U.S. patent application number 17/349916 was filed with the patent office on 2021-10-14 for solid dosage forms of palbociclib.
This patent application is currently assigned to PFIZER INC.. The applicant listed for this patent is PFIZER INC.. Invention is credited to Fady Makram Louiz Ibrahim, Matthew Patrick Mullarney, Ravi M. Shanker, Barbara Rodriguez Spong, Jian Wang.
Application Number | 20210315900 17/349916 |
Document ID | / |
Family ID | 1000005665974 |
Filed Date | 2021-10-14 |
United States Patent
Application |
20210315900 |
Kind Code |
A1 |
Ibrahim; Fady Makram Louiz ;
et al. |
October 14, 2021 |
SOLID DOSAGE FORMS OF PALBOCICLIB
Abstract
The present invention relates to solid dosage forms of
palbociclib comprising a water-soluble acid. The dosage forms
described herein have desirable pharmacokinetic
characteristics.
Inventors: |
Ibrahim; Fady Makram Louiz;
(East Lyme, CT) ; Mullarney; Matthew Patrick;
(Niantic, CT) ; Shanker; Ravi M.; (Stonington,
CT) ; Spong; Barbara Rodriguez; (Haddam, CT) ;
Wang; Jian; (Killingworth, CT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
PFIZER INC. |
New York |
NY |
US |
|
|
Assignee: |
PFIZER INC.
New York
NY
|
Family ID: |
1000005665974 |
Appl. No.: |
17/349916 |
Filed: |
June 17, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15578410 |
Nov 30, 2017 |
11065250 |
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PCT/IB2016/053040 |
May 24, 2016 |
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17349916 |
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62171177 |
Jun 4, 2015 |
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62332973 |
May 6, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2027 20130101;
A61K 9/28 20130101; A61K 47/12 20130101; A61K 9/2086 20130101; A61K
9/2018 20130101; A61K 9/2013 20130101; A61K 31/4439 20130101; A61K
9/2095 20130101; A61K 31/519 20130101; A61K 9/205 20130101; A61K
9/2009 20130101; A61K 9/2054 20130101 |
International
Class: |
A61K 31/519 20060101
A61K031/519; A61K 9/20 20060101 A61K009/20; A61K 9/28 20060101
A61K009/28; A61K 47/12 20060101 A61K047/12; A61K 31/4439 20060101
A61K031/4439 |
Claims
1. A solid dosage form comprising from about 10 wt % to about 35 wt
% of palbociclib, from about 5 wt % to about 25 wt % of a
water-soluble acid selected from the group consisting of succinic
acid, malic acid and tartaric acid, and a pharmaceutically
acceptable carrier.
2. The solid dosage form of claim 1, wherein the water-soluble acid
is succinic acid.
3. The solid dosage form of claim 1, wherein the pharmaceutically
acceptable carrier comprises at least one diluent, and wherein the
diluent comprises about 50 wt % to about 75 wt % of the solid
dosage form.
4. The solid dosage form of claim 3, wherein the diluent is
selected from the group consisting of microcrystalline cellulose,
lactose monohydrate, mannitol, sorbitol, xylitol, magnesium
carbonate, dibasic calcium phosphate and tribasic calcium
phosphate.
5. The solid dosage form of claim 1, wherein the pharmaceutically
acceptable carrier comprises at least one lubricant, and wherein
the lubricant comprises from about 0.5 wt % to about 10 wt % of the
solid dosage form.
6. The solid dosage form of claim 5, wherein the lubricant is
selected from the group consisting of magnesium stearate, calcium
stearate, zinc stearate and sodium stearyl fumarate.
7. The solid dosage form of claim 1, wherein the pharmaceutically
acceptable carrier comprises at least one disintegrant, and wherein
the disintegrant comprises from about 5 wt % to about 10 wt % of
the solid dosage form.
8. The solid dosage form of claim 7, wherein the disintegrant is
selected from the group consisting of crospovidone, croscarmellose
sodium and sodium starch glycolate.
9. The solid dosage form of claim 1, in the form of a tablet.
10. The solid dosage form of claim 9, wherein the tablet is film
coated.
11. The solid dosage form of claim 9, wherein the tablet is a
bilayer tablet.
12. The solid dosage form of claim 1, wherein the dosage form when
added to a test medium comprising 500 mL of 10 mM pH 5.5 acetate
buffer at 37.degree. C. in a standard USP 2 rotating paddle
apparatus with the paddles spinning at 50 rpm dissolves: (a) not
less than 35% of the palbociclib in 15 minutes; (b) not less than
45% of the palbociclib in 30 minutes; (c) not less than 55% in 60
minutes; or (d) two or more of (a), (b) and (c).
13. The solid dosage form of claim 1, wherein the dosage form when
added to a test medium comprising 500 mL of 50 mM pH 6.5 phosphate
buffer and 0.1 M NaCl at 37.degree. C. in a standard USP 2 rotating
paddle apparatus with the paddles spinning at 50 rpm dissolves: (a)
not less than 40% of the palbociclib in 15 minutes; (b) not less
than 35% of the palbociclib in 30 minutes; (c) not less than 25% of
the palbociclib in 60 minutes; or (d) two or more of (a), (b) and
(c).
14. A solid dosage form of claim 1, wherein the dosage form: (a)
has a mean fed/fasted ratio of the area under the plasma
concentration versus time curve (AUC) from about 0.8 to about 1.25
after administration of a single oral dose to a subject; (b) has a
mean fed/fasted ratio of the maximum plasma concentration
(C.sub.max) from about 0.8 to about 1.25 after administration of a
single oral dose to a subject; or (c) both (a) and (b).
15. The solid dosage form of claim 1, wherein the dosage form: (a)
provides a mean fasted AUC in the range of 80% to 125% of the mean
fasted AUC for a control immediate release (IR) oral capsule
containing an equivalent amount of palbociclib after administration
of a single oral dose to a subject; (b) provides a mean fasted
C.sub.max in the range of 80% to 125% of the mean fasted C.sub.max
for a control immediate release (IR) oral capsule containing an
equivalent amount of palbociclib after administration of a single
oral dose to a subject; or (c) both (a) and (b).
16. The solid dosage form of claim 1, wherein the dosage form
provides: (a) a mean AUC in the presence of a proton pump inhibitor
(PPI) in the range of 80% to 125% of the mean AUC in the absence of
the PPI after administration of a single oral dose to a subject;
(b) a mean C.sub.max in the presence of a proton pump inhibitor
(PPI) in the range of 80% to 125% of the mean C.sub.max in the
absence of the PPI after administration of a single oral dose to a
subject; or (c) both (a) and (b).
17. The solid dosage form of claim 16, wherein the PPI is
rabeprazole.
18. The solid dosage form of claim 1, wherein the dosage form
exhibits less than 0.05% acid adduct by weight after storage for 1
years at 25.degree. C. and 60% RH.
19. The solid dosage form of claim 1, wherein the amount of
palbociclib in the dosage form is 25 mg, 75 mg, 100 mg or 125
mg.
20. The solid dosage form of claim 19, wherein the amount of
palbociclib in the dosage form is 125 mg.
Description
BACKGROUND OF THE INVENTION
Field of the Invention
[0001] The present invention relates to solid dosage forms of
6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-
-pyrido[2,3-d]pyrimidin-7-one (hereinafter palbociclib), having
desirable pharmacokinetic characteristics which exhibit favorable
storage stability and dissolution properties.
Description of Related Art
[0002] Palbociclib is a potent and selective inhibitor of CDK4 and
CDK6, having the structure:
##STR00001##
[0003] Palbociclib is described in WHO Drug Information, Vol. 27,
No. 2, page 172 (2013). Palbociclib and pharmaceutically acceptable
salts thereof are disclosed in International Publication No. WO
2003/062236 and U.S. Pat. Nos. 6,936,612, 7,208,489 and 7,456,168;
International Publication No. WO 2005/005426 and U.S. Pat. Nos.
7,345,171 and 7,863,278; International Publication No. WO
2008/032157 and U.S. Pat. No. 7,781,583; and International
Publication No. WO 2014/128588. The contents of each of the
foregoing references are incorporated herein by reference in their
entirety.
[0004] Palbociclib is approved in the United States for the
treatment of hormone receptor (HR)-positive, human epidermal growth
factor 2 (HER2)-negative advanced or metastatic breast cancer in
combination with letrozole as initial endocrine therapy or in
combination with fulvestrant following disease progression on
endocrine therapy. The drug is sold by Pfizer under the trade name
IBRANCE.RTM. in the form of an immediate release (IR) capsule
dosage form comprising palbociclib as a free base for oral
administration.
[0005] Palbociclib is a dibasic compound and has two basic groups
with pKa's of approximately 7.3 (the secondary piperazine nitrogen)
and 4.1 (the pyridine nitrogen). The solubility of palbociclib free
base is pH dependent. Palbociclib is water soluble at low pH
(2.1-4.5), while the solubility dramatically decreases as pH rises
above 4.5. Palbociclib has poor water solubility (9 .mu.g/mL) at pH
7.9. Concomitant administration of agents which increase gastric pH
can alter the solubility and absorption of palbociclib free base
formulations.
[0006] The absorption and bioavailability of a therapeutic agent
can be affected by numerous factors when dosed orally, including
whether the subject is in a fed or fasted state, and the use of
certain medications, such as proton pump inhibitors (PPIs) or H2
receptor antagonists, as well as certain medical conditions.
Compounds having pH-dependent solubility, particularly basic
compounds, may exhibit undesirable pharmacokinetic properties, such
as poor absorption and/or reduced bioavailability, which may result
in significant inter-patient and intra-patient variability.
[0007] There remains a need to discover improved dosage forms of
palbociclib having favorable dissolution and pharmacokinetic
profiles, which also demonstrate good storage stability. We have
surprisingly found that the solid dosage forms according to the
present invention demonstrate excellent storage stability and
provide substantially pH-independent delivery of palbociclib with
no significant food effects or adverse interactions with PPIs.
BRIEF SUMMARY OF THE INVENTION
[0008] In a first aspect, the invention provides a solid dosage
form comprising palbociclib, a water-soluble acid, and a
pharmaceutically acceptable carrier.
[0009] In a second aspect, the invention provides a solid dosage
form of any of the embodiments described herein, wherein the dosage
form when added to a test medium comprising 500 mL of 10 mM pH 5.5
acetate buffer at 37.degree. C. in a standard USP 2 rotating paddle
apparatus with the paddles spinning at 50 rpm dissolves: (a) not
less than 35% of the palbociclib in 15 minutes; (b) not less than
45% of the palbociclib in 30 minutes; (c) not less than 55% in 60
minutes; or (d) two or more of (a), (b) and (c).
[0010] In a third aspect, the invention provides a solid dosage
form of any of the embodiments described herein, wherein the dosage
form when added to a test medium comprising 500 mL of 50 mM pH 6.5
phosphate buffer and 0.1 M NaCl at 37.degree. C. in a standard USP
2 rotating paddle apparatus with the paddles spinning at 50 rpm
dissolves: (a) not less than 15% of the palbociclib in 15 minutes;
(b) not less than 20% of the palbociclib in 30 minutes; (c) not
less than 25% of the palbociclib in 60 minutes; or (d) two or more
of (a), (b) and (c).
[0011] In some embodiments, the invention provides a solid dosage
form of any of the embodiments described herein, wherein the dosage
form when added to a test medium comprising 500 mL of 50 mM pH 6.5
phosphate buffer and 0.1 M NaCl at 37.degree. C. in a standard USP
2 rotating paddle apparatus with the paddles spinning at 50 rpm
dissolves: (a) not less than 20% of the palbociclib in 15 minutes;
(b) not less than 30% of the palbociclib in 30 minutes; (c) not
less than 25% of the palbociclib in 60 minutes; or (d) two or more
of (a), (b) and (c).
[0012] In other embodiments, the invention provides a solid dosage
form of any of the embodiments described herein, wherein the dosage
form when added to a test medium comprising 500 mL of 50 mM pH 6.5
phosphate buffer and 0.1 M NaCl at 37.degree. C. in a standard USP
2 rotating paddle apparatus with the paddles spinning at 50 rpm
dissolves: (a) not less than 40% of the palbociclib in 15 minutes;
(b) not less than 35% of the palbociclib in 30 minutes; (c) not
less than 25% of the palbociclib in 60 minutes; or (d) two or more
of (a), (b) and (c).
[0013] In a fourth aspect, the invention provides a solid dosage
form of any of the embodiments described herein, wherein the dosage
form: (a) has a mean fed/fasted ratio of the area under the plasma
concentration versus time curve (AUC) from about 0.8 to about 1.25
after administration of a single oral dose to a subject; (b) has a
mean fed/fasted ratio of the maximum plasma concentration
(C.sub.max) from about 0.8 to about 1.25 after administration of a
single oral dose to a subject; or (c) both (a) and (b).
[0014] In a fifth aspect, the invention provides a solid dosage
form of any of the embodiments described herein, wherein the dosage
form: (a) provides a mean fasted AUC in the range of 80% to 125% of
the mean fasted AUC for a control immediate release (IR) oral
capsule containing an equivalent amount of palbociclib after
administration of a single oral dose to a subject; or (b) provides
a mean fasted C.sub.max in the range of 80% to 125% of the mean
fasted C.sub.max for a control immediate release (IR) oral capsule
containing an equivalent amount of palbociclib after administration
of a single oral dose to a subject; or (c) both (a) and (b).
[0015] In a sixth aspect, the invention provides a solid dosage
form of any of the embodiments described herein, wherein the dosage
form: (a) provides a mean AUC in the presence of a proton pump
inhibitor (PPI) in the range of 80% to 125% of the mean AUC in the
absence of the PPI after administration of a single oral dose to a
subject; (b) provides a mean C.sub.max in the presence of a proton
pump inhibitor (PPI) in the range of 80% to 125% of the mean
C.sub.max in the absence of the PPI after administration of a
single oral dose to a subject; or (c) both (a) and (b). In some
such embodiments, the PPI is rabeprazole.
[0016] In a seventh aspect, the invention provides a solid dosage
form of any of the embodiments described herein, wherein the dosage
form exhibits less than 0.3% acid adduct by weight after storage
for 96 days at 30.degree. C. and 75% relative humidity (RH).
[0017] In an eighth aspect, the invention provides a solid dosage
form of any of the embodiments described herein, wherein the dosage
form exhibits less than 1.0% acid adduct by weight after storage
for 2 years at 30.degree. C. and 75% RH.
[0018] In a ninth aspect, the invention provides a solid dosage
form of any of the embodiments described herein, wherein the dosage
form exhibits less than 0.05% acid adduct by weight after storage
for 1 year at 25.degree. C./60% RH. In some such embodiments, the
dosage form is packaged with a desiccant canister in a bottle using
a heat-induction seal.
[0019] In some embodiments of each of the aspects of the invention,
the active pharmaceutical ingredient (API), palbociclib, comprises
from about 10% to about 35% of the dosage form by weight. In
specific embodiments, palbociclib comprises about 20% of the dosage
form by weight.
[0020] In some embodiments of each of the aspects of the invention,
the water-soluble acid comprises from about 5% to about 40% of the
dosage form by weight. In particular embodiments, the water-soluble
acid comprises from about 5% to about 25% of the dosage form by
weight. In other embodiments, the water-soluble acid comprises from
about 5% to about 15% of the dosage form by weight. In more
particular embodiments, the water-soluble acid comprises about 10%
of the dosage form by weight.
[0021] In some such embodiments, the water-soluble acid is selected
from the group consisting of succinic acid, malic acid and tartaric
acid. In specific embodiments, the water-soluble acid is succinic
acid. In other embodiments, the water-soluble acid is malic acid.
In further embodiments, the water-soluble acid is tartaric
acid.
[0022] In a preferred embodiment of each of the aspects described
herein, the solid dosage form comprises from about 10 wt % to about
35 wt % of palbociclib, from about 5 wt % to about 25 wt % of a
water-soluble acid selected from the group consisting of succinic
acid, malic acid and tartaric acid, and a pharmaceutically
acceptable carrier. In particular embodiments, the water-soluble
acid is succinic acid. In some such embodiments, the solid dosage
form comprises about 20 wt % of palbociclib, about 10 wt % of
succinic acid, and a pharmaceutically acceptable carrier.
[0023] In some embodiments of each of the aspects described herein,
the pharmaceutically acceptable carrier comprises one or more of
the following pharmaceutically acceptable excipients: diluents,
disintegrants, binders, lubricants, glidants and surface-active
agents. Such excipients may be incorporated into tablet forms
either intragranularly or extragranularly, and tablets may comprise
the same or different excipients as intragranular or extragranular
components. For example, a tablet formulation may comprise an
intragranular lubricant, an extragranular lubricant, or both an
intragranular and an extragranular lubricant which may be the same
or different.
[0024] In some embodiments of each of the aspects described herein,
the pharmaceutically acceptable carrier comprises at least one
diluent, wherein the diluent comprises about 50 wt % to about 75 wt
% of the solid dosage form. In certain embodiments, the carrier
comprises at least one diluent selected from the group consisting
of microcrystalline cellulose, lactose monohydrate, mannitol,
sorbitol, xylitol, magnesium carbonate, dibasic calcium phosphate
and tribasic calcium phosphate. In specific embodiments, the
diluent is microcrystalline cellulose. In some such embodiments,
the diluent is microcrystalline cellulose.
[0025] In other embodiments of each of the aspects described
herein, the pharmaceutically acceptable carrier comprises a
lubricant, wherein the lubricant comprises from about 0.5 wt % to
about 10 wt % of the solid dosage form. In certain embodiments, the
carrier comprises at least one lubricant selected from the group
consisting of magnesium stearate, calcium stearate, zinc stearate,
and sodium stearyl fumarate. In specific embodiments, the lubricant
is magnesium stearate, which may be included intragranularly,
extragranularly, or both. In other embodiments, the lubricant is
sodium stearyl fumarate. Other embodiments comprise both magnesium
stearate and sodium stearyl fumarate as lubricants, which may be
included intragranularly, extragranularly, or both.
[0026] In further embodiments of each of the aspects described
herein, the pharmaceutically acceptable carrier comprises at least
one disintegrant, wherein the disintegrant comprises from about 5
wt % to about 10 wt % of the solid dosage form. In certain
embodiments, the carrier comprises at least one disintegrant
selected from the group consisting of crospovidone, croscarmellose
sodium and sodium starch glycolate. In specific embodiments, the
disintegrant is crospovidone.
[0027] In frequent embodiments of each of the aspects described
herein, the solid dosage form of the invention is in the form of a
tablet. In some embodiments, the tablet is film coated. In some
embodiments, the tablet is a monolayer tablet. In other
embodiments, the tablet is a bilayer tablet. In particular
embodiments, the tablets of the invention comprise palbociclib in
the amount of 25 mg, 75 mg, 100 mg or 125 mg. In specific
embodiments, the tablets of the invention comprise palbociclib in
the amount of 125 mg.
[0028] The frequent embodiments of each of the aspects of the
invention, the solid dosage form is in the form of a tablet. In
some embodiments, the tablet is a monolayer tablet. In other
embodiments, the tablet is a bilayer tablet.
[0029] In some embodiments of the aspects and embodiments described
herein, the amount of palbociclib in the dosage form is 25 mg, 75
mg, 100 mg or 125 mg. In specific embodiments, the amount of
palbociclib in the dosage form is 125 mg.
Each of the embodiments of the present invention described herein
may be combined with one or more other embodiments of the present
invention described herein that are not inconsistent with the
embodiment(s) with which it is combined.
BRIEF DESCRIPTION OF THE DRAWINGS
[0030] FIG. 1. In vitro dissolution data for prototype formulations
comprising eight test water soluble acids (malic, maleic, succinic,
fumaric, tartaric, tosylic, benzoic and benzenesulfonic acids) at
37.degree. C. in a pH 5.5, 10 mM sodium acetate buffer solution in
a USP 2 apparatus with paddles spinning at 50 rpm.
[0031] FIG. 2. In vitro dissolution data for prototype formulations
comprising succinic acid, malic acid and tartaric acid at
37.degree. C. in a pH 5.5, 10 mM sodium acetate buffer solution in
a USP 2 apparatus with paddles spinning at 50 rpm.
[0032] FIG. 3. Non-sink in vitro dissolution data for prototype
formulations comprising succinic acid at 37.degree. C. in a pH 6.5,
50 mM phosphate buffer solution containing+0.1 M NaCl, in a USP 2
apparatus with paddles spinning at 50 rpm.
[0033] FIG. 4. Non-sink in vitro dissolution data for formulations
A1, A2 and B at 37.degree. C. in a pH 6.5, 50 mM phosphate buffer
solution containing+0.1 M NaCl, in a USP 2 apparatus with paddles
spinning at 50 rpm.
DETAILED DESCRIPTION OF THE INVENTION
[0034] The present invention may be understood more readily by
reference to the following detailed description of the preferred
embodiments of the invention and the Examples included herein. It
is to be understood that the terminology used herein is for the
purpose of describing specific embodiments only and is not intended
to be limiting. It is further to be understood that unless
specifically defined herein, the terminology used herein is to be
given its traditional meaning as known in the relevant art.
[0035] As used herein, the singular form "a", "an", and "the"
include plural references unless indicated otherwise. For example,
"an" excipient includes one or more excipients.
[0036] The term "about" means having a value falling within an
accepted standard of error of the mean when considered by one of
ordinary skill in the art. Frequently, the term "about" refers to
.+-.15%, preferably .+-.10%, and more preferably .+-.5% of the
value or range to which it refers. For example, "about 10 wt %"
means 10 wt %.+-.1.5 wt %, preferably 10 wt %.+-.1 wt %, and more
preferably 10 wt %.+-.0.5 wt %.
[0037] Unless otherwise indicated herein, palbociclib refers the
free base form of
6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-yla-
mino)-8H-pyrido[2,3-d]pyrimidin-7-one, which may be present in
crystalline or amorphous form, or a mixture of amorphous and
crystalline forms.
[0038] The absorption of orally administered drugs may be affected
by changes in pH as the drug passes through the gastrointestinal
(GI) tract. Absorption may occur at different locations along the
GI tract, e.g., at the cheek lining, or in the stomach, duodenum,
jejunum, ileum or colon. The pH differs at each site of absorption,
with the pH of the stomach (pH 1-3.5) differing significantly from
the pH of the small intestine (pH 4.5-8). Drugs having pH-dependent
solubility may precipitate from solution as the drug passes through
the GI tract, resulting in inter- or intra-patient variability in
the extent and/or rate of absorption between doses or patients.
[0039] The pH of the GI tract may also vary based on whether a
patient or subject is in a fed or fasted state. In general, the
gastric residence time of a drug is longer in the presence of food
than in the fasted state. If the bioavailability of a drug is
significantly affected by the presence or absence of food in the GI
tract, the drug is said to exhibit a "food effect". The rate of
gastric emptying may also influence the concentration of drug in
solution available for absorption at different sites along the GI
tract.
[0040] Co-administration of certain medications, as well as medical
conditions such as achlorhydria, may also affect the pH of the GI
tract. The use of acid-reducing agents, such as proton pump
inhibitors (PPIs) or H2 receptor antagonists, may result in a
relatively high stomach pH, which can result in only partial
dissolution of drugs having pH-dependent solubility in the stomach.
Further dissolution of the undissolved drug may be inhibited by low
solubility in the higher pH environment of the upper intestine.
This can result in non-uniform dissolution of drugs having
pH-dependent solubility, increasing the risk of drug-drug
interactions, and potentially leading to decreased absorption and
reduced therapeutic benefit.
[0041] A study in healthy volunteers showed that exposure with
palbociclib treatment (125 mg administered once daily as a free
base capsule) was marginally increased in fed (AUCinf, 23%-27%; C
max, 21%-24%) versus fasted (AUCinf, 39%; C max, 73%) subjects, and
PK variability was greatly reduced in the fed state. Ruiz-Garcia et
al., Annals of Oncology (2014) 25 (suppl_4): iv146-iv164.
10.1093/annonc/mdu331. Because of the reduced inter-patient
variability observed in the fed state, it is recommended on the
U.S. package insert that commercial free base capsules of
palbociclib be taken with food.
[0042] When formulating a compound into a tablet or other solid
dosage form, it is desirable to develop a formulation which is
storage stable at temperatures and relative humidity levels above
those typically encountered. Other desirable properties in a
formulation may also be sought, such as fast dissolution so that
the tablet quickly dissolves and the drug is available for
absorption. Accordingly, good storage stability and fast
dissolution were, inter alia, features that were sought as
desirable characteristics for the instant invention.
[0043] Drug dissolution represents a critical factor affecting the
rate of systemic absorption. A variety of in vitro methods have
been developed for assessing the dissolution properties of
pharmaceutical formulations, and dissolution testing is sometimes
used as a surrogate for the direct evaluation of drug
bioavailability. See, e.g., Emmanuel et al., Pharmaceutics (2010),
2:351-363, and references cited therein. Dissolution testing
measures the percentage of the API that has been released from the
drug product (i.e., tablet or capsule) and dissolved in the
dissolution medium under controlled testing conditions over a
defined period of time. To maintain sink conditions, the saturation
solubility of the drug in the dissolution media should be at least
three times the drug concentration. For low solubility compounds,
dissolution may sometimes be determined under non-sink conditions.
Dissolution is affected by the properties of the API (e.g.,
particle size, crystal form, bulk density), the composition of the
drug product (e.g., drug loading, excipients), the manufacturing
process (e.g., compression forces) and the stability under storage
conditions (e.g., temperature, humidity).
[0044] Methods for assessing the chemical storage stability of
solid dosage forms under accelerated aging conditions have been
described in the literature. See, e.g., S. T. Colgan, T. J. Watson,
R. D. Whipple, R. Nosal, J. V. Beaman, D. De Antonis, "The
Application of Science and Risk Based Concepts to Drug Substance
Stability Strategies" J. Pharm. Innov. 7:205-2013 (2012); Waterman
K C, Carella A J, Gumkowski M J, et al. Improved protocol and data
analysis for accelerated shelf-life estimation of solid dosage
forms. Pharm Res 2007; 24(4):780-90; and S. T. Colgan, R. J.
Timpano, D. Diaz, M. Roberts, R. Weaver, K. Ryan, K. Fields, G.
Scrivens, "Opportunities for Lean Stability Strategies" J. Pharm.
Innov. 9:259-271 (2014).
[0045] For the solid dosage forms of the present invention, the
formation of an acid adduct of the piperazinyl moiety of
palbociclib and the water-soluble acid is a key degradant that is
monitored to assess storage stability.
[0046] As further described herein, the present invention provides
solid dosage forms comprising palbociclib, a water-soluble acid,
and a pharmaceutically acceptable carrier, and methods for their
production and use.
[0047] Solid dosage forms include, but are not limited to,
immediate release tablets and capsules, controlled-release (CR)
tablets and capsules, fast-dissolve dosage forms, chewable dosage
forms, sachets, etc. Preferably, the dosage form of the present
invention is in the form of a tablet, including monolayer or
bilayer tablets.
[0048] A "solid dosage form" of the present invention is a
pharmaceutically-acceptable solid dosage form that is safe for oral
administration to humans, where all excipients in the dosage form
are pharmaceutically acceptable for use in oral formulations, in
other words safe for human ingestion. In frequent embodiments, the
solid dosage form is a tablet.
[0049] As used herein, the term "unit dose" or "unit dosage" refers
to a physically discrete unit that contains a predetermined
quantity of active ingredient calculated to produce a desired
therapeutic effect. The unit dose or unit dosage may be in the form
of a tablet, capsule, sachet, etc. referred to herein as a "unit
dosage form."
[0050] The term "fasted" as used herein is defined as follows: the
dosing state which is defined following an overnight fast (wherein
0 caloric intake has occurred) of at least 10 hours (i.e., 0
hours). Subjects may administer the dosage form with 240 mL of
water. No food should be allowed for at least 4 hours post-dose.
Water may be allowed as desired except for one hour before and
after drug administration.
[0051] The term "fed" as used herein is defined as follows: the
dosing state which is defined following an overnight fast (wherein
0 caloric intake has occurred) of at least 10 hours, subjects then
begin the recommended meal. Subjects should eat this meal in 30
minutes or less; however the drug product should be administered 30
minutes after the start of the meal. The drug product may be
administered with 240 mL of water. No food should be allowed for at
least 4 hours post-dose. Water may be allowed as desired except for
one hour before and after drug administration.
[0052] To assess the fed/fasted ratio, a single oral dose of
palbociclib may be administered: 30 minutes after a high-fat,
high-calorie meal (.about.800-1000 calories with 150, 250, and
500-600 calories from protein, carbohydrate, and fat,
respectively); 30 minutes after a low-fat, low-calorie meal
(.about.400-500 calories with 120, 250, and 28-35 calories from
protein, carbohydrate, and fat, respectively); or between meals (1
hour after/2 hours before) for a moderate fat and calorie content
meal (.about.500-700 calories consisting of 15% protein, 50%
carbohydrate, and 35% fat).
[0053] A high fat and high calorie meal may be used as the test
meal under the fed condition. An example high fat test meal would
be two eggs fried in butter, two strips of bacon, two slices of
toast with butter, four ounces of hash brown potatoes and eight
ounces of whole milk.
[0054] The calculation of the mean area under the serum
concentration versus time curve (AUC) is a well-known procedure in
the pharmaceutical arts and is described, for example, in Welling,
"Pharmacokinetics Processes and Mathematics," ACS Monograph 185
(1986). AUC as used herein includes area under the
concentration-time curve from time zero extrapolated to infinite
time following a single dose or the area under the
concentration-time curve from time zero to time of the end of
dosing interval following steady state/multiple doses.
[0055] In addition, the calculations for C.sub.max, C.sub.min,ss,
T.sub.max, and elimination half-life (t 1/2), are also known to
this of ordinary skill in the art and is described, for example, in
Shargel, Wu-Pong, and Yu, Applied Biopharmaceutics and
Pharmacokinetics (2005).
[0056] To determine the mean fed/fasted ratio, the individual ratio
of the mean area under the plasma concentration versus time curve
of palbociclib (e.g. AUC.sub.0-inf) in the fed state to the mean
area under the plasma concentration versus time curve of
palbociclib (e.g. AUC.sub.0-inf) in the fasted state is first
calculated, and then the corresponding individual ratios are
averaged together. In this way, it is the average of each
corresponding individual's ratio which is determined.
[0057] Proton-pump inhibitors (PPIs) are a well-known class of
drugs that reduce the production of gastric acid, thereby modifying
gastric pH. Representative PPIs include, for example, rabeprazole,
omeprazole (including S- and B-forms, Na and Mg salts),
lansoprazole, pantoprazole, esomeprazole, and the like.
[0058] As used herein, the term "control immediate release (IR)
oral capsule" refers to the commercial IR capsule formulation of
palbociclib as described in Example 11. This formulation, along
with an isethionate salt formulation (ISE) and a free base tablet
dosage form that lacks the water-soluble acid but is otherwise
substantially the same as the formulation in Example 1 may be
referenced herein as controls.
[0059] "Dissolution Test 1" refers to the following test of dosage
forms of palbociclib. The dissolution test is conducted in a
standard USP 2 rotating paddle apparatus as disclosed in United
States Pharmacopoeia (USP) Dissolution Test Chapter 711, Apparatus
2. Paddles are rotated at 50 rpm and the dosage form is added to
500 mL of 10 mM pH 5.5 acetate buffer at 37.degree. C. At
appropriate times following test initiation (e.g., insertion of the
dosage form into the apparatus), filtered aliquots (typically 1.5
mL) from the test medium are analyzed for palbociclib by high
performance liquid chromatography (HPLC). Dissolution results are
reported as the percent of the total dose of palbociclib tested
dissolved versus time.
[0060] "Dissolution Test 2" refers to the following test of dosage
forms of palbociclib. The dissolution test is conducted in a
standard USP 2 rotating paddle apparatus as disclosed in United
States Pharmacopoeia (USP) Dissolution Test Chapter 711, Apparatus
2. Paddles are rotated at 50 rpm and the dosage form is added to
500 mL of 50 mM pH 6.5 phosphate buffer and 0.1 M NaCl at
37.degree. C. At appropriate times following test initiation (e.g.,
insertion of the dosage form into the apparatus), filtered aliquots
(typically 1.5 mL) from the test medium are analyzed for
palbociclib by high performance liquid chromatography (HPLC).
Dissolution results are reported as the percent of the total dose
of palbociclib tested dissolved versus time.
[0061] The term "dry granulation" means the process of blending
bulk active product with at least one excipient. The blend is then
compressed, or compacted, to form a compressed material or
"compact". This material may be broken apart to form granules by
crushing, grinding or cutting into dry granulated particles.
Optionally, the particles may be further processed. Crushing,
grinding, or cutting processes involve an operation that reduces
the size of the compressed material such as accomplished by milling
or by other operations known to those skilled in the art.
[0062] The term "water-soluble" used herein in relation to the acid
present in the composition refers to an acid that has a solubility
of at least 0.2% by weight in water at 25.degree. C. The
water-soluble acid may be an organic or inorganic acid, and
preferably is an organic acid having at least one pKa value which
is at least one (preferably at least two) pK unit lower than the
highest pKa of the basic groups present in the drug. In the case of
the palbociclib, which has pKa values of approximately 4.1 and 7.3,
the acid preferably has a pKa of less than 6.3, and more preferably
a pKa of less than 5.3. Water-soluble organic acids include, for
example, C.sub.2-C.sub.8 or C.sub.2-C.sub.6 aliphatic mono or
poly-carboxylic acids, and preferably C.sub.4-C.sub.6 aliphatic
mono or poly-carboxylic acids. Particularly preferred are
C.sub.4-C.sub.6 dicarboxylic acids, which may be saturated or
unsaturated.
[0063] Solid dosage forms of the invention may comprise a single
water-soluble acid, or may include a combination of two or more
such acids. In selected embodiments of the invention, the
water-soluble acid is selected from the group consisting of
succinic acid, malic acid and tartaric acid. In certain preferred
embodiments of the invention, the water-soluble acid is succinic
acid.
[0064] The water-soluble acid may be combined with the drug prior
to granulation or it may be incorporated into the dosage form along
with extragranular excipients. In a bilayer tablet, the
water-soluble acid may be present in the active layer containing
palbociclib, incorporated into a separate acid layer, or
water-soluble acids (which may be the same or different) may be
incorporated into both the active and acid layers.
[0065] Without wishing to be bound by theory, it is thought that
the presence of an acid in the solid dosage form in close contact
with the drug increases solubilization by way of an interaction
between palbociclib and the acid. The solid dosage forms of the
invention thereby provide an increased local concentration of the
drug in solution following oral administration to a subject as
compared to administration of palbociclib formulations lacking the
water-soluble acid.
[0066] In some embodiments, the solid dosage form of any of the
embodiments described herein, under the conditions of Dissolution
Test 1 (pH 5.5 acetate buffer, 37.degree. C.), dissolves: (a) not
less than 35% of the palbociclib in 15 minutes; (b) not less than
45% of the palbociclib in 30 minutes; (c) not less than 55% in 60
minutes; or (d) two or more of (a), (b) and (c).
[0067] In further embodiments, the solid dosage form of the
invention under the conditions of Dissolution Test 1 dissolves: (a)
not less than 25%, 30%, 35%, 40%, 45%, or 50%, or more than 50% of
the palbociclib is dissolved in 15 minutes; (b) not less than 35%,
40%, 45%, 50%, 55%, or 60%, or more than 60% of the palbociclib is
dissolved in 30 minutes; and/or (c) not less than 45%, 50%, 55%,
60%, 65%, or 70% or more than 70% of the palbociclib is dissolved
in 60 minutes.
[0068] In some embodiments, the solid dosage form of any of the
embodiments described herein, under the non-sink conditions of
Dissolution Test 2 (pH 6.5 phosphate buffer and 0.1 M NaCl,
37.degree. C.) dissolves: (a) not less than 40% of the palbociclib
in 15 minutes; (b) not less than 35% of the palbociclib in 30
minutes; (c) not less than 25% of the palbociclib in 60 minutes; or
(d) two or more of (a), (b) and (c).
[0069] In other embodiments, the solid dosage form of any of the
embodiments described herein, under the non-sink conditions of
Dissolution Test 2 (pH 6.5 phosphate buffer and 0.1 M NaCl,
37.degree. C.) dissolves: (a) not less than 15% of the palbociclib
in 15 minutes; (b) not less than 20% of the palbociclib in 30
minutes; (c) not less than 25% of the palbociclib in 60 minutes; or
(d) two or more of (a), (b) and (c).
[0070] In other embodiments under Dissolution Test 2: (a) not less
than 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%, or more than
50% of the palbociclib is dissolved in 15 minutes; (b) not less
than 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%, or more than 50% of
the palbociclib is dissolved in 30 minutes; and/or (c) not less
than 15%, 20%, 25%, 30%, 35%, or 40%, or more than 40% of the
palbociclib is dissolved in 60 minutes.
[0071] In further embodiments under Dissolution Test 2: (a) not
less than 30%, 35%, 40%, 45%, or 50%, or more than 50% of the
palbociclib is dissolved in 15 minutes; (b) not less than 25%, 30%,
35%, 40%, 45%, or 50%, or more than 50% of the palbociclib is
dissolved in 30 minutes; and/or (c) not less than 15%, 20%, 25%,
30%, 35%, or 40%, or more than 40% of the palbociclib is dissolved
in 60 minutes.
[0072] In some embodiments, the invention provides a solid dosage
form comprising palbociclib, a water-soluble acid, and a
pharmaceutically acceptable carrier, wherein the dosage form
provides: (a) a mean fed/fasted ratio of the area under the plasma
concentration versus time curve (AUC) from about 0.8 to about 1.25
after administration of a single oral dose to a subject; (b) a mean
fed/fasted ratio of the maximum plasma concentration (C.sub.max)
from about 0.8 to about 1.25 after administration of a single oral
dose to a subject; or (c) both (a) and (b).
[0073] In some embodiments, the invention provides a solid dosage
form comprising palbociclib, a water-soluble acid, and a
pharmaceutically acceptable carrier, wherein the dosage form
provides: (a) a mean fasted AUC in the range of 80% to 125% of the
mean fasted AUC for a control immediate release (IR) oral capsule
containing an equivalent amount of palbociclib after administration
of a single oral dose to a subject; (b) a mean fasted C.sub.max in
the range of 80% to 125% of the mean fasted C.sub.max for a control
immediate release (IR) oral capsule containing an equivalent amount
of palbociclib after administration of a single oral dose to a
subject; or (c) both (a) and (b).
[0074] In further embodiments, the invention provides a solid
dosage form comprising palbociclib, a water-soluble acid, and a
pharmaceutically acceptable carrier, wherein the dosage form
provides: (a) a mean AUC in the presence of a proton pump inhibitor
(PPI), preferably rabeprazole, in the range of 80% to 125% of the
mean AUC in the absence of the PPI after administration of a single
oral dose to a subject; (b) a mean C.sub.max in the presence of a
proton pump inhibitor (PPI), preferably rabeprazole, in the range
of 80% to 125% of the mean C.sub.max in the absence of the PPI
after administration of a single oral dose to a subject; or (c)
both (a) and (b).
[0075] In other embodiments, the invention provides a solid dosage
form comprising palbociclib, a water-soluble acid, and a
pharmaceutically acceptable carrier, wherein the dosage form
exhibits less than 0.4%, 0.35%, 0.3%, 0.25%, 0.2%, 0.15% or 0.1%
acid adduct by weight after storage for 96 days at 30.degree. C.
and 75% relative humidity (RH).
[0076] In still other embodiments, the invention provides a solid
dosage form comprising palbociclib, a water-soluble acid, and a
pharmaceutically acceptable carrier, wherein the dosage form
exhibits less than 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%,
0.7%, 0.6%, 0.5%, 0.4% or 0.3% acid adduct by weight after storage
for 2 years at 30.degree. C. and 75% RH.
[0077] In some embodiments of each of the aspects and embodiments
of the invention, the water-soluble acid is selected from the group
consisting of succinic acid, malic acid and tartaric acid. In
specific embodiments of each of the aspects and embodiments herein,
the water-soluble acid is succinic acid. In other embodiments, the
water-soluble acid is malic acid. In further embodiments, the
water-soluble acid is tartaric acid.
[0078] In some embodiments of each of the aspects of the invention,
the water-soluble acid comprises from about 5% to about 40% of the
dosage form by weight. In particular embodiments, the water-soluble
acid comprises from about 5% to about 25% of the dosage form by
weight. In some embodiments, the water-soluble acid comprises about
5%, 10%, 15%, 20%, 25%, 30%, 35% or 40% of the dosage form by
weight.
[0079] In some embodiments of each of the aspects of the invention,
palbociclib comprises from about 10% to about 35% of the dosage
form by weight. In specific embodiments, palbociclib comprises
about 20% of the dosage form by weight. In some embodiments, the
palbociclib comprises about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%,
45% or 50% of the dosage form by weight.
[0080] In frequent embodiments of each of the aspects and
embodiments herein, the solid dosage form is a tablet, preferably a
tablet formed by dry-granulation. In some such embodiments, the
tablet is a bilayer tablet. In particular embodiments, the bilayer
tablet comprises: (a) an active layer comprising palbociclib and a
pharmaceutically acceptable carrier; and (b) an acid layer
comprising a water-soluble acid and a pharmaceutically acceptable
carrier. In some embodiments, the bilayer tablet comprises: (a) an
active layer comprising palbociclib, a water-soluble acid, and a
pharmaceutically acceptable carrier; and (b) an acid layer
comprising a water-soluble acid and a pharmaceutically acceptable
carrier, wherein the water-soluble acid in the active layer may be
the same or different than the water-soluble acid in the acid
layer. In a specific embodiment, the water-soluble acid in the
active layer is succinic acid and the water-soluble acid in the
acid layer is tartaric acid.
[0081] In another aspect, the invention provides a method of
treating cancer comprising administering to a subject in need
thereof a therapeutically effective amount of the solid dosage form
of any of the aspects and embodiments described herein. In
particular embodiments, the cancer is breast cancer. In some such
embodiments, the breast cancer is hormone-receptor positive (HR+)
breast cancer. In some such embodiments, the breast cancer is
estrogen-receptor positive (ER+) breast cancer. In some such
embodiments, the breast cancer is human epidermal growth factor
receptor 2 negative (HER-) breast cancer. In other such
embodiments, the breast cancer is human epidermal growth factor
receptor 2 positive (HER+) breast cancer. In further embodiments,
the breast cancer is advanced or metastatic breast cancer, which
may be characterized as HR+, HER2- or ER+, HER2-.
[0082] Palbociclib may be administered alone or in combination with
other drugs, in particular aromatase inhibitors, e.g., letrozole,
fulvestrant or exemestane, and will generally be administered as a
formulation in association with one or more pharmaceutically
acceptable excipients. The term "excipient" describes any
ingredient other than palbociclib or a salt thereof.
[0083] Palbociclib may be administered orally. Oral administration
may involve swallowing, so that the compound enters the
gastrointestinal tract, or buccal or sublingual administration may
be employed by which the compound enters the blood stream directly
from the mouth.
[0084] A therapeutically effective amount of dosage form of the
invention may be administered to a subject in need of such
treatment. The term "therapeutically effective amount" as used
herein refers to that amount of a compound being administered which
will relieve to some extent one or more of the symptoms of the
disorder being treated. In reference to the treatment of cancer, a
therapeutically effective amount refers to that amount which has
the effect of (1) reducing the size of the tumor, (2) inhibiting
(that is, slowing to some extent, preferably stopping) tumor
metastasis, (3) inhibiting to some extent (that is, slowing to some
extent, preferably stopping) tumor growth or tumor invasiveness,
and/or (4) relieving to some extent (or, preferably, eliminating)
one or more signs or symptoms associated with the cancer.
[0085] As used herein, "subject" refers to a human or animal
subject. In certain preferred embodiments, the subject is a human.
In some embodiments, the subject is a patient afflicted with a
disease state. In other embodiments, the subject may be a healthy
volunteer.
[0086] The term "treating", as used herein, unless otherwise
indicated, means reversing, alleviating, inhibiting the progress
of, or preventing the disorder or condition to which such term
applies, or one or more symptoms of such disorder or condition. The
term "treatment", as used herein, unless otherwise indicated,
refers to the act of treating as defined immediately above. The
term "treating" also includes adjuvant and neo-adjuvant treatment
of a subject. Palbociclib may be administered alone, or in
combination with an aromatase inhibitor, such as letrozole,
fulvestrant or exemestane.
[0087] As used herein "cancer" refers to any malignant and/or
invasive growth or tumor caused by abnormal cell growth. As used
herein "cancer" refers to solid tumors named for the type of cells
that form them (e.g., breast cancer), and cancers of blood, bone
marrow, or the lymphatic system. Examples of solid tumors include
but not limited to sarcomas and carcinomas. Examples of cancers of
the blood include but not limited to leukemias, lymphomas and
myeloma. The term "cancer" includes but is not limited to a primary
cancer that originates at a specific site in the body, a metastatic
cancer that has spread from the place in which it started to other
parts of the body, a recurrence from the original primary cancer
after remission, and a second primary cancer that is a new primary
cancer in a person with a history of previous cancer of different
type from latter one.
[0088] More specifically, examples of cancer in connection with the
present invention include, inter alia, breast cancer, preferably in
combination with an aromatase inhibitor. For example, the cancer
may be hormone receptor positive (HR+) breast cancer, and in
particular estrogen receptor positive (ER+) breast cancer. In some
embodiments, said ER+ breast cancer is human epidermal growth
factor 2 (HER2)-negative. In further embodiments, the cancer is
ER+, HER2- advanced metastatic breast cancer, wherein the drug is
administered in combination with an aromatase inhibitor for
treatment of metastatic disease.
[0089] Formulations suitable for oral administration include solid
formulations such as tablets, capsules, powders, lozenges
(including liquid-filled), sachets and the like. In a preferred
aspect of the invention, the solid dosage form provided herein is a
tablet. In some such embodiments, the tablet is film coated. In
other such embodiments, the tablet is a bilayer tablet.
[0090] For tablet dosage forms, depending on dose, palbociclib may
make up from 1 wt % to 80 wt % of the dosage form, typically from 5
wt % to 60 wt %, more typically from about 10 wt % to about 35 wt
%, or even more typically from about 15 wt % to about 25 wt % of
the dosage form. In specific embodiments, palbociclib comprises
about 20 wt % of the dosage form by weight.
[0091] In the solid dosage forms of the invention, the carrier may
comprise a variety of pharmaceutically acceptable excipients,
including, for example, diluents, disintegrants, binders,
lubricants, glidants and surface-active agents. Formulations may
also include excipients such as preservatives, anti-oxidants,
flavors and colorants, as well as other excipients known in the
art.
[0092] Solid dosage forms, such as tablets, typically contain
diluents, e.g., lactose (monohydrate, spray-dried monohydrate,
anhydrous and the like), mannitol, xylitol, dextrose, sucrose,
sorbitol, compressible sugar, microcrystalline cellulose, powdered
cellulose, starch, pregelatinized starch, dextrates, dextran,
dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium
phosphate, tribasic calcium phosphate, calcium sulfate, magnesium
carbonate, magnesium oxide, poloxamers, polyethylene oxide,
hydroxypropyl methyl cellulose and mixtures thereof. Different
types of microcrystalline cellulose may be suitable for use in the
formulations described herein. Examples of microcrystalline
cellulose include Avicel.RTM. types: PH101, PH102, PH103, PH105, PH
112, PH113, PH200, PH301, and other types of microcrystalline
cellulose, such as silicified microcrystalline cellulose (SMCC). In
some embodiments, the diluent is selected from the group consisting
of microcrystalline cellulose, lactose monohydrate, mannitol,
sorbitol, xylitol, magnesium carbonate, dibasic calcium phosphate,
tribasic calcium phosphate, or mixtures thereof. In certain
embodiments, the diluent comprises microcrystalline cellulose. In
some embodiments, the diluent comprises one or more types of
microcrystalline cellulose, for example Avicel.RTM. PH105,
Avicel.RTM. PH200 or mixtures thereof. In some such embodiments,
the diluent excludes lactose monohydrate. In other such
embodiments, the diluent comprises microcrystalline cellulose and
further comprises lactose monohydrate. Diluents frequently comprise
from about 25 wt % to about 75 wt % of the solid dosage form, and
preferably from about 50 wt % to about 75 wt % of the dosage
form.
[0093] Solid dosage forms frequently contain disintegrants.
Examples of disintegrants include sodium starch glycolate, sodium
carboxymethyl cellulose, calcium carboxymethyl cellulose,
croscarmellose sodium, crospovidone, polyvinylpyrrolidone,
methylcellulose, microcrystalline cellulose, lower
alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized
starch, and sodium alginate. In some embodiments, the disintegrant
is crospovidone. Any grade of crospovidone can be used; for example
CL, CL-SF and XL grades of crospovidone are suitable for use in the
formulations described herein. Specific examples include Kollidon,
Kollidon CL.RTM., Kollidon CL-M.RTM., Polyplasdone XL.RTM.,
Polyplasdone XL-10.RTM., and Polyplasdone INF-10.RTM.. In some
embodiments, the carrier comprises at least one disintegrant
selected from the group consisting of crospovidone, croscarmellose
sodium and sodium starch glycolate. In specific embodiments, the
disintegrant is crospovidone. Disintegrants frequently comprise
from about 1 wt % to about 25 wt %, preferably from about 5 wt % to
about 20 wt %, more preferably from about 5 wt % to about 10 wt %
of the dosage form.
[0094] Binders may be used to impart cohesive qualities to a tablet
formulation. Suitable binders include microcrystalline cellulose,
gelatin, sugars, polyethylene glycol, natural and synthetic gums,
polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl
cellulose, and hydroxypropyl methylcellulose. In some embodiments,
the binder is selected from the group consisting of
microcrystalline cellulose, hydroxypropyl cellulose and
hydroxypropyl methylcellulose. In specific embodiments, the binder
is microcrystalline cellulose, e.g. Avicel.RTM. PH105. When
present, binders may comprise from about 0 wt % to about 15 wt %,
or from about 0.2 wt % to about 10 wt % of the dosage form. In some
embodiments, the binder comprises about 5 wt % to about 10 wt % of
the dosage form. In particular embodiments, the binder comprises
about 10 wt % of the dosage form.
[0095] Solid dosage forms frequently contain one or more
lubricants. Examples of lubricants include magnesium stearate,
calcium stearate, zinc stearate, sodium stearyl fumarate, mixtures
of magnesium stearate with sodium lauryl sulfate, or mixtures of
two or more of these. In some embodiments, the lubricant is
magnesium stearate and/or sodium stearyl fumarate. In some
embodiments, the lubricant is magnesium stearate. In some such
embodiments, the solid dosage form is a tablet comprising
intragranular and extragranular magnesium stearate. In other
embodiments, the solid dosage form is a tablet comprising
intragranular magnesium stearate and extragranular sodium stearyl
fumarate. When present, lubricants frequently comprise from about
0.25 wt % to about 10 wt %, preferably from about 0.5 wt % to about
6 wt % of the dosage form.
[0096] Tablets may also compromise glidants, for example silicon
dioxide, colloidal silicon dioxide, magnesium silicate, magnesium
trisilicate, talc, and other forms of silicon dioxide, such as
aggregated silicates and hydrated silica. In some embodiments, the
glidant is silicon dioxide. When present, glidants may comprise
from about 0 wt % to about 10 wt %, preferably from about 0.2 wt %
to about 5 wt %, or from about 0.5 wt % to about 2 wt % of the
tablet.
[0097] Tablets may optionally include surface-active agents, such
as sodium lauryl sulfate and polysorbate 80. When present,
surface-active agents may comprise from 0 wt % to 10 wt %, or
preferably 0.2 wt % to 5 wt % of the tablet.
[0098] In general, the solid dosage forms of the invention are
prepared according to methods usual in pharmaceutical chemistry.
Selected excipients may be incorporated along with the API into
either or both of the extragranular or intragranular
compartments.
[0099] Exemplary tablet formulations contain from about 10 wt % to
about 35 wt % palbociclib, typically from about 15 wt % to about 25
wt % palbociclib; from about 5 wt % to about 15 wt % water-soluble
acid; from about 25 wt % to about 75 wt % diluent; from about 5 wt
% to about 10 wt % disintegrant; from about 0.5 wt % to about 6 wt
% lubricant; and optionally from about 0 wt % to about 5 wt %
glidant, and from about 0 wt % to about 15 wt % binder.
[0100] Further exemplary tablet formulations contain about 20 wt %
palbociclib; about 10 wt % water-soluble acid, preferably succinic
acid; from about 50 wt % to about 75 wt % diluent, preferably
microcrystalline cellulose; from about 5 wt % to about 10 wt %
disintegrant, preferably crospovidone; from about 0.5 wt % to about
6 wt % lubricant, preferably magnesium stearate or sodium stearyl
fumarate, or both; optionally from about 0 wt % to about 5 wt %
glidant; and optionally from about 0 wt % to about 15 wt % binder.
When present, the glidant is preferably silicon dioxide and the
binder is preferably microcrystalline cellulose of an appropriate
type (e.g., Avicel.RTM. PH105) as a dry binder.
[0101] Solid formulations for oral administration may be formulated
to be immediate and/or modified release. Modified release
formulations include delayed-, sustained-, pulsed-, controlled-,
targeted-, and programmed-release. For a general description of
modified release formulations, see U.S. Pat. No. 6,106,864.
[0102] Pharmaceuticals in the form of solid shaped tablets are
typically manufactured by compressing the materials that make up
the final product into the desired tablet form. Such materials may
include active pharmaceutical ingredients as well as
pharmaceutically non-active excipients that impart necessary or
useful properties to the product during and after the manufacturing
process. Tablet hardness, or tensile strength can be used as a
measure of the cohesiveness of the ingredients of a tablet. If a
tablet does not possess sufficient cohesive properties the tablet
may fall apart on handling. The final formulation may comprise one
or more layers and may be coated or uncoated.
[0103] As is known in the art, granulation is a process used to
improve the handling and manufacturing properties of a formulation,
for example by increasing particle size to improve flow.
Granulation does not substantially change the physical form of the
drug such as its crystalline or amorphous character. Various
processes are used by those of skill in the art for preparing
tablet dosage forms. Examples of such processes include
dry-granulation, wet-granulation, fluid-bed granulation and direct
compression. The type of method used may depend upon factors such
as physical characteristics of the active pharmaceutical
ingredients in the formulation, the types of excipients used and
the desired physical characteristics of the final product. Each of
these processes include steps involving mixing of the ingredients
of the dosage form. In certain embodiments of the present
invention, dry-granulation is preferred.
[0104] Some amount of mixing of the ingredients of a dosage form is
usually necessary in order to have a homogeneous and consistent
final product. However, in the preparation of pharmaceutical
tablets by wet and dry granulation it has been found that the
extent and intensity of the mixing of the ingredients prior to
compression is related to a loss of compressibility and
cohesiveness of the formulation, resulting in reduced tablet
hardness.
[0105] A similar result may be observed when roller compaction is
used, for example, in dry granulation methods. Roller compaction
may be employed as a method to form the granules that are
subsequently compressed into tablets. Roller compaction may reduce
the subsequent compressibility and cohesiveness of the dosage
form.
[0106] Dry granulation is a process in which granulates are formed
by a compaction step that is followed by sizing the compacts into
particles that can be processed easily. It is often used to improve
flow properties and/or densify the formulation which can facilitate
further manufacturing processes such as tableting, encapsulation
and powder filling. The compacts are made directly from powder
blends that usually contain an active ingredient and other
excipients including a lubricant.
[0107] The use of dry granulation techniques may be preferred to
wet granulation methods because of shorter processing times and
cost advantages. However, dry granulation is generally limited to
those situations in which the drug or active ingredient has
physical characteristics suitable for forming pharmaceutically
acceptable granulations and dosage forms such as tablets.
[0108] The addition of at least one excipient to the formulation is
generally required and will contribute to increasing the tablet
size of the final product. As tablet size must be within certain
parameters to function as a suitable dosage form, there is a limit
beyond which increasing tablet size to accommodate increasing
amounts of excipients to enhance compactability is not practical.
As a result, manufacturers are often limited to using the dry
granulation method for formulations containing a low dose of the
active ingredient per compressed tablet such that the formulation
may accommodate sufficient levels of excipient to make dry
granulation practical.
[0109] In the development of pharmaceutical dosage forms, it is
important to balance several different objectives. It is important
to prepare a pharmaceutical dosage form as economically as
possible. It would be desirable to have a simple production method
comprising a few processing steps. The dosage form should also
optimally make available the active compound contained therein to
the patient. Further, the dosage form should be easy to swallow.
Smaller dosage forms are better accepted by patients and increase
patient compliance.
[0110] The final pharmaceutical composition is processed into a
unit dosage form (e.g., tablet or capsule) and then packaged for
distribution. The processing step will vary depending upon the
particular unit dosage form. For example, a tablet is generally
compressed under pressure into a desired shape and a capsule
employs a simple fill operation. Those skilled in the art are well
aware of the procedures used for manufacturing the various unit
dosage forms.
[0111] Tablets are typically formed by pressure being applied to
the material to be tableted on a tablet press. A formulation must
have good flow properties for precise volumetric feeding of the
material to the die cavity and suitable compressibility,
compactability, and ejection properties to form a tablet.
[0112] There are a number of tablet presses, each varying in
productivity but similar in basic function and operation. All
compress a tablet formulation within a die cavity by pressure
exerted between two steel punches, a lower punch and an upper
punch. Tablet presses are typically designed to have a hopper for
holding and feeding the formulation, a feeding mechanism for
feeding the formulation to the die cavity, provision for placement
of punches and dies, and in rotary tablet presses a cam track for
guiding the movement of the punches. Two types of tablet presses
are the single station or single-punch press and the multistation
rotary press. Some tablet presses provide longer dwell times than
others, allowing increased bonding to occur. Other presses may
provide precompression.
[0113] Wet granulation methods may also be employed for preparing
the granules of the pharmaceutical composition. Wet granulation
methods are described in Remington: The Science and Practice of
Pharmacy, Mack Publishing Company, Easton, Pa., 19th Edition 1995.
These and other methods are generally known by those skilled in the
art. If wet granulation is employed, a volatilizable agent may be
incorporated in the mixture before, during or after mixing of the
ingredients, but prior to formation of granules. For example, a
solid volatilizable agent can be blended with the powders of the
mixture prior to, during or after the addition of binding agent
solutions. Other solid dosage forms may be prepared using
techniques including rotary bed granulation or spray-dried
dispersion (SDD).
[0114] The invention will be illustrated in the following
non-limiting examples.
EXAMPLES
Example 1
Free Base Plus Succinic Acid
[0115] A tablet comprising the free base form of the API
(palbociclib) dry granulated with succinic acid was prepared using
the following procedure. The tablet had the composition in Table
1.
TABLE-US-00001 TABLE 1 Component Amount (mg/tablet) Intragranular
components Palbociclib (API) 125.000 Succinic Acid 62.500
Microcrystalline cellulose (Avicel PH105) 62.500 Microcrystalline
cellulose (Avicel PH102) 196.875 Lactose Monohydrate (Fast Flo 316)
96.875 Crospovidone (Kollidon CL) 31.250 Colloidal silicon dioxide
(Aerosil 200 Pharma) 6.250 Magnesium Stearate 6.250 Extragranular
components Crospovidone 31.250 Magnesium Stearate 6.25 TOTAL
625.000
[0116] Microcrystalline cellulose (Avicel PH105) was added to a
blender (bin blender or equivalent) and mixed at low speed for
approximately 25 revolutions (2 minutes at 12 rpm). The API was
added to the blender, rinsing the API container with a portion of
the lactose monohydrate, and folded to mix. The batch quantities of
succinic acid, lactose monohydrate, crospovidone, and colloidal
silicon dioxide were added to the blender which was mixed at low
speed for approximately 180 revolutions (15 minutes at 12 rpm).
[0117] A mill and bag were pre-coated with 50% of the batch
quantity of microcrystalline cellulose (Avicel PH102). The blend
was passed from above through the mill. The mill was flushed with
the remaining portion of the microcrystalline cellulose (Avicel
PH102), and the milled material transferred from the bag to a
blender (bin blender or equivalent) and mixed at low speed for
approximately 180 revolutions (15 minutes at 12 rpm). The
intragranular magnesium stearate was sieved through an
appropriately sized screen and added to the blender from the
previous step. The mixture was mixed at low speed for approximately
60 revolutions (5 minutes at 12 rpm). The blend was Roller
compacted (Gerteis Minipactor or equivalent), without separating or
recycling fines. If in-line milling was not employed, the roller
compacted blend was passed through a Comil U5 or U10 equipped with
a 1601 impeller, with a screen size of 050G, and a speed of 1000 or
700 rpm, respectively.
[0118] The extragranular crospovidone was added to the blender from
the previous step. The mixture was mixed at low speed for
approximately 180 revolutions (15 minutes at 12 rpm). The
extragranular magnesium stearate was sieved through an
appropriately sized screen. It was added to the blender from the
previous step, and mixed for approximately 60 revolutions (5
minutes at 12 rpm).
[0119] To form the tablets, a single station press (Korsch XP 1 or
equivalent) or rotary press was used.
Example 2
Bilayer Tablet Formulation
[0120] Bilayer tablets containing an active layer and an acid layer
were prepared. The active layer consisted of the granulation blend
from Example 1.
[0121] The active and acid layers had the composition in Table
2.
TABLE-US-00002 TABLE 2 Component Amount (mg/tablet) Active Layer
Granulation Total according to Example 1 625.000 Acid Layer Blend
Tartaric acid, granular 180.00 Microcrystalline cellulose 143.100
Crospovidone 36.00 Magnesium Stearate 0.900 TOTAL Acid Layer
360.000
[0122] The acid layer blend was formed by combining
microcrystalline cellulose, tartaric acid and crospovidone into an
appropriate sized container. The combination was blended for
approximately 120 revolutions, and then passed through a Comil U5
or U10 equipped with a 1601 impeller, with a screen size of 018R
and a speed of 1000 rpm or 700 rpm, respectively.
[0123] The milled material was transferred to a blender and the
components were then blended for approximately 120 revolutions. The
magnesium stearate was sieved through an appropriately sized screen
(1 mm screen, US Sieve #20) and then added to the blender, and
blended for approximately 50 revolutions.
[0124] Bilayer tablets were formed using the following procedures
using a suitable rotary bilayer tablet press, such as a Korsch XP1.
The active layer granulation, (formed according to the procedures
outlined in Example 1) was compressed to a target active layer
weight of 625 mg and a recommended active layer thickness of 6.66
mm. The acid layer blend was added and the acid layer and active
layers compressed to the desired fill weight of 985 mg.
Example 3
Fluid Bed Granulation
[0125] The fluid bed coater (a Niro MP-2 Fluid Bed Coater, equipped
with a MP-1 bowl, with top spray granulation set-up) was pre-heated
using the following conditions until the inlet air dew point
(12.degree. C.) and product bowl temperatures stabilized (greater
than or equal to 45.degree. C.) to the targets. The spray nozzle
was a Schlick 970 with a 0.8 mm liquid tip, and a nozzle to bowl
bottom distance of 33 cm.
[0126] To form the fluid bed granulation, succinic acid was first
milled manually using a mortar and pestle. Periodically, the milled
powder was placed on a #60 mesh screen, using manual shaking to
pass the material into a collection container. The material
retained on the screen was returned to the mortar and more
un-milled material was added. Milling was continued until the
required amount had passed through the screen.
[0127] In addition to succinic acid, each of the following dry bed
components in required amounts were individually screened through a
#30 mesh into their separate collection containers.
TABLE-US-00003 TABLE 3 Component Amount (wt %) Microcrystalline
cellulose (Avicel PH102) 37.9 Mannitol 23.3 Succinic Acid 30.0
Crospovidone (Polyplasdone XL) 8.8 TOTAL 100
[0128] The binder suspension was formed by adding water to an
appropriately sized container. Mannitol and hydroxypropyl cellulose
were then added to the container. The solution was mixed for a
minimum of 2 hours, and was visually free of agglomerations.
[0129] The API was then slowly added to the solution to form the
binder suspension. The binder suspension was stirred during
processing until it was used. The binder suspension contained the
following components in Table 4:
TABLE-US-00004 TABLE 4 Component Amount (wt %) Palbociclib (API)
14.24 Mannitol 2.73 Hydroxypropyl Cellulose (Klucel LF) 2.73 Water
80.3 TOTAL 100.0
[0130] After the fluid bed product bowl temperature had stabilized,
the dry-bed materials were then loaded into the fluid bed in the
following order mannitol, microcrystalline cellulose, succinic
acid, and crospovidone.
[0131] The fluid bed granulation then commenced at a bed
temperature of 29-31.degree. C., spray rate of 12-30 g/min, airflow
of 70-115 CMH (m.sup.3/h) and atomization pressure of 1.1 bar to
provide the fluid bed granulation.
Example 4
Fluid Bed Granulation Tablets
[0132] Tablets were formed from the fluid bed granulation (FBG) of
Example 3, using the following procedures. First, the granulation
was dry-sized by passing the granules through a Comil U5 equipped
with a 1601 impeller, with a screen size of 018R, and a speed of
1500 rpm. The granules were fed into the Comil as uniformly as
possible by visual assessment (20 to 25 minutes for 2 kg
granulation). The milled granules were passed through a #60 mesh
screen, and the material that passes through the screen was
collected in a bag and set aside. Material that was retained on the
#60 mesh screen was milled in a Comil a second time. The milled
granules were passed through a #60 mesh screen, and the material
collected in a bag. Material retained on the #60 mesh screen after
the second pass was gently pushed through the screen using a
spatula/scraper until all had passed through. The material was
added to the bag.
[0133] The final tablet blend for the FBG tablets is given in Table
5:
TABLE-US-00005 TABLE 5 Component Amount (mg/tablet) Intragranular
Fluid Bed Granules FBG according to Example 3 400.0 Extragranular
Components Microcrystalline Cellulose (Avicel PH102) 252.0 Succinic
acid 80.0 Crospovidone (Polyplasdone XL) 64.0 Magnesium Stearate
4.0 TOTAL 800.0
[0134] An adjusted weight of extragranular components was
calculated, if needed, based on the total weight of milled granules
from the previous step.
[0135] The succinic acid was manually milled (with mortar and
pestle) in small aliquots. A sufficient amount was used to ensure
the quantity of milled material was sufficient. The milled material
was passed through a #60 mesh screen and collected in a new bag.
Any material retained on the screen was returned to the mortar with
the next aliquot. The required amount of milled succinic acid was
subdivided.
[0136] Next, the microcrystalline cellulose and crospovidone were
passed through a #30 mesh screen and added to a blender. The milled
succinic acid and the dry-sized fluid bed granules were added to an
appropriate sized blender. The bulk density was 0.39 g/cc. The
mixture was blended for 11.25 minutes at 16 rpm (180
revolutions).
[0137] Next, the magnesium stearate was combined with 3 to 10 times
(volume, estimated visually) of the blend from the previous step in
an appropriately sized bottle. The mixture was manually mixed by
gently shaking for approximately 30 seconds, and then passing
through a 30-mesh screen. The contents were added to the blender
and blended for 3.75 minutes at 16 rpm (60 revolutions).
[0138] The batch was compressed to the target specifications using
a suitable tablet press, such as a Korsch XM12.
Example 5
Spray Dried Dispersion
[0139] A solution of hypromellose (HPMC E3 Prem) was prepared by
dissolving 3.25 wt % HPMC E3 in a solvent blend of 90/10
methanol/water (w/w) to form a 3.25 wt % HPMC solution. A
sufficient quantity of palbociclib (API) was added to this solution
to form a spray suspension of the following composition: 1.75 wt %
API, 3.25 wt % hypromellose, 85.5 wt % methanol, and 9.5 wt %
water. The suspension was then stirred continuously to keep the API
from settling in the suspension tank.
[0140] The spray dryer was preheated using a heated drying gas
(nitrogen) at a flow rate of 1850 g/min and at an inlet drying gas
temperature of 130.degree. C. Following preheating, a 90/10 (w/w)
methanol/water blend was sprayed until steady-state thermodynamic
conditions were achieved. Once the spray dryer reached
steady-state, the spray suspension was then introduced into the
spray dryer via flash atomization at a feed rate of 130 g/min, at a
solution temperature of 130.degree. C., and at a pressure of 250
psi. A secondary nitrogen gas stream was utilized around the nozzle
at a pressure of 60 psi to prevent fouling of the nozzle. The
particles were collected at a temperature of 45.degree. C. at the
outlet of the spray dryer.
[0141] After collection, the particles were placed into a
convection tray dryer operated at 40.degree. C./15% relative
humidity for a minimum of 6 hours. This reduced residual solvent in
the particles to no more than 0.3 wt % residual methanol).
[0142] The particle sizes of the secondary dried particles were
measured by Malvern Particle Size Analyzer, available from Malvern
Instruments Ltd. of Framingham, Mass., using low dispersive
pressures of 0.5 to 1.0 bar, where D(4,3) is the volume mean
diameter; DV.sub.10 is the diameter that makes up 10% of the total
volume containing the particles; DV.sub.50 is the diameter that
makes up 50% of the total volume containing the particles; and
DV.sub.90 is the diameter that makes up 90% of the total volume
containing the particles. The particle size is given in Table
6:
TABLE-US-00006 TABLE 6 Particle Size Diameter (.mu.m) D(4, 3) 11
DV.sub.10 3 DV.sub.50 10 DV.sub.90 22
[0143] The Span of the particles (DV.sub.90-DV.sub.10)/DV.sub.50
was 1.96. The bulk specific volume of the particles was 5.6 cc/g,
while the tapped specific volume was 3.0 cc/g.
[0144] The glass-transition temperature (Tg) of the particles,
measured at less than 5% relative humidity was 117.5.degree. C. as
measured by Differential Scanning calorimetry (DSC). Powder X Ray
diffraction (PXRD) showed the API to be amorphous, with no
detectable crystallinity. The particle morphology as measured by
scanning electron microscopy (SEM) showed the particles to have
whole and collapsed spheres.
Example 6
[0145] Comparative Spray Dried Dispersion Tablet Tablets lacking a
water-soluble acid were formed from the spray dried dispersion
(SDD) of Example 5 using the following procedure. Half the quantity
of microcrystalline cellulose was added to a blender (bin blender
or equivalent), and mixed at low speed for approximately 25
revolutions (2 minutes at 12 rpm). The SDD was added to the
blender. The blender was rinsed with a portion of sodium chloride
and mixed.
[0146] Batch quantities of sodium chloride, croscarmellose sodium,
and colloidal silicon dioxide were added and mixed at low speed for
approximately 180 revolutions (15 minutes at 12 rpm). The final
blend is given in Table 7.
TABLE-US-00007 TABLE 7 Component Amount (mg/tablet) Intragranular
components SDD (Example 5) 357.143 Microcrystalline cellulose
(Avicel PH-101) 191.657 Sodium Chloride 191.200 Croscarmellose
Sodium (AC-DI-SOL) 48.00 Colloidal silicon dioxide (Cab-O-Sil MP5)
4.00 Magnesium Stearate 2.00 Extragranular components
Croscarmellose Sodium (AC-DI-SOL) 32.00 Colloidal Silicon Dioxide
(Cab-O-Sil M5P 4.00 Untreated) Magnesium Stearate 2.00 TOTAL
800.00
[0147] A mill and bag were pre-coated with 25 wt % of the quantity
of microcrystalline cellulose. The blend was passed from the above
step through the mill, using a Comil U5 equipped with a 1601
impeller, with a screen size of 032R, and a speed of 1000 rpm. The
mill was flushed with the remaining batch portion of
microcrystalline cellulose, the milled material transferred from
the bag to a blender (bin blender or equivalent) and mixed at low
speed for approximately 180 revolutions (15 minutes at 12 rpm).
[0148] The intragranular magnesium stearate was sieved through an
appropriately sized screen and added to the blender from the
previous step then mixed at low speed for approximately 60
revolutions (5 minutes at 12 rpm).
[0149] The blend was compacted using a Korsch XP 1 or
equivalent.
[0150] The compacted blend was passed through a mill using a Comil
U5 equipped with a 1601 impeller, with a screen size of 050G, and a
speed 1000 rpm.
[0151] The granulation was transferred from the bag to a blender
(bin blender or equivalent). The amount of extragranular colloidal
silicon dioxide was calculated and added to the blender from the
previous step then mixed for approximately 180 revolutions (15
minutes at 12 rpm). The amount of extragranular magnesium stearate
required was calculated, sieved through an appropriately sized
screen and added to the blender from the previous step, then mixed
for approximately 60 revolutions (5 minutes at 12 rpm).
[0152] The tablets were compressed using a single station press
(Korsch XP 1 or equivalent).
Example 7
Spray Dried Dispersion Tablet
[0153] Tablets were formed from the SDD of Example 5 using the
following procedures. Half the quantity of microcrystalline
cellulose was added to a blender (bin blender or equivalent), and
mixed at low speed for approximately 25 revolutions (2 minutes at
12 rpm). The SDD was added to the blender and the blender was
rinsed with a portion of sodium chloride and mixed. The batch
quantities of succinic acid, sodium chloride, croscarmellose
sodium, and colloidal silicon dioxide were added and mixed at low
speed for approximately 180 revolutions (15 minutes at 12 rpm). The
final composition of the blend is given in Table 8.
TABLE-US-00008 TABLE 8 Component Amount (mg/tablet) Intragranular
components SDD (Example 5) 357.143 Microcrystalline cellulose
(Avicel PH-101) 76.457 Succinic Acid 143.20 Sodium Chloride 127.20
Croscarmellose Sodium (AC-DI-SOL) 48.00 Colloidal silicon dioxide
(Cab-O-Sil MP5) 8.00 Magnesium Stearate 2.00 Extragranular
components Croscarmellose Sodium (AC-DI-SOL) 32.00 Colloidal
Silicon Dioxide (Cab-O-Sil M5P 4.00 Untreated) Magnesium Stearate
2.00 TOTAL 800.00
[0154] A mill and bag was pre-coated with 25 wt % of the quantity
of microcrystalline cellulose. The blend was passed from the above
step through the mill, using a Comil U5 equipped with a 1601
impeller, with a screen size of 018R, and a speed of 1000 rpm. The
mill was flushed with the remaining batch portion of
microcrystalline cellulose, the milled material transferred from
the bag to a blender (bin blender or equivalent) and mixed at low
speed for approximately 180 revolutions (15 minutes at 12 rpm).
[0155] The intragranular magnesium stearate was sieved through an
appropriately sized screen and added to the blender from the
previous step, then mixed at low speed for approximately 60
revolutions (5 minutes at 12 rpm).
[0156] The blend was compacted using a Korsch XP 1 or
equivalent.
[0157] The compacted blend was passed through a mill using a Comil
U5 equipped with a 1601 impeller, with a screen size of 050G, and a
speed of 1000 rpm. The amount of extragranular magnesium stearate
required was calculated, and sieved through an appropriately sized
screen, and added to the blender from the previous step. The
mixture was mixed for approximately 60 revolutions (5 minutes at 12
rpm).
[0158] The tablets were compressed using a single station press
(Korsch XP 1 or equivalent).
Example 8
Dissolution Test 1 at pH 5.5
[0159] Test tablet formulations comprising the free base form of
palbociclib (API), a water-soluble acid, microcrystalline cellulose
(Avicel PH102), lactose monohydrate (Fast Flo 316), crospovidone
(Kollidon CL), and magnesium stearate were prepared for dissolution
testing. Test tablets were prepared using the dry granulation (DG)
method described in Example 1 for the following acids: malic acid,
maleic acid, succinic acid, fumaric acid, tartaric acid, tosylic
acid, benzoic acid and benzenesulfonic acid. Test tablets were
prepared via direct compression (DC) (without dry granulation) for
malic acid and citric acid.
[0160] The tablets were dissolution tested in a USP 2 apparatus
with paddles spinning at 50 rpm, in 500 mL of 10 mM sodium acetate
buffer at pH 5.5 and a temperature of 37.degree. C. At each pull
point, 6 mL of sample was collected and passed through a 10-.mu.m
full-flow filter. Analysis was performed off line at a UV wave
length of 367 nm.
[0161] Comparative dissolution data were generated for the
palbociclib isethionate salt (ISE) capsule and a free base API
tablet prepared using the dry granulation method of Example 1,
using a blend lacking the water-soluble acid. The results of the
dissolution test for tablets comprising succinic acid, maleic acid,
malic acid, fumaric acid and tartaric acid are shown in FIG. 1.
Tablets comprising succinic acid, malic acid and tartaric acid
exhibited superior dissolution performance, with greater than 50%
of the drug dissolved at 30 minutes as shown in FIG. 2.
Example 9
Chemical Stability of Formulations
[0162] The test tablets prepared in Example 8 were stored at
70.degree. C./75% RH for 8 days. The tablets were crushed and
analyzed for impurities using a high-performance liquid
chromatography (HLPC) method as follows: Waters CSH C18,
2.1.times.100 mm, 1.7 .mu.m column; mobile phase (gradient elution)
A: 0.03% trifluoroacetic acid, and B: 0.03% trifluoroacetic acid in
acetonitrile; column temperature of 45.degree. C.; flow rate of 0.5
mL/min; UV detection at 234 nm; injection volume of 2 .mu.L; and
run time of 10.72 minutes. The results are summarized in Table
9.
TABLE-US-00009 TABLE 9 Storage at 70.degree. C./75% RH for 8 Days
Formulation API Free API Total Impurities Base plus an Acid (Area
%) (Area %) Malic acid 99.35 0.645 Maleic acid 93.71 6.288 Succinic
acid 98.81 1.190 Benzoic acid 99.94 0.06 Tosylic acid 99.46 0.54
Tartaric acid 99.18 0.82 Citric acid 97.18 2.82 Benzenesulfonic
acid 99.55 0.45 Fumaric acid 91.94 8.06
[0163] Tablets comprising malic acid, succinic acid, benzoic acid,
tosylic acid, tartaric acid and benzenesulfonic acid had acceptable
total impurities after storage at 70.degree. C./75% RH for 8 days.
On the basis of the superior dissolution and stability experiments,
formulations comprising succinic acid, malic acid and tartaric acid
were selected for further development.
Example 10
Non-Sink Dissolution Test 2
[0164] To screen the formulations, a non-sink in vitro dissolution
method was developed. In this method, the tablets were placed into
USP 2 (paddles) apparatus, with stirring at 50 rpm, and 500 mL of a
50 mM phosphate buffer+0.1 M NaCl (pH 6.5), at a temperature of
37.degree. C. Samples were collected periodically, and filtered
through 10-.mu.m filters. The concentration of the API was measured
off line at a UV of 367 nm. Dissolution data were generated for the
tablets prepared in Example 1 (FB+succinic, tablet), Example 2
(FB+succinic, bi-layer tablet), Example 4 (FB+succinic, FBG
tablet), Example 6 (SDD, tablet) and Example 7 (SDD+succinic,
tablet). Dissolution profiles are shown in FIG. 3. Also shown is
the dissolution data for the commercial free base capsules of
palbociclib (free base capsules) having the formulation in Table
10:
TABLE-US-00010 TABLE 10 125 mg Free base capsule Component Amount
(mg/capsule) Palbociclib (mg) 125.000 Microcrystalline cellulose
(mg) 185.917 Lactose monohydrate 92.958 Sodium starch glycolate
27.000 Colloidal silicon dioxide 10.125 Magnesium stearate 9.000
Total fill weight 450.000 Total capsule weight 546.000
[0165] As shown in FIG. 3, subjecting the dosage forms of Examples
1, 2 and 4 to the non-sink dissolution conditions dissolves (a) not
less than 40% of the palbociclib in 15 minutes; (b) not less than
35% of the palbociclib in 30 minutes; (c) not less than 25% of the
palbociclib in 60 minutes; or (d) two or more of (a), (b) and
(c).
Example 11
Drug Exposure Levels with Commercial Free Base Capsules
[0166] A randomized, single-dose, open-label, 4-sequence, 4-period
cross-over study was run in healthy volunteers. Twenty-eight (28)
subjects each received a single dose of palbociclib 125 mg under 4
different conditions or treatments (overnight fasted [A], high-fat
meal predose [B], low-fat meal predose [C], and moderate-fat meal 1
hour before and 2 hours post dose [D]).
[0167] The treatment sequences used for Periods 1 through 4 are
presented in Table 11. There was a washout period of at least 10
days between study periods. Following treatment administration,
subjects underwent PK sampling for 144 hours. The pharmacokinetic
parameter values are given in Table 12.
TABLE-US-00011 TABLE 11 Study Design Sequence Period 1 Period 2
Period 3 Period 4 1 (n = 7) A D B C 2 (n = 7) B A C D 3 (n = 7) C B
D A 4 (n = 7) D C A B
TABLE-US-00012 TABLE 12 Parameter B: Fed C: Fed D: Fed (units) A:
Fasted High Fat Low Fat Moderate Fat N 28 28 27 28 AUC.sub.inf
(ng-hr/mL) 1408 1672 1573 1580 AUC.sub.last (ng-hr/mL) 1284 1627
1524 1533 T.sub.last (hr) 119 119 118 119 C.sub.last (ng/mL) 39.22
53.67 50.20 48.64 T.sub.max (hr) 8.00 8.00 8.00 8.00 T.sub.1/2 (hr)
23.9 22.1 22.0 22.9 CL/F (L/hr) 88.77 74.74 79.45 79.10 V.sub.z/F
(L) 2993 2342 2475 2573
[0168] The palbociclib 125 mg commercial capsule formulation
exhibited lower AUC and C max when administered under fasted
conditions relative to the exposure levels under the three fed
conditions. Accordingly, it was recommended that the commercial
capsule be administered with food.
Example 12
Effect of Antacid on Bioavailability of Palbociclib
[0169] The objective of this study was to investigate the potential
effect of increased gastric pH achieved by the treatment of
multiple doses of a proton pump inhibitor (PPI, specifically
rabeprazole) on the pharmacokinetics (PK) of a single oral 125 mg
commercial capsule of palbociclib given under fasted
conditions.
[0170] The results are summarized in Table 13 below. The
palbociclib 125 mg commercial capsule formulation exhibited
significantly lower AUC and C max when administered in the presence
of rabeprazole relative to administration of palbociclib alone.
TABLE-US-00013 TABLE 13 Palbociclib + Parameter (units) Palbociclib
Alone Rabeprazole N, n 26, 26 25, 23 AUC.sub.inf (ng-hr/mL) 1716
(45) 754.4 (38) AUC.sub.last (ng-hr/mL) 1656 (47) 672.8 (40)
T.sub.last (hr) 120 (72.0-120) 96.0 (72.0-120) C.sub.max (ng/mL)
49.31 (72) 12.25 (44) T.sub.max (hr) 7.00 (6.00-24.0) 24.0
(6.00-48.0) T.sub.1/2 (hr) 21.97 .+-. 2.9721 22.45 .+-. 4.2139 CL/F
(L/hr) 72.85 (45) 165.7 (38) V.sub.z/F (L) 2290 (49) 5289 (31)
Example 13
Effect of Antacid on Bioavailability of Test Formulations
[0171] A crossover, open label, non-randomized, pharmacokinetic
study in healthy volunteers was conducted to estimate the effect of
antacid treatment on the bioavailability of a 125 mg tablet (single
dose) of six experimental formulations of palbociclib in the
presence of rabeprazole relative to administration of palbociclib
alone under fasted conditions. Table 14(A)-(F) shows the results
for Cohorts 1-6, Example 1; Example 6; Example 7; Example 2;
Example 4; and 125 mg palbociclib oral solution, respectively.
TABLE-US-00014 TABLE 14 Plasma Adjusted Geometric Means Ratios
Palbociclib Palbociclib + Palbociclib (Test/Reference) Parameters
Rabeprazole Alone of Adjusted 90% CIs [Units] (Test) (Reference)
Means for Ratios (A) Summary results for Cohort 1 (tablets of
Example 1). AUCinf [ng hr/mL] 1458 1449 100.61 (95.25, 106.27) Cmax
[ng/mL] 45.91 49.25 93.22 (81.71, 106.35) (B) Summary results for
Cohort 2 (tablets of Example 6). AUCinf [ng hr/mL] 1079 1120 96.31
(90.78, 102.18) Cmax [ng/mL] 36.54 39.86 91.68 (80.91, 103.88) (C)
Summary results for Cohort 3 (tablets of Example 7). AUCinf [ng
hr/mL] 1548 1495 103.6 (94.39, 113.70) Cmax [ng/mL] 46.83 48.21
97.13 (84.41, 111.78) (D) Summary results for Cohort 4 (tablets of
Example 2) AUCinf [ng hr/mL] 1443 1418 101.78 (94.95, 109.09) Cmax
[ng/mL] 45.18 47.50 95.12 (87.03, 103.96) (E) Summary results for
Cohort 5 (tablets of Example 4) AUCinf [ng hr/mL] 1962 1803 108.83
(103.64, 114.28) Cmax [ng/mL] 64.91 62.52 103.83 (94.55, 114.02)
(F) Summary results for Cohort 6 (Oral solution) AUCinf [ng hr/mL]
1478 1451 101.83 (93.67, 110.69) Cmax [ng/mL] 47.77 50.24 95.07
(85.18, 106.11)
Example 14
Accelerated Stability Tests
[0172] The tablets of Example 1 (dry granulation+succinic acid)
were placed on accelerated stability using the following
conditions. Tablets were place into beakers at the conditions
listed below. Humidity control was achieved either through oven
control or saturated salt solutions. Samples were removed from the
conditions periodically as shown in Table 15 below. Samples
(including unexposed controls) were stored in a refrigerator until
analysis.
[0173] The following saturated salt solutions maintained the
designated relative humidity: 22% RH controlled via potassium
acetate; 50% RH controlled via sodium bromide for the 30.degree.
and 40.degree. C. conditions; and 75% RH via humidity controlled
ovens.
TABLE-US-00015 TABLE 15 Temperature Relative Degradant* (.degree.
C.) Humidity (%) Time (days) (wt %) 0 0 0 (initial) 0 (initial) 30
22 96 0.05 30 50 96 0.07 30 75 96 0.12
[0174] The degradant is the succinyl adduct of the API, having the
structure:
##STR00002##
[0175] Samples were prepared by adding each tablet to a 100 mL
volumetric flask, adding a stir bar and approximately 100 mL of the
dissolving solvent (1440 mL water:400 mL acetonitrile:160 mL 1N
HCl; 0.1 N HCl: acetonitrile 80:20). The flask was placed on a stir
plate and sample was stirred for one hour at the highest useable
stir speed. An aliquot was then removed and centrifuged in a
polypropylene tube at 3000 RPM for 5 minutes. The supernatant was
diluted 1:5 with dissolving solvent and sampled into an HPLC vial
for analysis. Each tablet contained 125 mg API for a final solution
concentration of 0.25 mg/mL. The samples were analyzed using the
HPLC method below. The results are presented in Table 15 above, and
show excellent long-term stability.
Dissolving Solvent (Diluent):
[0176] 1440 mL water: 400 mL acetonitrile: 160 mL 1N HCl//(0.1 N
HCl: acetonitrile 80:20) Mobile Phase:
[0177] Mobile Phase A: 0.03% trifluoroacetic acid (0.6 mL of
trifluoroacetic acid into 2000 mL of water)
[0178] Mobile Phase B: 0.03% trifluoroacetic acid in acetonitrile
(0.6 mL of trifluoroacetic acid into 2000 mL of acetonitrile) 0.5
mL/min
TABLE-US-00016 Gradient Initial 88% A 12% B 0.22 min 88% A 12% B
8.72 min 15% A 85% B 8.82 min 88% A 12% B 10.72 min Total run
time
2 .mu.L injection of samples (prepared as directed below). Sample
chamber maintained at 5.degree. C.
Sample Preparation
[0179] Samples were prepared by adding each tablet to a 100 mL
volumetric flask, adding a stir bar and approximately 100 mL of the
dissolving solvent. The flask was placed on a stir plate and sample
was stirred for one hour at the highest useable stir speed. An
aliquot was then removed and centrifuged in a polypropylene tube at
3000 RPM for 5 minutes. The supernatant was diluted 1:5 with
dissolving solvent and sampled into an HPLC vial for analysis. Each
tablet contained 125 mg palbociclib for a final solution
concentration of 0.25 mg/mL.
[0180] In addition, the tablets of Example 4 (fluid bed
granulation+succinic acid) were analyzed in the same manner. The
results are presented in the following Table 16, and show that the
degradant concentration was unacceptable for long-term
stability.
TABLE-US-00017 TABLE 16 Temperature Relative Degradant* (.degree.
C.) Humidity (%) Time (days) (wt %) 0 0 0 (initial) 0 (initial) 30
22 96 0.211 30 50 96 0.263 30 75 96 0.444 *The degradant is the
succinyl adduct of the API
Example 15
Long Term Storage Stability
[0181] The tablets of Example 1 were packaged with a desiccant
canister in a bottle using a heat-induction seal. After storage for
1 year at 25.degree. C./60% RH, the tablets had a succinyl adduct
level of less than 0.05%. The tablets of Example 4 were packaged
with a desiccant canister in a HDPE bottle using a heat-induction
seal. After storage for 6 months at 25.degree. C./60% RH, the
tablets had a succinyl adduct level of 0.23%.
Example 16
Film Coated Tablet Formulations
[0182] Table 17 describes optimized Formulations A1, A2 and B,
which showed acceptable manufacturing performance for solid dosage
form commercialization. The tablets were formed using the following
procedure. The microcrystalline cellulose PH102, colloidal silicon
dioxide, intragranular crospovidone CL, and API were blended
together and passed through a Comil for homogenization.
Intragranular magnesium stearate was blended in. The mixture was
dry granulated using roller compaction and granule milling.
[0183] Sieved succinic acid, microcrystalline cellulose PH-200, and
extragranular crospovidone (CL or CL-SF grade) were blended into
the granules. Extragranular magnesium stearate or sodium stearyl
fumarate was mixed into the final blend as a tableting lubricant.
Tablets were formed using a rotary tablet press with
pre-compression. Formulation A2 used an external lubrication system
(ELS) to apply a nominal amount of lubricant directly to the tablet
punch tips.
[0184] Tablets were film coated to a weight gain of 2 to 4% using
Opadry Pink (03K140024) and purified water to a solids content of
12% w/w.
TABLE-US-00018 TABLE 17 Optimized formulations Quantity/unit:
(mg/tablet) Formulation Formulation Formulation Component: A2 A1 B
Intragranular Components Palbociclib (API) 125.000 Microcrystalline
Cellulose 244.812 (Avicel PH102) Colloidal Silicon Dioxide 6.250
(Aerosil 200 Pharma) Crospovidone (Kollidon CL) 18.750 Magnesium
Stearate 2.063 Extragranular Components Succinic Acid extra pure,
62.500 (100 to 350 micron) Microcrystalline Cellulose 143.750
134.375 115.625 (Avicel PH-200) Crospovidone (Kollidon CL 18.750
18.750 or CL-SF) (CL) (CL-SF) Sodium Stearyl Fumarate -- 31.250
(PRUV) Magnesium Stearate 3.125 12.500 -- (standard or fine grade)
(standard) (fine) Tablet Core 625.000 Opadry Pink (03K140024)
18.750 Purified Water (removed (137.500) during final processing)
Final Coated Tablet 643.750
Example 17
Optimization of Lubricant Level
[0185] Formulations were prepared as described for Formulation A2
in Example 16 with different levels of intragranular and
extragranular magnesium stearate lubricant, as shown in Table 17.
Hardness (tablet breaking force, USP <1217>), friability (USP
<1216> for 100 revolutions), extended friability (USP
<1216> for 375 revolutions), and punch sticking (Hutchins,
MacDonald, Mullarney, Assessing Tablet-Sticking Propensity,
Pharmaceutical Technology, Volume 36, Issue 1, 2012) were measured
for each formulation as reported in Table 18. Reduced sample sizes
were used for the USP methods.
[0186] Reducing both the intragranular and extragranular lubricant
levels significantly increased tablet hardness and reduced
friability. Tablet sticking was more sensitive to extragranular
lubricant level than intragranular lubricant level. Sticking was
significantly reduced by increasing extragranular magnesium
stearate level. No difference in knurled/smooth roller sticking was
observed with different intragranular magnesium stearate levels. As
shown in Table 18, reducing the intragranular/extragranular
lubricant ration from 1 wt %/0 wt % to 0.33 wt %/0.5 wt % provided
with good tablet strength, reduced friability, and reduced sticking
for tablets of Formulation A2. Lubricant levels of about 5 wt %
sodium stearyl fumarate or 2 wt % fine grade stearate (CaSt 2249)
alleviated punch sticking and tablet defects.
TABLE-US-00019 TABLE 18 Optimization of lubricant level. Extra-
Intragranular granular Extended Lubricant Lubricant Hardness
Friability friability Sticking Level (%) Level (%) (kP) (%) (%)
(ug) 0.33 0 22 0.08 0.23 2914 0.5 19 0.09 0.28 766 1 16 0.15 0.54
304 0.67 0 21 0.13 0.45 1977 0.5 18 0.13 0.38 563 1 16 0.11 0.49
142 1 0 18 0.00 0.36 1346 0.5 18 0.09 0.43 428 1 15 0.14 0.57
242
Example 18
Optimization of Tablet Hardness and Friability
[0187] Formulations were prepared as generally described for
Formulation A2 in Example 16, with changes to the order of addition
of acid, addition of lactose monohydrate, addition of dry binders
(Kollidon SF, Avicel PH105, Klucel EXF), and change in the
intragranular to extragranular ratio of microcrystalline cellulose.
The properties of these different formulations were measured:
initial blend bulk density (USP <616>), roller compacted
ribbon tensile strength (Zinchuk A V, Mullarney M P, Hancock B C.
Simulation of roller compaction using a laboratory scale compaction
simulator. Int J Pharm. 2004 Jan. 28; 269(2):403-15.), punch
sticking (Hutchins, MacDonald, Mullarney, Assessing Tablet-Sticking
Propensity, Pharmaceutical Technology, Volume 36, Issue 1, 2012),
tablet hardness (tablet breaking force, USP <1217>),
friability (USP <1216> for 375 revolutions), and
disintegration time (USP <701>). Reduced sample sizes were
used for the USP methods.
[0188] Formulations without lactose showed higher tablet hardness
and lower friability. Additionally, adding the SF (superfine) grade
of Kollidon helped decrease disintegration time while increasing
tablet hardness. Adding the acid extragranularly was found to be
preferable to obtain shorter disintegration times.
[0189] Removal of lactose from the formulation provided tablets
having reduced friability which maintained rapid disintegration.
The inclusion of dry binders did not provide additional benefit to
reducing friability, but marginally reduced sticking. However, the
inclusion of binders can in some cases negatively impact
disintegration/swelling.
TABLE-US-00020 TABLE 19 Optimization of diluent and binder
components Initial Ribbon blend bulk Tensile density Strength
Sticking Hardness Friability Disint. Time Example (g/cc) (MPa) (ug)
(kp) (%) (m:s) Control 0.33 1.4 1074 16 0.44 1:51 (incl. lactose)
Remove lactose 0.31 1.8 1029 20 0.27 2:41 Move Acid 0.40 1.0 N/A 19
0.21 8:15 from EG to IG (incl. lactose) Add Kollidon 0.24 3.1 728
22 0.37 1:20 SF (no lactose) Add Avicel 0.31 2.1 975 19 0.47 2:26
PH105 (no lactose) Add Klucel 0.31 1.5 842 18 0.25 50:41 EXF (no
lactose) Move EG 0.33 2.8 1392 18 0.28 03:30 Avicel to IG (no
lactose)
Example 19
In Vitro Dissolution of Formulations A1, A2 and B
[0190] In vitro dissolution of optimized formulations A1, A2 and B
was determined using Dissolution Test 2, under the non-sink
conditions (pH 6.5, 50 mM phosphate buffer, 0.1 M NaCl) described
in Example 10. The dissolution profiles of these formulations were
compared to the tablets prepared according to Examples 1-7. The
tablet of Example 1 showed no drug-drug interaction with a proton
pump inhibitor in the fasted state in human volunteers and was set
as the minimum target dissolution profile. Comparative dissolution
data are presented in FIG. 4. Formulations A1, A2 and B were all
superior to both the commercial free base capsules (prepared as
described in Example 10) and the palbociclib isethionate salt (ISE)
capsules used in early development having the formulation in Table
20, After 10 minutes, the formulations A1, A2 and B were all
superior to the tablets of Examples 1-7, and therefore met the
solid dosage form dissolution target.
TABLE-US-00021 TABLE 20 25 mg ISE 100 mg ISE capsule capsule Amount
Amount Component (mg/capsule) (mg/capsule) Palbociclib isethionate
(mg) 32.048 128.200 (eq. 25 mg FB) (eq. 100 mg FB) Microcrystalline
cellulose (mg) 102.802 148.500 Sodium starch glycolate 8.700 13.500
Magnesium stearate 1.450 2.300 Corn starch 145.000 157.500 Total
fill weight 290.00 450.000
Example 20
Impact of Succinic Acid Particle Size Distribution
[0191] The impact of succinic acid particle size distribution on
the rate of formation of the succinyl adduct was assessed for
as-received acid (broad particle size distribution up to 1 mm
diameter) and three sieve cuts of the acid. Smaller acid particle
size resulted in a greater rate of impurity formation because of
its larger specific surface area enabling a higher frequency of
contacts of the acid with the free base API. Therefore acid with a
particle size greater than approximately 100 microns was preferred
in the drug product formulation to improve chemical stability.
TABLE-US-00022 TABLE 21 Impact of succinic acid particle size
distribution on adduct formation Acid degradation rate (%/year)
Storage As-received Acid Acid Acid Condition acid, without sieved
to sieved to sieved to (.degree. C./% RH) sieving <106 .mu.m
150-250 .mu.m 425-600 .mu.m 25.degree. C./22% RH 0.092 0.150 0.071
0.035 25.degree. C./60% RH 0.253 0.346 0.167 0.082 30.degree.
C./22% RH 0.203 0.294 0.150 0.075 30.degree. C./75% RH 0.837 0.942
0.494 0.249
Example 21
Physical Stability Analysis
[0192] A quantitative Raman spectroscopic method was developed to
evaluate the physical stability of the formulations. The Raman
method uses a Kaiser Optical Systems PhAT probe and the
quantitation model was built utilizing a set of calibration
standards prepared from API, API succinate complex and excipients.
The relative stability of Formulations A1 and B were assessed by
determining the amount of API succinate complex in the formulation
after storing the tablets at 30 to 50.degree. C. and up to 75% RH
for up to 1 month.
[0193] Formulation B showed lower conversion to the succinate
complex relative to Formulation A1. The amount of conversion
increased over time and was accelerated by storage conditions with
higher temperature and humidity.
[0194] The amount of API succinate complex formed under various
temperature and humidity conditions for formulation A1 and B is
shown in Table 22 as a function of time, where "LOD" refers to the
limit of detection and "LOQ" refers to the limit of
quantification.
TABLE-US-00023 TABLE 22 Conversion of free base API to API
succinate complex Storage 2 weeks 2 weeks 1 month 1 month Condition
Formulation Formulation Formulation Formulation (.degree. C./% RH)
A1 B A1 B Initial <2% (LOD) <2% (LOD) <2% (LOD) <2%
(LOD) 50/75 56% 32% -- -- 50/low <5% (LOQ) <5% (LOQ) -- --
40/75 -- -- 56% 33% 30/75 -- -- 13% 10%
[0195] The physical stability of prototype non-coated tablet
formulation A1 under open conditions was assessed. Tables were
subjected to elevated temperatures and humidity. Conversion to the
succinate complex was observed in stressed samples using Raman
spectroscopy.
[0196] The chemical purity of Formulations A1 and B were compared
after storage for 1 month at 40.degree. C./75% RH. As shown in
Table 23, Formulation B showed a significantly lower extent of
total impurity formation relative to Formulation A1.
TABLE-US-00024 TABLE 23 Degradation of Formulations A1 and B after
1 month at 40 C./75% RH Formulation A1 Formulation B Impurity %
Impurity % Impurity Oxidative degradant 1 0.15% NMT Oxidative
degradant 2 0.19% 0.05% Fumarate adduct ND 0.15% Oxidative
degradant 3 0.35% 0.07% Unidentified degradant 0.13% ND Oxidative
degradant 4 0.38% 0.08% Succinyl adduct 0.18% 0.18% Oxidative
degradant 5 0.21% NMT Formyl adduct 0.45% 0.15% Total Impurity 2.1%
0.75%
[0197] Based on these data, humidity (% RH) was determined to have
a significant impact on the rate of API conversion from free-base
to succinate complex. Increasing temperature also impacted
conversion to the complex, but had a weaker effect than
humidity.
[0198] Tablets which were pre-equilibrated in 60% RH before
foil-foil packaging displayed rapid succinate complex formation.
The 9 week stability data indicated that control of water activity
in tablets was required to minimize formation of the palbociclib
succinate complex in the drug product. Formulation B (which
contains extragranular sodium stearyl fumarate as the lubricant)
showed less succinate complex conversion in comparison to
formulation A1 (which incorporates magnesium stearate as the
extragranular lubricant) under conditions of high humidity (75%
RH).
* * * * *