
powder. The temperature of the apparatus is typically set to
37.degree. C. The amount of powder added into the cell depends on
drug load of the powder: The exact amount of powder can be
calculated from results obtained from drug load analysis of the
powders. The PKI may be added into the flow through cell and a flow
rate between 5 and 25 ml medium/min is pumped through the powder.
One ml samples of the medium passing through the cell is collected
at predetermined times and subsequently analyzed by HPLC (e.g. C18
column Eclipse, 4.6 mm.times.15 cm, 1 ml/min, detection 254 to 400
nm). Samples are typically taken after 0, 0.5, 1, 1.5, 2, 3, 4, 5,
6, 7, 8, 9, 10, 15, 20, 25, 30, 35 and 40 min from the moment the
medium comes out from the flow through cell. The accumulated %
solubilized of the amount of active substance added into the flow
through cell, can be calculated and plotted against time (min). The
initial slope ("initial dissolution rate", representing 0-10
minutes) of the graph can be estimated and taken as the dissolution
rate of the material in sink condition at 37.degree. C. in the
given dissolution medium.
[0110] In another embodiment of this aspect, there is provided a
method of producing stable, amorphous hybrid nanoparticles
comprising at least one protein kinase inhibitor and at least one
polymeric stabilizing and matrix-forming component, which produces
particles that provides a solubility increase of inhibitor in a
solution, said increase measured as the area under the curve (AUC)
during about from 40 minutes to about 90 minutes, in said solution
as compared with the AUC of inhibitor in raw, crystalline form.
Preferably, said increase is from about 2:1 to about 10 000:1,
wherein 1 represents AUC of inhibitor in raw, crystalline form.
Preferably, said increase is measured in a solution with gastric
pH, such as SGF, or measured in a solution with intestinal pH, such
as FaSSIF or FeSSIF. The methods may produce particles that provide
a solubility increase of inhibitor in a solution up to
supersaturation, said increase measured as the area under the curve
(AUC) during about from 40 minutes to about 90 minutes, in said
solution as compared with the AUC of inhibitor in raw, crystalline
form.
[0111] In another embodiment of this aspect, there is provided a
method of producing stable, amorphous hybrid nanoparticles
comprising at least one protein kinase inhibitor and at least one
polymeric stabilizing and matrix-forming component, characterized
by providing an amorphous powder X-ray diffraction pattern.
[0112] In another embodiment of this aspect, there is provided a
method of producing stable, amorphous hybrid nanoparticles
comprising at least one protein kinase inhibitor and at least one
polymeric stabilizing and matrix-forming component, wherein the
dissolution rate of said stable, amorphous hybrid nanoparticles
remain stable to at least about 90%, after 6 months of storage or
more, at room temperature.
[0113] In another embodiment of this aspect, said protein kinase
inhibitor is a tyrosine kinase inhibitor selected from the group
consisting of lapatinib, pazopanib, nilotinib, erlotinib,
dasatinib, gefitinib, sorafenib, crizotinib, vemurafenib and
axitinib; or salts or hydrates or solvates thereof, or combinations
thereof. In some embodiments it may be advantageous to use other
PKIs. Examples of PKI include, but are not limited to afatinib,
bosutinib, cediranib, fostamatinib, imatinib, lenvatinib,
lestaurtinib, motesanib, mubritinib, pegaptanib, ruxolitinib,
semaxanib, sunitinib, tandunitib, tipifamib and vandetanib; or
salts or hydrates or solvates thereof, or combinations thereof.
[0114] In another embodiment of this aspect, said hybrid
nanoparticles has an average particle diameter size of less than
about 1000 nm, such as less than about 500 nm, preferably less than
250 nm.
[0115] In another embodiment of this aspect, said solvent is an
organic solvent selected from DMSO and trifluoroethanol, or a
mixture of these solvents, or mixture of these solvents with other
organic solvent such as DMSO/acetone, DMSO/tetrahydrofurane or
trifluoroethanol/ethyl acetate.
[0116] In another embodiment of this aspect, said particles further
comprise a solubilizer within the particles. Said solubilizer may
be polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol
copolymer, d-.alpha.-tocopherol acid polyethylene glycol 1000
succinate, or a hydrogenated castor oil, such as PEG-40
hydrogenated castor oil or PEG-35 hydrogenated castor oil.
[0117] In another embodiment of this aspect, the method further
comprises formulating the particles retained in step (c) as a
pharmaceutical composition containing the particles and optionally
further pharmaceutically acceptable excipients.
[0118] In another aspect of the invention, there is provided
stable, amorphous hybrid nanoparticles, comprising at least one
protein kinase inhibitor and at least one polymeric stabilizing and
matrix-forming component, obtainable by the methods described
above.
[0119] The hybrid nanoparticles produced by the methods of the
present invention may also dissolve and the protein kinase
inhibitor may be systemically absorbed independently of the pH in
the surrounding environment, and typically approximately in equal
amounts, especially at both a gastric pH, such as from about pH 1.2
to about pH 2.1, preferably about 1.7 and at a intestinal pH such
as from about pH 4.5 to about pH 8, preferably at a pH of about 6.
With systemically absorbed, is meant that the protein kinase
inhibitor is released from the hybrid nanoparticles and taken up by
the systemic blood stream. Therefore, in another embodiment of this
aspect, there is provided a method, wherein said protein kinase
inhibitor is systemically absorbed independently of the pH.
Typically, said protein kinase inhibitor is systemically absorbed
with approximately equal amounts at both a gastric pH and at an
intestinal pH. Preferably, said acid pH is about pH 1.4 and
preferably said neutral pH is about pH 6.5.
[0120] With approximately equal amounts is meant that the
concentration of protein kinase inhibitor in the blood stream,
after exposure is approximately similar. This may be illustrated by
a ratio, wherein the concentration of protein kinase inhibitor in
the blood stream is measured after administration in gastric pH
conditions (A) and compared with the concentration of protein
kinase inhibitor in the blood stream is measured after
administration in intestinal pH conditions (N). Typically, the
ratio A:N is from about 0.75:1 to about 1.5:1 and preferably from
about 1:1 to about 1.25:1. The concentration measurement of protein
kinase inhibitor in the blood stream may be carried out as an area
under the curve (AUC) during 0-24 hours, the maximum concentration
(Cmax) or as bioavailability.
[0121] Consequently, in another embodiment of this aspect, there is
provided a method of producing stable, amorphous hybrid
nanoparticles, comprising at least one protein kinase inhibitor and
at least one polymeric stabilizing and matrix-forming component,
wherein the concentration of systemically absorbed protein kinase
inhibitor in gastric pH conditions compared with the concentration
of systemically absorbed protein kinase inhibitor in intestinal pH
conditions is in a ratio of from about 0.75:1 to about 1.5:1,
preferably of from about 1:1 to about 1.25:1. Typically said
gastric pH condition represents a pH of about 1.4 and said
intestinal pH condition represents a pH of about 6. Typically, the
concentration is measured as area under the curve (AUC) during 0-24
hours of exposure of the composition or as the maximum
concentration (Cmax).
[0122] The amounts of systemically absorbed protein kinase
inhibitor may be measured in various ways. There is provided, in
Example 14 in the present disclosure, a method for measurement of
systemically absorbed protein kinase inhibitors at various pHs,
i.e. under both acid and neutral conditions.
[0123] In another embodiment of this aspect, there is provided a
method of producing stable, amorphous hybrid nanoparticles,
comprising at least one protein kinase inhibitor and at least one
polymeric stabilizing and matrix-forming component, which produces
a solubility increase of inhibitor in a solution up to
supersaturation, said increase measured as the area under the curve
(AUC) during about 90 minutes, in said solution and compared with
the AUC of inhibitor in crystalline form. Said increase may be from
to about 2:1 to about 1000:1, wherein 1 represents AUC of inhibitor
in crystalline form.
[0124] For understanding how the hybrid nanoparticles produced by
the methods of the invention will dissolve in vivo in the different
environments of the stomach, small intestine, large intestine and
colon, it is important to choose an appropriate solution for in
vitro dissolution testing. It is critical that the in vitro test
conditions mimic the in vivo environment as closely as possible,
for example pH and osmolarity. Typically, for intestinal uptake,
the pH is between 6 and 7. Therefore, the solution may hold a pH
from about pH 6 to about pH 7, such as about pH 6.5.
[0125] Therefore, in embodiments of the invention, the solution for
testing has a pH from about pH 4.5 to about pH 8, such as about pH
6.5 or such as about pH 5. The solutions may represent Fasted
Simulated State Intestinal Fluid (FaSSIF) or Fed Simulated State
Intestinal Fluid (FeSSIF).
[0126] Typically, for gastric uptake, the pH is between 1 and 2.
Therefore, the solution may hold a pH from about pH 1 to about pH
2, such as about pH 1.4. Therefore, in embodiments of the
invention, the solution for testing may represent Simulated Gastric
Fluid (SGF).
[0127] The choice of solution will be dependent on where in the
intestinal tract and under what conditions (fasted or fed) the
composition is desired to dissolve and be taken up. Recipes and
preparation of these solutions are obtainable from the manufacturer
(Biorelevant, Croydon, U.K.). Further details are also disclosed in
Jantratid, E., and Dressman, J. (2009) Dissolut. Technol. 8,
21-25).
[0128] In another embodiment of this aspect, there is provided a
method of producing stable, amorphous hybrid nanoparticles,
comprising at least one protein kinase inhibitor and at least one
polymeric stabilizing and matrix-forming component and further a
solubilizer selected from polyvinyl caprolactam-polyvinyl
acetate-polyethylene glycol copolymer, d-.alpha.-tocopherol acid
polyethylene glycol 1000 succinate, Poloxamers (e.g. Pluronics,
Kolliphor) and a hydrogenated castor oil, such as PEG-40
hydrogenated castor oil or PEG-35 hydrogenated castor oil.
Preferably said solubilizer is polyvinyl caprolactam-polyvinyl
acetate-polyethylene glycol copolymer or a hydrogenated castor oil,
such as PEG-40 hydrogenated castor oil or PEG-35 hydrogenated
castor oil.
[0129] It may further be advantageous to use different dispersion
agents and/or other excipients to achieve different dissolution
profiles. For example using Nilotinib HCl powder with HPC EF, HPMC
(e.g. Methocel) and poloxamer (e.g. Lutrol.RTM. F127) result in
hybrid nanoparticles with different dissolution profiles.
[0130] The amount of PKI in the hybrid nanoparticles produced by
the methods of the present invention may be less or more, such as
wherein the amount of PKI in the hybrid nanoparticles is from about
0.01% by weight to about 99.9% by weight.
[0131] In another embodiment of this aspect, there is provided
hybrid nanoparticles produced by the methods of the present
invention, wherein the amount of PKI in the hybrid nanoparticles is
from about 10% by weight to about 70% by weight.
[0132] In another embodiment of this aspect, there is provided
hybrid nanoparticles produced by the methods of the present
invention, wherein the amount of PKI in the hybrid nanoparticles is
from about 10% by weight to about 50% by weight.
[0133] In some embodiments, it may be advantageous that the amount
of PKI in the hybrid nanoparticles is from 5% by weight to about
50% by weight, from 10% by weight to about 40% by weight, from
about 10% by weight to about 30% by weight, or from about 10% by
weight to about 20% by weight.
[0134] Control of the characteristics of the particles may be
convenient for specific applications. Particle size, particle
agglomeration, particles porosity and the choice and ratio of the
polymeric stabilizing and matrix-forming agent could be modified in
order to increase or decrease the surface area to volume ratio of
the particle or behaviour of the particles in a gastroinstestinal
fluids, leading to an increase or decrease of the dissolution rate.
Dependent on the desired dissolution characteristics such particles
characteristics may be adapted. Furthermore, particles with
different characteristics may be present in the same pharmaceutical
composition to provide an initial dose and a prolonged or delayed
dose of active ingredient. Additionally, it may be advantageous to
provide different PKIs and/or other active ingredient(s) in
different primary particles with different characteristics adapted
to provide desired dissolution rates for each active
ingredient(s).
[0135] Other embodiments of the invention provide pharmaceutical
compositions comprising the hybrid nanoparticles obtainable by the
methods of the invention. Such compositions may further comprise at
least one pharmaceutically acceptable solubilizer. Said solubilizer
may be present separated from the hybrid nanoparticles in the
composition or be randomly intermixed with the hybrid nanoparticles
in the pharmaceutical composition. The pharmaceutical composition
may also be in a dosage form consisting of several layers, for
example laminated or multilayered tablets, such that the hybrid
nanoparticles are separated from the solubilizer. The solubilizer
may be selected from polyvinyl caprolactam-polyvinyl
acetate-polyethylene glycol copolymer, d-.alpha.-tocopherol acid
polyethylene glycol 1000 succinate and a hydrogenated castor oil,
such as PEG-40 hydrogenated castor oil or PEG-35 hydrogenated
castor oil. Said solubilizer may also be a poloxamer.
[0136] In another embodiment of this aspect, there is provided
stable, amorphous hybrid nanoparticles, comprising at least one
protein kinase inhibitor and at least one polymeric stabilizing and
matrix-forming component, obtainable by methods of the present
invention.
[0137] In another embodiment of this aspect, there is provided a
method of the present invention, further comprising formulating the
particles retained in step (c) as a pharmaceutical composition
containing the particles and optionally further pharmaceutically
acceptable excipients.
[0138] It will be appreciated that the amount of a protein kinase
inhibitor in the hybrid nanoparticles produced by the methods of
the present invention required for use in treatment will vary not
only with the particular inhibitor selected but also with the route
of administration, the nature of the condition for which treatment
is required and the age, weight and condition of the patient and
will be ultimately at the discretion of the attendant physician. In
general however a suitable dose may be in the range of from about
0.005 to about 30 mg/kg of body weight per day, preferably in the
range of 0.05 to 10 mg/kg/day.
[0139] The desired dose is conveniently presented in a single dose
or as a divided dose administered at appropriate intervals, for
example as two, three, four or more doses per day. Dependent on the
need of the treatment and/or prevention, the desired dose may also
be, for example, once every two days, once every three days, or
even once a week.
[0140] The composition is conveniently administered in unit dosage
form; for example containing 0.5 to 1500 mg, conveniently 1 to 1000
mg, most conveniently 5 to 700 mg of active ingredient per unit
dosage form. The compositions of the invention will normally be
administrated via the oral, parenteral, intravenous, intramuscular,
subcutaneous or other injectable ways, buccal, rectal, vaginal,
transdermal and/or nasal route and/or via inhalation, in a
pharmaceutically acceptable dosage form. Depending upon the
disorder and patient to be treated and the route of administration,
the compositions may be administered at varying doses.
[0141] Pharmaceutical compositions include but are not limited to
those suitable for oral, rectal, nasal, topical (including buccal
and sub-lingual), transdermal, vaginal or parenteral (including
intramuscular, subcutaneous and intravenous) administration or in a
form suitable for administration by inhalation or insufflation. The
compositions may, where appropriate, be conveniently presented in
discrete dosage units and may be prepared by any of the methods
well known in the art of pharmacy. Pharmaceutical compositions
suitable for oral administration are conveniently presented as
discrete units such as capsules, cachets or tablets, each
containing a predetermined amount of the active substance.
[0142] Tablets and capsules for oral administration may contain
conventional excipients such as binding agents, fillers,
lubricants, disintegrants, or wetting agents. The tablets may be
coated according to methods well known in the art.
[0143] The compositions may be formulated for parenteral
administration (e.g. by injection, for example bolus injection or
continuous infusion) and may be presented in unit dose form in
ampoules, pre-filled syringes, small volume infusion or in
multi-dose containers with an added preservative. The compositions
may take such forms as suspensions, solutions, or emulsions in oily
or aqueous vehicles, and may contain formulation agents such as
suspending, stabilizing and/or dispersing agents.
[0144] The above described compositions may be adapted to give
sustained release of the active inhibitor.
[0145] The following examples are provided to illustrate various
embodiments of the present invention and shall not be considered as
limiting in scope.
EXAMPLES
[0146] Below follows a number of non-limiting examples of hybrid
nanoparticles produced by the methods of the present invention. In
the tables, the following abbreviations to "compositions"
apply:
[0147] "I" represents the protein kinase inhibitor (PKI);
[0148] "P" represents the polymeric stabilizing and matrix-forming
component;
[0149] "S" represents the solubilizer;
[0150] "I+P" represents a physical mix of the inhibitor with the
polymeric stabilizing and matrix-forming component, i.e. without
further processing;
[0151] "I+S" represents a physical mix of the inhibitor with the
solubilizer;
[0152] "I+P+S" represents a physical mix of the inhibitor, the
polymeric stabilizing and matrix-forming component and the
solubilizer;
[0153] "I/P" represents hybrid nanoparticles with the inhibitor and
the polymeric stabilizing and matrix-forming component;
[0154] "I/P+S" represents hybrid nanoparticles with the inhibitor
and the polymeric stabilizing and matrix-forming component and a
separate solubilizer added;
[0155] "I/P/S" represents hybrid nanoparticles with the inhibitor,
the polymeric stabilizing and matrix-forming component and the
solubilizer.
[0156] "Exp" represents the experiment number.
[0157] The hybrid nanoparticles were produced with exemplary PKIs,
polymeric stabilizing and matrix-forming components ("Polymers"),
solubilizers, solution concentrations, ratios, solvents,
antisolvents, temperatures and pressures as set out below and in
Table A.
[0158] A 3-6% w/v PKI/polymer solution in solvent, with a ratio
PKI/polymer of about 20-70% w/w, was pumped through XSpray's
RightSize nozzle at the flow rate of 1 ml/min using a
high-performance liquid chromatography pump, together with a 100
g/min CO.sub.2 (super- or subcritical) stream. The pressure in the
precipitation chamber was set to about 100-175 bar and the
temperature was set to about 10 to 50.degree. C. Both streams
contact within the nozzle and the hybrid nanoparticles were formed
and subsequently collected in the particle in the collecting
chamber. The scCO.sub.2 and solvent passed through the filtering
system of the collecting chamber and were drained via the back
pressure regulator outlet which maintains the pressure within the
precipitation and collecting chambers. After pumping of the
PKI/polymer solution and cleaning of the tubing with the same
solvent used to prepare the PKI/polymer solution, residual solvents
left within both the precipitation and collecting chambers were
removed by flushing these chambers with pure CO.sub.2. After the
flushing process, the CO.sub.2 was slowly drained off from the
collecting chamber. Once the CO.sub.2 had been completely removed,
the particles on the filtering system were collected for
analysis.
[0159] For I/P/S type particles, a defined amount of solubilizer is
added and dissolved into the PKI/polymer solution before pumping
the solution through the nozzle for precipitation according to the
methods described above.
[0160] For I/P+S type particles, a defined amount of solubilizer is
added to the hybrid nanoparticles in a glass vial. The glass vial
is slowly rotated for mixing of the solubilizer with the hybrid
nanoparticles.
TABLE-US-00001 TABLE A Stable, amorphous hybrid nanoparticles with
exemplary PKIs, polymeric stabilizing and matrix-forming
components, solvents, antisolvents and conditions. Solution Ratio
conc. % PKI/Polymer Solvent Temperature PKI/Polymer Exp. # (w/v) %
(w/w) & Antisolvent & Pressure Axitinib/ 160, 162 & 5%
25% DMSO 25.degree. C. Kollidon 581 & CO.sub.2 & 125 Bars
VA64 Crizotinib/ 153, 155, 5% 25% DMSO 25.degree. C. PVP 30K 156
& 571 & CO.sub.2 & 125 Bars Dasatinib/ 140, 141 &
4% 35% DMSO/Acetone 15.degree. C. Kollidon 551 (1:2) & CO.sub.2
& 125 Bars VA64 Erlotinib HCl/ 511 3.6% 35% TFE 25.degree. C.
HPMC AS & CO.sub.2 & 150 Bars Gefitinib/ 135, 137 & 4%
35% DMSO/Acetone 40.degree. C. HPMCP HP55 541 (1:2) & CO2 &
150 Bars Lapatinib base/ 531 5% 66% DMSO/Acetone 40.degree. C. HPC
If (1:2) & CO2 & 150 Bars Nilotinib base/ 501 5% 40% TFE
15.degree. C. HPMCP HP55 & CO.sub.2 & 125 Bars Pazopanib
HCl/ 521 3.6% 35% TFE 25.degree. C. PVP 90K & CO.sub.2 &
150 Bars Sorafenib 561 4% 35% DMSO/Acetone 40.degree. C. tosylate/
(1:2) & CO2 & 150 Bars HPMCP HP55 Vemurafenib/ 168, 170
& 5% 25% DMSO 25.degree. C. CAP 592 & CO.sub.2 & 125
Bars
General Description of Dissolution Measurement Assay
[0161] The method consists of adding the wished amount of powder of
hybrid nanoparticles into a glass vial and then pouring in it the
appropriate medium (typically FaSSIF, FeSSIF or SGF). The medium
was prepared in accordance with the manufacturer's instructions.
The amount of powder added depends on the wished "total PKI
concentration". For some experiments where powders with high drug
loads were tested and compared, the real amount of PKI in the
hybrid nanoparticles was not taken in account. For other
experiments, the drug load was first estimated by HPLC and the
amount of powder to obtain the drug concentration was
calculated.
[0162] Typically, the powder was added in a 8 mL glass bottle and 7
mL of solution was added (typically FaSSIF, FeSSIF or SGF). The
glass bottle was put on a shaker (approximately 1 rotation per
minute) for dissolution. Samples of 500 .mu.l where taken after
different times, and subsequently centrifuged at approximately
15000 g for 3 minutes. The resulting supernatant was then analyzed
by HPLC (C.sub.18 column Eclipse, 4.6 mm.times.15 cm, 1 mL/min,
detection at 254-400 nM. Generally samples were taken after 5, 30
and 90 min and eventually 150 min.
Example 1
Stable, Amorphous Hybrid Nanoparticles with Nilotinib--Solubility
at pH 6.5 and pH 5
[0163] A number of experiments were carried out, wherein nilotinib
base or nilotinib HCl represented the protein kinase inhibitor. The
experiments were carried out by measuring concentration of
solubilized PKI (mg/L) after 5, 30 and 90 minutes dissolution in a
solution at about pH 6.5, namely FaSSIF (Fasted State Simulated
Intestinal Fluid). Further, experiments were carried out in an
alternative solution at about pH 5, namely FeSSIF (Fed State
Simulated Intestinal Fluid). Samples of the solution were taken at
various time intervals and the amount of protein kinase inhibitor
was measured by the dissolution measurement assay described
above.
[0164] Representative results in FaSSIF solution are provided below
in Table 1 and 2, where Table 1 provides data of concentration of
nilotinib HCl (mg/L) after 5, 30 and 90 minutes dissolution,
whereas Table 2 provides data of % solubilized nilotinib HCl after
30 minutes dissolution, the Area Under the Curve (AUC--mg/min/L)
during 90 minutes dissolution and the AUC increase of hybrid
nanoparticles, compared to nilotinib HCl in raw, crystalline form
added to the solution (experiments 1-40). In Tables 3 and 4, there
is provided dissolution data in FeSSIF solution, presented
similarly as Table 1 and 2 (experiments 41-55). Table 5 provides
data from a comparative experiment with similar hybrid
nanoparticles, carried out in FaSSIF and FeSSIF, respectively
(experiments 56-57). Table 6 presents further comparative data for
experiments carried out in FaSSIF and FeSSIF, respectively, with
hybrid nanoparticles produced by the methods of the invention.
TABLE-US-00002 TABLE 1 Nilotinib - concentration of nilotinib HCl
(mg/L) after 5, 30 and 90 minutes dissolution in FaSSIF solution
(pH 6.5). Drug Polymeric load stab. matrix. Conc Conc Conc ratio
Component Solubilizer (mg/L) (mg/L) (mg/L) Exp Comp. Inhibitor (I)
(%) (P) (S) 5 min 30 min 90 min 1 I Nilotinib HCl 100 -- -- 0.1 0.2
0.1 (raw) 100 mg 2 I Nilotinib HCl 100 -- -- 0.2 0.2 0.2 (raw) 500
mg 3 I Nilotinib HCl 100 -- -- 0.2 0.3 0.2 (raw) 1000 mg 4 I
Nilotinib Base 100 -- -- 0.6 0.5 0.2 (raw) 500 mg 5 I + P Nilotinib
HCl 100 HPMCP HP55 -- 0.2 0.5 0.5 (raw) 1000 mg 2000 mg 6 I + P
Nilotinib HCl 100 PVAP -- 1.3 0.2 0.4 (raw) 1000 mg 2000 mg 7 I + P
Nilotinib HCl 100 Eudragit L100 -- 0.2 0.4 0.2 (raw) 1000 mg 2000
mg 8 I + P Nilotinib HCl 100 Methocel E15 -- 0.1 0.1 0.1 (raw) 1000
mg 2000 mg 9 I + S Nilotinib HCl 100 -- Soluplus 0.4 0.3 0.4 (raw)
1000 mg 357.5 mg 10 I + S Nilotinib HCl 100 -- Soluplus 0.4 0.5 0.5
(raw) 1000 mg 715 mg 11 I + S Nilotinib HCl 100 -- Soluplus 0.4 0.5
0.6 (raw) 1000 mg 1072 mg 12 I + P + S Nilotinib HCl 100 HPMCP HP55
Soluplus 0.4 0.6 1.0 (raw) 500 mg 750 mg 715 mg 13 I + P + S
Nilotinib HCl 100 PVAP Soluplus 0.2 0.2 0.3 (raw) 500 mg 750 mg 715
mg 14 I + P + S Nilotinib HCl 100 HPMCP HP55 TPGS 0.5 0.9 1.1 (raw)
500 mg 750 mg 1000 mg 15 I + P + S Nilotinib HCl 100 PVAP TPGS 0.2
0.4 0.5 (raw) 500 mg 750 mg 1000 mg 16 I + P + S Nilotinib Base 100
HPMCP HP55 Soluplus 0.2 0.5 0.4 (raw) 500 mg 750 mg 715 mg 17 I/P
Nilotinib HCl 50 HPMCP HP55 -- 9.5 5.6 4.5 100 mg 100 mg 18 I/P
Nilotinib HCl 40 HPMCP HP55 -- 10.4 5.0 3.7 100 mg 150 mg 19 I/P
Nilotinib HCl 50 PVAP -- 7.3 5.0 4.1 100 mg 100 mg 20 I/P Nilotinib
HCl 40 PVAP -- 8.7 5.0 3.4 100 mg 150 mg 21 I/P Nilotinib HCl 50
Methocel E15 -- 1.4 1.5 1.8 100 mg 100 mg 22 I/P Nilotinib HCl 50
Eudragit L100 -- 5.1 5.9 4.9 100 mg 100 mg 23 I/P Nilotinib Base 40
HPMCP HP55 -- 9.7 4.7 3.8 100 mg 150 mg 24 I/P + S Nilotinib HCl 50
HPMCP HP55 Soluplus 53.4 46.1 35.6 500 mg 500 mg 715 mg 25 I/P + S
Nilotinib HCl 50 HPMCP HP55 Soluplus 85.9 87.9 80.8 500 mg 500 mg
1430 mg 26 I/P + S Nilotinib HCl 50 HPMCP HP55 Soluplus 117.0 127.1
116.9 500 mg 500 mg 2145 mg 27 I/P + S Nilotinib HCl 50 HPMCP HP55
TPGS 49.6 30.1 22.3 500 mg 500 mg 1000 mg 28 I/P + S Nilotinib HCl
50 HPMCP HP55 TPGS 98.4 57.4 42.6 500 mg 500 mg 2000 mg 29 I/P + S
Nilotinib HCl 40 HPMCP HP55 Soluplus 93.5 45.2 14.1 500 mg 750 mg
357.5 mg 30 I/P + S Nilotinib HCl 40 HPMCP HP55 Soluplus 145.0
134.3 36.8 500 mg 750 mg 715 mg 31 I/P + S Nilotinib HCl 40 HPMCP
HP55 TPGS 93.8 31.0 22.4 500 mg 750 mg 1000 mg 32 I/P + S Nilotinib
HCl 40 PVAP Soluplus 82.9 137.9 42.9 500 mg 750 mg 715 mg 33 I/P +
S Nilotinib HCl 40 PVAP TPGS 77.8 32.3 22.8 500 mg 750 mg 1000 mg
34 I/P + S Nilotinib HCl 50 Methocel E15 Soluplus 3.3 4.0 5.8 500
mg 500 mg 715 mg 35 I/P + S Nilotinib HCl 50 Methocel E15 TPGS 4.8
5.4 6.7 500 mg 500 mg 1000 mg 36 I/P + S Nilotinib Base 40 HPMCP
HP55 Soluplus 178.1 120.4 33.7 500 mg 750 mg 715 mg 37 I/P/S
Nilotinib HCl 25.4 HPMCP HP55 Soluplus 25.9 15.8 16.3 500 mg 750 mg
715 mg 38 I/P/S Nilotinib HCl 25.4 PVAP Soluplus 9.5 13.2 10.1 500
mg 750 mg 715 mg 39 I/P/S Nilotinib HCl 22.2 HPMCP HP55 TPGS 16.2
13.7 3.9 500 mg 750 mg 1000 mg 40 I/P/S Nilotinib HCl 22.2 PVAP
TPGS 13.3 12.1 9.7 500 mg 750 mg 1000 mg
TABLE-US-00003 TABLE 2 Percentage solubilized nilotinib HCl after
30 minutes dissolution, the Area Under the Curve (AUC - mg/min/L)
during 90 minutes dissolution and the AUC increase of stable,
amorphous hybrid nanoparticles produced by the methods of the
invention, compared to nilotinib HCl in raw, crystalline form added
to the FaSSIF solution (pH 6.5). Drug Polymeric load stab. matrix.
AUC/ ratio Component Solubilizer % solubilized 90 min AUC Exp Comp.
Inhibitor (I) (%) (P) (S) 30 min. Mg/min/L increase 1 I Nilotinib
HCl 100 -- -- 0.20 13.0 -- (raw) 100 mg 2 I Nilotinib HCl 100 -- --
0.04 23.5 -- (raw) 500 mg 3 I Nilotinib HCl 100 -- -- 0.03 21.8 --
(raw) 1000 mg 4 I Nilotinib Base 100 -- -- 0.50 36.5 -- (raw) 500
mg 5 I + P Nilotinib HCl 100 HPMCP HP55 -- 0.05 39.3 2.0 (raw) 1000
mg 2000 mg 6 I + P Nilotinib HCl 100 PVAP 2000 mg -- 0.02 40.0 2.1
(raw) 1000 mg 7 I + P Nilotinib HCl 100 Eudragit L100 -- 0.04 26.0
1.3 (raw) 1000 mg 2000 mg 8 I + P Nilotinib HCl 100 Methocel E15 --
0.01 8.8 0.5 (raw) 1000 mg 2000 mg 9 I + S Nilotinib HCl 100 --
Soluplus 0.03 30.8 1.6 (raw) 1000 mg 357.5 mg 10 I + S Nilotinib
HCl 100 -- Soluplus 0.05 42.3 2.2 (raw) 1000 mg 715 mg 11 I + S
Nilotinib HCl 100 -- Soluplus 0.05 45.3 2.3 (raw) 1000 mg 1072 mg
12 I + P + S Nilotinib HCl 100 HPMCP HP55 Soluplus 0.12 61.5 3.2
(raw) 500 mg 750 mg 715 mg 13 I + P + S Nilotinib HCl 100 PVAP
Soluplus 0.04 20.5 1.1 (raw) 500 mg 750 mg 715 mg 14 I + P + S
Nilotinib HCl 100 HPMCP HP55 TPGS 0.18 78.8 4.1 (raw) 500 mg 750 mg
1000 mg 15 I + P + S Nilotinib HCl 100 PVAP TPGS 0.08 35.0 1.8
(raw) 500 mg 750 mg 1000 mg 16 I + P + S Nilotinib Base 100 HPMCP
HP55 Soluplus 0.10 36.3 1.9 (raw) 500 mg 750 mg 715 mg 17 I/P
Nilotinib HCl 50 HPMCP HP55 -- 5.6 515.5 26.6 100 mg 100 mg 18 I/P
Nilotinib HCl 40 HPMCP HP55 -- 5.0 479.5 24.7 100 mg 150 mg 19 I/P
Nilotinib HCl 50 PVAP -- 5.0 445.0 22.9 100 mg 100 mg 20 I/P
Nilotinib HCl 40 PVAP -- 5.0 445.0 22.9 100 mg 150 mg 21 I/P
Nilotinib HCl 50 Methocel E15 -- 1.5 138.8 7.2 100 mg 100 mg 22 I/P
Nilotinib HCl 50 Eudragit L100 -- 5.9 474.3 24.2 100 mg 100 mg 23
I/P Nilotinib Base 40 HPMCP HP55 -- 4.7 459.3 23.7 100 mg 150 mg 24
I/P + S Nilotinib HCl 50 HPMCP HP55 Soluplus 9.2 3828.3 197.3 500
mg 500 mg 715 mg 25 I/P + S Nilotinib HCl 50 HPMCP HP55 Soluplus
17.6 7448.3 383.9 500 mg 500 mg 1430 mg 26 I/P + S Nilotinib HCl 50
HPMCP HP55 Soluplus 25.4 10663.8 549.7 500 mg 500 mg 2145 mg 27 I/P
+ S Nilotinib HCl 50 HPMCP HP55 TPGS 6.0 2692.3 138.8 500 mg 500 mg
1000 mg 28 I/P + S Nilotinib HCl 50 HPMCP HP55 TPGS 11.5 5193.5
267.7 500 mg 500 mg 2000 mg 29 I/P + S Nilotinib HCl 40 HPMCP HP55
Soluplus 9.0 3746.5 193.1 500 mg 750 mg 357.5 mg 30 I/P + S
Nilotinib HCl 40 HPMCP HP55 Soluplus 26.9 8974.8 462.6 500 mg 750
mg 715 mg 31 I/P + S Nilotinib HCl 40 HPMCP HP55 TPGS 6.2 3396.5
175.1 500 mg 750 mg 1000 mg 32 I/P + S Nilotinib HCl 40 PVAP
Soluplus 27.6 8391.3 432.5 500 mg 750 mg 715 mg 33 I/P + S
Nilotinib HCl 40 PVAP TPGS 6.5 3223.8 166.2 500 mg 750 mg 1000 mg
34 I/P + S Nilotinib HCl 50 Methocel E15 Soluplus 0.8 393.5 20.3
500 mg 500 mg 715 mg 35 I/P + S Nilotinib HCl 50 Methocel E15 TPGS
1.1 505.5 25.9 500 mg 500 mg 1000 mg 36 I/P + S Nilotinib Base 40
HPMCP HP55 Soluplus 24.1 8799.5 453.6 500 mg 750 mg 715 mg 37 I/P/S
Nilotinib HCl 25.4 HPMCP HP55 Soluplus 3.2 1549.0 79.8 500 mg 750
mg 715 mg 38 I/P/S Nilotinib HCl 25.4 PVAP Soluplus 2.6 1006.5 51.9
500 mg 750 mg 715 mg 39 I/P/S Nilotinib HCl 22.2 HPMCP HP55 TPGS
2.7 942.3 48.6 500 mg 750 mg 1000 mg 40 I/P/S Nilotinib HCl 22.2
PVAP TPGS 2.4 1004.8 51.8 500 mg 750 mg 1000 mg
TABLE-US-00004 TABLE 3 Nilotinib - concentration of nilotinib HCl
(mg/L) after 5, 30 and 90 minutes dissolution in FeSSIF solution
(pH 5). Drug Polymeric load stab. matrix. Conc Conc Conc ratio
Component Solubilizer (mg/L) (mg/L) (mg/L) Exp Comp. Inhibitor (I)
(%) (P) (S) 5 min 30 min 90 min 41 I Nilotinib HCl 100 -- -- 0.6
0.9 0.9 (raw) 500 mg 42 I + P + S Nilotinib HCl 100 HPMCP HP55
Soluplus 0.4 0.6 1.0 (raw) 500 mg 750 mg 715 mg 43 I + P + S
Nilotinib HCl 100 HPMCP HP55 Soluplus 0.2 0.2 0.3 (raw) 500 mg 750
mg 1000 mg 44 I + P + S Nilotinib HCl 100 PVAP Soluplus 0.5 0.9 1.1
(raw) 500 mg 750 mg 715 mg 45 I + P + S Nilotinib HCl 100 PVAP TPGS
0.2 0.4 0.5 (raw) 500 mg 750 mg 1000 mg 46 I/P Nilotinib HCl 40
HPMCP HP55 -- 16.2 45.6 63.3 500 mg 750 mg 47 I/P Nilotinib HCl 40
PVAP -- 3 7.7 11.2 500 mg 150 mg 48 I/P + S Nilotinib HCl 40 HPMCP
HP55 Soluplus 47.7 85.5 109.4 500 mg 750 mg 715 mg 49 I/P + S
Nilotinib HCl 40 HPMCP HP55 TPGS 74.8 112.4 125.5 500 mg 750 mg
1000 mg 50 I/P + S Nilotinib HCl 40 PVAP Soluplus 12.9 21.3 27.3
500 mg 750 mg 715 mg 51 I/P + S Nilotinib HCl 40 PVAP TPGS 20.5
29.8 31.8 500 mg 750 mg 1000 mg 52 I/P/S Nilotinib HCl 40 HPMCP
HP55 Soluplus 42.3 81.5 108.1 500 mg 750 mg 715 mg 53 I/P/S
Nilotinib HCl 40 HPMCP HP55 TPGS 86.3 116.3 128.8 500 mg 750 mg
1000 mg 54 I/P/S Nilotinib HCl 40 PVAP Soluplus 6.3 18.8 28.2 500
mg 750 mg 715 mg 55 I/P/S Nilotinib HCl 40 PVAP TPGS 20.5 29.8 31.8
500 mg 750 mg 1000 mg
TABLE-US-00005 TABLE 4 Percentage solubilized nilotinib HCl after
30 minutes dissolution, the Area Under the Curve (AUC - mg/min/L)
during 90 minutes dissolution and the AUC increase of stable,
amorphous hybrid nanoparticles produced by the methods of the
invention, compared to nilotinib HCl in raw, crystalline form added
to the FeSSIF solution (pH 5). Drug Polymeric load stab. matrix.
AUC/ ratio Component Solubilizer % solubilized 90 min AUC Exp Comp.
Inhibitor (I) (%) (P) (S) 30 min. Mg/min/L increase 41 I Nilotinib
HCl 100 -- -- 0.18 74.3 -- (raw) 500 mg 42 I + P + S Nilotinib HCl
100 HPMCP HP55 Soluplus 0.12 61.5 0.8 (raw) 500 mg 750 mg 715 mg 43
I + P + S Nilotinib HCl 100 HPMCP HP55 Soluplus 0.04 20.5 0.3 (raw)
500 mg 750 mg 1000 mg 44 I + P + S Nilotinib HCl 100 PVAP Soluplus
0.18 78.8 1.1 (raw) 500 mg 750 mg 715 mg 45 I + P + S Nilotinib HCl
100 PVAP TPGS 0.08 35.0 0.5 (raw) 500 mg 750 mg 1000 mg 46 I/P
Nilotinib HCl 40 HPMCP HP55 -- 9.1 4080.0 54.9 500 mg 750 mg 47 I/P
Nilotinib HCl 40 PVAP -- 7.7 708.3 9.5 500 mg 150 mg 48 I/P + S
Nilotinib HCl 40 HPMCP HP55 Soluplus 17.1 7631.3 102.8 500 mg 750
mg 715 mg 49 I/P + S Nilotinib HCl 40 HPMCP HP55 TPGS 22.5 9664.0
130.2 500 mg 750 mg 1000 mg 50 I/P + S Nilotinib HCl 40 PVAP
Soluplus 4.3 1917.8 25.8 500 mg 750 mg 715 mg 51 I/P + S Nilotinib
HCl 40 PVAP TPGS 6.0 2528.0 34.0 500 mg 750 mg 1000 mg 52 I/P/S
Nilotinib HCl 40 HPMCP HP55 Soluplus 16.3 7341.3 98.9 500 mg 750 mg
715 mg 53 I/P/S Nilotinib HCl 40 HPMCP HP55 TPGS 23.3 10101.3 136.0
500 mg 750 mg 1000 mg 54 I/P/S Nilotinib HCl 40 PVAP Soluplus 3.8
1739.5 23.4 500 mg 750 mg 715 mg 55 I/P/S Nilotinib HCl 40 PVAP
TPGS 6.0 2528.0 34.0 500 mg 750 mg 1000 mg
TABLE-US-00006 TABLE 5 Nilotinib - concentration of nilotinib HCl
(mg/L) after 5, 30, 90 and 150 minutes dissolution in FaSSIF and
FeSSIF solution, respectively. Drug Polymeric load stab. matrix.
Conc Conc Conc Conc ratio Component Solubilizer (mg/L) (mg/L)
(mg/L) (mg/L) Exp Comp. Inhibitor (I) (%) (P) (S) 5 min 30 min 90
min 150 min 56 I/P + S Nilotinib HCl 40 HPMCP HP55 Soluplus 51.2 66
62.3 53.2 FaSSIFF 75 mg 112.5 mg 715 mg 57 I/P + S Nilotinib HCl 40
HPMCP HP55 Soluplus 24.8 43.1 50.7 53 FeSSIFF 75 mg 112.5 mg 715
mg
TABLE-US-00007 TABLE 6 Nilotinib - concentration of nilotinib HCl
(mg/L) after 5, 30, 90 and 150 minutes dissolution in FaSSIF and
FeSSIF solution, respectively presented as comparative data. Drug
Polymeric load stab. matrix. Compare Compare Compare Compare ratio
Component Solubilizer (%) (%) (%) (%) Exp Comp. Inhibitor (I) (%)
(P) (S) 5 min 30 min 90 min 150 min 2 & 41 I Nilotinib HCl 100
-- -- 300 450 225 -- (raw) 1000 mg 12 & 42 I + P + S Nilotinib
HCl 100 HPMCP HP55 Soluplus 100 200 250 -- (raw) 750 m g 715 mg 500
mg 18 & 46 I/P Nilotinib HCl 40 HPMCP HP55 -- 156 912 1711 --
100/500 mg 150/750 mg 30 & 48 I/P + S Nilotinib HCl 40 HPMCP
HP55 Soluplus 33 64 301 -- 500 mg 750 mg 715 mg 56 & 57 I/P + S
Nilotinib HCl 40 HPMCP HP55 Soluplus 48 65 81 100 (raw) 75 mg 112.5
mg 715 mg 37 & 52 I/P/S Nilotinib HCl 40 HPMCP HP55 Soluplus
163 516 663 -- 500 mg 750 mg 715 mg
Conclusions Example 1
[0165] Experiments 17-23 show that a solubility increase is
obtained with stable, amorphous hybrid nanoparticles produced by
the methods of the invention with nilotinib HCl and a polymeric
stabilizing and matrix-forming component. Particular improvements
are achieved with the polymeric stabilizing and matrix-forming
components hydroxypropyl methylcellulose phthalate (HPMCP HP55) and
polyvinyl acetate phthalate (PVAP). These improvements are not
obtained when physically mixing nilotinib HCl with a polymeric
stabilizing and matrix-forming component. Experiments 24-36 clearly
shows that a further solubility increase is obtained with hybrid
nanoparticles produced by the methods of the invention with
nilotinib HCl and a polymeric stabilizing and matrix-forming
component, wherein a separate solubilizer is added. Particular
improvements are achieved by the addition of a separate solubilizer
such as polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol
copolymer (Soluplus) or d-.alpha.-tocopherol acid polyethylene
glycol 1000 succinate (TPGS). These improvements were not obtained
when physically mixing nilotinib HCl, solubilizer and/or polymeric
stabilizing and matrix-forming component (I+S or I+P+S). No
particular improvements were obtained with hybrid nanoparticles
with nilotinib HCl, a polymeric stabilizing and matrix-forming
component and a solubilizer (I/P/S).
[0166] The results carried out in FaSSIF and FeSSIF, respectively,
indicate that the stable, amorphous hybrid nanoparticles produced
by the methods of the invention provide a similar increase in
solubility. One issue with PKI formulation is the food effect.
Several of the PKIs are labeled for administration in fasted state
despite the fact that food in most cases increases their
bioavailability. Low bioavailability might partly explain the
digestive problems that are associated with the PKIs. The similar
dissolution rate in FaSSIF and FeSSIF indicates that the hybrid
nanoparticles produced by the methods of the invention (e.g.
experiments 56/57) may reduce food effect and patient digestive
problems by its solubility improvement that allows reducing dosage.
Thus hybrid nanoparticles produced by the methods of the invention
may be given in conjunction with food intake.
Example 2
Stable, Amorphous Hybrid Nanoparticles with Erlotinib
HCl--Solubility at pH 6.5 and pH 5
[0167] A number of experiments were carried out, wherein erlotinib
HCl represented the PKI. The experiments were carried out by
measuring concentration of PKI (mg/L) after 5, 30 and 90 minutes
dissolution in a solution at about pH 6.5, namely FaSSIF (Fasted
State Simulated Intestinal Fluid). Further, experiments were
carried out in an alternative solution at about pH 5, namely FeSSIF
(Fed State Simulated Intestinal Fluid). Samples of the solution
were taken at various time intervals and the amount of PKI was
measured by the dissolution measurement assay described above.
[0168] Representative results in FaSSIF solution are provided below
in Table 7 and 8, where Table 7 provides data of concentration of
erlotinib HCl (mg/L) after 5, 30 and 90 minutes dissolution,
whereas Table 8 provides data of % solubilized erlotinib HCl after
30 minutes dissolution, the Area Under the Curve (AUC--mg/min/L)
during 90 minutes dissolution and the AUC increase of hybrid
nanoparticles produced by the methods of the invention, compared to
erlotinib HCl in raw, crystalline form added to the solution
(experiments 58-68). In Tables 9 and 10, there is provided
dissolution data in FeSSIF solution, presented similarly as Table 7
and 8 (experiments 69-73). In Table 11, data from a comparative
experiment with similar hybrid nanoparticles produced by the
methods of the invention, carried out in FaSSIF and FeSSIF,
respectively (experiments 74-83). Table 12 presents further
comparative data for experiments carried out in FaSSIF and FeSSIF,
respectively, with stable, amorphous hybrid nanoparticles produced
by the methods of the invention.
TABLE-US-00008 TABLE 7 Erlotinib - concentration of erlotinib HCl
(mg/L) after 5, 30 and 90 minutes dissolution in FaSSIF solution
(pH 6.5). Drug Polymeric load stab. matrix. Conc Conc Conc ratio
Component Solubilizer (mg/L) (mg/L) (mg/L) Exp Comp. Inhibitor (I)
(%) (P) (S) 5 min 30 min 90 min 58 I Erlotinib HCl 100 -- -- 28.9
6.25 4.6 (raw) 1000 mg 59 I + P Erlotinib HCl 100 HPMC-AS -- 23
53.2 84 (raw) 1000 mg 2000 mg 60 I + S Erlotinib HCl 100 --
Soluplus 92.8 156.6 176 (raw) 1000 mg 715 mg 61 I + S Erlotinib HCl
100 -- TPGS 51.4 14.7 11.6 (raw) 1000 mg 1000 mg 62 I + P + S
Erlotinib HCl 100 HPMC-AS Soluplus 96.7 256.6 361.8 (raw) 1000 mg
1850 mg 715 mg 63 I + P + S Erlotinib HCl 100 HPMC-AS TPGS 81.3
188.1 256.6 (raw) 1000 mg 1850 mg 1000 mg 64 I/P Erlotinib HCl 35
HPMC-AS -- 83.4 79.6 44.8 1000 mg 1850 mg 65 I/P + S Erlotinib HCl
35 HPMC-AS Soluplus 187.3 269.7 284 1000 mg 1850 mg 715 mg 66 I/P +
S Erlotinib HCl 35 HPMC-AS TPGS 155.2 210.6 225.3 1000 mg 1850 mg
1000 mg 67 I/P/S Erlotinib HCl 28 HPMC-AS Soluplus 90.1 95 96.4
1000 mg 1850 mg 715 mg 68 I/P/S Erlotinib HCl 26 HPMC-AS TPGS 93.7
85.4 52.8 1000 mg 1850 mg 1000 mg
TABLE-US-00009 TABLE 8 Percentage solubilized erlotinib HCl after
30 minutes dissolution, the Area Under the Curve (AUC - mg/min/L)
during 90 minutes dissolution and the AUC increase of stable,
amorphous hybrid nanoparticles produced by the methods of the
invention, compared to erlotinib in raw, crystalline form added to
the FaSSIF solution (pH 6.5). Drug Polymeric load stab. matrix.
AUC/ ratio Component Solubilizer % solubilized 90 min AUC Exp Comp.
Inhibitor (I) (%) (P) (S) 30 min. Mg/min/L increase 58 I Erlotinib
HCl 100 -- -- 0.6 837 -- (raw) 1000 mg 59 I + P Erlotinib HCl 100
HPMC-AS -- 5.3 5126 6.1 (raw) 1000 mg 2000 mg 60 I + S Erlotinib
HCl 100 -- Soluplus 15.7 13328 15.9 (raw) 1000 mg 715 mg 61 I + S
Erlotinib HCl 100 -- TPGS 1.5 1744 2.1 (raw) 1000 mg 1000 mg 62 I +
P + S Erlotinib HCl 100 HPMC-AS Soluplus 25.7 23210 27.7 (raw) 1000
mg 1850 mg 715 mg 63 I + P + S Erlotinib HCl 100 HPMC-AS TPGS 18.8
16912 20.2 (raw) 1000 mg 1850 mg 1000 mg 64 I/P Erlotinib HCl 35
HPMC-AS -- 8.0 5978 7.1 1000 mg 1850 mg 65 I/P + S Erlotinib HCl 35
HPMC-AS Soluplus 27.0 22792 27.2 1000 mg 1850 mg 715 mg 66 I/P + S
Erlotinib HCl 35 HPMC-AS TPGS 21.1 18038 21.5 1000 mg 1850 mg 1000
mg 67 I/P/S Erlotinib HCl 28 HPMC-AS Soluplus 9.5 8281 9.9 1000 mg
1850 mg 715 mg 68 I/P/S Erlotinib HCl 26 HPMC-AS TPGS 8.5 6619 7.9
1000 mg 1850 mg 1000 mg
TABLE-US-00010 TABLE 9 Erlotinib - concentration of erlotinib HCl
(mg/L) after 5, 30 and 90 minutes dissolution in FeSSIF solution
(pH 5). Drug Polymeric load stab. matrix. Conc Conc Conc ratio
Component Solubilizer (mg/L) (mg/L) (mg/L) Exp Comp. Inhibitor (I)
(%) (P) (S) 5 min 30 min 90 min 69 I Erlotinib HCl 100 -- -- 156.8
189.9 196 (raw) 1000 mg 70 I + P + S Erlotinib HCl 100 HPMC-AS
Soluplus 25.5 75.1 126.2 (raw) 1000 mg 1850 mg 715 mg 71 I/P
Erlotinib HCl 35 HPMC-AS -- 258.2 402.1 464.5 1000 mg 1850 mg 72
I/P + S Erlotinib HCl 35 HPMC-AS Soluplus 260.1 422.8 498.8 1000 mg
1850 mg 715 mg 73 I/P/S Erlotinib HCl 28 HPMC-AS Soluplus 293.6
395.2 434.9 1000 mg 1850 mg 715 mg
TABLE-US-00011 TABLE 10 Percentage solubilized erlotinib HCl after
30 minutes dissolution, the Area Under the Curve (AUC - mg/min/L)
during 90 minutes dissolution and the AUC increase of stable,
amorphous hybrid nanoparticles produced by the methods of the
invention, compared to erlotinib in raw, crystalline form added to
the FeSSIF solution (pH 5). Drug Polymeric load stab. matrix. AUC/
ratio Component Solubilizer % solubilized 90 min AUC Exp Comp.
Inhibitor (I) (%) (P) (S) 30 min. Mg/min/L increase 69 I Erlotinib
HCl 100 -- -- 19.0 16303 -- (raw) 1000 mg 70 I + P + S Erlotinib
HCl 100 HPMC-AS Soluplus 7.5 7360 0.5 (raw) 1000 mg 1850 mg 715 mg
71 I/P Erlotinib HCl 35 HPMC-AS -- 40.2 34897 2.1 1000 mg 1850 mg
72 I/P + S Erlotinib HCl 35 HPMC-AS Soluplus 42.3 36835 2.3 1000 mg
1850 mg 715 mg 73 I/P/S Erlotinib HCl 28 HPMC-AS Soluplus 35.5
34244 2.1 1000 mg 1850 mg 715 mg
TABLE-US-00012 TABLE 11 Erlotinib - concentration of erlotinib HCl
after 5, 30 and 90 minutes dissolution in FaSSIF and FeSSIF
solution, respectively. Drug Polymeric load stab. matrix. Conc Conc
Conc ratio Component Solubilizer (mg/L) (mg/L) (mg/L) Exp Comp.
Inhibitor (I) (%) (P) (S) 5 min 30 min 90 min 74 I + P + S
Erlotinib HCl 100 HPMC-AS Soluplus 134.1 369.8 533.4 FaS (raw) 1000
mg 1850 mg 1430 mg SIF 75 I + P + S Erlotinib HCl 100 HPMC-AS
Soluplus 24.4 88.8 154.4 FeS (raw) 1000 mg 1850 mg 1430 mg SIF 76
I/P + S Erlotinib HCl 35 HPMC-AS Soluplus 275.4 441.4 508 FaS 1000
mg 1850 mg 1430 mg SIF 77 I/P + S Erlotinib HCl 35 HPMC-AS Soluplus
292.2 476.2 546.5 FeS 1000 mg 1850 mg 1430 mg SIF 78 I/P/S
Erlotinib HCl 23 HPMC-AS Soluplus 90.4 108 114.8 FaS 1000 mg 1850
mg 1430 mg SIF 79 I/P/S Erlotinib HCl 23 HPMC-AS Soluplus 259.3
354.8 405.5 FeS 1000 mg 1850 mg 1430 mg SIF 80 I + P + S Erlotinib
HCl 100 HPMC-AS Soluplus 78.6 216.4 304.6 FaS (raw) 500 mg 925 mg
715 mg SIF 81 I + P + S Erlotinib HCl 100 HPMC-AS Soluplus 16.2
55.8 104.7 FeS (raw) 500 mg 925 mg 715 mg SIF 82 I/P + S Erlotinib
HCl 35 HPMC-AS Soluplus 171.6 284.6 334.6 FaS 500 mg 925 mg 715 mg
SIF 83 I/P + S Erlotinib HCl 35 HPMC-AS Soluplus 168.3 268.7 317.9
FeS 500 mg 925 mg 715 mg SIF
TABLE-US-00013 TABLE 12 Erlotinib - concentration of erlotinib HCl
(mg/L) after 5, 30 and 90 minutes dissolution in FaSSIF and FeSSIF
solution, respectively presented as comparative data. Drug
Polymeric load stab. matrix. Compare Compare Compare ratio
Component Solubilizer (%) (%) (%) Exp Comp. Inhibitor (I) (%) (P)
(S) 5 min 30 min 90 min 58 & 69 I Erlotinib HCl 100 -- -- 543
3038 4261 (raw) 1000 mg 74 & 75 I + P + S Erlotinib HCl 100
HPMC-AS Soluplus 18 24 29 (raw) 1000 mg 1850 mg 1430 mg 80 & 81
I + P + S Erlotinib HCl 100 HPMC-AS Soluplus 21 26 34 (raw) 925 mg
715 mg 500 mg 64 & 71 I/P Erlotinib HCl 35 HPMC-AS -- 310 505
1037 1000 mg 1850 mg 76 & 77 I/P + S Erlotinib HCl 35 HPMC-AS
Soluplus 106 108 108 1000 mg 1850 mg 1430 mg 82 & 83 I/P + S
Erlotinib HCl 35 HPMC-AS Soluplus 98 94 95 500 mg 925 mg 715 mg 78
& 79 I/P/S Erlotinib HCl 23 HPMC-AS Soluplus 287 329 353 1000
mg 1850 mg 1430 mg
Conclusions Example 2
[0169] The experiments show that a solubility increase is obtained
with stable, amorphous hybrid nanoparticles produced by the methods
of the invention with erlotinib HCl and a polymeric stabilizing and
matrix-forming component. Particular improvements are achieved with
the polymeric stabilizing and matrix-forming component
hydroxypropyl methylcellulose acetate succinate (HPMC-AS).
Experiments 65-66 and 72 show that a further solubility increase is
obtained with hybrid nanoparticles produced by the methods of the
invention with erlotinib HCl and a polymeric stabilizing and
matrix-forming component, wherein a separate solubilizer is added.
Particular improvements are achieved by the addition of a separate
solubilizer added, wherein said solubilizer is selected from
polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol
copolymer (Soluplus) and d-.alpha.-tocopherol acid polyethylene
glycol 1000 succinate (TPGS). This improvement was not observed
when the solubilizer was incorporated into the hybrid nanoparticles
produced by the methods of the invention.
[0170] Physical mixes of erlotinib HCl with a solubilizer and/or
HPMC AS improve also the solubility in FaSSIF (experiments 59,
60-61, 62-63) but not in FeSSIF (experiment 69-72). One issue with
PKI formulation is the food effect. Several of the PKIs are labeled
for administration in fasted state despite the fact that food in
most cases increases their bioavailability. Low bioavailability
might partly explain the digestive problems that are associated
with the PKIs. The data indicates that the hybrid nanoparticles
produced by the methods of the invention may reduce food effect and
patient digestive problems by its equal solubility improvement in
both FaSSIF and FeSSIF (experiment 76/77 and 82/83) that moreover
potentially may allow reducing of dosage. Thus stable, amorphous
hybrid nanoparticles produced by the methods of the invention may
be given in conjunction with food intake.
Example 3
Stable, Amorphous Hybrid Nanoparticles with Pazopanib--Solubility
at pH 6.5 and pH 5
[0171] A number of experiments were carried out, wherein pazopanib
represented the PKI. The experiments were carried out by measuring
concentration of PKI (mg/L) after 5, 30 and 90 minutes dissolution
in a solution at about pH 6.5, namely FaSSIF (Fasted State
Simulated Intestinal Fluid). Further, experiments were carried out
in an alternative solution at about pH 5, namely FeSSIF (Fed State
Simulated Intestinal Fluid). Samples of the solution were taken at
various time intervals and the amount of PKI was measured by the
dissolution measurement assay described above.
[0172] Representative results in FaSSIF solution are provided below
in Table 13 and 14, where Table 13 provides data of concentration
of pazopanib (mg/L) after 5, 30 and 90 minutes dissolution, whereas
Table 14 provides data of % solubilized pazopanib after 30 minutes
dissolution, the Area Under the Curve (AUC--mg/min/L) during 90
minutes dissolution and the AUC increase with hybrid nanoparticles
produced by the methods of the invention, compared to pazopanib in
raw, crystalline form added to the solution (experiments 84-93). In
Tables 15 and 16, there is provided dissolution data in FeSSIF
solution, presented similarly as Table 13 and 14 (experiments
94-101). In Table 17, data from a comparative experiment with
similar hybrid nanoparticles produced by the methods of the
invention, carried out in FaSSIF and FeSSIF, respectively
(experiments 102-109). Table 18 presents further comparative data
for experiments carried out in FaSSIF and FeSSIF, respectively,
with hybrid nanoparticles produced by the methods of the
invention.
TABLE-US-00014 TABLE 13 Pazopanib - concentration of pazopanib
(mg/L) after 5, 30 and 90 minutes dissolution in FaSSIF solution
(pH 6.5). Drug Polymeric load stab. matrix. Conc Conc Conc ratio
Component Solubilizer (mg/L) (mg/L) (mg/L) Exp Comp. Inhibitor (I)
(%) (P) (S) 5 min 30 min 90 min 84 I Pazopanib (raw) 100 -- -- 46.2
24.4 15.0 1000 mg 85 I + P Pazopanib (raw) 100 PVP 90K -- 82.7 83.8
67.7 1000 mg 2000 mg 86 I + S Pazopanib (raw) 100 -- Soluplus 116.3
177.7 204.3 1000 mg 357 mg 87 I + S Pazopanib (raw) 100 -- Soluplus
177.6 270.8 324.2 1000 mg 715 mg 88 I + P + S Pazopanib (raw) 100
PVP 90K Soluplus 198.8 312.2 394.1 1000 mg 1857 mg 715 mg 89 I + P
+ S Pazopanib (raw) 100 PVP 90K TPGS 182.6 196.7 49.2 1000 mg 1857
mg 1000 mg 90 I/P Pazopanib 35 PVP 90K -- 89.4 103.4 92.8 1000 mg
1857 mg 91 I/P + S Pazopanib 35 PVP 90K Soluplus 238.9 409.4 469.3
1000 mg 1857 mg 715 mg 92 I/P + S Pazopanib 35 PVP 90K TPGS 207.5
244.8 76.3 1000 mg 1857 mg 1000 mg 93 I/P/S Pazopanib 28 PVP 90K
Soluplus 127.2 128.3 82.0 1000 mg 1857 mg 715 mg
TABLE-US-00015 TABLE 14 Percentage solubilized pazopanib after 30
minutes dissolution, the Area Under the Curve (AUC - mg/min/L)
during 90 minutes dissolution and the AUC increase with stable,
amorphous hybrid nanoparticles produced by the methods of the
invention, compared to pazopanib in raw, crystalline form added to
the FaSSIF solution (pH 6.5). Drug Polymeric load stab. matrix.
AUC/ ratio Component Solubilizer % solubilized 90 min AUC Exp Comp.
Inhibitor (I) (%) (P) (S) 30 min. Mg/min/L increase 84 I Pazopanib
(raw) 100 -- -- 2.4 2180 -- 1000 mg 85 I + P Pazopanib (raw) 100
PVP 90K -- 8.4 6833 3.1 1000 mg 2000 mg 86 I + S Pazopanib (raw)
100 -- Soluplus 17.8 15426 7.1 1000 mg 357 mg 87 I + S Pazopanib
(raw) 100 -- Soluplus 27.1 23899 11.0 1000 mg 715 mg 88 I + P + S
Pazopanib (raw) 100 PVP 90K Soluplus 31.2 28074 12.9 1000 mg 1857
mg 715 mg 89 I + P + S Pazopanib (raw) 100 PVP 90K TPGS 19.7 12575
5.8 1000 mg 1857 mg 1000 mg 90 I/P Pazopanib 35 PVP 90K -- 10.3
8520 3.9 1000 mg 1857 mg 91 I/P + S Pazopanib 35 PVP 90K Soluplus
40.9 35062 16.1 1000 mg 1857 mg 715 mg 92 I/P + S Pazopanib PVP 90K
TPGS 24.5 15806 7.3 1000 mg 1857 mg 1000 mg 93 I/P/S Pazopanib 28
PVP 90K Soluplus 12.8 9821 4.5 1000 mg 1857 mg 715 mg
TABLE-US-00016 TABLE 15 Pazopanib - concentration of pazopanib
(mg/L) after 5, 30 and 90 minutes dissolution in FeSSIF solution
(pH 5). Drug Polymeric load stab. matrix. Conc Conc Conc ratio
Component Solubilizer (mg/L) (mg/L) (mg/L) Exp Comp. Inhibitor (I)
(%) (P) (S) 5 min 30 min 90 min 94 I Pazopanib (raw) 100 -- --
231.3 321.4 239.3 1000 mg 95 I + P Pazopanib (raw) 100 PVP 90K --
234.8 309.7 269.7 1000 mg 2000 mg 96 I + S Pazopanib (raw) 100 --
Soluplus 209.3 309.6 229.1 1000 mg 357 mg 97 I + P + S Pazopanib
(raw) 100 PVP 90K Soluplus 307.5 475.3 578.0 1000 mg 1857 mg 715 mg
98 I + P + S Pazopanib (raw) 100 PVP 90K TPGS 320.9 395.1 325.6
1000 mg 1857 mg 1000 mg 99 I/P Pazopanib 35 PVP 90K -- 348.4 362.1
335.8 1000 mg 1857 mg 100 I/P + S Pazopanib 35 PVP 90K Soluplus
450.0 684.4 777.6 1000 mg 1857 mg 715 mg 101 I/P/S Pazopanib 28 PVP
90K Soluplus 226.1 347.3 361.0 1000 mg 1857 mg 715 mg
TABLE-US-00017 TABLE 16 Percentage solubilized pazopanib after 30
minutes dissolution, the Area Under the Curve (AUC - mg/min/L)
during 90 minutes dissolution and the AUC increase with stable,
amorphous hybrid nanoparticles produced by the methods of the
invention, compared to pazopanib in raw, crystalline form added to
the FeSSIF solution (pH 5). Drug Polymeric load stab. matrix. AUC/
ratio Component Solubilizer % solubilized 90 min AUC Exp Comp.
Inhibitor (I) (%) (P) (S) 30 min. Mg/min/L increase 94 I Pazopanib
(raw) 100 -- -- 32.1 24308 -- 1000 mg 95 I + P Pazopanib (raw) 100
PVP 90K -- 31.0 24775 1.0 1000 mg 2000 mg 96 I + S Pazopanib (raw)
100 -- Soluplus 31.0 23171 1.0 1000 mg 357 mg 97 I + P + S
Pazopanib (raw) 100 PVP 90K Soluplus 47.5 42153 1.7 1000 mg 1857 mg
715 mg 98 I + P + S Pazopanib (raw) 100 PVP 90K TPGS 39.5 31373 1.3
1000 mg 1857 mg 1000 mg 99 I/P Pazopanib 35 PVP 90K -- 36.2 30689
1.3 1000 mg 1857 mg 100 I/P + S Pazopanib 35 PVP 90K Soluplus 68.4
59165 2.4 1000 mg 1857 mg 715 mg 101 I/P/S Pazopanib 28 PVP 90K
Soluplus 34.7 28982 1.2 1000 mg 1857 mg 715 mg
TABLE-US-00018 TABLE 17 Pazopanib - concentration of pazopanib
after 5, 30 and 90 minutes dissolution in FaSSIF and FeSSIF
solution, respectively. Drug Polymeric load stab. matrix. Conc Conc
Conc ratio Component Solubilizer (mg/L) (mg/L) (mg/L) Exp Comp.
Inhibitor (I) (%) (P) (S) 5 min 30 min 90 min 102 I + P + S
Pazopanib (raw) 100 PVP 90K Soluplus 76.8 113.8 139.6 FaSSIF 300 mg
557 mg 428 mg 103 I + P + S Pazopanib (raw) 100 PVP 90K Soluplus
116.7 193.6 246.9 FeSSIF 300 mg 557 mg 428 mg 104 I/P + S Pazopanib
35 PVP 90K Soluplus 154.7 214.7 223 FaSSIF 300 mg 557 mg 428 mg 105
I/P + S Pazopanib 35 PVP 90K Soluplus 186 273.3 303.1 FeSSIF 300 mg
557 mg 428 mg 106 I + P + S Pazopanib (raw) 100 PVP 90K Soluplus
261.1 421.6 508.5 FaSSIF 1000 mg 1857 mg 1428 mg 107 I + P + S
Pazopanib (raw) 100 PVP 90K Soluplus 275.8 495.4 588.0 FeSSIF 1000
mg 1857 mg 1428 mg 108 I/P + S Pazopanib 35 PVP 90K Soluplus 508.9
705.8 758.4 FeSSIF 1000 mg 1857 mg 1428 mg 109 I/P + S Pazopanib 35
PVP 90K Soluplus 469.1 715.2 747.4 FeSSIF 1000 mg 1857 mg 1428
mg
TABLE-US-00019 TABLE 18 Pazopanib - concentration of pazopanib
(mg/L) after 5, 30 and 90 minutes dissolution in FaSSIF and FeSSIF
solution, respectively presented as comparative data. Drug
Polymeric load stab. matrix. Compare Compare Compare ratio
Component Solubilizer (%) (%) (%) Exp Comp. Inhibitor (I) (%) (P)
(S) 5 min 30 min 90 min 84 & 94 I Pazopanib 100 -- -- 501 1317
1595 (raw) 1000 mg 85 & 95 I + P Pazopanib 100 PVP 90K -- 284
370 398 (raw) 1857 mg 1000 mg 87 & 96 I + S Pazopanib 100 --
Soluplus 118 114 71 (raw) 715 mg 1000 mg 88 & 97 I + P + S
Pazopanib 100 PVP 90K Soluplus 155 152 147 (raw) 1857 mg 715 mg
1000 mg 102 & I + P + S Pazopanib 100 PVP 90K Soluplus 152 170
177 103 (raw) 557 mg 428 mg 300 mg 90 & 99 I/P Pazopanib 35 PVP
90K -- 390 350 362 1000 mg 1857 mg 89 & I/P + S Pazopanib 35
PVP 90K Soluplus 188 167 166 100 1000 mg 1857 mg 715 mg 104 &
I/P + S Pazopanib 35 PVP 90K Soluplus 120 127 136 105 300 mg 557 mg
428 mg 93 & I/P/S Pazopanib 28 PVP 90K Soluplus 178 271 440 101
1000 mg 1857 mg 715 mg
Conclusions Example 3
[0173] The experiments show that a solubility increase is obtained
with stable, amorphous hybrid nanoparticles produced by the methods
of the invention with pazopanib and a polymeric stabilizing and
matrix-forming component. Particular improvements are achieved with
the polymeric stabilizing and matrix-forming component
polyvinylpyrrolidone K-90 (PVP 90K). Experiments 91-92 show that a
further solubility increase is obtained with hybrid nanoparticles
produced by the methods of the invention with pazopanib and a
polymeric stabilizing and matrix-forming component, wherein a
separate solubilizer is added. Particular improvements are achieved
by the addition of a separate solubilizer added, wherein said
solubilizer is selected from polyvinyl caprolactam-polyvinyl
acetate-polyethylene glycol copolymer (Soluplus) and
d-.alpha.-tocopherol acid polyethylene glycol 1000 succinate
(TPGS). This improvement was not observed when the solubilizer was
incorporated into the hybrid nanoparticles produced by the methods
of the invention.
[0174] The results carried out in FaSSIF and FeSSIF, respectively,
indicates that the hybrid nanoparticles produced by the methods of
the invention provide a similar increase in solubility. One issue
with PKI formulation is the food effect. Several of the PKIs are
labeled for administration in fasted state despite the fact that
food in most cases increases their bioavailability. Low
bioavailability might partly explain the digestive problems that
are associated with the PKIs. The similar dissolution rate in
FaSSIF and FeSSIF indicates that the hybrid nanoparticles produced
by the methods of the invention may reduce food effect and patient
digestive problems by its equal solubility improvement in both
FaSSIF and FeSSIF (experiments 89/100 and 104/105) that moreover
allows reducing dosage. Thus stable, amorphous hybrid nanoparticles
produced by the methods of the invention may be given in
conjunction with food intake.
Example 4
Stable, Amorphous Hybrid Nanoparticles with Lapatinib--Solubility
at pH 6.5
[0175] A number of experiments were carried out, wherein lapatinib
base or lapatinib ditosylate salt represented the PKI. The
experiments were carried out by measuring concentration of PKI
(mg/L) after 5, 30 and 90 minutes dissolution in a solution at
about pH 6.5, namely FaSSIF (Fasted State Simulated Intestinal
Fluid). Samples of the solution were taken at various time
intervals and the amount of PKI was measured by the dissolution
measurement assay described above.
[0176] Representative results in FaSSIF solution are provided below
in Table 19 and 20, where Table 19 provides data of concentration
of lapatinib (mg/L) after 5, 30 and 90 minutes dissolution, whereas
Table 20 provides data of % solubilized lapatinib after 30 minutes
dissolution, the Area Under the Curve (AUC--mg/min/L) during 90
minutes dissolution and the AUC increase with hybrid nanoparticles
produced by the methods of the invention, compared to
non-formulated lapatinib ditosylate salt added to the solution
(experiments 110-126).
TABLE-US-00020 TABLE 19 Lapatinib - concentration of lapatinib
(mg/L) after 5, 30 and 90 minutes dissolution in FaSSIF solution
(pH 6.5). Drug Polymeric load stab. matrix. Conc Conc Conc ratio
Component Solubilizer (mg/L) (mg/L) (mg/L) Exp Comp. Inhibitor (I)
(%) (P) (S) 5 min 30 min 90 min 110 I Lapatinib (base) 100 -- --
2.9 6.0 6.5 2000 mg 111 I Lapatinib (salt) 100 -- -- 57.7 132.2
124.2 2000 mg 112 I + S Lapatinib (salt) 100 -- Soluplus 67.6 142.9
140.0 2000 mg 285 mg 113 I-S Lapatinib (salt) 100 -- Soluplus 144.7
283.6 204.0 2000 mg 645 mg 114 I + P Lapatinib (base) 100 HPC LF --
1.9 4.9 6.1 2000 mg 4000 mg 115 I + P Lapatinib (salt) 100 HPC LF
-- 56.7 93.8 81.8 2000 mg 4000 mg 116 I + P + S Lapatinib (base)
100 HPC LF Soluplus 5.5 22.5 52.0 660 mg 340 mg 715 mg 117 I + P +
S Lapatinib (salt) 100 HPC LF Soluplus 71.7 182.5 240.4 660 mg 340
mg 715 mg 118 I + P + S Lapatinib (base) 100 HPC LF TPGS 11.8 40.6
82.9 660 mg 340 mg 1000 mg 119 I + P + S Lapatinib (salt) 100 HPC
LF TPGS 65.1 176.7 175.3 660 mg 340 mg 1000 mg 120 I/P Lapatinib
(base) 66 HPC EF -- 162.5 184.0 157.1 660 mg 340 mg 121 I/P
Lapatinib (base) 66 HPC LF -- 190.9 193.5 48.0 660 mg 340 mg 122
I/P + S Lapatinib (base) 66 HPC EF Soluplus 220.4 259.6 280.0 660
mg 340 mg 715 mg 123 I/P + S Lapatinib (base) 66 HPC LF Soluplus
200.7 315.6 327.6 660 mg 340 mg 715 mg 124 I/P + S Lapatinib (base)
66 HPC EF TPGS 202.2 237.5 242.5 660 mg 340 mg 500 mg 125 I/P + S
Lapatinib (base) 66 HPC LF TPGS 288.4 327.3 301.5 660 mg 340 mg 500
mg 126 I/P/S Lapatinib (base) 66 HPC LF Soluplus 57.6 107.2 126.3
660 mg 340 mg 715 mg
TABLE-US-00021 TABLE 20 Percentage solubilized lapatinib after 30
minutes dissolution, the Area Under the Curve (AUC - mg/min/L)
during 90 minutes dissolution and the AUC increase with stable,
amorphous hybrid nanoparticles produced by the methods of the
invention, compared to non-formulated lapatinib ditosylate salt
added to the FaSSIF solution (pH 6.5). Drug Polymeric load stab.
matrix. AUC/ ratio Component Solubilizer % solubilized 90 min AUC
Exp Comp. Inhibitor (I) (%) (P) (S) 30 min. Mg/min/L increase 110 I
Lapatinib (base) 100 -- -- 0.3 494 -- 2000 mg 111 I Lapatinib
(salt) 100 -- -- 6.6 10210 -- 2000 mg 112 I + S Lapatinib (salt)
100 -- Soluplus 7.1 11287 1.1 2000 mg 285 mg 113 I + S Lapatinib
(salt) 100 -- Soluplus 14.2 20344 2.0 2000 mg 645 mg 114 I + P
Lapatinib (base) 100 HPC LF -- 0.2 420 0.04 2000 mg 4000 mg 115 I +
P Lapatinib (salt) 100 HPC LF -- 4.7 7291 0.7 2000 mg 4000 mg 116 I
+ P + S Lapatinib (base) 100 HPC LF Soluplus 3.4 2599 0.3 660 mg
340 mg 715 mg 117 I + P + S Lapatinib (salt) 100 HPC LF Soluplus
27.7 16044 1.6 660 mg 340 mg 715 mg 118 I + P + S Lapatinib (base)
100 HPC LF TPGS 6.2 4390 0.4 660 mg 340 mg 1000 mg 119 I + P + S
Lapatinib (salt) 100 HPC LF TPGS 26.8 13745 1.3 660 mg 340 mg 1000
mg 120 I/P Lapatinib (base) 66 HPC EF -- 27.9 14971 1.5 660 mg 340
mg 121 I/P Lapatinib (base) 66 HPC LF -- 29.3 12527 1.2 660 mg 340
mg 122 I/P + S Lapatinib (base) 66 HPC EF Soluplus 39.3 22739 2.2
660 mg 340 mg 715 mg 123 I/P + S Lapatinib (base) 66 HPC LF
Soluplus 47.8 26252 2.6 660 mg 340 mg 715 mg 124 I/P + S Lapatinib
(base) 66 HPC EF TPGS 36.0 20402 2.0 660 mg 340 mg 500 mg 125 I/P +
S Lapatinib (base) 66 HPC LF TPGS 49.6 27281 2.7 660 mg 340 mg 500
mg 126 I/P/S Lapatinib (base) 66 HPC LF Soluplus 16.2 9209 0.9 660
mg 340 mg 715 mg
Conclusions Example 4
[0177] The experiments 122-125 clearly shows that a solubility
increase is obtained with stable, amorphous hybrid nanoparticles
produced by the methods of the invention, with lapatinib, in
particular lapatinib base and a polymeric stabilizing and
matrix-forming component, wherein a separate solubilizer is added
to the composition. Particular improvements are achieved with the
polymeric stabilizing and matrix-forming component hydroxypropyl
cellulose EF and hydroxypropyl cellulose LF. Further, improvements
are achieved by the addition of a separate solubilizer added,
wherein said solubilizer is selected from polyvinyl
caprolactam-polyvinyl acetate-polyethylene glycol copolymer
(Soluplus) and d-.alpha.-tocopherol acid polyethylene glycol 1000
succinate (TPGS).
Example 5
Stable, Amorphous Hybrid Nanoparticles with Nilotinib HCl
Solubility at pH 1.4
[0178] A number of experiments were carried out, wherein nilotinib
HCl represented the PKI. The experiments were carried out by
measuring concentration of PKI (mg/L) after 5, 30 and 90 minutes
dissolution in a solution at about pH 1.4, namely SGF (Simulated
Gastric Fluid). Samples of the solution were taken at various time
intervals and the amount of PKI was measured by the dissolution
measurement assay described above.
[0179] Representative results in SGF solution are provided below in
Table 21, which provides percentage of solubilized nilotinib HCl
from both a physical mix with nilotinib HCl in raw, crystalline
form and hybrid nanoparticles produced by the methods of the
invention after 5, 30 and 90 minutes dissolution. Nilotinib present
in the physical mix of nilotinib HCl raw with the polymeric
stabilizing and matrix-forming component PVAP and the solubilizer
Soluplus (Exp. 129) is dissolved completely within 5 minutes in SGF
while nilotinib is only partially dissolved after 90 min in SGF
with hybrid nanoparticles produced by the methods of the invention,
wherein the components are comprised as hybrid nanoparticles, with
the addition of a solubilizer (Exp. 128) or without the addition of
a solubilizer (Exp. 127).
TABLE-US-00022 TABLE 21 Nilotinib HCl - concentration of nilotinib
HCl (mg/L) after 5, 30 and 90 minutes dissolution in SGF solution
(pH 1.4). Drug Polymeric load stab. matrix. % % % ratio Component
Solubilizer solubilized solubilized solubilized Exp Comp. Inhibitor
(I) (%) (P) (S) 5 min 30 min 90 min 127 I/P Nilotinib HCl 100 PVAP
-- 32 40 42 500 mg 750 mg 128 I/P + S Nilotinib HCl 100 PVAP
Soluplus 38 48 50 500 mg 750 mg 715 mg 129 I + P + S Nilotinib HCl
100 PVAP Soluplus 100 100 100 (raw) 750 mg 715 mg 1000 mg
Conclusions Example 5
[0180] The experiments 127-129 shows that a nilotinib HCl, in
stable, amorphous hybrid nanoparticles produced by the methods of
the invention (exp 127 and 128) are partially solubilized at pH
1.4. The stable, amorphous hybrid nanoparticles produced by the
methods with a enteric coating polymer such as PVAP is partially
protected from the acidic environment.
Example 6
Stable, Amorphous Hybrid Nanoparticles with Gefitinib--Solubility
at pH 6.5
[0181] A number of experiments were carried out, wherein gefitinib
represented the PKI. The experiments were carried out by measuring
concentration of PKI (mg/L) after 3, 40 and 80 minutes dissolution
in a solution at about pH 6.5, namely FaSSIF (Fasted State
Simulated Intestinal Fluid). Samples of the solution were taken at
various time intervals and the amount of PKI was measured by the
dissolution measurement assay described above.
[0182] Representative results in FaSSIF solution are provided below
in Table 22 and 23, where Table 22 provides data of concentration
of gefitinib (mg/L) after 3, 40 and 80 minutes dissolution, whereas
Table 23 provides data of % solubilized gefitinib after 40 minutes
dissolution, the Area Under the Curve (AUC--mg/min/L) during 80
minutes dissolution and the AUC increase with hybrid nanoparticles
produced by the methods of the invention, compared to
non-formulated gefitinib added to the solution (experiments
131-137).
TABLE-US-00023 TABLE 22 Gefitinib - concentration of gefitinib
(mg/L) after 3, 40 and 80 minutes dissolution in FaSSIF solution
(pH 6.5). Drug Polymeric load stab. matrix. Conc Conc Conc ratio
Component Solubilizer (mg/L) (mg/L) (mg/L) Exp Comp. Inhibitor (I)
(%) (P) (S) 3 min 40 min 80 min 131 I Gefitinib (raw) 100 -- --
121.8 153.1 148.1 1000 mg 132 I + P + S Gefitinib (raw) 35 PVP30K
Soluplus 63.6 158.3 191.1 1000 mg 1850 mg 715 mg 133 I + P + S
Gefitinib (raw) 35 HPMCP HP55 Soluplus 70.6 230.3 296.4 1000 mg
1850 mg 715 mg 134 I/P Gefitinib 35 PVP30K -- 501.2 267.2 250.9
1000 mg 1850 mg 135 I/P Gefitinib 35 HPMCP HP55 -- 254.1 321.4
332.1 1000 mg 1850 mg 136 I/P + S Gefitinib 35 PVP30K Soluplus
561.4 430.2 410.9 1000 mg 1850 mg 715 mg 137 I/P + S Gefitinib 35
HPMCP HP55 Soluplus 319.8 576.3 594.2 1000 mg 1850 mg 715 mg
TABLE-US-00024 TABLE 23 Percentage solubilized gefitinib after 40
minutes dissolution, the Area Under the Curve (AUC - mg/min/L)
during 80 minutes dissolution and the AUC increase with stable,
amorphous hybrid nanoparticles produced by the methods of the
invention, compared to non-formulated gefitinib added to the FaSSIF
solution (pH 6.5). Drug Polymeric load stab. matrix. AUC/ ratio
Component Solubilizer % solubilized 80 min. AUC Exp Comp. Inhibitor
(I) (%) (P) (S) 40 min. Mg/min/L increase 131 I Gefitinib (raw) 100
-- -- 15.3 5967 -- 1000 mg 132 I + P + S Gefitinib (raw) 35 PVP30K
Soluplus 15.8 6630 1.1 1000 mg 1850 mg 715 mg 133 I + P + S
Gefitinib (raw) 35 HPMCP HP55 Soluplus 23.0 9826 1.6 1000 mg 1850
mg 715 mg 134 I/P Gefitinib 35 PVP30K -- 26.7 10954 1.8 1000 mg
1850 mg 135 I/P Gefitinib 35 HPMCP HP55 -- 32.1 12794 2.1 1000 mg
1850 mg 136 I/P + S Gefitinib 35 PVP30K Soluplus 43.0 12282 2.9
1000 mg 1850 mg 715 mg 137 I/P + S Gefitinib 35 HPMCP HP55 Soluplus
57.6 22774 3.8 1000 mg 1850 mg 715 mg
[0183] The experiments 131-137 show that a solubility increase is
obtained with stable, amorphous hybrid nanoparticles produced by
the methods of the invention, with gefitinib, in particular
gefitinib and a polymeric stabilizing and matrix-forming component,
wherein a separate solubilizer is added to the composition.
Particular improvements are achieved with the polymeric stabilizing
and matrix-forming component polyvinylpyrrolidone K-30 (PVP 30K)
and hydroxy propyl methyl cellulose phthalate (HPMCP HP55).
Further, improvements are achieved by the addition of a separate
solubilizer added, wherein said solubilizer is polyvinyl
caprolactam-polyvinyl acetate-polyethylene glycol copolymer
(Soluplus).
Example 7
Stable, Amorphous Hybrid Nanoparticles with Dasatinib--Solubility
at pH 6.5
[0184] A number of experiments were carried out, wherein dasatinib
represented the PKI. The experiments were carried out by measuring
concentration of PKI (mg/L) after 3, 40 and 80 minutes dissolution
in a solution at about pH 6.5, namely FaSSIF (Fasted State
Simulated Intestinal Fluid). Samples of the solution were taken at
various time intervals and the amount of PKI was measured by the
dissolution measurement assay described above.
[0185] Representative results in FaSSIF solution are provided below
in Table 24 and 25, where Table 24 provides data of concentration
of dasatinib (mg/L) after 3, 40 and 80 minutes dissolution, whereas
Table 25 provides data of % solubilized dasatinib after 40 minutes
dissolution, the Area Under the Curve (AUC--mg/min/L) during 80
minutes dissolution and the AUC increase with hybrid nanoparticles
produced by the methods of the invention, compared to
non-formulated dasatinib added to the solution (experiments
138-141).
TABLE-US-00025 TABLE 24 Dasatinib - concentration of dasatinib
(mg/L) after 3, 40 and 80 minutes dissolution in FaSSIF solution
(pH 6.5). Drug Polymeric load stab. matrix. Conc Conc Conc ratio
Component Solubilizer (mg/L) (mg/L) (mg/L) Exp Comp. Inhibitor (I)
(%) (P) (S) 3 min 40 min 80 min 138 I Dasatinib (raw) 100 -- --
34.5 59.7 63.5 1000 mg 139 I + P + S Dasatinib (raw) 35 Kollidon
VA64 Soluplus 24.2 64.9 82.5 1000 mg 1850 mg 715 mg 140 I/P
Dasatinib 35 Kollidon VA64 -- 54.7 382.0 417.6 1000 mg 1850 mg 141
I/P + S Dasatinib 35 Kollidon VA64 Soluplus 199.9 599.8 643.8 1000
mg 1850 mg 715 mg
TABLE-US-00026 TABLE 25 Percentage solubilized dasatinib after 40
minutes dissolution, the Area Under the Curve (AUC - mg/min/L)
during 80 minutes dissolution and the AUC increase with stable,
amorphous hybrid nanoparticles produced by the methods of the
invention, compared to non-formulated dasatinib added to the FaSSIF
solution (pH 6.5). Drug Polymeric load stab. matrix. AUC/ ratio
Component Solubilizer % solubilized 80 min. AUC Exp Comp. Inhibitor
(I) (%) (P) (S) 40 min. Mg/min/L increase 138 I Dasatinib (raw) 100
-- -- 6.0 2396 -- 1000 mg 139 I + P + S Dasatinib (raw) 35 Kollidon
VA64 Soluplus 6.5 2750 1.1 1000 mg 1850 mg 715 mg 140 I/P Dasatinib
35 Kollidon VA64 -- 35.3 15252 6.4 1000 mg 1850 mg 141 I/P + S
Dasatinib 35 Kollidon VA64 Soluplus 58.6 24156 10.1 1000 mg 1850 mg
715 mg
[0186] Experiments 138-141 show that a solubility increase is
obtained with stable, amorphous hybrid nanoparticles produced by
the methods of the invention, with dasatinib, in particular
dasatinib and a polymeric stabilizing and matrix-forming component,
wherein a separate solubilizer is added to the composition.
Particular improvements are achieved with the polymeric stabilizing
and matrix-forming component copolyvidone (Kollidon VA64). Further,
improvements are achieved by the addition of a separate solubilizer
added, wherein said solubilizer is polyvinyl caprolactam-polyvinyl
acetate-polyethylene glycol copolymer (Soluplus).
Example 8
Stable, Amorphous Hybrid Nanoparticles with Sorafenib
Tosylate--Solubility at pH 6.5
[0187] A number of experiments were carried out, wherein sorafenib
tosylate represented the PKI. The experiments were carried out by
measuring concentration of PKI (mg/L) after 3, 40 and 80 minutes
dissolution in a solution at about pH 6.5, namely FaSSIF (Fasted
State Simulated Intestinal Fluid). Samples of the solution were
taken at various time intervals and the amount of PKI was measured
by the dissolution measurement assay described above.
[0188] Representative results in FaSSIF solution are provided below
in Table 26 and 27, where Table 26 provides data of concentration
of sorafenib (mg/L) after 3, 40 and 80 minutes dissolution, whereas
Table 27 provides data of % solubilized sorafenib after 40 minutes
dissolution, the Area Under the Curve (AUC--mg/min/L) during 80
minutes dissolution and the AUC increase of compositions, compared
to non-formulated sorafenib tosylate added to the solution
(experiments 142-145).
TABLE-US-00027 TABLE 26 Sorafenib tosylate - concentration of
sorafenib (mg/L) after 3, 40 and 80 minutes dissolution in FaSSIF
solution (pH 6.5). Drug Polymeric load stab. matrix. Conc Conc Conc
ratio Component Solubilizer (mg/L) (mg/L) (mg/L) Exp Comp.
Inhibitor (I) (%) (P) (S) 3 min 40 min 80 min 142 I Sorafenib 100
-- -- 59.1 343.5 311.5 tosylate (raw) 1000 mg 143 I + P + S
Sorafenib 35 HPMCP HP55 Soluplus 33.9 297.1 352.2 tosylate (raw)
1850 mg 715 mg 1000 mg 144 I/P Sorafenib 35 HPMCP HP55 -- 245.3
520.3 613.8 tosylate 1850 mg 1000 mg 145 I/P + S Sorafenib 35 HPMCP
HP55 Soluplus 335.1 1202.6 1738.1 tosylate 1850 mg 715 mg 2000
mg
TABLE-US-00028 TABLE 27 Percentage solubilized sorafenib after 40
minutes dissolution, the Area Under the Curve (AUC - mg/min/L)
during 80 minutes dissolution and the AUC increase with stable,
amorphous hybrid nanoparticles produced by the methods of the
invention, compared to non-formulated sorafenib tosylate added to
the FaSSIF solution (pH 6.5). Drug Polymeric load stab. matrix.
AUC/ ratio Component Solubilizer % solubilized 80 min. AUC Exp
Comp. Inhibitor (I) (%) (P) (S) 40 min. Mg/min/L increase 142 I
Sorafenib 100 -- -- 34.4 12001 -- tosylate (raw) 1000 mg 143 I + P
+ S Sorafenib 35 HPMCP HP55 Soluplus 33.9 11588 1.0 tosylate (raw)
1850 mg 715 mg 1000 mg 144 I/P Sorafenib 35 HPMCP HP55 -- 245.3
21838 1.8 tosylate 1850 mg 1000 mg 145 I/P + S Sorafenib 35 HPMCP
HP55 Soluplus 335.1 52948 4.4 tosylate 1850 mg 715 mg 2000 mg
[0189] Experiments 138-141 show that a solubility increase is
obtained with stable, amorphous hybrid nanoparticles produced by
the methods of the invention, with dasatinib, in particular
dasatinib and a polymeric stabilizing and matrix-forming component,
wherein a separate solubilizer is added to the composition.
Particular improvements are achieved with the polymeric stabilizing
and matrix-forming component hydroxy propyl methyl cellulose
phthalate (HPMCP HP55). Further, improvements are achieved by the
addition of a separate solubilizer added, wherein said solubilizer
is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol
copolymer (Soluplus).
Example 9
Stable, Amorphous Hybrid Nanoparticles with Nilotinib
Base--Solubility at pH 6.5
[0190] A number of experiments were carried out, wherein nilotinib
base represented the PKI. The experiments were carried out by
measuring concentration of PKI (mg/L) after 3, 40 and 80 minutes
dissolution in a solution at about pH 6.5, namely FaSSIF (Fasted
State Simulated Intestinal Fluid). Samples of the solution were
taken at various time intervals and the amount of PKI was measured
by the dissolution measurement assay described above.
[0191] Representative results in FaSSIF solution are provided below
in Table 28 and 29, where Table 28 provides data of concentration
of nilotinib base (mg/L) after 3, 40 and 80 minutes dissolution,
whereas Table 29 provides data of % solubilized nilotinib base
after 40 minutes dissolution, the Area Under the Curve
(AUC--mg/min/L) during 80 minutes dissolution and the AUC increase
of compositions, compared to non-formulated nilotinib base added to
the solution (experiments 146-149).
TABLE-US-00029 TABLE 28 Nilotinib base - concentration of nilotinib
base (mg/L) after 3, 40 and 80 minutes dissolution in FaSSIF
solution (pH 6.5). Drug Polymeric load stab. matrix. Conc Conc Conc
ratio Component Solubilizer (mg/L) (mg/L) (mg/L) Exp Comp.
Inhibitor (I) (%) (P) (S) 3 min 40 min 80 min 146 I/P Nilotinib
base 40 HPMCP HP55 -- 12.7 5.3 3.7 500 mg 750 mg 147 I/P Nilotinib
base 40 PVAP -- 12.3 8.6 7.0 500 mg 750 mg 148 I/P + S Nilotinib
base 40 HPMCP HP55 Soluplus 136.8 88.8 41.2 500 mg 750 mg 715 mg
149 I/P + S Nilotinib base 40 PVAP Soluplus 20.7 115.9 60.4 500 mg
750 mg 715 mg
TABLE-US-00030 TABLE 29 Percentage solubilized nilotinib base after
40 minutes dissolution, the Area Under the Curve (AUC - mg/min/L)
during 80 minutes dissolution and the AUC increase with stable,
amorphous hybrid nanoparticles produced by the methods of the
invention, compared to non- formulated nilotinib base added to the
FaSSIF solution (pH 6.5). Drug Polymeric load stab. matrix. AUC/
ratio Component Solubilizer % solubilized 80 min. AUC Exp Comp.
Inhibitor (I) (%) (P) (S) 40 min. Mg/min/L increase 146 I/P
Nilotinib base 40 HPMCP HP55 -- 1.1 242 8.3 500 mg 750 mg 147 I/P
Nilotinib base 40 PVAP -- 1.7 328 11.2 500 mg 750 mg 148 I/P + S
Nilotinib base 40 HPMCP HP55 Soluplus 17.8 3529 120.9 500 mg 750 mg
715 mg 149 I/P + S Nilotinib base 40 PVAP Soluplus 23.2 3544 121.4
500 mg 750 mg 715 mg
Example 10
Stable, Amorphous Hybrid Nanoparticles with Crizotinib--Solubility
at pH 6.5
[0192] A number of experiments were carried out, wherein crizotinib
represented the PKI. The experiments were carried out by measuring
concentration of PKI (mg/L) after 3, 40 and 80 minutes dissolution
in a solution at about pH 6.5, namely FaSSIF (Fasted State
Simulated Intestinal Fluid). Samples of the solution were taken at
various time intervals and the amount of PKI was measured by the
dissolution measurement assay described above. Representative
results in FaSSIF solution are provided below in Table 30 and 31,
where Table 30 provides data of concentration of crizotinib (mg/L)
after 3, 40 and 80 minutes dissolution, whereas Table 31 provides
data of % solubilized crizotinib after 40 minutes dissolution, the
Area Under the Curve (AUC--mg/min/L) during 80 minutes dissolution
and the AUC increase with stable, amorphous hybrid nanoparticles
produced by the methods of the invention, compared to
non-formulated crizotinib added to the solution (experiments
150-156).
TABLE-US-00031 TABLE 30 Crizotinib - concentration of crizotinib
(mg/L) after 3, 40 and 80 minutes dissolution in FaSSIF solution
(pH 6.5). Drug Polymeric load stab. matrix. Conc Conc Conc ratio
Component Solubilizer (mg/L) (mg/L) (mg/L) Exp Comp. Inhibitor (I)
(%) (P) (S) 3 min 40 min 80 min 150 I Crizotinib 100 -- -- 89.3
226.5 295.6 (raw) 1000 mg 151 I + P + S Crizotinib 25 PVP30K
Soluplus 176.2 368.5 414.6 (raw) 1000 mg 3000 mg 715 mg 152 I + P +
S Crizotinib 25 PVP30K Cremophor 161.2 428.4 497.7 (raw) 1000 mg
3000 mg RH40 715 mg 153 I/P Crizotinib 25 PVP30K -- 325.9 390.4
398.8 1000 mg 3000 mg 154 I/P Crizotinib 25 Kollidon VA64 -- 297.5
447.6 449.9 1000 mg 3000 mg 155 I/P + S Crizotinib 25 PVP30K
Soluplus 457.6 581.4 578.9 1000 mg 3000 mg 715 mg 156 I/P + S
Crizotinib 25 PVP30K Cremophor 573.9 855.1 867.2 1000 mg 3000 mg
RH40 715 mg
TABLE-US-00032 TABLE 31 Percentage solubilized crizotinib after 40
minutes dissolution, the Area Under the Curve (AUC - mg/min/L)
during 80 minutes dissolution and the AUC increase with stable,
amorphous hybrid nanoparticles produced by the methods of the
invention, compared to non-formulated crizotinib added to the
FaSSIF solution (pH 6.5). Drug Polymeric load stab. matrix. AUC/
ratio Component Solubilizer % solubilized 80 min AUC Exp Comp.
Inhibitor (I) (%) (P) (S) 40 min. Mg/min/L increase 150 I
Crizotinib 100 -- -- 22.7 16773 (raw) 1000 mg 151 I + P + S
Crizotinib 25 PVP30K Soluplus 36.8 27185 1.6 (raw) 1000 mg 3000 mg
715 mg 152 I + P + S Crizotinib 25 PVP30K Cremophor 42.8 30423 1.8
(raw) 1000 mg 3000 mg RH40 715 mg 153 I/P Crizotinib 25 PVP30K --
39.1 29958 1.8 1000 mg 3000 mg 154 I/P Crizotinib 25 Kollidon VA64
-- 44.8 33611 2.0 1000 mg 3000 mg 155 I/P + S Crizotinib 25 PVP30K
Soluplus 58.1 44862 2.7 1000 mg 3000 mg 715 mg 156 I/P + S
Crizotinib 25 PVP30K Cremophor 85.5 64338 3.8 1000 mg 3000 mg RH40
715 mg
[0193] Experiments 150-156 show that a solubility increase is
obtained with stable, amorphous hybrid nanoparticles produced by
the methods of the invention, with crizotinib, in particular
crizotinib and a polymeric stabilizing and matrix-forming
component, wherein a separate solubilizer is added to the
composition. Particular improvements are achieved with the
polymeric stabilizing and matrix-forming component
polyvinylpyrrolidone K-30 (PVP 30K) and copolyvidone (Kollidon
VA64). Further, improvements are achieved by the addition of a
separate solubilizer added, wherein said solubilizer is selected
from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol
copolymer (Soluplus) and PEG-40 hydrogenated castor oil (Cremophor
RH40).
Example 11
Stable, Amorphous Hybrid Nanoparticles with Axitinib--Solubility at
pH 6.5
[0194] A number of experiments were carried out, wherein axitinib
represented the PKI. The experiments were carried out by measuring
concentration of PKI (mg/L) after 3, 40 and 80 minutes dissolution
in a solution at about pH 6.5, namely FaSSIF (Fasted State
Simulated Intestinal Fluid). Samples of the solution were taken at
various time intervals and the amount of PKI was measured by the
dissolution measurement assay described above. Representative
results in FaSSIF solution are provided below in Table 32 and 33,
where Table 32 provides data of concentration of axitinib (mg/L)
after 3, 40 and 80 minutes dissolution, whereas Table 33 provides
data of % solubilized axitinib after 40 minutes dissolution, the
Area Under the Curve (AUC--mg/min/L) during 80 minutes dissolution
and the AUC increase with stable, amorphous hybrid nanoparticles
produced by the methods of the invention, compared to
non-formulated axitinib added to the solution (experiments
157-163).
TABLE-US-00033 TABLE 32 Axitinib - concentration of axitinib (mg/L)
after 3, 40 and 80 minutes dissolution in FaSSIF solution (pH 6.5).
Drug Polymeric load stab. matrix. Conc Conc Conc ratio Component
Solubilizer (mg/L) (mg/L) (mg/L) Exp Comp. Inhibitor (I) (%) (P)
(S) 3 min 40 min 80 min 157 I Axitinib 100 -- -- 0.6 0.6 0.6 (raw)
500 mg 158 I + P + S Axitinib 25 Kollidon VA64 Soluplus 0.2 0.8 4.3
(raw) 500 mg 1500 mg 715 mg 159 I + P + S Axitinib 25 HPMC AS
Soluplus 0.2 3.0 3.1 (raw) 500 mg 1500 mg 715 mg 160 I/P Axitinib
25 Kollidon VA64 -- 71.1 25.9 9.1 500 mg 1500 mg 161 I/P Axitinib
25 HPMC AS -- 17.6 21.0 16.4 500 mg 1500 mg 162 I/P + S Axitinib 25
Kollidon VA64 Soluplus 77.6 223.6 266.1 500 mg 1500 mg 715 mg 163
I/P + S Axitinib 25 HPMC AS Soluplus 40.3 110.3 129.9 500 mg 1500
mg 715 mg
TABLE-US-00034 TABLE 33 Percentage solubilized axitinib after 40
minutes dissolution, the Area Under the Curve (AUC - mg/min/L)
during 80 minutes dissolution and the AUC increase with stable,
amorphous hybrid nanoparticles produced by the methods of the
invention, compared to non-formulated axitinib added to the FaSSIF
solution (pH 6.5). Drug Polymeric load stab. matrix. AUC/ ratio
Component Solubilizer % solubilized 80 min AUC Exp Comp. Inhibitor
(I) (%) (P) (S) 40 min. Mg/min/L increase 157 I Axitinib 100 -- --
0.1 47 (raw) 500 mg 158 I + P + S Axitinib 25 Kollidon VA64
Soluplus 0.2 126 2.7 (raw) 500 mg 1500 mg 715 mg 159 I + P + S
Axitinib 25 HPMC AS Soluplus 0.6 193 4.1 (raw) 500 mg 1500 mg 715
mg 160 I/P Axitinib 25 Kollidon VA64 -- 5.2 3255 69.0 500 mg 1500
mg 161 I/P Axitinib 25 HPMC AS -- 4.2 1571 33.0 500 mg 1500 mg 162
I/P + S Axitinib 25 Kollidon VA64 Soluplus 44.7 16070 341.0 500 mg
1500 mg 715 mg 163 I/P + S Axitinib 25 HPMC AS Soluplus 22.1 7954
169.0 500 mg 1500 mg 715 mg
[0195] Experiments 157-163 show that a solubility increase is
obtained with stable, amorphous hybrid nanoparticles produced by
the methods of the invention, with axitinib, in particular axitinib
and a polymeric stabilizing and matrix-forming component, wherein a
separate solubilizer is added to the composition. Particular
improvements are achieved with the polymeric stabilizing and
matrix-forming component copolyvidone (Kollidon VA64) and
hydroxypropyl methylcellulose acetate succinate (HPMC AS). Further,
improvements are achieved by the addition of a separate solubilizer
added, wherein said solubilizer is polyvinyl caprolactam-polyvinyl
acetate-polyethylene glycol copolymer (Soluplus).
Example 12
Stable, Amorphous Hybrid Nanoparticles with Vemurafenib--Solubility
at pH 6.5
[0196] A number of experiments were carried out, wherein
vemurafenib represented the PKI. The experiments were carried out
by measuring concentration of PKI (mg/L) after 3, 40 and 80 minutes
dissolution in a solution at about pH 6.5, namely FaSSIF (Fasted
State Simulated Intestinal Fluid). Samples of the solution were
taken at various time intervals and the amount of PKI was measured
by the dissolution measurement assay described above.
[0197] Representative results in FaSSIF solution are provided below
in Table 34 and 35, where Table 34 provides data of concentration
of vemurafenib (mg/L) after 3, 40 and 80 minutes dissolution,
whereas Table 35 provides data of % solubilized vemurafenib after
40 minutes dissolution, the Area Under the Curve (AUC--mg/min/L)
during 80 minutes dissolution and the AUC increase with stable,
amorphous hybrid nanoparticles produced by the methods of the
invention, compared to non-formulated vemurafenib added to the
solution (experiments 164-170).
TABLE-US-00035 TABLE 34 Vemurafenib - concentration of vemurafenib
(mg/L) after 3, 40 and 80 minutes dissolution in FaSSIF solution
(pH 6.5). Drug Polymeric load stab. matrix. Conc Conc Conc ratio
Component Solubilizer (mg/L) (mg/L) (mg/L) Exp Comp. Inhibitor (I)
(%) (P) (S) 3 min 40 min 80 min 164 I Vemurafenib 100 -- -- 0.3 0.3
0.4 (raw) 500 mg 165 I + P + S Vemurafenib 25 Kollidon VA64
Soluplus 0.2 0.2 0.4 (raw) 500 mg 1500 mg 715 mg 166 I + P + S
Vemurafenib 25 CAP Soluplus 0.1 0.2 0.4 (raw) 500 mg 1500 mg 715 mg
167 I/P Vemurafenib 25 Kollidon VA64 -- 35.5 107.6 122.9 500 mg
1500 mg 168 I/P Vemurafenib 25 CAP -- 75.1 47.5 11.8 500 mg 1500 mg
169 I/P + S Vemurafenib 25 Kollidon VA64 Soluplus 27.4 111.3 172.3
500 mg 1500 mg 715 mg 170 I/P + S Vemurafenib 25 CAP Soluplus 55.4
105.7 118.9 500 mg 1500 mg 715 mg
TABLE-US-00036 TABLE 35 Percentage solubilized vemurafenib after 40
minutes dissolution, the Area Under the Curve (AUC - mg/min/L)
during 80 minutes dissolution and the AUC increase with stable,
amorphous hybrid nanoparticles produced by the methods of the
invention, compared to non-formulated vemurafenib added to the
FaSSIF solution (pH 6.5). Drug Polymeric load stab. matrix. AUC/
ratio Component Solubilizer % solubilized 80 min AUC Exp Comp.
Inhibitor (I) (%) (P) (S) 40 min. Mg/min/L increase 164 I
Vemurafenib 100 -- -- 0.1 27 (raw) 500 mg 165 I + P + S Vemurafenib
25 Kollidon VA64 Soluplus 0.1 21 0.8 (raw) 500 mg 1500 mg 715 mg
166 I + P + S Vemurafenib 25 CAP Soluplus 0.0 18 0.7 (raw) 500 mg
1500 mg 715 mg 167 I/P Vemurafenib 25 Kollidon VA64 -- 21.5 7669
288.0 500 mg 1500 mg 168 I/P Vemurafenib 25 CAP -- 9.5 3761 141.0
500 mg 1500 mg 169 I/P + S Vemurafenib 25 Kollidon VA64 Soluplus
22.3 8564 322.0 500 mg 1500 mg 715 mg 170 I/P + S Vemurafenib 25
CAP Soluplus 21.1 7899 297.0 500 mg 1500 mg 715 mg
[0198] Experiments 164-170 show that a solubility increase is
obtained with stable, amorphous hybrid nanoparticles produced by
the methods of the invention, with vemurafenib, in particular
vemurafenib and a polymeric stabilizing and matrix-forming
component, wherein a separate solubilizer is added to the
composition. Particular improvements are achieved with the
polymeric stabilizing and matrix-forming component copolyvidone
(Kollidon VA64) and cellulose acetate phthalate (CAP). Further,
improvements are achieved by the addition of a separate solubilizer
added, wherein said solubilizer is polyvinyl caprolactam-polyvinyl
acetate-polyethylene glycol copolymer (Soluplus).
Example 13
Dissolution Rate Measurement in Sink Conditions Stable, Amorphous
Hybrid Nanoparticles Produced by the Methods of the Invention
[0199] Dissolution measurement in sink conditions of stable,
amorphous hybrid nanoparticles produced by the methods of the
invention were measured in a method consisting of adding the wished
amount of powder into a flow through cell system (SOTAX,
Allschwill, Switzerland), mounting the cell onto its apparatus and
then pumping the appropriate medium (typically FaSSIF, FeSSIF, SGF)
through the powder. The temperature of the apparatus was set to
37.degree. C. The amount of powder added into the cell depends on
drug load of the powder: The exact amount of powder was calculated
from results obtained from drug load analysis of the powders.
[0200] Typically, 3.5 to 7 mg PKI was added into the flow through
cell and a flow rate between 8 and 16 ml medium/min (preferably
about 8 ml medium/min) was pumped through the powder. One ml
samples of the medium passing through the cell were collected at
predetermined times. These samples were analyzed by HPLC (e.g. C18
column Eclipse, 4.6 mm.times.15 cm, 1 ml/min, detection 254-400
nm). Samples were taken after 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8,
9, 10, 15, 20, 25, 30, 35 and 40 min from the moment the medium
comes out from the flow through cell. The accumulated % solubilized
of the amount of active substance added into the flow through cell
was calculated and plotted against time (min). The initial slope
("initial dissolution rate") of the graph was estimated, as
measured during 0 to 10 minutes, and taken as the dissolution rate
of the material in sink condition at 37.degree. C. in the given
dissolution medium.
[0201] Each experiment comprises a comparison between the PKI in
raw form with stable, amorphous hybrid nanoparticles produced by
the methods of the invention with the inhibitor and a
representative polymeric stabilizing and matrix-forming
component.
Example 13.1
Dissolution Rate Measurement in Sink Conditions with Stable,
Amorphous Hybrid Nanoparticles Produced by the Methods of the
Invention, Comprising Nilotinib HCl
[0202] In experiments with nilotinib HCl, 4 mg was weighed in the
flow through cell (experiment 500) and compared with stable,
amorphous hybrid nanoparticles produced by the methods of the
invention with nilotinib base and the polymeric stabilizing and
matrix-forming component HPMCP HP55 (experiment 501). The results
are depicted in Table 36 below.
TABLE-US-00037 TABLE 36 Nilotinib HCl sink condition in FaSSIF.
Experiment 500 Experiment 501 Composition type I I/P Inhibitor (I)
nilotinib HCl (raw) nilotinib base Polymeric stab. -- HPMCP HP55
matrix. Component (P) Drug load % -- 40% Accumulated % of
solubilized of remaining active substance at a given time (min)
Min. % % 0 0.13 3.07 0.5 0.33 7.96 1 0.49 12.23 1.5 0.63 15.22 2
0.76 17.91 3 1.02 23.25 4 1.24 28.03 5 1.48 32.70 6 1.71 37.32 7
1.92 42.04 8 2.13 45.78 9 2.34 49.52 10 2.56 52.34 15 3.51 59.66 20
4.31 66.28 25 5.04 70.92 30 5.7 74.38 35 6.4 76.25 40 7.0 80.33
Initial Dissolution Rate EXP 500 0.27 EXP 501 6.58 Ratio 501/500
24.0
[0203] Experiments 500-501 show that the initial dissolution rate
of the stable, amorphous hybrid nanoparticles produced by the
methods of the invention, with nilotinib base, is superior to the
initial dissolution rate of nilotinib HCl in raw, crystalline
form.
Example 13.2
Dissolution Rate Measurement in Sink Conditions of Stable,
Amorphous Hybrid Nanoparticles Produced by the Methods of the
Invention Comprising Erlotinib HCl
[0204] In experiments with erlotinib HCl, 3.5 mg was weighed in the
flow through cell (experiment 510) and compared with stable,
amorphous hybrid nanoparticles produced by the methods of the
invention with erlotinib HCl and the polymeric stabilizing and
matrix-forming component HPMC AS (experiment 511). The results are
depicted in Table 37 below.
TABLE-US-00038 TABLE 37 Erlotinib HCl sink condition in FaSSIF.
Experiment 510 Experiment 511 Composition type I I/P Inhibitor (I)
erlotinib HCl (raw) erlotinib HCl Polymeric stab. -- HPMC AS
matrix. Component (P) Drug load % -- 35% Accumulated % of
solubilized of remaining active substance at a given time (min)
Min. % % 0 0.26 2.3 0.5 0.49 3.9 1 0.63 5.4 1.5 0.71 6.4 2 0.77 7.2
3 0.85 8.5 4 0.91 9.5 5 0.96 10.3 6 1.01 11.1 7 1.06 11.8 8 1.10
12.5 9 1.13 13.1 10 1.17 13.8 20 1.58 19.3 30 1.93 22.0 40 2.24
24.6 Initial Dissolution Rate EXP 510 0.303 EXP 511 2.754 Ratio
511/510 9.1
[0205] Experiments 510-511 show that the initial dissolution rate
of the stable, amorphous hybrid nanoparticles produced by the
methods of the invention, with erlotinib HCl, is superior to the
initial dissolution rate of erlotinib HCl in raw, crystalline
form.
Example 13.3
Dissolution Rate Measurement in Sink Conditions of Stable,
Amorphous Hybrid Nanoparticles Produced by the Methods of the
Invention Comprising Pazopanib HCl
[0206] In experiments with pazopanib HCl, 3.5 mg was weighed in the
flow through cell (experiment 520) and compared with stable,
amorphous hybrid nanoparticles produced by the methods of the
invention with pazopanib HCl and the polymeric stabilizing and
matrix-forming component PVP90K (experiment 521). The results are
depicted in Table 38 below.
TABLE-US-00039 TABLE 38 Pazopanib HCl sink condition in FaSSIF.
Experiment 520 Experiment 521 Composition type I I/P Inhibitor (I)
pazopanib pazopanib HCl HCl (raw) Polymeric stab. -- PVP90K matrix.
Component (P) Drug load % -- 35% Accumulated % of solubilized of
remaining active substance at a given time (min) Min. % % 0 1.6 1.9
0.5 4.7 4.6 1 7.7 6.8 1.5 9.6 8.8 2 11.2 10.6 3 13.4 15.2 4 14.7
19.7 5 15.4 22.7 6 16.0 26.2 7 16.4 30.1 8 16.9 33.8 9 17.2 38.2 10
17.6 41.7 20 19.2 73.2 30 20.5 91.3 40 21.6 97.1 Initial
Dissolution Dissolution Rate Rate (5-10 min) EXP 520 4.8 0.428 EXP
521 4.33 3.85 Ratio 521/520 0.9 9.0
[0207] Experiments 520-521 show that the initial dissolution rate
of the stable, amorphous hybrid nanoparticles produced by the
methods of the invention, with pazopanib HCl, is superior to the
initial dissolution rate of pazopanib HCl in raw, crystalline
form.
Example 13.4
Dissolution Rate Measurement in Sink Conditions of Stable,
Amorphous Hybrid Nanoparticles Produced by the Methods of the
Invention Comprising Lapatinib Ditosylate
[0208] In experiments with lapatinib ditosylate, 4 mg was weighed
in the flow through cell (experiment 530) and compared with stable,
amorphous hybrid nanoparticles produced by the methods of the
invention with lapatinib base and the polymeric stabilizing and
matrix-forming component HPC If (experiment 531). The results are
depicted in Table 39 below.
TABLE-US-00040 TABLE 39 Lapatinib ditosylate sink condition in
FaSSIF. Experiment 530 Experiment 531 Composition type I I/P
Inhibitor (I) Lapatinib ditosylate (raw) Lapatinib base Polymeric
stab. -- HPC If matrix. Component (P) Drug load % -- 66%
Accumulated % of solubilized of remaining active substance at a
given time (min) Min. % % 0 0.032 0.442 0.5 0.088 1.736 1 0.141
3.053 1.5 0.190 4.448 2 0.238 5.771 3 0.332 7.504 4 0.422 8.783 5
0.505 9.736 6 0.582 10.573 7 0.655 11.209 8 0.725 11.732 9 0.790
12.179 10 0.851 12.576 20 1.272 14.128 30 1.607 15.168 40 1.944
15.802 Initial Dissolution Rate EXP 530 0.103 EXP 531 2.674 Ratio
531/530 25.9
[0209] Experiments 530-531 show that the initial dissolution rate
of the stable, amorphous hybrid nanoparticles produced by the
methods of the invention, with lapatinib base, is superior to the
initial dissolution rate of lapatinib ditosylate in raw,
crystalline form.
Example 13.5
Dissolution Rate Measurement in Sink Conditions of Stable,
Amorphous Hybrid Nanoparticles Produced by the Methods of the
Invention Comprising Gefitinib
[0210] In experiments with gefitinib, 3.5 mg was weighed in the
flow through cell (experiment 540) and compared with stable,
amorphous hybrid nanoparticles produced by the methods of the
invention with gefitinib and the polymeric stabilizing and
matrix-forming component HPMCP HP55 (experiment 541). The results
are depicted in Table 40 below.
TABLE-US-00041 TABLE 40 Gefitinib sink condition in FaSSIF.
Experiment 540 Experiment 541 Composition type I I/P Inhibitor (I)
Gefitinib (raw) Gefitinib Polymeric stab. -- HPMCP HP55 matrix.
Component (P) Drug load % -- 35% Accumulated % of solubilized of
remaining active substance at a given time (min) Min. % % 0 0.1 1.8
0.5 0.9 6.7 1 1.9 11.3 1.5 3.2 15.4 2 4.5 19.0 3 7.0 23.6 4 9.5
27.4 5 11.9 30.5 6 14.3 33.5 7 16.6 36.0 8 18.8 37.8 9 20.7 39.9 10
22.7 42.6 20 29.9 50.6 30 34.1 56.7 40 36.7 61.8 Initial
Dissolution Rate EXP 540 2.2 EXP 541 8.6 Ratio 541/540 3.9
[0211] Experiments 540-541 show that the initial dissolution rate
of the stable, amorphous hybrid nanoparticles produced by the
methods of the invention, with gefitinib, is superior to the
initial dissolution rate of the gefinib in raw, crystalline
form.
Example 13.6
Dissolution Rate Measurement in Sink Conditions of Stable,
Amorphous Hybrid Nanoparticles Produced by the Methods of the
Invention Comprising Dasatinib
[0212] In experiments with dasatinib, 3.5 mg was weighed in the
flow through cell (experiment 550) and compared with stable,
amorphous hybrid nanoparticles produced by the methods of the
invention with dasatinib and the polymeric stabilizing and
matrix-forming component copolyvidon-Kollidon VA64 (experiment
551). The results are depicted in Table 41 below.
TABLE-US-00042 TABLE 41 Dasatinib sink condition in FaSSIF.
Experiment 550 Experiment 551 Composition type I I/P Inhibitor (I)
Dasatinib (raw) Dasatinib Polymeric stab. -- Kollidon VA64 matrix.
Component (P) Drug load % -- 35% Accumulated % of solubilized of
remaining active substance at a given time (min) Min. % % 0 0.3 0.4
0.5 0.7 1.0 1 1.2 1.7 1.5 1.6 2.3 2 2.0 2.9 3 2.8 4.2 4 3.7 5.5 5
4.4 6.8 6 5.2 8.2 7 6.0 9.5 8 6.8 10.8 9 7.6 12.1 10 8.3 13.4 20
15.9 25.9 30 22.1 40.9 40 26.4 54.9 Initial Dissolution Rate EXP
550 0.8 EXP 551 1.3 Ratio 551/550 1.6
[0213] Experiments 550-551 show that the initial dissolution rate
of the stable, amorphous hybrid nanoparticles produced by the
methods of the invention, with dasatinib, is superior to the
initial dissolution rate of the dasatinib raw, crystalline
form.
Example 13.7
Dissolution Rate Measurement in Sink Conditions of Stable,
Amorphous Hybrid Nanoparticles Produced by the Methods of the
Invention Comprising Sorafenib Tosylate
[0214] In experiments with sorafenib tosylate, 3.5 mg was weighed
in the flow through cell (experiment 560) and compared with stable,
amorphous hybrid nanoparticles produced by the methods of the
invention with sorafenib tosylate and the polymeric stabilizing and
matrix-forming component HPMCP HP55 (experiment 561). The results
are depicted in Table 42 below.
TABLE-US-00043 TABLE 42 Sorafenib tosylate sink condition in
FaSSIF. Experiment 560 Experiment 561 Composition type I I/P
Inhibitor (I) Sorafenib tosylate (raw) Sorafenib tosylate Polymeric
stab. -- HPMCP HP55 matrix. Component (P) Drug load % -- 35%
Accumulated % of solubilized of remaining active substance at a
given time (min) Min. % % 0 0.2 0.8 0.5 0.4 1.7 1 0.7 2.4 1.5 1.0
3.1 2 1.3 3.7 3 1.8 4.8 4 2.2 5.8 5 2.6 6.9 6 3.0 8.1 7 3.4 9.7 8
3.8 11.3 9 4.2 13.3 10 4.6 15.6 20 8.8 32.7 30 12.6 61.5 40 16.4
96.1 Initial Dissolution Rate EXP 560 0.47 EXP 561 1.17 Ratio
561/560 2.5
[0215] Experiments 560-561 show that the initial dissolution rate
of the stable, amorphous hybrid nanoparticles produced by the
methods of the invention, with sorafenib tosylate, is superior to
the initial dissolution rate of sorafenib tosylate in raw,
crystalline form.
Example 13.8
Dissolution Rate Measurement in Sink Conditions of Stable,
Amorphous Hybrid Nanoparticles Produced by the Methods of the
Invention Comprising Crizotinib
[0216] In experiments with crizotinib, 3.5 mg was weighed in the
flow through cell (experiment 570) and compared with stable,
amorphous hybrid nanoparticles produced by the methods of the
invention with crizotinib and the polymeric stabilizing and
matrix-forming component PVP 30K (experiment 571). The results are
depicted in Table 43 below.
TABLE-US-00044 TABLE 43 Crizotinib sink condition in FaSSIF.
Experiment 570 Experiment 571 Composition type I I/P Inhibitor (I)
Crizotinib (raw) Crizotinib Polymeric stab. -- PVP 30K matrix.
Component (P) Drug load % -- 25% Accumulated % of solubilized of
remaining active substance at a given time (min) Min. % % 0 2.0 8.8
0.5 5.7 30.3 1 8.9 47.9 1.5 11.9 58.3 2 14.6 67.5 4 23.1 81.7 6
30.1 83.8 8 36.0 84.2 10 41.0 84.4 20 58.9 85.1 30 73.1 85.3 40
86.3 85.5 Initial Dissolution Rate EXP 570 6.6 EXP 571 33.3 Ratio
571/570 5.0
[0217] Experiments 570-571 show that the initial dissolution rate
of the stable, amorphous hybrid nanoparticles produced by the
methods of the invention, with crizotinib, is superior to the
initial dissolution rate of crizotinib in raw, crystalline
form.
Example 13.9
Dissolution Rate Measurement in Sink Conditions of Stable,
Amorphous Hybrid Nanoparticles Produced by the Methods of the
Invention Comprising Axitinib
[0218] In experiments with axitinib, 3.5 mg was weighed in the flow
through cell (experiment 580) and compared with stable, amorphous
hybrid nanoparticles produced by the methods of the invention with
axitinib and the polymeric stabilizing and matrix-forming component
Kollidon VA64 (experiment 581) or HPMC AS (experiment 582). The
results are depicted in Table 44 below.
TABLE-US-00045 TABLE 44 Axitinib sink condition in FaSSIF.
Experiment 580 Experiment 581 Experiment 582 Composition type I I/P
I/P Inhibitor (I) Axitinib (raw) Axitinib Axitinib Polymeric stab.
-- Kollidon VA64 HPMC AS matrix. Component (P) Drug load % -- 25%
25% Accumulated % of solubilized of remaining active substance at a
given time (min) Min. % % % 0 0.03 0.75 0.22 0.5 0.06 1.60 0.59 1
0.08 2.33 1.04 1.5 0.11 2.97 1.50 2 0.13 3.56 1.92 4 0.23 6.03 3.25
6 0.31 7.76 4.39 8 0.40 9.74 5.34 10 0.49 11.81 6.17 20 0.97 22.04
9.03 30 1.46 27.42 11.43 40 1.96 30.53 13.52 Initial Dissolution
Rate EXP 580 0.051 EXP 581 & 582 1.396 0.865 Ratio 581/580 27.5
17.1 & 582/580
[0219] Experiments 580-582 show that the initial dissolution rate
of the stable, amorphous hybrid nanoparticles produced by the
methods of the invention, with axitinib, is superior to the initial
dissolution rate of axitinib in raw, crystalline form.
Example 13.10
Dissolution Rate Measurement in Sink Conditions of Stable,
Amorphous Hybrid Nanoparticles Produced by the Methods of the
Invention Comprising Vemurafenib
[0220] In experiments with vemurafenib, 3.5 mg was weighed in the
flow through cell (experiment 590) and compared with stable,
amorphous hybrid nanoparticles produced by the methods of the
invention with vemurafenib and the polymeric stabilizing and
matrix-forming component Kollidon VA64 (experiment 591) or CAP
(experiment 592). The results are depicted in Table 45 below.
TABLE-US-00046 TABLE 45 Vemurafenib sink condition in FaSSIF.
Experiment Experiment 590 Experiment 591 592 Composition type I I/P
I/P Inhibitor (I) Vemurafenib (raw) Vemurafenib Vemurafenib
Polymeric stab. -- Kollidon VA64 CAP matrix. Component (P) Drug
load % -- 25% 25% Accumulated % of solubilized of remaining active
substance at a given time (min) Min. % % % 0 0.0 0.1 0.4 0.5 0.0
0.2 1.1 1 0.0 0.3 1.8 1.5 0.0 0.4 2.4 2 0.0 0.5 3.1 4 0.0 1.2 6.3 6
0.0 1.9 9.4 8 0.0 2.4 11.0 10 0.0 2.9 12.1 20 0.0 4.7 14.9 30 0.1
5.9 16.8 40 0.1 7.1 18.3 Initial Dissolution Rate EXP 590 0.002 EXP
591 & 592 0.209 1.346 Ratio 591/590 104 673 & 592/590
[0221] Experiments 590-592 clearly shows that the initial
dissolution rate of the stable, amorphous hybrid nanoparticles
produced by the methods of the invention, with vemurafenib, is
superior to the initial dissolution rate of vemurafenib in raw,
crystalline form.
Example 14
In Vivo Measurement of Plasma Levels after Oral Administration of
Stable, Amorphous Hybrid Nanoparticles Produced by the Methods of
the Invention
[0222] Groups of four male beagle dogs received single oral doses
(5 mg/kg) of capsule compositions comprising stable, amorphous
hybrid nanoparticles produced by the methods of the invention with
nilotinib base and either of the polymeric stabilizing and
matrix-forming components PVAP or HPMCP HP55, optionally with
addition of the solubilizer polyvinyl caprolactam-polyvinyl
acetate-polyethylene glycol copolymer, and compared with a marketed
formulation comprising nilotinib HCl. The stable, amorphous hybrid
nanoparticles tested are as set out in experiments 146-149, in
Example 9. The stomach contents of the dogs were either neutralized
with a sodium bicarbonate solution 5 min prior to capsule dosing or
acidified with an HCl-KCl buffer 10 min prior to dose. One group of
dogs also received a single iv dose (1 mg/kg) of nilotinib. Plasma
levels of nilotinib were determined with a selective LC-MS/MS
method. There were no side-effects observed in any animal
studied.
Results and Conclusions
[0223] Mean.+-.SEM plasma concentration-time profiles of nilotinib
base are shown in FIGS. 22-25, and pharmacokinetic parameters and
results are displayed in Tables 46A and 46B.
[0224] Outliers were calculated and excluded based on if one value
is a significant outlier from the rest at 95% confidence intervals
(alpha=5%) according to Grubb's test. The critical Z value for the
Grubb's test at the 95% confidence interval with n=4 is 1.48.
Z=(Mean-Questionable value)/SD
TABLE-US-00047 TABLE 46A Pharmacokinetic data following single oral
administration of different nilotinib compositions comprising
stable, amorphous hybrid nanoparticles produced by the methods of
the invention, in male dogs. I/P + S I/P Nilotinib I/P Marketed
Marketed Nilotinib base/PVAP + Nilotinib nilotinib nilotinib
base/PVAP Soluplus base/PVAP formulation formulation Exp 147 Exp
149 Exp 147 Acidic Neutral Acidic Acidic Neutral Stomach Stomach
Stomach Stomach Stomach Cmax, 86 .+-. 52 73 .+-. 26 240 .+-. 87 360
.+-. 89 490 .+-. 350 ng/mL Tmax, hr 7.6 .+-. 11 1.3 .+-. 0.3 1.3
.+-. 0.3 1.3 .+-. 0.3 1.4 .+-. 0.5 T1/2, hr 9.9; 10.7 1.9 .+-. 0.3
4.3 .+-. 3.0 3.3 .+-. 2.0 3.4 .+-. 1.2 AUC 0-24 h, 400 .+-. 140 220
.+-. 90 650 .+-. 240 1260 .+-. 70 1820 .+-. 1200 ng * hr/mL F (%)
7.9 .+-. 2.9 4.4 .+-. 1.8 13 .+-. 5 25 .+-. 1 36 .+-. 24
[0225] Values are given as Mean.+-.SD, except for T 1/2 of the
Marketed nilotinib formulation given too acid stomach where only
two values were obtained.
[0226] Intravenous (IV) data were obtained by constant rate IV
infusion of 1 mg/kg, of a solution of Nilotinib at 0.2 mg/mL, in a
10% HP.beta.CD, pH adjustment to pH 3.3 to 3.5. Co: 511.+-.46
ng/mL; T1/2: 3.3.+-.1.8 hr; AUC0-24 hr: 1000.+-.300 ng*hr/mL.
TABLE-US-00048 TABLE 46B Pharmacokinetic data following single oral
administration of different nilotinib formulations comprising
stable, amorphous hybrid nanoparticles produced by the methods of
the invention, in male dogs. I/P I/P I/P Nilotinib base/ I/P
Nilotinib base/ Nilotinib base/ HPMCP HP55 + Nilotinib base/ HPMCP
HP55 + HPMCP HP55 Soluplus HPMCP HP55 Soluplus Exp 146 Exp 148 Exp
146 Exp 148 Neutral Neutral Acidic Acidic Stomach Stomach Stomach
Stomach Cmax, 210 .+-. 97 560 .+-. 220 380 .+-. 90 270 .+-. 130
ng/mL Tmax, hr 1.1 .+-. 0.5 1.3 .+-. 0.29 1.2 .+-. 0.3 1.0 .+-. 0.0
T1/2, hr 1.9 .+-. 0.2 3.0 .+-. 1.4 3.3 .+-. 1.3 3.8 .+-. 0.8 AUC
0-24 h, 730 .+-. 390 1600 .+-. 580 1230 .+-. 110 910 .+-. 630 ng *
hr/mL F (%) 15 .+-. 8 32 .+-. 12 24 .+-. 2 18 .+-. 13
[0227] Values are given as Mean.+-.SD
[0228] Intravenous (IV) data were obtained by constant rate IV
infusion of 1 mg/kg, of a solution of Nilotinib at 0.2 mg/mL, in a
10% HP.beta.CD, pH adjustment to pH 3.3 to 3.5. Co: 511.+-.46
ng/mL; T1/2: 3.3.+-.1.8 hr; AUC0-24 hr: 1000.+-.300 ng*hr/mL.
[0229] The marketed nilotinib formulation administrated to an
acidified stomach showed plasma levels about 2 times higher than
those after the same formulation administered to a neutralized
stomach. Both formulations comprising stable, amorphous hybrid
nanoparticles produced by the methods of the invention with
nilotinib base with PVAP and HPMCP HP55 as polymeric stabilizing
and matrix-forming components showed significant improvements in
plasma exposure, with plasma levels about 2-fold higher than those
of the marketed formulation given to an acidified stomach. In
addition, combining hybrid nanoparticles produced by the methods of
the invention could give a plasma exposure that is be more or less
independent of stomach pH.
[0230] Further improvements in oral availability were observed when
formulations with stable, amorphous hybrid nanoparticles produced
by the methods of the invention were combined with the solubilizer
polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol
copolymer. Thus, hybrid nanoparticles produced by the methods of
the invention with nilotinib base with PVAP and HPMCP HP55 as
polymeric stabilizing and matrix-forming components, where the
solubilizer polyvinyl caprolactam-polyvinyl acetate-polyethylene
glycol copolymer was added and administered to an acidified stomach
resulted in plasma levels 2.3- to 3.1-fold higher than those of the
marketed formulation. In this study, high oral bioavailability was
achieved with stable, amorphous hybrid nanoparticles produced by
the methods of the invention with nilotinib base with HPMCP HP55 as
polymeric stabilizing and matrix-forming components, where the
solubilizer polyvinyl caprolactam-polyvinyl acetate-polyethylene
glycol copolymer was added (I/P+S) and administrated to neutralized
stomach contents. In this case the exposure increased about 7-fold
over that of the marketed oral formulation administered under the
same neutralized conditions. Highest bioavailability, 36.+-.24%, in
this study was achieved when stable, amorphous hybrid nanoparticles
produced by the methods of the invention with nilotinib base with
PVAP as polymeric stabilizing and matrix-forming components was
administered to a neutralized stomach. However, this study leg was
also accompanied with the highest standard deviation in the
study.
[0231] There was an improvement in the in vivo performance of the
novel formulations of nilotinib with stable, amorphous hybrid
nanoparticles produced by the methods of the invention, that are
based on improving absorption and bioavailability by optimization
of the solid state properties of the dosage form. The results of
the in vivo study in dogs may predict similar absorption properties
of hybrid nanoparticles produced by the methods of the invention,
in patients, as there appears to be a close correlation in
dog-human gastrointestinal drug absorption processes (Persson, E.
M. et al. Pharm. Res. 2005, 22, 2141-2151). The hybrid
nanoparticles produced by the methods of the invention, with
advantageous absorption properties, also predicts that the oral
doses used in clinical practice today may be lowered. Furthermore,
the stable, amorphous hybrid nanoparticles produced by the methods
of the invention may cause less pH-dependency in the absorption and
bioavailability of PKIs.
Example 15
Measurement of Degree/Level of Stability of Stable, Amorphous
Hybrid Nanoparticles Produced by the Methods of the Invention
[0232] In stability tests of stable, amorphous hybrid nanoparticles
produced by the methods of the invention, it was shown that
particles were stable over at least 11 months at room temperature
(18-25.degree. C.), as measured by X-Ray powder diffraction and
dissolution rate by measurement of AUC.
[0233] In series of experiments with hybrid nanoparticles
comprising nilotinib and HPMCP HP55 produced by the methods of the
invention, the resulting particles provided stable, amorphous
hybrid nanoparticles at 40% drug load (I/P nilotinib base/HPMCP
HP55: exp 146), as measured by XRPD as well as dissolution rate by
measurement of AUC. The material showed one glass transition
temperature at ca 127.degree. C., which indicate a single amorphous
phase with inherent stability. Partially crystalline batches also
processed similar inherent stability. 6 months storage at room
temperature (18-25.degree. C.) of partly crystalline hybrid
nanoparticles at 40% drug load, I/P nilotinib base/HPMCP HP55, did
not show any signs of physical instability.
[0234] Thermalgravimetric analysis provided a mass loss of 1.7%
from ambient temperature to 120.degree. C.
[0235] Dynamic vapor absorption analysis at 25.degree. C. gave a
relative mass increase of ca 7% from 0 to 90% RH (Three cycles from
0 to 90% RH, did not induce a phase change).
[0236] The high glass transition temperature, 1.7% mass loss from
ambient temperature to 120.degree. C. and moderate hygroscopicity
propose an inherent stability. This is supported by stability
testing of several batches at various conditions. The longest
stability point is 12 months at room temperature (18-25.degree.
C.). No batches or conditions have shown any signs of physical
instability (FIG. 27).
Modulated Differential Scanning Calorimetry (mDSC)
[0237] Modulated Differential Scanning calorimetry (mDSC) analysis
was run on a TA Instruments Model Q200 (New Castle, USA), equipped
with a RC90 refrigerated cooling system (Home Automation, New
Orleans, USA). Samples were weighed to 7.+-.2 mg in Tzero Low-mass
aluminum pans and sealed with Tzero lids. They were then heated at
a heating rate of 3.degree. C./min from 0 to 170.degree. C. with
conventional modulation temperature amplitude of 1.degree. C. and a
modulation period of 40 seconds. Ultra-high purity nitrogen was
used as purge gas at a flow rate of 50 mL/min. All data analyses
were performed using TA Universal Analysis software, version 4.7A.
Cell constant and temperature calibrations were conducted with the
use of an indium standard prior to instrument operation. DSC
results were evaluated in terms of both forward and reverse
components of heat flow.
[0238] Thermogravimetry (TG) was performed on a Seiko TG/DTA 6200
and open 90 .mu.l Pt-pans with ca 10 to 20 mg of sample and a
nitrogen flow of 200 mL/min. The temperature program was ambient
(20.degree. C.) to 400.degree. C. with a heating rate of 10.degree.
C./min. A blank was subtracted and the TG data was normalized with
respect to sample size and analyzed using the Muse Standard
Analysis software, version 6.1 U.
Dynamic Vapour Sorption (DVS)
[0239] The hygroscopicity of the samples was studied by Dynamic
Vapor Sorption Gravimetry (DVS), using a DVS-1 (Surface Measurement
Ltd., UK). Approximately 10 mg of the substance was weighed into a
glass cup. The relative weight was recorded at 20 second interval
when the target relative humidity (RH) over the sample was
increased stepwise from 0% to 90%, and then similarly decreased
back to 0% RH, with 10% RH per step. Each sample was run in three
consecutive full cycles. The condition to proceed to the next level
of RH was a weight change below or equal to 0.002% within 15
minutes, with a maximum total time per step of 24 hours. Due to
slow equilibration in experiments of this type, the numbers
obtained should be regarded as lower estimates of water uptake. The
temperature was kept at 25.degree. C.
X-Ray Powder Diffraction (XRPD)
[0240] XRD experiments were run on an X'Pert Pro diffractometer
(PANanalytical, Almelo, Netherlands) set in Bragg-Brentano
geometry. The diffractometer was equipped with 20 .mu.m nickel
filter and an X'Celerator RTMS detector with an active length of
2.122.degree. 20. A representative sample was placed on a zero
background quarts single crystal specimen support (Siltronix,
Archamps, France). Experiments were run using Cu K.sub..alpha.
radiation (45 kV and 40 mA) at ambient temperature and humidity.
Scans were run in continuous mode in the range 4.5-40.degree. 20
using automatic divergence and anti-scatter slits with observed
length of 10 mm, a common counting time of 299.72 seconds, and step
size of 0.0167.degree. 2.theta.. Data collection was done using the
application software X'Pert Data Collector V.2.2j and instrument
control software V.2.1E, while pattern analysis was done using
X'Pert Data Viewer V.1.2c (all software being from PANanalytical,
Almelo, Netherlands).
Dissolution Rate by Measurement of AUC
[0241] The stable, amorphous hybrid nanoparticles described in Exp
171 & Exp172 (I/P) as set out below, were produced according to
Exp 148, with nilotinib base, HPMCP HP55 and stored at room
temperature for 11 months. The non-sink dissolution rate was tested
at different time points and the results are presented in Table 47
and FIG. 26. Polyvinyl caprolactam-polyvinyl acetate-polyethylene
glycol copolymer was added to enhance solubility. A comparison of
the AUC over 80 minutes show clearly that the dissolution rate
profile of the particles is practically unchanged after 11 months
storage, e.g. the ratio between the AUC of particles produced and
tested, compared to particles produced, tested and stored for 11
months is over 97%.
TABLE-US-00049 TABLE 47 Ratio 0 1 min 5 min 10 min 20 min 40 min 80
min AUC (%) Exp 171 (t = 0, 0 70.5 144.8 172.8 155.8 67.7 46.0
7411.9 n = 1) Exp 171 (t = 11 0 20.2 110.7 149.5 158.5 83.6 34.0
7234.5 97.6 months, n = 3) Standard 0 5.8 14.3 19.6 19.6 3.5 1.5
deviation
* * * * *