Note: Descriptions are shown in the official language in which they were submitted.
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PHARMACEUTICAL COMBINATION COMPOSITION COMPRISING COMPLEX
FORMULATIONS OF IVACAFTOR AND LUMACAFTOR AND THEIR SALTS
AND DERIVATIVES, PROCESS FOR THEIR PREPARATION THEREOF AND
PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
FIELD OF THE INVENTION
[001] The invention is directed to a pharmaceutical composition comprising
stable complexes
with controlled particle size, increased apparent solubility and increased
dissolution rate
comprising as active compound Ivacaftor and Lumacaftor, their salts, or
derivatives thereof,
which is useful in the treatment of cystic fibrosis transmembrane conductance
regulator (CFTR)
mediated disease. More specifically, the pharmaceutical composition comprising
the complexes
of the present invention possess instantaneous redispersibility, increased
apparent solubility and
permeability, no observable food effect which deliver the opportunity of
precise dosing and ease
of administration of the reconstituted complex in solution form. The invention
also relates to
methods of formulating and manufacturing complexes according to the invention,
pharmaceutical compositions containing it, its uses and methods of treatment
using the complex
and its compositions.
BACKGROUND OF THE INVENTION
[002] The active ingredient in KALYDECOO tablets is Ivacaftor, which has the
following
chemical name: N-(2,4-di-tert-butyl-5-hydroxypheny1)-1,4-dihydro-4oxoquinoline-
3-carboxamide.
Its molecular formula is C241-128N203 and its molecular weight is 392.49.
Ivacaftor has the
following structural formula:
OH
0 0 401X
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[003] Ivacaftor is a white to off-white powder that is practically insoluble
in water (< 0.05
microgram/mL). Due to poor aqueous solubility, extensive formulation efforts
were required and
resulted in a spray-dried dispersion of Ivacaftor suitable for oral
administration. KALYDECOO
containing the spray-dried dispersion of Ivacaftor is available as a light
blue capsule-shaped, film-
coated tablet for oral administration containing 150 mg of Ivacaftor. Each
tablet contains the
inactive ingredients colloidal silicon dioxide, croscarmellose sodium,
hypromellose acetate
succinate, lactose monohydrate, magnesium stearate, microcrystalline
cellulose, and sodium lauryl
sulfate. The tablet film coat contains carnauba wax, FD&C Blue #2, PEG 3350,
polyvinyl
alcohol, talc, and titanium dioxide. The printing ink contains ammonium
hydroxide, iron oxide
black, propylene glycol, and shellac.
[004] Ivacaftor is a potentiator of the CFTR protein. The CFTR protein is a
chloride channel
present at the surface of epithelial cells in multiple organs. Ivacaftor
facilitates increased chloride
transport by potentiating the channel-open probability (or gating) of the CFTR
protein.
[005] After oral administration of a single 150 mg dose to healthy volunteers
in a fed state, peak
plasma concentrations (tmL,) occurred at approximately 4 hours, and the mean (
SD) for AUC
and Cm ax were 10,600 (5260) ng-thr/mL and 768 (233) ng/mL, respectively.
After every 12-hour
dosing, steady-state plasma concentrations of Ivacaftor were reached by days 3
to 5, with an
accumulation ratio ranging from 2.2 to 2.9.
[006] The exposure of Ivacaftor increased approximately 2-to 4-fold when given
with food
containing fat. Therefore, KALYDECOO should be administered with fat-
containing food.
Examples of fat-containing foods include eggs, butter, peanut butter, and
cheese pizza. The
median (range) tmax is approximately 4.0 (3.0; 6.0) hours in the fed state.
[007] The mean apparent volume of distribution (Vz/F) of Ivacaftor after a
single dose of 275
mg of KALYDECOO in the fed state was similar for healthy subjects and patients
with CF.
After oral administration of 150 mg every 12 hours for 7 days to healthy
volunteers in a fed state,
the mean ( SD) for apparent volume of distribution was 353 (122) L.
[008] Ivacaftor is extensively metabolized in humans. In-vitro and clinical
studies indicate that
Ivacaftor is primarily metabolized by CYP3A. M1 and M6 are the two major
metabolites of
Ivacaftor in humans. M1 has approximately one-sixth the potency of Ivacaftor
and is considered
pharmacologically active. M6 has less than one-fiftieth the potency of
Ivacaftor and is not
considered pharmacologically active.
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[009] Following oral administration, the majority of Ivacaftor (87.8%) is
eliminated in the feces
after metabolic conversion. The major metabolites M1 and M6 accounted for
approximately 65%
of the total dose eliminated with 22% as M1 and 43% as M6. There was
negligible urinary
excretion of Ivacaftor as unchanged parent. The apparent terminal half-life
was approximately 12
.. hours following a single dose. The mean apparent clearance (CL/F) of
Ivacaftor was similar for
healthy subjects and patients with CF. The CL/F (SD) for the 150 mg dose was
17.3 (8.4) L/hr
in healthy subjects.
[0010] Lumacaftor is one of the active ingredients in ORKAMBIO tablets, which
has the
following chemical name:
346-( { [1 -(2,2-difluoro-1,3-b enz odioxo1-5-
yl)cyclopropyl]carbonyll amino)-3-methylpyridin-2-yl]benzoic acid. The
molecular formula for
lumacaftor is C24H18F2N205. The molecular weight for Lumacaftor is 452.41. The
structural
formula is:
HO
0
OXp
[0011] Lumacaftor is a white to off-white powder that is practically insoluble
in water (0.02
mg/mL).
[0012] ORKAMBIO is available as a pink, oval-shaped, film-coated tablet for
oral administration
containing 200 mg of Lumacaftor and 125 mg of Ivacaftor. Each ORKAMBIO tablet
contains
200 mg of Lumacaftor and 125 mg of Ivacaftor, and the following inactive
ingredients: cellulose,
microcrystalline; croscarmellose sodium; hypromellose acetate succinate;
magnesium stearate;
povidone; and sodium lauryl sulfate. The tablet film coat contains carmine,
FD&C Blue #1,
FD&C Blue #2, polyethylene glycol, polyvinyl alcohol, talc, and titanium
dioxide. The printing
ink contains ammonium hydroxide, iron oxide black, propylene glycol, and
shellac.
[0013] Lumacaftor improves the conformational stability of F508del-CFTR,
resulting in
increased processing and trafficking of mature protein to the cell surface. In-
vitro studies have
demonstrated that Lumacaftor acts directly on the CFTR protein in primary
human bronchial
epithelial cultures and other cell lines harboring the F508del-CFTR mutation
to increase the
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quantity, stability, and function of F508del-CFTR at the cell surface,
resulting in increased
chloride ion transport.
[0014] Following multiple oral dose administrations of Lumacaftor, the
exposure of Lumacaftor
increased roughly proportionally with dose from 50 to 1000 mg qd. In subjects
with CF, the
Lumacaftor Cm ax and AUC also increases approximately proportional with the
dose over the
Lumacaftor 25 mg qd to 400 mg q12h dose range. The exposure of Lumacaftor
increased
approximately 1.6-to 2.0-fold when given with fat containing food. The median
(range) time of
the maximum concentration (tn.) is approximately 4.0 (2.0, 9.0) hours in the
fed state.
[0015] Lumacaftor is approximately 99% bound to plasma proteins, primarily to
albumin. After
oral administration of 200 mg every 24 hours for 28 days to patients with
cystic fibrosis (CF) in a
fed state, the mean ( SD) for apparent volumes of distribution was 86.0
(69.8) L.
[0016] The half-life of Lumacaftor is approximately 26 hours in patients with
CF. The typical
apparent clearance, CL/F (CV), of Lumacaftor was estimated to be 238 L/hr
(29.4%) for patients
with CF.
.. [0017] Lumacaftor is not extensively metabolized in humans with the
majority (51%) of
Lumacaftor excreted unchanged in the feces. There was minimal elimination of
Lumacaftor and
its metabolites in urine (only 8.6% of total radioactivity was recovered in
the urine with 0.18% as
unchanged parent). In-vitro and in vivo data indicate that Lumacaftor is
mainly metabolized via
oxidation and glucuronidation.
[0018] Lumacaftor has low aqueous solubility and high permeability assessed
via the colorectal
adenocarcinoma (Caco-2) cell system. Although pH-dependent solubility was
observed, the
Lumacaftor drug substance is practically insoluble in water and buffer
solutions of pH 1.0 to pH
8Ø Therefore, Lumacaftor is suggested to be a BCS Class 2 (low
solubility/high permeability)
compound.
[0019] Since Lumacaftor is considered a BCS class II, the drug substance was
jet-milled early in
development to reduce the particle size and potentially improve
bioavailability. Based on these
studies a control on Lumacaftor particle size in the drug substance
specification was established.
[0020] Various formulations have been used in the development of Lumacaftor
alone and in
combination which includes suspension, capsules and tablets. Comparative
exposure of the
different formulations of Lumacaftor was seen in single dose studies in
healthy volunteers.
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Exposure of the suspension is lower than that seen for capsules and tablets.
Early clinical studies
were conducted with the co-administration of both Ivacaftor and Lumacaftor. A
cross-over study
(007) was conducted to evaluate the relative bioavailability of the fixed dose
combination tablet as
compared to the separate tablets. The tablet and FDC appear to be
bioequivalent, and the only
5 parameter that did not meet standard bioequivalence criteria is the Cmax
of Ivacaftor (GLSMR
[90% CI] - 1.20 [1.09, 1.33]). However, for practical purposes this is
acceptable and the PK
results from tablet formulation can be considered applicable to the FDC as
well.
[0021] When a single dose of Lumacaftor/Ivacaftor was administered with fat-
containing foods,
Lumacaftor exposure was approximately 2 times higher and Ivacaftor exposure
was
approximately 3 times higher than when taken in a fasting state.
[0022] Following multiple oral dose administration of Lumacaftor in
combination with Ivacaftor,
the exposure of Lumacaftor generally increased proportional to dose over the
range of 200 mg
every 24 hours to 400 mg every 12 hours. The median (range) tniax of
Lumacaftor is approximately
4.0 hours (2.0; 9.0) in the fed state.
[0023] Following multiple oral dose administration of Ivacaftor in combination
with Lumacaftor,
the exposure of Ivacaftor generally increased with dose from 150 mg every 12
hours to 250 mg
every 12 hours. The median (range) tinax of ivacaftor is approximately 4.0
hours (2.0; 6.0) in the
fed state.
[0024] The main medical concerns surrounding the administration of Ivacaftor
and Lumacaftor
are related to the positive food effect both compounds exhibit which does not
allow the precise
administration of the current formulations. This is extensively true for
pediatric patients where
the current, fix dose tablet formulation does not allow the administration of
the compound to
children.
[0025] In order to overcome the problems associated with prior conventional
formulations and
available drug delivery systems containing Ivacaftor in combination with
Lumacaftor, novel
pharmaceutical composition comprising complex formulations of Ivacaftor or its
salts or its
derivatives thereof and complexation agents and pharmaceutically acceptable
excipients and
complex formulations of Lumacaftor or its salts or its derivatives thereof and
complexation
agents and pharmaceutically acceptable excipients were prepared. Novel
pharmaceutical
composition of the present invention is characterized by instantaneous
redispersibility, increased
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apparent solubility, instantaneous dissolution, increased apparent
permeability that exhibits no
food effect which allows the precise dosing the active ingredients.
[0026] A variety of strategies have been used to attempt to overcome these
issues, see for
example WO/2014/118805, WO/2014/125506, WO/2015/070336, WO/2014/135096,
JP2014097964, CN104725314, US20150246031, US20150182517, W02015160787,
US20150246031, US20150182517, US20150246031, US20150182517, W02015073231,
EP2872122, US20150024047, EP2826776, US20150010628, EP2819670, US20140255483,
US20140221424, US20140163068, US7495103, US8324242, US8354427, US8754224, US
7,495,103, US 8,507,534, US 8,653,103 US 8,716,338, US 8,846,718, US 8,993,600
W02015175773, W02009076141, W02011127290, W02013112804, W02011127241,
U520130085158, U520130296379, U520140221430, U520140163068, U520150196539,
U520160039800, U520150140094 and W02015073231.
BRIEF DESCRIPTION OF THE INVENTION
1. A pharmaceutical combination composition with improved physicochemical
characteristics
and enhanced biological performance comprising
i. complex Ivacaftor formulation or its pharmaceutical composition; and
ii. complex Lumacator formulation or its pharmaceutical composition; and
iii. optionally, pharmaceutically acceptable excipients;
wherein said complex Ivacaftor formulation or its pharmaceutical composition
comprising
i. Ivacaftor, or a salt or derivative thereof;
ii. at least one complexing agent chosen from polyethylene glycol
glycerides composed of
mono-, di- and triglycerides and mono- and diesters of polyethylene glycol,
hydroxypropylcellulose, poloxamers (copolymers of ethylene oxide and propylene
oxide
blocks), copolymers of vinylpyrrolidone and vinyl acetate, poly(2-ethyl-2-
oxazoline),
polyvinylpyrrolidone, poly(maleic acid/methyl vinyl ether), polyvinyl
caprolactam-
polyvinyl acetate-polyethylene glycol graft copolymer, ethylene
oxide/propylene oxide
tetra functional block copolymer, and d-alpha tocopheryl polyethylene glycol
1000
succinate; and
iii. optionally, pharmaceutically acceptable excipients;
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wherein said complex Lumacaftor formulation or its pharmaceutical composition
comprises
i. Lumacaftor, or a salt or derivative thereof;
ii. at least one complexation agent chosen from polyethylene glycol
glycerides composed
of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol,
hydroxypropylcellulose, poloxamers (copolymers of ethylene oxide and propylene
oxide blocks), vinylpyrrolidone/vinyl acetate copolymer, poly(2-ethyl-2-
oxazoline),
polyvinylpyrrolidone, poly(maleic acid/methyl vinyl ether), polyvinyl
caprolactam-
polyvinyl acetate-polyethylene glycol graft copolymer, polyoxyl 15
hydroxystearate,
ethylene oxide/propylene oxide tetra functional block copolymer, and d-alpha
tocopheryl polyethylene glycol 1000 succinate; and
iii. optionally, pharmaceutically acceptable excipients;
wherein said complex formulations or their pharmaceutical combination
compositions have
particle size between 10 nm and 600 nm, and the said pharmaceutical
combination composition
possesses at least one of following features:
a) is instantaneously redispersable in physiological relevant media;
b) is stable in solid form and in colloid solution and/or dispersion;
c) complex Ivacaftor and complex Lumacaftor formulations or their
pharmaceutical
composition have an apparent solubility in water of at least 1 mg/mL;
d) complex Ivacaftor and complex Lumacaftor formulations or their
pharmaceutical
compositions have a PAMPA permeability of at least 0.2*10 cm/s for Ivacaftor
and 2*10' cm/s for Lumacaftor when dispersed in FaSSIF or FeSSIF biorelevant
media, which does not decrease in time for at least 6 month;
e) has increased dissolution rate: 80 `)/0 of Ivacaftor and 80% of
Lumacaftor released
from the pharmaceutical composition within 5 minutes in biological relevant
media;
f) exhibits no observable food effect;
g) has improved bioavailability both for Ivacaftor and Lumacaftor.
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2. The pharmaceutical combination composition according to Point 1, wherein
said complexes
have particle size in the range between 10 nm and 600 nm.
3. The pharmaceutical combination composition according to Point 2, wherein
said complexes
have particle size in the range between 10 nm and 400 nm.
4. The pharmaceutical combination composition according to Point 1, wherein
said complexes
exhibit X-ray amorphous character in the solid form.
5. The pharmaceutical combination composition according to Point 1, wherein
said complexes or
their pharmaceutical compositions or said pharmaceutical combination
composition possess at
least two of the properties described in a) ¨ g).
.. 6. The pharmaceutical combination composition according to Point 5, wherein
said complexes or
their pharmaceutical compositions or pharmaceutical combination composition
possess at least
three of the properties described in a) ¨g).
7. The complex according to Point 6, wherein said pharmaceutical combination
composition or
said complexes or their pharmaceutical combination compositions possess
instantaneous
redispersibility, has an apparent solubility in water of at least 1 mg/mL,
exhibits no observable
food effect which deliver the opportunity of precise dosing and ease of
administration of the
reconstituted pharmaceutical combination composition in solution form.
8. The pharmaceutical combination composition according to Point 6, wherein
said complexes or
their pharmaceutical combination compositions possess instantaneous
redispersibility, have a
PAMPA permeability of at least 0.2*10-6 cm/s for Ivacaftor and 2*10-6 cm/s for
Lumacaftor
when dispersed in water, FaSSIF or FeSSIF biorelevant media, which does not
decrease in time
for at least 6 month, exhibits no observable food effect which deliver the
opportunity of precise
dosing and ease of administration of the reconstituted pharmaceutical
combination composition
in solution form.
9. The pharmaceutical combination composition according to Point 1, wherein
the complexing
agent of complex Ivacaftor formulation is a copolymer of vinylpyrrolidone and
vinylacetate and
optionally a poloxamer; and the complexing agent of complex Lumacaftor
formulation is a
copolymer of vinylpyrrolidone and vinylacetate.
10. The pharmaceutical combination composition according to Point 1, wherein
said
pharmaceutically acceptable excipient of said complex Ivacaftor and complex
Lumacaftor
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formulations is chosen from sodium deoxycholate, dioctyl sodium
sulfosuccinate, sodium acetate,
cetylpyridinium chloride, citric acid, meglumine and sodium lauryl sulfate.
11. The pharmaceutical combination composition according to Point 10, wherein
said
pharmaceutically acceptable excipient is sodium lauryl sulfate.
12. The pharmaceutical combination composition according to Point 1 comprising
i. complex Ivacaftor formulation; and
ii. complex Lumacaftor formulation; and
iii. optionally, pharmaceutically acceptable excipients;
wherein said complex Ivacaftor formulation comprising
i. Ivacaftor;
ii. copolymer of vinylpyrrolidone and vinylacetate and optionally a
poloxamer as
complexing agents; and
iii. sodium lauryl sulfate as an excipient;
wherein said complex Ivacaftor formulation is characterized by infrared (ATR)
peaks 588 cm-',
628 cm-', 767 cm-', 842 cm-', 962 cm-', 1019 cm-', 1108 cm-', 1148 cm-', 1240
cm-', 1343 cm-',
1370 cm-', 1425 cm-', 1465 cm-', 1525 cm-', 1567 cm-', 1666 cm-' and 1732 cm';
and is
characterized by Raman shifts at 552 cm-', 648 cm-', 826 cm-', 845 cm-', 888
cm-', 932 cm-', 1026
cm-', 1062 cm-', 1082 cm-', 1129 cm-', 1140 cm-', 1208 cm-', 1233 cm-', 1262
cm-', 1284 cm-',
1295 cm-', 1361 cm-', 1450 cm-', 1528 cm-', 1573 cm-', 1618 cm-', 1677 cm-',
1738 cm-', 746 cm-',
2884 cm-' and 2936 cm-'
and wherein said complex Lumacaftor formulation composition comprises
i. Lumacaftor;
ii. copolymer of vinylpyrrolidone and vinylacetate as complexing agent; and
iii. sodium lauryl sulfate as an excipient;
wherein said complex Lumacaftor formulations is characterized by infrared
(ATR) peaks at 635
cm-', 703 cm-', 747 cm-', 837 cm-', 1021 cm-', 1165 cm-', 1231 cm-', 1288 cm-
', 1369 cm-', 1423
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cm', 1462 cm', 1494 cm', 1667 cm' and 1731 cm-'; and is characterized by Raman
shifts at 553
cm', 602 cm', 635 cm', 654 cm', 747 cm', 841 cm', 899 cm', 934 cm', 1002 cm',
1021 cm',
1117 cm', 1205 cm', 1232 cm', 1310 cm', 1352 cm', 1372 cm', 1428 cm', 1444
cm', 1497 cm
1, 1592 cm', 1609 cm', 1677 cm-' and 1737 cm-'.
5 13. The pharmaceutical combination composition according to Point 1,
wherein said
pharmaceutical combination composition comprises of 50 to 300 mg Ivacaftor
equivalent
complex Ivacaftor formulation in combination with 25 to 250 mg Lumacaftor
equivalent
complex Lumacaftor formulation.
14. A pharmaceutical combination composition to either of Point 1 or Point 12
comprising
10 complex Ivacaftor formulation or its pharmaceutical composition and
complex Lumacaftor
formulation or its pharmaceutical composition in a total amount ranging from
about 10.0 weight
A to 100.0 weight A based on the total weight of the pharmaceutical
composition.
15. A pharmaceutical combination composition to either of Point 1 or Point 12
comprising
complex Ivacaftor formulation or its pharmaceutical composition and complex
Lumacaftor
formulation or its pharmaceutical composition in a total amount ranging from
about 50.0 weight
% to 100.0 weight A based on the total weight of the pharmaceutical
composition.
16. The pharmaceutical combination composition according to Point 1, wherein
said
pharmaceutical combination composition has an increased dissolution rate.
17. A process for the preparation of the complexes of Ivacaftor according to
Point 1, said
process comprising the step of mixing a pharmaceutically acceptable solution
containing
Ivacaftor and complexing agents which is a copolymer of vinylpyrrolidone and
vinylacetate and
optionally a poloxamer with an aqueous solution containing at least one
pharmaceutically
acceptable excipient which is sodium lauryl sulfate.
18. A process for the preparation of the complexes of Lumacaftor according to
Point 1, said
process comprising the step of mixing a pharmaceutically acceptable solution
containing
Lumacaftor, and complexing agent which is a copolymer of vinylpyrrolidone and
vinylacetate
with an aqueous solution containing at least one pharmaceutically acceptable
excipient which is
sodium lauryl sulfate.
19. A process for the preparation of the complexes of Ivacaftor and Lumacaftor
according to
Point 1, said process comprising the step of mixing a pharmaceutically
acceptable solution
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containing Ivacaftor and Lumacaftor, and complexing agent which is a copolymer
of
vinylpyrrolidone and vinylacetate with an aqueous solution containing at least
one
pharmaceutically acceptable excipient which is sodium lauryl sulfate.
20. The process according to Point 17-19, wherein said process are performed
in a continuous
flow instrument.
21. The process according to Point 20, wherein said continuous flow instrument
is a microfluidic
flow instrument.
22. The process according to Point 17-21, wherein the pharmaceutically
acceptable solvent of
said pharmaceutically acceptable solution is chosen from water, methanol,
ethanol, isopropanol,
.. n-propanol, acetone, acetonitrile, dimethyl-sulfoxide, tetrahydrofuran, or
combinations thereof.
23. The process according to Point 22, wherein the pharmaceutically acceptable
solvent of said
pharmaceutically acceptable solution is methanol, tetrahydrofuran or a solvent
mixture of
tetrahydrofuran and methanol.
24. The process according to Point 17-19, wherein said pharmaceutically
acceptable solvents are
miscible with each other and the aqueous solution; and the aqueous solution
comprises 0.1 to
99.9% weight of the final solution.
25. A pharmaceutical combination composition comprising the pharmaceutical
combination
composition according to Point 1 together with a pharmaceutically acceptable
carrier.
26. The pharmaceutical combination composition according to Point 25, wherein
said
pharmaceutical composition is suitable for oral, pulmonary, rectal, colonic,
parenteral,
intracisternal, intravaginal, intraperitoneal, ocular, otic, local, buccal,
nasal, or topical
administration.
27. The pharmaceutical combination composition according to Point 26, wherein
said
pharmaceutical composition is suitable for oral administration.
28. The pharmaceutical combination composition comprising the pharmaceutical
composition
according to Point 25, wherein said pharmaceutical composition comprises fast
dissolving
granules of the complex formulations according to Point 1.
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29. The pharmaceutical combination composition according to Point 28, wherein
said fast
dissolving granules are suitable for the preparation of sachet dosage form.
30. A pharmaceutical combination composition according to Point 1 for use in
the treatment of
CFTR mediated diseases.
31. The use of Point 28, wherein said CFTR mediated disease is selected from
cystic fibrosis,
asthma, smoke induced COPD, chronic bronchitis, rhinosinusitis, constipation,
pancreatitis,
pancreatic insufficiency, male infertility caused by congenital bilateral
absence of the vas deferens
(CBAVD), mild pulmonary disease, idiopathic pancreatitis, allergic
bronchopulmonary
aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary
hemochromatosis,
coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1
hereditary angioedema,
lipid processing deficiencies, such as familial hypercholesterolemia, Type 1
chylomicronemia,
abetalipoproteinemia, lysosomal storage diseases, such as I-cell
disease/pseudo-Hurler,
mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type
polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism,
myleoperoxidase
.. deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1,
congenital
hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT
deficiency,
Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie Tooth
syndrome,
Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's
disease,
Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear
plasy, Pick's disease,
several polyglutamine neurological disorders such as Huntington's,
spinocerebullar ataxia type I,
spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic
dystrophy, as well
as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease
(due to prion
protein processing defect), Fabry disease, Straussler-Scheinker syndrome,
COPD, dry-eye disease,
or Sjogren's disease, Osteoporosis, Osteopenia, bone healing and bone growth
(including bone
repair, bone regeneration, reducing bone resorption and increasing bone
deposition), Gorham's
Syndrome, chloride channelopathies such as myotonia congenita (Thomson and
Becker forms),
Bartter's syndrome type III, Dent's disease, hyperekplexia, epilepsy,
lysosomal storage disease,
Angelman syndrome, and Primary Ciliary Dyskinesia (PCD), a term for inherited
disorders of the
structure and/or function of cilia, including PCD with situs inversus (also
known as Kartagener
syndrome), PCD without situs inversus and ciliary aplasia.
32. A method of treatment of CFTR mediated diseases comprising administration
of a
therapeutically effective amount of the pharmaceutical combination composition
according to
Point 1 or the pharmaceutical composition according to Point 25.
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33. The pharmaceutical combination composition according to Point 1, wherein
said
pharmaceutical composition further comprises one or more additional active
agents.
34. The pharmaceutical combination composition according to Point 31, wherein
said additional
active agent chosen from agents used for the treatment of CFTR mediated
diseases.
DESCRIPTION OF THE INVENTION
[0027] Disclosed herein is a pharmaceutical combination composition comprising
a mixture of:
a) a stable complex Ivacaftor formulation; and
b) a stable complex Lumacaftor formulation; and
c) optionally, pharmaceutically acceptable excipients.
[0028] In some embodiments, the pharmaceutical combination composition of the
present
invention may additionally include one or more pharmaceutically acceptable
excipients, auxiliary
materials, carriers, active agents or combinations thereof.
[0029] In an embodiment, said pharmaceutical combination composition is
suitable for oral
administration.
[0030] In some embodiment, said pharmaceutical combination composition is
suitable for oral
administration as liquid dispersible granules in a sachet form.
[0031] In some embodiment, the daily human dose of said pharmaceutical
combination
composition can be adjusted based on the body weight by administering the
pharmaceutical
composition of the present invention in the required amount.
[0032] In an embodiment, said pharmaceutical combination composition can be
administered
orally from the age of 0.
[0033] In an embodiment, said complex formulations and said pharmaceutical
composition are
for use in the manufacture of a medicament for the treatment of CFTR mediated
diseases.
[0034] In an embodiment, said complex formulations and said pharmaceutical
composition is
used for the treatment of CFTR mediated diseases.
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[0035] CFTR mediated disease is selected from cystic fibrosis, asthma, smoke
induced COPD,
chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic
insufficiency, male
infertility caused by congenital bilateral absence of the vas deferens
(CBAVD), mild pulmonary
disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis
(ABPA), liver disease,
hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis
deficiencies, such as
protein C deficiency, Type 1 hereditary angioedema, lipid processing
deficiencies, such as familial
hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal
storage diseases,
such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-
Sachs, Crigler-Naj jar
type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism,
myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis
CDG type 1,
congenital hyperthyroidism, osteogenesis imperfecta, hereditary
hypofibrinogenemia, ACT
deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-
Marie Tooth
syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as
Alzheimer's
disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive
supranuclear plasy, Pick's
disease, several polyglutamine neurological disorders such as Huntington's,
spinocerebullar ataxia
type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and
myotonic dystrophy,
as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob
disease (due to
prion protein processing defect), Fabry disease, Straussler-Scheinker
syndrome, COPD, dry-eye
disease, or Sjogren's disease, Osteoporosis, Osteopenia, bone healing and bone
growth (including
bone repair, bone regeneration, reducing bone resorption and increasing bone
deposition),
Gorham's Syndrome, chloride channelopathies such as myotonia congenita
(Thomson and
Becker forms), Bartter's syndrome type III, Dent's disease, hyperekplexia,
epilepsy, lysosomal
storage disease, Angelman syndrome, and Primary Ciliary Dyskinesia (PCD), a
term for inherited
disorders of the structure and/or function of cilia, including PCD with situs
inversus (also known
as Kartagener syndrome), PCD without situs inversus and ciliary aplasia.
[0036] In an embodiment, a method of treatment of CFTR mediated diseases
comprises
administration of a therapeutically effective amount of complex formulations
or their
pharmaceutical combination compositions as described herein.
[0037] In an embodiment, said pharmaceutical composition further comprises one
or more
additional active agents.
[0038] In an embodiment, said additional active agent is chosen from agents
used for the
treatment of CFTR mediated diseases.
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[0039] In an embodiment said pharmaceutical composition comprising complex
Ivacaftor
formulation in combination with complex Lumacaftor formulation and optionally
further
pharmaceutically acceptable excipients characterized in that it possesses at
least one of the
following properties:
5 a) is instantaneously redispersable in physiological relevant media;
b) is stable in solid form and in colloid solution and/or dispersion;
c) complex Ivacaftor and/or complex Lumacaftor formulations have an apparent
solubility
in water of at least 1 mg/mL;
d) complex Ivacaftor and/or complex Lumacaftor formulation have a PAMPA
permeability
10 of
at least 0.2*10 cm/s for Ivacaftor and 2*10' cm/s for Lumacaftor when
dispersed in
FaSSIF or FeSSIF biorelevant media, which does not decrease in time for at
least 6
month;
e) has increased dissolution rate: 80 `)/0 of Ivacaftor and 80 A of
Lumacaftor released from
the pharmaceutical composition within 5 minutes in biological relevant media;
15 f) exhibits no observable food effect;
g) has increased bioavailability both for Ivacaftor and Lumacaftor.
[0040] In the following the Ivacaftor complex used in the present invention
will be detailed.
[0041] The complex Ivacaftor formulation used in the present invention
comprises Ivacaftor; a
complexing agent which is a copolymer of vinylpyrrolidone and vinylacetate and
optionally a
poloxamer; and sodium lauryl sulfate as a pharmaceutically acceptable
excipient; said complexes
characterized in that they possess at least one of the following properties:
a) is instantaneously redispersable in physiological relevant media;
b) is stable in solid form and in colloid solution and/or dispersion;
c) has an apparent solubility in water of at least 1 mg/mL;
d) has a PAMPA permeability of at least 0.2*10' cm/s when dispersed in FaSSIF
or FeSSIF
biorelevant media, which does not decrease in time for at least 6 month;
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e) exhibits no observable food effect.
[0042] In an embodiment, said Ivacaftor complex used in the present invention
possesses at least
two of the properties described in a) ¨ e).
[0043] In an embodiment, said Ivacaftor complex used in the present invention
possesses at least
three of the properties described in a) ¨ e).
[0044] Ivacaftor formulations used in the present invention possess
instantaneous
redispersibility, increased apparent solubility and permeability, no
observable food effect which
deliver the opportunity of precise dosing and ease of administration of the
reconstituted complex
in solution form.
[0045] The expression Ivacaftor is generally used for Ivacaftor, or its salts
or its derivatives.
[0046] In an embodiment, said complexation agent used in the Ivacaftor complex
as used in the
present invention is a copolymer of vinylpyrrolidone and vinylacetate and
optionally a poloxamer.
[0047] In an embodiment, said complexation agent used in the Ivacaftor complex
as used in the
present invention is a copolymer of vinylpyrrolidone and vinylacetate.
[0048] In an embodiment, said copolymer of vinylpyrrolidone and vinylacetate
has a 60:40
weight ratio of vinylpyrrolidone:vinyl acetate monomers.
[0049] In an embodiment, said poloxamer is poloxamer 338.
[0050] In an embodiment, said poloxamer is poloxamer 407.
[0051] In an embodiment, said pharmaceutically acceptable excipient used in
the Ivacaftor
complex as used in the present invention is sodium lauryl sulfate.
[0052] In an embodiment, the complexation agents used in the Ivacaftor complex
as used in the
present invention are copolymer of vinylpyrrolidone and vinyl acetate and
poloxamer and said
pharmaceutically acceptable excipient is sodium lauryl sulfate, and
a) said Ivacaftor complex is characterized by infrared (ATR) spectrum having
characteristic
absorption peaks at 588 cm-', 628 cm-', 767 cm-', 842 cm-', 962 cm-', 1019 cm-
', 1108 cm-', 1148
cm-', 1240 cm-', 1343 cm-', 1370 cm-', 1425 cm-', 1465 cm-', 1525 cm-', 1567
cm-', 1666 cm-' and
1732 cm'; and
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b) said Ivacaftor complex has characteristic Raman shifts at 552 cm-1, 648 cm-
1, 826 cm-1, 845 cm
1, 888 cm-1, 932 cm-1, 1026 cm-1, 1062 cm-1, 1082 cm-1, 1129 cm-1, 1140 cm-1,
1208 cm-1, 1233 cm-1,
1262 cm-1, 1284 cm-1, 1295 cm-1, 1361 cm-1, 1450 cm-1, 1528 cm-1, 1573 cm-1,
1618 cm-1, 1677 cm
1, 1738 cm-1, 746 cm-1, 2884 cm-1 and 2936 cm-1.
.. [0053] In some embodiments, the compositions may additionally include one
or more
pharmaceutically acceptable excipients, auxiliary materials, carriers, active
agents or combinations
thereof.
[0054] In an embodiment, said Ivacaftor complex used in the present invention
has a particle
size between 10 nm and 600 nm.
[0055] In an embodiment said Ivacaftor complex used in the present invention
has a particle size
in the range between 10 nm and 400 nm.
[0056] In an embodiment, said Ivacaftor complex used in the present invention
is
instantaneously redispersible in physiological relevant media.
[0057] In an embodiment, said Ivacaftor complex used in the present invention
has increased
dissolution rate compared to the commercially available form of Ivacaftor,
both alone and in
combination (KALYDECOO and ORKAMBIO).
[0058] In an embodiment, said Ivacaftor complex used in the present invention
is stable in solid
form and in colloid solution and/or dispersion.
[0059] In an embodiment, said Ivacaftor complex used in the present invention
has apparent
solubility in water is at least 1 mg/mL.
[0060] In an embodiment, said Ivacaftor complex used in the present invention
exhibits X-ray
amorphous character in the solid form.
[0061] In an embodiment, said Ivacaftor complex used in the present invention
has a PAMPA
permeability of at least 0.2*10-6 cm/s when dispersed in distilled water,
which does not decrease
in time for at least 6 months.
[0062] In an embodiment, the variability of exposure of the Ivacaftor complex
used in the
present invention is significantly reduced compared to the commercially
available form, both
alone and in combination (KALYDECOO and ORKAMBIO).
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[0063] In an embodiment, said Ivacaftor complex used in the present invention
has no
observable food effect, which allows the opportunity of precise dosing and
ease of administration
of the reconstituted complex in solution form.
[0064] In an embodiment said Ivacaftor complex used in the present invention,
containing
copolymer of vinylpyrrolidone and vinylacetate and poloxamer and sodium lauryl
sulfate, or its
pharmaceutical composition characterized by the Raman spectrum shown in Figure
11 and ATR
spectrum shown in Figure 12.
[0065] In an embodiment, said Ivacaftor complex used in the present invention
is characterized
by characteristic Raman shifts at 552 cm-1, 648 cm-1, 826 cm-1 ,845 cm-1, 888
cm-1, 932 cm-1, 1026
cm-1, 1062 cm-1, 1082 cm-1, 1129 cm-1, 1140 cm-1, 1208 cm-1, 1233 cm-1, 1262
cm-1, 1284 cm-1,
1295 cm-1, 1361 cm-1, 1450 cm-1, 1528 cm-1, 1573 cm-1, 1618 cm-1, 1677 cm-1,
1738 cm-1, 746 cm-1,
2884 cm-1 and 2936 cm-1.
[0066] In an embodiment, said Ivacaftor complex used in the present invention
is characterized
by characteristic Raman shifts at 1082 cm-1, 1233 cm-1, 1284 cm-1, 1361 cm-1,
1528 cm-1, 1618 cm-1
and 1738 cm-1.
[0067] In an embodiment, said Ivacaftor complex used in the present invention
is characterized
by ATR spectrum having characteristic peaks at 588 cm-1, 628 cm-1, 767 cm-1,
842 cm-1 , 962 cm-1,
1019 cm-1, 1108 cm-1, 1148 cm-1, 1240 cm-1, 1343 cm-1, 1370 cm-1, 1425 cm-1,
1465 cm-1, 1525 cm
1, 1567 cm-1, 1666 cm-land 1732 cm-1.
[0068] In an embodiment, said Ivacaftor complex used in the present invention
is characterized
by ATR spectrum having characteristic peaks at 628 cm-1, 767 cm-1, 1108 cm-1,
1370 cm-1, 1465
_
cm' and 1666 cm'.
[0069] In an embodiment said Ivacaftor complex used in the present invention
comprises
a) Ivacaftor; or a combination of active compounds including Ivacaftor;
b) a complexing agent which is a copolymer of vinylpyrrolidone and
vinylacetate and
optionally a poloxamer; and
c) sodium lauryl sulfate as a pharmaceutically acceptable excipient.
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[0070] In an embodiment, said Ivacaftor complex used in the present invention
comprises a
complexation agent which is a copolymer of vinylpyrrolidone and vinylacetate
and optionally a
poloxamer which is poloxamer 407 or poloxamer 338 and a pharmaceutically
acceptable
excipient which is sodium lauryl sulfate, in a total amount comprising from
about 1.0 weight% to
about 95.0 weight `)/0 based on the total weight of the complex.
[0071] In an embodiment, said Ivacaftor complex used in the present invention
comprises a
complexation agent which is a copolymer of vinylpyrrolidone and vinylacetate
and optionally a
poloxamer which is poloxamer 407 or poloxamer 338 and a pharmaceutically
acceptable
excipient which is sodium lauryl sulfate, in a total amount comprising from
about 50 weight% to
about 95 weight% of the total weight of the complex.
[0072]
[0073] The stable complex of Ivacaftor as used in the present invention
comprises
a. 5 ¨ 40% by weight of Ivacaftor, or a salt or derivative thereof;
b. 20 ¨ 80% by weight of a copolymer of vinylpyrrolidone and vinylacetate;
c. 5 ¨ 40 `)/0 by weight of sodium lauryl sulfate; and optionally
d. 0 ¨ 50 `)/0 by weight of a poloxamer.
[0074] The manufacturing of the stable complex of Ivacaftor used in the
present invention
comprises the step of mixing a pharmaceutically acceptable solution containing
Ivacaftor and at
least one complexing agent and optionally one or more pharmaceutically
acceptable excipients
with an aqueous solution containing optionally least one pharmaceutically
acceptable excipient.
[0075] In an embodiment said Ivacaftor complex used in the present invention
is obtained via a
mixing process.
[0076] In an embodiment said Ivacaftor complex used in the present invention
is obtained via a
continuous flow mixing process.
[0077] In an embodiment said process is performed in a continuous flow
instrument.
[0078] In an embodiment said continuous flow instrument is a microfluidic flow
instrument.
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[0079] In an embodiment, said Ivacaftor complex used in the present invention
is not obtained
via a milling process, high pressure homogenization process, encapsulation
process and solid
dispersion processes.
[0080] In an embodiment, the solvent of said pharmaceutically acceptable
solution is chosen
5 from water, methanol, ethanol, 1-propanol, 2-propanol, acetone,
acetonitrile, dimethyl-sulfoxide,
tetrahydrofuran, methyl-ethyl ketone or combinations thereof.
[0081] In an embodiment, said pharmaceutically acceptable solvent is
tetrahydrofuran.
[0082] In an embodiment, said pharmaceutically acceptable solvent and said
aqueous solution are
miscible with each other.
10 [0083] In an embodiment, said aqueous solution comprises 0.1 to 99.9%
weight of the final
solution.
[0084] In an embodiment, said aqueous solution comprises 50 to 90% weight of
the final
solution.
[0085] In an embodiment, said aqueous solution comprises 50 to 80% weight of
the final
15 .. solution.
[0086] In an embodiment, said aqueous solution comprises 50 to 70% weight of
the final
solution.
[0087] In an embodiment, said aqueous solution comprises 50 to 60% weight of
the final
solution.
20 [0088] In an embodiment, said aqueous solution comprises 45 to 55%
weight of the final
solution.
[0089] In an embodiment, said aqueous solution comprises 50 % weight of the
final solution.
[0090] In an embodiment, said aqueous solution comprises 35 to 45 % weight of
the final
solution.
[0091] In an embodiment, said aqueous solution comprises 25 to 35 % weight of
the final
solution.
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[0092] In an embodiment, said aqueous solution comprises 15 to 25 % weight of
the final
solution.
[0093] In an embodiment, said aqueous solution comprises 5 to 15 % weight of
the final
solution.
[0094] In an embodiment, a pharmaceutical composition comprising the Ivacaftor
complex
together with pharmaceutically acceptable carrier.
[0095] In the following the Lumacaftor complex used in the present invention
will be detailed.
[0096] The complex Lumacaftor formulation used in the present invention
comprises
Lumacaftor; a complexing agent which is a copolymer of vinylpyrrolidone and
vinylacetate and
sodium lauryl sulfate as a pharmaceutically acceptable excipient; said
complexes characterized in
that they possess at least one of the following properties:
a) is instantaneously redispersable in physiological relevant media;
b) is stable in solid form and in colloid solution and/or dispersion;
c) has apparent solubility in water of at least 1 mg/mL;
d) has a PAMPA permeability of at least 2*10' cm/s when dispersed in FaSSIF or
FeSSIF
biorelevant media, which does not decrease in time at least for at least 1,
preferably 6
month;
e) exhibits no observable food effect in-vitro.
[0097] In an embodiment, said Lumacaftor complex used in the present invention
possesses at
least two of the properties described in a)-e).
[0098] In an embodiment, said Lumacaftor complex used in the present invention
possesses at
least three of the properties described in a)-e).
[0099] Lumacaftor complex formulations used in the present invention possess
instantaneous
redispersibility, increased apparent solubility and permeability in fasted and
fed state simulation
that is expected to deliver full absorption and the elimination of the food
effect which deliver the
opportunity of precise dosing and ease of administration of the reconstituted
complex in solution
form.
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[00100]The expression Lumacaftor is generally used for Lumacaftor, or its
salts or its derivatives.
[00101]In an embodiment, said complexation agent used in the Lumacaftor
complex as used in
the present invention is a copolymer of vinylpyrrolidone and vinylacetate.
[00102]In an embodiment, said copolymer of vinylpyrrolidone and vinyl acetate
has a 60:40 ratio
of vinylpyrrolidone:vinyl acetate monomers.
[00103]In an embodiment, said pharmaceutically acceptable excipient used in
the Lumacaftor
complex as used in the present invention is sodium lauryl sulfate.
[00104]In an embodiment, said Lumacaftor complex formulation is characterized
by
a) Raman shifts at 553 cm-', 602 cm-' , 635 cm-', 654 cm-', 747 cm-', 841 cm-
', 899 cm-', 934 cm-',
1002 cm-', 1021 cm-', 1117 cm-', 1205 cm-', 1232 cm-', 1310 cm-', 1352 cm-',
1372 cm-', 1428 cm
1, 1444 cm-', 1497 cm-', 1592 cm-', 1609 cm-', 1677 cm-' and 1737 cm'; and
b) infrared (ATR) peaks at 635 cm-', 703 cm-', 747 cm-' , 837 cm-', 1021 cm-',
1165 cm-', 1231 cm
1, 1288 cm-', 1369 cm-', 1423 cm-', 1462 cm-', 1494 cm-', 1667 cm-' and 1731
cm-'.
[00105]In some embodiments, the pharmaceutical compositions may additionally
include one or
more pharmaceutically acceptable excipients, auxiliary materials, carriers,
active agents or
combinations thereof.
[00106]In an embodiment, said Lumacaftor complexes used in the present
invention have
particle size between 10 nm and 500 nm.
[00107]In an embodiment, said particle size is between 10 nm and 250 nm.
[00108]In an embodiment, said Lumacaftor complex used in the present invention
has increased
dissolution rate compared to the commercially available form of Lumacaftor
(crystalline form of
Lumacaftor).
[00109]In an embodiment, said Lumacaftor complex used in the present invention
is stable in
solid form and in colloid solution and/or dispersion.
[00110]In an embodiment, said Lumacaftor complex used in the present invention
has apparent
solubility in water is at least 1 mg/mL.
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[00111]In an embodiment, said Lumacaftor complex used in the present invention
exhibits X-ray
amorphous character in the solid form.
[00112]In an embodiment, said Lumacaftor complex used in the present invention
has a PAMPA
permeability of at least 2*10-6 cm/s when dispersed in distilled water, which
does not decrease in
time at least for 1, preferably 6 months.
[00113]In an embodiment, the variability of exposure of said Lumacaftor
complex used in the
present invention is significantly reduced compared to the commercially
available form
(0 RKAMB IO) .
[00114]In an embodiment, said Lumacaftor complex used in the present invention
has no
observable food effect in-vitro, which allows the opportunity of precise
dosing and ease of
administration of the reconstituted complex in solution form.
[00115]In an embodiment said Lumacaftor complex used in the present invention
or its
pharmaceutical composition characterized by Raman spectrum shown in Figure 13
and ATR
spectrum shown in Figure 14.
[00116]In an embodiment said Lumacaftor complex used in the present invention
is
characterized by Raman shifts at 553 cm-1, 602 cm-1 ,635 cm-1, 654 cm-1, 747
cm-1, 841 cm-1, 899
cm-1, 934 cm-1, 1002 cm-1, 1021 cm-1, 1117 cm-1, 1205 cm-1, 1232 cm-1, 1310 cm-
1, 1352 cm-1, 1372
cm-1, 1428 cm-1, 1444 cm-1, 1497 cm-1, 1592 cm-1, 1609 cm-1, 1677 cm-1 and
1737 cm-1.
[00117]In an embodiment said Lumacaftor complex used in the present invention
is
characterized by infrared (ATR) peaks at 635 cm-1, 703 cm-1, 747 cm', 837 cm-
1, 1021 cm-1, 1165
cm-1, 1231 cm-1, 1288 cm-1, 1369 cm-1, 1423 cm-1, 1462 cm-1, 1494 cm-1, 1667
cm-1 and 1731 cm-1.
[00118]In an embodiment said Lumacaftor complex used in the present invention
comprises
a) Lumacaftor; or a combination of active compounds including Lumacaftor;
b) a complexing agent which is a copolymer of vinylpyrrolidone and
vinylacetate; and
c) sodium lauryl sulfate as an excipient.
[00119]In an embodiment, said complex Lumacaftor formulation used in the
present invention
comprises complexation agent which is a copolymer of vinylpyrrolidone and
vinylacetate and a
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pharmaceutically acceptable excipient which is sodium lauryl sulfate, in a
total amount ranging
from about 1.0 weight `)/0 to about 95.0 weight `)/0 based on the total weight
of the complex.
[00120]In an embodiment, said Lumacaftor complex used in the present invention
comprises
complexation agent which is copolymer of vinylpyrrolidone and vinylacetate and
pharmaceutically acceptable excipient which is sodium lauryl sulfate comprise
50 weight `)/0 to
about 95 weight `)/0 of the total weight of the complex.
[00121]The stable complex of Lumacaftor as used in the present invention
comprises
a. 5 ¨ 40% by weight of Lumacaftor, its salt, or derivatives thereof;
b. 50 ¨ 90% by weight of copolymer of vinylpyrrolidone and vinylacetate;
c. 0.01 ¨ 40 `)/0 by weight of sodium lauryl sulfate
[00122]The manufacturing of the stable complex of Lumacaftor used in the
present invention
comprises the step of mixing a pharmaceutically acceptable solution containing
Lumacaftor and
at least one complexing agent and optionally one or more pharmaceutically
acceptable excipient
with an aqueous solution containing optionally at least one pharmaceutically
acceptable excipient.
[00123]In an embodiment said Lumacaftor complex used in the present invention
is obtained via
a mixing process.
[00124]In an embodiment said Lumacaftor complex used in the present invention
is obtained via
a continuous flow mixing process.
[00125]In an embodiment said process is performed in a continuous flow
instrument.
[00126]In an embodiment said continuous flow instrument is a microfluidic flow
instrument.
[00127]In an embodiment, said Lumacaftor complex used in the present invention
is not
obtained via a milling process, high pressure homogenization process,
encapsulation process and
solid dispersion processes.
[00128]In an embodiment, the solvent of said pharmaceutically acceptable
solution is chosen
from methanol, ethanol, 1-propanol, 2-propanol, acetone, acetonitrile,
dimethyl-sulfoxide,
tetrahydrofuran, methyl-ethyl ketone or combinations thereof.
[00129]In an embodiment, said pharmaceutically acceptable solvent is methanol.
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[00130]In an embodiment, said pharmaceutically acceptable solvent and said
aqueous solution are
miscible with each other.
[00131]In an embodiment, said aqueous solution comprises 0.1 to 99.9% weight
of the final
solution.
5 .. [00132]In an embodiment, said aqueous solution comprises 50 to 90% weight
of the final
solution.
[00133]In an embodiment, said aqueous solution comprises 50 to 80% weight of
the final
solution.
[00134]In an embodiment, said aqueous solution comprises 50 to 70% weight of
the final
10 solution.
[00135]In an embodiment, said aqueous solution comprises 50 to 60% weight of
the final
solution.
[00136]In an embodiment, said aqueous solution comprises 45 to 55% weight of
the final
solution.
15 [00137]In an embodiment, said aqueous solution comprises 50 % weight of
the final solution.
[00138]In an embodiment, said aqueous solution comprises 35 to 45 % weight of
the final
solution.
[00139]In an embodiment, said aqueous solution comprises 25 to 35 % weight of
the final
solution.
20 [00140]In an embodiment, said aqueous solution comprises 15 to 25 %
weight of the final
solution.
[00141]In an embodiment, said aqueous solution comprises 5 to 15 % weight of
the final
solution.
[00142]In an embodiment, a pharmaceutical composition comprising the complex
together with
25 pharmaceutically acceptable carriers.
[00143]In an embodiment, the complexing agents themselves or together with the
pharmaceutically acceptable excipients have the function to form a complex
structure with an
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active pharmaceutical ingredient through non-covalent secondary interactions.
The secondary
interactions can form through electrostatic interactions such as ionic
interactions, H-bonding,
dipole-dipole interactions, dipole-induced dipole interactions, London
dispersion forces, 71-7C
interactions, and hydrophobic interactions. The complexing agents,
pharmaceutically accepted
excipients and active ingredients are selected from the group of complexing
agents,
pharmaceutically accepted excipients and active ingredients which are able to
form such complex
structures through non-covalent secondary interactions.
[00144]In the following the pharmaceutical combination composition used in the
present
invention will be detailed.
[00145]The pharmaceutical combination composition used in the present
invention comprises
a) Complex Ivacaftor formulation comprising Ivacaftor, a complexing agent
which is a
copolymer of vinylpyrrolidone and vinylacetate and optionally a poloxamer and
sodium
lauryl sulfate as a pharmaceutically acceptable excipient; and
b) Complex Lumacaftor formulation comprising Lumacaftor, a complexing agent
which is a
copolymer of vinylpyrrolidone and vinylacetate and sodium lauryl sulfate as a
pharmaceutically acceptable excipient; and
c) optionally, additional pharmaceutically acceptable excipients
wherein said pharmaceutical combination composition characterized in that they
possess at least
one of the following properties:
a) is instantaneously redispersable in physiological relevant media;
b) is stable in solid form and in colloid solution and/or dispersion;
c) apparent solubility both for Ivacaftor and Lumacaftor in water is at least
1 mg/mL;
d) PAMPA permeability both for Ivacaftor and Lumacaftor complex formulations
is at least
0.2*10' cm/s for Ivacaftor and 2*10' cm/s for Lumacaftor when dispersed in
FaSSIF or
FeSSIF biorelevant media, which does not decrease in time at least for 6
month;
e) exhibits no observable food effect in-vitro.
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[00146]In an embodiment, said pharmaceutical combination composition used in
the present
invention possesses at least two of the properties described in a)-e).
[00147]In an embodiment, said pharmaceutical combination composition used in
the present
invention possesses at least three of the properties described in a)-e).
[00148]The pharmaceutical combination composition used in the present
invention possesses
instantaneous redispersibility, increased apparent solubility and permeability
in fasted and fed
state simulation that is expected to deliver full absorption and the
elimination of the food effect
which deliver the opportunity of precise dosing and ease of administration of
the reconstituted
pharmaceutical combination composition in solution form.
[00149]In some embodiments, said pharmaceutical combination composition may
additionally
include one or more pharmaceutically acceptable excipients, auxiliary
materials, carriers, active
agents or combinations thereof.
[00150]In an embodiment, said pharmaceutical combination composition used in
the present
invention has increased dissolution rate compared to the commercially
available form
(0 RKAMB IO) .
[00151]In an embodiment, said pharmaceutical combination composition used in
the present
invention is stable in solid form and in colloid solution and/or dispersion.
[00152]In an embodiment, said pharmaceutical combination composition used in
the present
invention has PAMPA permeability both for Ivacaftor and Lumacaftor complex
formulations is
at least 0.2*10-6 cm/s for Ivacaftor and 2*10' cm/s for Lumacaftor when
dispersed in water or
biorelevant media, which does not decrease in time at least for 6 months.
[00153]In an embodiment, the variability of exposure of said pharmaceutical
combination
composition used in the present invention is significantly reduced compared to
the commercially
available form (ORKAMBIO).
[00154]In an embodiment, said pharmaceutical combination composition used in
the present
invention has no observable food effect in-vitro, which allows the opportunity
of precise dosing
and ease of administration of the reconstituted pharmaceutical combination
composition in
solution form.
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[00155]In an embodiment, said pharmaceutical combination composition used in
the present
invention comprises complexation agent which is a copolymer of
vinylpyrrolidone and
vinylacetate and optionally a poloxamer and a pharmaceutically acceptable
excipient which is
sodium lauryl sulfate, in a total amount ranging from about 1.0 weight `)/0 to
about 95.0 weight A)
based on the total weight of the pharmaceutical combination composition.
[00156]In an embodiment, said pharmaceutical combination composition used in
the present
invention comprises complexation agent which is a copolymer of
vinylpyrrolidone and
vinylacetate and optionally a poloxamer and a pharmaceutically acceptable
excipient which is
sodium lauryl sulfate comprise 50 weight `)/0 to about 95 weight `)/0 of the
total weight of the
pharmaceutical combination composition.
[00157]In an embodiment, said pharmaceutical combination composition comprises
of 50 to 300
mg Ivacaftor equivalent complex Ivacaftor formulation in combination with 25
to 250 mg
Lumacaftor equivalent complex Lumacaftor formulation.
[00158]In an embodiment, the manufacturing of the pharmaceutical combination
composition
used in the present invention includes the step of mixing a pharmaceutically
acceptable solution
containing Ivacaftor and at least one complexing agent and optionally one or
more
pharmaceutically acceptable excipients with an aqueous solution containing
optionally at least one
pharmaceutically acceptable excipient and solidification of the resulted
solution mixture; and the
step of mixing a pharmaceutically acceptable solution containing Lumacaftor
and at least one
complexing agent and optionally one or more pharmaceutically acceptable
excipients with an
aqueous solution containing optionally at least one pharmaceutically
acceptable excipient and
solidification of the resulted solution mixture; and the step of blending and
granulation of the
solidified Ivacaftor and Lumacaftor complex formulations.
[00159]In an embodiment, the manufacturing of the pharmaceutical combination
composition
used in the present invention comprises the step of mixing a pharmaceutically
acceptable solution
containing Ivacaftor and Lumacaftor and at least one complexing agent and
optionally one or
more pharmaceutically acceptable excipients with an aqueous solution
containing optionally at
least one pharmaceutically acceptable excipient.
[00160]In an embodiment said Ivacaftor complex used in the present invention
is obtained via a
mixing process.
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[00161]In an embodiment said Lumacaftor complex used in the present invention
is obtained via
a mixing process.
[00162]In an embodiment said complex of Ivacaftor and Lumacaftor used in the
present
invention is obtained via a mixing process.
[00163]In an embodiment said mixing process is a continuous flow mixing
process.
[00164]In an embodiment said process is performed in a continuous flow
instrument.
[00165]In an embodiment said continuous flow instrument is a microfluidic flow
instrument.
[00166]In an embodiment, the solvent of said pharmaceutically acceptable
solution is chosen
from methanol, ethanol, 1-propanol, 2-propanol, acetone, acetonitrile,
dimethyl-sulfoxide,
tetrahydrofuran, methyl-ethyl ketone or combinations thereof.
[00167]In an embodiment, said pharmaceutically acceptable solvent is a solvent
mixture of
methanol and tetrahydrofurane.
[00168]In an embodiment, said pharmaceutically acceptable solvent and said
aqueous solution are
miscible with each other.
[00169]In an embodiment, said aqueous solution comprises 0.1 to 99.9% weight
of the final
solution.
[00170]In an embodiment, said aqueous solution comprises 50 to 90% weight of
the final
solution.
[00171]In an embodiment, said aqueous solution comprises 50 to 80% weight of
the final
solution.
[00172]In an embodiment, said aqueous solution comprises 50 to 70% weight of
the final
solution.
[00173]In an embodiment, said aqueous solution comprises 50 to 60% weight of
the final
solution.
[00174]In an embodiment, said aqueous solution comprises 45 to 55% weight of
the final
solution.
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[00175]In an embodiment, said aqueous solution comprises 50 A weight of the
final solution.
[00176]In an embodiment, said aqueous solution comprises 35 to 45 % weight of
the final
solution.
[00177]In an embodiment, said aqueous solution comprises 25 to 35 % weight of
the final
5 .. solution.
[00178]In an embodiment, said aqueous solution comprises 15 to 25 % weight of
the final
solution.
[00179]In an embodiment, said aqueous solution comprises 5 to 15 % weight of
the final
solution.
10 [00180]In an embodiment, a pharmaceutical composition comprising the
complex together with
pharmaceutically acceptable carriers.
[00181]The pharmaceutical combination composition of the invention comprising
complex
Ivacaftor and complex Lumacaftor formulations can be formulated: (a) for
administration
selected from the group consisting of oral, pulmonary, rectal, colonic,
parenteral, intracisternal,
15 intravaginal, intraperitoneal, ocular, otic, local, buccal, nasal, and
topical administration; (b) into a
dosage form selected from the group consisting of liquid dispersions, gels,
aerosols, ointments,
creams, lyophilized formulations, tablets, capsules; (c) into a dosage form
selected from the group
consisting of controlled release formulations, fast melt formulations, delayed
release
formulations, extended release formulations, pulsatile release formulations,
and mixed immediate
20 release and controlled release formulations; or (d) any combination of
(a), (b), and (c).
[00182]The pharmaceutical combination compositions can be formulated by adding
different
types of pharmaceutically acceptable excipients for oral administration in
solid, liquid, local
(powders, ointments or drops), or topical administration, and the like.
[00183]In an embodiment, the dosage form of the invention is a solid dosage
form, although any
25 pharmaceutically acceptable dosage form can be utilized.
[00184]Solid dosage forms for oral administration include, but are not limited
to, capsules,
tablets, pills, powders (sachet), and granules. In such solid dosage forms,
the complex
formulations of the present invention is admixed with at least one of the
following: one or more
inert excipients (or carriers): (a) fillers or extenders, such as, lactose,
sucrose, glucose, mannitol,
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sorbitol, dextrose, dextrates, dextrin, erythritol, fructose, isomalt,
lactitol, maltitol, maltose,
maltodextrin, trehalose, xylitol, starches, microcrystalline cellulose,
dicalcium phosphate, calcium
carbonate, magnesium carbonate, magnesium oxide; (b) sweetening, flavoring,
aromatizing and
perfuming agents such as saccharin, saccharin sodium, acesulfame potassium,
alitame, aspartame,
glycine, inulin, neohesperidin dihydrochalcone, neotame, sodium cyclamate,
sucralose, tagatose,
thaumatin, citric acid, adipic acid, fumaric acid, leucine, malic acid,
menthol, propionic acid,
tartaric acid; (c) binders, such as cellulose derivatives, acrylic acid
derivatives, alginates, gelatin,
polyvinylpyrrolidone, starch derivatives, dextrose, dextrates, dextrin,
maltose, maltodextrin; (d)
disintegrating agents, such as crospovidon, effervescent compositions,
croscarmellose sodium
and other cellulose derivatives, sodium starch glycolate and other starch
derivatives, alginic acid,
certain complex silicates and sodium carbonate; (e) solution retarders, such
as acrylates, cellulose
derivatives, paraffin; (f) absorption accelerators, such as quaternary
ammonium compounds; (g)
wetting agents, such as polysorbates, cetyl alcohol and glycerol monostearate;
(h) lubricants such
as talc, stearic acid and its derivatives, solid polyethylene glycols, sodium
lauryl sulfate, glyceryl
behenate, medium-chain triglycerides or mixtures thereof. For capsules,
tablets, and pills, the
dosage forms may also comprise buffering agents.
[00185]In an embodiment, the dosage form of the invention is a liquid
dispersible granules in a
sachet form.
[00186]In an embodiment, said liquid dispersible granules comprise said
complex Ivacaftor
.. formulation and said complex Lumacaftor formulation and optionally
pharmaceutically
acceptable excipients.
[00187]In an embodiment, said pharmaceutically acceptable excipients selected
from the group
of fillers or extenders, such as, lactose, sucrose, glucose, mannitol,
sorbitol, dextrose, dextrates,
dextrin, erythritol, fructose, isomalt, lactitol, maltitol, maltose,
maltodextrin, trehalose, xylitol,
starches, microcrystalline cellulose, dicalcium phosphate, calcium carbonate,
magnesium
carbonate, magnesium oxide.
[00188]In an embodiment, pharmaceutically acceptable excipients selected from
the group of
sweetening, flavoring, aromatizing and perfuming agents such as saccharin,
saccharin sodium,
acesulfame potassium, alitame, aspartame, glycine, inulin, neohesperidin
dihydrochalcone,
neotame, sodium cyclamate, sucralose, tagatose, thaumatin, citric acid, adipic
acid, fumaric acid,
leucine, malic acid, menthol, propionic acid, tartaric acid.
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[00189]Further disclosed herein is a liquid dispersible granules comprising
a. 25 ¨95 `)/0 pharmaceutical combination composition comprising complex
Ivacaftor and
complex Lumacaftor formulations;
b. 5 ¨75 A fillers or extenders;
c. 0.5 ¨25 A binders;
d. 0.1 ¨5 `)/0 sweetening, flavoring, aromatizing and perfuming agents;
wherein said liquid dispersible granules disperses within 3 min in liquid; and
wherein said liquid
dispersible granules obtained by wet or dry processes.
[00190]In an embodiment, said dispersion time is between 0.1 min and 10 min.
[00191] In an embodiment, said dispersion time is between 0.1 min and 5 min.
[00192]In an embodiment, said dispersion time is between 0.1 min and 3 min.
[00193]In an embodiment, said dispersion time is between 0.1 min and 1 min.
[00194]In an embodiment, Hausner-ratio of the said liquid dispersible granules
is less than 1.25
more preferably 1.00-1.18
[00195]In an embodiment, Hausner-ratio of the said liquid dispersible granules
is between 1.00
and 1.18.
[00196]In an embodiment, the particle size (D(90)) of said liquid dispersible
granules is less than
2000 micrometers.
[00197]In an embodiment, 60-99 A of the said liquid dispersible granules are
in the size range of
160-1200 micrometers.
[00198]In an embodiment, said liquid is water, saliva, other physiologically
or biologically
acceptable fluid.
[00199] Advantages of the pharmaceutical combination composition of
the invention
include, but are not limited to (1) physical and chemical stability, (2)
instantaneous
redispersibility, (3) stability in colloid solution or dispersion in the
therapeutic time window, (4)
increased apparent solubility and permeability compared to the conventional
formulations, (5) no
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observable food effect which deliver the opportunity of precise dosing and
ease of administration
of the reconstituted complex formulation in solution form, (6) good
processability.
[00200] Beneficial features of the present invention are as follows:
the good/instantaneous
redispersibility of the pharmaceutical composition of the present invention in
water, biologically
relevant media, e.g.; physiological saline solution, pH=2.5 HC1 solution,
FessiF and FassiF media
and gastro intestinal fluids and adequate stability in colloid solutions
and/or dispersion in the
therapeutic time window.
[00201] In an embodiment, the pharmaceutical combination composition
of the present
invention has increased apparent solubility and permeability. In some
embodiments, the apparent
solubility and permeability of the pharmaceutical combination composition is
at least 1 mg/mL
and 0.2*10' cm/s.
[00202] The pharmaceutical combination composition of the present
invention possess
instantaneous redispersibility, increased apparent solubility and
permeability, no observable food
effect which deliver the opportunity of precise dosing and ease of
administration of the
redispersed solid.
BRIEF DESCRIPTION OF THE DRAWINGS
[00203]The accompanying figures, which are incorporated and form part of the
specification,
merely illustrate certain embodiments of the present invention and should not
be construed as
limiting the invention. They are meant to serve to explain specific modes of
the present invention
to those skilled in the art.
Figure 1. shows physical appearance and stability of the produced complex
Ivacaftor formula
during the flow optimization.
Figure 2. shows apparent solubility of complex Ivacaftor and Lumacaftor
formulations alone
and in combinations.
Figure 3. shows GI tract simulated dissolution of Ivacaftor and Lumacaftor
from the
pharmaceutical composition of the present invention.
Figure 4. shows Ivacaftor and Lumacaftor dissolution from the pharmaceutical
combination
composition prepared by spray drying in combination and powder blending.
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Figure 5. shows PAMPA permeabilities of complex Ivacaftor formulation and
complex
Lumacaftor formulation.
Figure 6. shows PAMPA permeabilities of complex Ivacaftor formulation and
complex
Lumacaftor formulation in the pharmaceutical combination composition prepared
by powder
blending.
Figure 7. shows PAMPA permeabilities of complex Ivacaftor formulation and
complex
Lumacaftor formulation in the pharmaceutical combination composition prepared
by spray-
drying in combination.
Figure 8. shows PAMPA permeability of complex Ivacaftor and complex Lumacaftor
formulations stored at different conditions.
Figure 9. shows PAMPA permeability of complex Ivacaftor and complex Lumacaftor
formulations in the pharmaceutical composition stored at different conditions.
Figure 10. shows SEM photos of complex Ivacaftor (A) and complex Lumacaftor
(B)
formulations.
Figure 11. shows Raman spectra of crystalline Ivacaftor (A), freeze-dried
Ivacaftor (B), Complex
Ivacaftor formulation (C), Placebo sample (prepared in the absence of
Ivacaftor) (D), Luviskol
VA64 (E), sodium lauryl sulfate (F) and poloxamer (Poloxamer 338 ¨ Pluronic
F108) Pluronic
F108 (G).
Figure 12. shows ATR spectra of crystalline Ivacaftor (A), amorphous Ivacaftor
(B), complex
Ivacaftor formulation (C), placebo (prepared in the lack of Ivacaftor) (D),
Luviscol VA64 (E),
sodium lauryl sulfate (F) and poloxamer (Poloxamer 338 ¨ Pluronic F108) (G).
Figure 13. shows Raman spectra of crystalline Lumacaftor (A), amorphous
Lumacaftor (B),
complex Lumacaftor formulation (C), placebo (D), Luviscol VA64 (E), SDS (F)
Figure 14. shows ATR spectra of crystalline Lumacaftor (A), amorphous
Lumacaftor (B),
complex Lumacaftor formulation (C), placebo (D), Luviscol VA64 (E), SDS (F).
Figure 15. shows XRD diffractograms of crystalline Ivacaftor (A, C), complex
Ivacaftor
formulation (A), crytalline Lumacaftor (B, C) and complex Lumacaftor
formulation (B) and
Spray-dried complex Ivacaftor and complex Lumacaftor formulations in
combination (C)
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Figure 16. shows PAMPA permeability of crystalline Ivacaftor, solid dispersion
of Ivacaftor and
complex Ivacaftor formulation.
Figure 17. shows comparative apparent solubility data of different Ivacaftor
formulations.
Figure 18. shows comparative dissolution tests of solid dispersion of
Ivacaftor and complex
5 Ivacaftor formulation.
Figure 19. shows particle size of different of Ivacaftor and Lumacaftor
formulation.
Figure 20. shows apparent solubility of Lumacaftor formulations.
Figure 21. shows comparative PAMPA permeability of Lumacaftor formulations.
Figure 22. shows dissolution of Ivacaftor from different pharmaceutical
formulations.
10 Figure 23. shows dissolution of Lumacaftor from different pharmaceutical
formulations.
Figure 24. shows comparative PAMPA permeability of different, ORKAMBII`
equivalent
Ivacaftor and Lumacaftor formulations.
Figure 25. shows plasma concentrations of Ivacaftor following the oral
administration of novel
complex in the fasted and in the fed state to beagle dogs at 3 mg/kg dose
(N=4).
15 Figure 26. shows pharmacokinteic parameters following the oral
administration of novel
complex in the fasted and in the fed state to beagle dogs at 3 mg/kg dose
(N=4).
EXAMPLES
[00204] Specific embodiments of the present invention will further be
demonstrated by the
following examples. It should be understood that these examples are disclosed
only by way of
20 illustration and should not be construed as limiting the scope of the
present invention.
Manufacturing of complex Ivacaftor formulation
[00205]A solution mixture of complex Ivacaftor formulation of the present
invention was
prepared by mixing process. Solution 1 containing 500 mg Ivacaftor and 1500 mg
vinylpyrrolidone and vinylacetate copolymer (Luviskol VA 64) and 1000 mg
poloxamer
25 (Poloxamer 338 ¨ Pluronic F108) in 100 mL tetrahydrofuran was mixed with
aqueous Solution 2
containing 500 mg sodium lauryl sulfate in 100 mL ultrapurified water in
different flow rates. 1:1
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Solvent 1: Solvent 2 ratio was used. The colloid solution of the complex
Ivacaftor formulation
was produced at atmospheric pressure and 20-50 C temperature. The appearance
and stability of
the produced colloid solution were monitored. Based on the physical appearance
and stability of
the produced complex Ivacaftor formulation in colloid solution, the best
composition was
selected for spray-drying experiments. Figure 1 summarizes the results.
[00206]The solidification of the colloid solution was performed by spray-
drying technique. 5
mg/mL Ivacaftor, 15 mg/mL vinylpyrrolidone and vinylacetate copolymer
(Luviskol VA 64) and
mg/mL poloxamer (Poloxamer 338 ¨ Pluronic F108) in tetrahydrofurane and 5mg/mL
sodium lauryl sulfate in water were chosen for starting concentrations. The
ratio of the solutions
10 was found to be optimal at 1:1 ratio. The colloid solution of the
complex Ivacaftor formulation
prepared by the optimal parameter sets was spray-dried (Yamato DL-410 /
GAS410) in order to
obtain solid powder. The spray-drying process was optimized. The optimal
production
parameters were found to be Tmlet=95 C, Va,r=0.8 m3/min, M18 mL/min, p=1 bar,
Tout= 58-
59 C.
Manufacturing of complex Lumacaftor formulation
[00207[A solution mixture of Lumacaftor complex formulation was prepared by
continuous flow
mixing approach. 20 mL Solution 1 was prepared by dissolving 40 mg Lumacaftor
and 180 mg
copolymer of vinylpyrrolidone and vinylacetate in 20 mL methanol. The prepared
Solution 1 was
mixed with Solution 2 containing 24 mg sodium lauryl sulfate in 80 mL water at
1:4 volume ratio
.. in order to produce complex Lumacaftor formulation. The solution mixture of
the complex
Lumacaftor formulation was produced at atmospheric pressure and ambient
temperature. The
produced solution mixture was frozen on dry-ice and then it was lyophilized
using a freeze drier
equipped with -110 C ice condenser, with a vacuum pump. Spray-drying was also
applicable to
produce solid powder from the solution mixture of complex Lumacaftor
formulation.
Manufacturing of pharmaceutical combination composition
[00208] Pharmaceutical composition of the present invention was prepared by
blending the
powders of complex Ivacaftor and Lumacaftor formulations. The resulted
pharmaceutical
composition contained the complex Ivacaftor and complex Lumacaftor formulation
in 125:200
active compound equivalent ratio.
[00209[A solution mixture of pharmaceutical combination composition of the
present invention
was prepared by mixing process. Solution 1 containing 192 mg Ivacaftor and 308
mg Lumacaftor
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and 1000 mg vinylpyrrolidone and vinylacetate copolymer (Luviskol VA 64) in
100 mL solvent
mixture of methanol and tetrahydrofuran having volume ratio of 5:2 was mixed
with aqueous
Solution 2 containing 150 mg sodium lauryl sulfate in 400 mL ultrapurified
water in different
flow rates. Solvent 1: Solvent 2 ratio was 1:4. The colloid solution of the
complex Ivacaftor
formulation was produced at atmospheric pressure and 25 C temperature. The
solidification of
the colloid solution was performed by spray-drying technique. 1.92 mg/mL
Ivacaftor, 3.08
mg/mL Lumacaftor and 10 mg/mL vinylpyrrolidone and vinylacetate copolymer
(Luviskol VA
64) in methanol:tetrahydrofuran solvent mixture at volume ratio of 5:2 and
0.375 mg/mL sodium
lauryl sulfate in water were chosen for starting concentrations. The ratio of
the Solution 1 and
Solution 2 was found to be optimal at 1:4 ratio. The prepared solution mixture
was spray-dried
(Yamato DL-410 / GAS410) in order to obtain solid powder. The spray-drying
process was
optimized. The optimal production parameters were found to be Tõ=90 C,
Va,r=0.85 m3/min,
1\420 mL/min, atomizing pressure=1 bar, Tout= 50 C.
Preparation of liquid dispersible granules of complex Ivacaftor formulation
[00210]Liquid dispersible granules comprising the complex Ivacaftor
formulations of the present
invention can be obtained by wet or dry granulation processes.
[00211]Dry granulation process includes, but not limited to the slugging or
roll compaction of
the powder formulation of complex Ivacaftor into compacts and breaking of the
compacts into
granules with appropriate mesh size. The obtained granules can be mixed with
pharmaceutically
acceptable excipients.
[00212]Dry granulation technique can be also applied on the powder blend of
complex Ivacaftor
formulations. Powder blend consists of the powder formulation of complex
Ivacaftor and
pharmaceutically acceptable excipients and prepared by mixing of powders.
Slugging or roll
compaction are used to manufacture compacts from the powder blend. Then the
compacts are
broken into granules with appropriate mesh size.
[00213]Wet granulation process covers the moisturizing of the powder
formulations of complex
Ivacaftor (direct granulation) or moisturizing the pharmaceutically acceptable
excipients with
aqueous solution of pharmaceutically acceptable binders and mixing it with the
powder
formulations of complex Ivacaftor (indirect granulation). The particle size of
the granules can be
controlled by physical impact before and after the drying step.
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[00214]Liquid dispersible granules of complex Ivacaftor formulation of the
present invention
were prepared by compacting appropriate amount of complex Ivacaftor powder
blend using 0.5
ton load. The powder blend comprised of the solid formulation of the complex
of Ivacaftor and
pharmaceutically acceptable excipients selected from the group of sweetening,
flavouring,
aromatizing and perfuming agents. The height of the compact was found to be
optimal between
0.8-1.0 mm. The compacts were broken up by physical impact to form granulates.
The particle
size of the granules was controlled by sieving with appropriate mesh size to
achieve 160-800
micrometres particle size.
Preparation of liquid dispersible granules of complex Lumacaftor formulation
[00215]Liquid dispersible granules comprising the complex Lumacaftor
formulations of the
present invention can be obtained by wet or dry granulation processes.
[00216]Dry granulation process includes, but not limited to the slugging or
roll compaction of
the powder formulation of complex Lumacaftor into compacts and breaking of the
compacts
into granules with appropriate mesh size. The obtained granules can be mixed
with
pharmaceutically acceptable excipients.
[00217]Dry granulation technique can be also applied on the powder blend of
complex
Lumacaftor formulations. Powder blend consists of the powder formulation of
complex
Lumacaftor and pharmaceutically acceptable excipients and prepared by mixing
of powders.
Slugging or roll compaction are used to manufacture compacts from the powder
blend. Then the
compacts are broken into granules with appropriate mesh size.
[00218]Wet granulation process covers the moisturizing of the powder
formulations of complex
Lumacaftor (direct granulation) or moisturizing the pharmaceutically
acceptable excipients with
aqueous solution of pharmaceutically acceptable binders and mixing it with the
powder
formulations of complex Lumacaftor (indirect granulation). The particle size
of the granules can
be controlled by physical impact before and after the drying step.
[00219]Liquid dispersible granules of complex Lumacaftor formulation of the
present invention
were prepared by compacting appropriate amount of complex Lumacaftor powder
blend using
0.5 ton load. The powder blend comprised of the solid formulation of the
complex of
Lumacaftor and pharmaceutically acceptable excipients selected from the group
of sweetening,
flavouring, aromatizing and perfuming agents. The height of the compact was
found to be
optimal between 0.8-1.0 mm. The compacts were broken up by physical impact to
form
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granulates. The particle size of the granules was controlled by sieving with
appropriate mesh size
to achieve 160-800 micrometres particle size.
[00220]
Preparation of liquid dispersible granules of pharmaceutical combination
composition of
the present invention
[00221]Liquid dispersible granules of pharmaceutical combination composition
of the present
invention can be obtained by blending the liquid dispersible granule or
pellets of complex
Ivacaftor formulation and complex Lumacaftor formulation; or mixing the
complex Ivacaftor
formulation with the complex Lumacaftor formulation before granulation,
pelletising; or
blending the liquid dispersible granules or pellets of the complex Ivacaftor
formulation or
complex Lumacaftor formulation with the solid form of the complex Ivacaftor
formulation or
complex Lumacaftor formulation.
[00222]Liquid dispersible granules of pharmaceutical combination composition
of the present
invention can be obtained by compacting appropriate amount of pharmaceutical
combination
composition prepared by spray-drying in combination using 0.5-3 ton load. The
powder
comprised of the solid formulation of the pharmaceutical combination
composition and
pharmaceutically acceptable excipients selected from the group of sweetening,
flavouring,
aromatizing and perfuming agents. The height of the compact was found to be
optimal between
0.8-1.0 mm. The compacts were broken up by physical impact to form granulates.
The particle
size of the granules was controlled by sieving with appropriate mesh size to
achieve 160-800
micrometres particle size.
[00223]Blending and mixing include but not limited to container rotating or
high shear mixing.
Comparative solubility tests
[00224] The apparent solubility was measured by UV-VIS spectroscopy or
RP-HPLC at
room temperature. The samples were dispersed in ultrapurified water in 1-20
mg/mL active
ingredient equivalent concentration range. The resulting solutions were
filtered by 100 nm
disposable syringe filter. The active ingredient content in the filtrate was
measured by UV-Vis
spectrophotometry or RP-HPLC and the apparent solubility was calculated. The
filtrate may
contain particles which could not be filtrated out using 100 nm pore size
filter. Figure 2 shows
the results.
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[00225]The apparent solubility of complex Ivacaftor formulation of the present
invention was
0.991; 2.356; 4.924; 9.463 mg/mL and 18.474, when 1; 2.5; 5; 10 and 20 mg/mL
Ivacator
equivalent formulations were dispersed in ultrapurified water, respectively.
[00226]Apparent solubility of complex Ivacaftor formulation was 18.474 mg/mL.
5 [00227]The apparent solubility of complex Lumacaftor formulation of the
present invention was
0.950; 9.839 and 14.913 mg/mL, when 1; 10 and 20 mg/mL Lumacaftor equivalent
formulations
were dispersed in ultrapurified water, respectively. The apparent solubility
of unformulated
crystalline Lumacaftor was found to be 0.032 mg/mL.
[00228] Solubility of complex Lumacaftor formula was 14.913 mg/mL.
10 [00229]The apparent solubility of pharmaceutical combination composition
of the present
invention prepared by powder blending was 1.009; 4.6967; 9.591 mg/mL and
19.9493 mg/mL
for Lumacaftor and 0.6117; 2.8444; 5.7553 mg/mL and 11.3187 mg/mL for
Ivacaftor, when 1; 5;
10 and 20 mg/mL Lumacaftor equivalent formulations were dispersed in
ultrapurified water,
respectively.
15 [00230]Apparent solubility of pharmaceutical combination composition of
the present invention
prepared by powder blending was 19.9493 mg/mL for Lumacaftor and 11.3187 mg/mL
for
Ivacaftor.
[00231]The apparent solubility of pharmaceutical combination composition of
the present
invention prepared by spray drying in combination was 0.9656; 4.8253; 8.9099
mg/mL and
20 19.2660 mg/mL for Lumacaftor and 0.5969; 3.0105; 5.5397 mg/mL and
12.0467 mg/mL for
Ivacaftor, when 1; 5; 10 and 20 mg/mL Lumacaftor equivalent formulations were
dispersed in
ultrapurified water, respectively.
[00232]Apparent solubility of pharmaceutical combination composition of the
present invention
prepared by spray drying was 19.2660 mg/mL for Lumacaftor and 12.0467 mg/mL
for Ivacaftor.
25 Dissolution test
[00233] Gastro-intestinal tract simulated drug dissolution tests were
performed by dispersing the
blended pharmaceutical combination composition described above in purified
water. The
dispersion contained 1 mg/mL Lumacaftor and 0.625mg/mL Ivacaftor (identical
mixture to
ORKAMBIO). After 30 minutes holding time, simulated gastric fluid (SGF V2) was
added to
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41
dispersion in order to set-up the pH to 1.6 (fasted state simulation) or
FeSSIF buffer to increase
the pH to 5.8 (fed state simulation). After 60 minutes holding time, the pH of
the fasted state
simulated dispersion was set-up to pH=6.5 adding maleic acid solution. FaSSIF
solution was also
added to the dispersion to ensure the fasted condition in the intestine
simulation. In case of fed
state simulation FeSSIF solution was added to the dispersion.
[00234]The dissolved amount of Lumacaftor and Ivacaftor from the blended
pharmaceutical
combination composition was measured by RP-HPLC after filtration with 0.1 1,1m
pore size filter
at different time points. Dissolution of Ivacaftor and Lumacaftor from the
blended and
granulated complex formulation was instantaneous, within 5 minutes more than
85 % of the
Ivacaftor and Lumacaftor dissolved from the pharmaceutical composition of
present invention
both in fasted and fed state simulated condition. (Figure 3).
[00235]Drug dissolution tests were performed by dispersing the pharmaceutical
combination
composition prepared by powder blending or spray-drying in combination in
water. The
dissolved amount of Lumacaftor and Ivacaftor was measured by RP-HPLC after
filtration with
0.1 1,1m pore size filter at different time points. Dissolution of Ivacaftor
and Lumacaftor prepared
by spray drying in combination was instantaneous, within 5 minutes more than
85 % of the
Ivacaftor and Lumacaftor dissolved from the pharmaceutical composition of
present invention in
water. (Figure 4).
Comparative in-vitro PAMPA assays
[00236]PAMPA permeability of the complex formulations was measured and
compared to the
unformulated crystalline reference active compounds. PAMPA permeability
measurements were
performed as described by M. Kansi et al. (Journal of medicinal chemistry, 41,
(1998) pp 1007)
with modifications based on S. Bendels et al (Pharmaceutical research, 23
(2006) pp 2525).
Permeability was measured in a 96-well plate assay across an artificial
membrane composed of
dodecane with 20% soy lecithin supported by a PVDF membrane (Millipore, USA).
The receiver
compartment was phosphate buffered saline (pH 7.0) supplemented with 1% sodium
dodecyl
sulfate. The assay was performed at room temperature; incubation time was 4
hours in
ultrapurified water, FaSSIF and FeSSIF, respectively. The concentration in the
receiver
compartment was determined by UV-VIS spectrophotometry or RP-HPLC method
(Thermo
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42
Scientific multiscan GO spectrophotometer or Thermo Surveyor HPLC or Rigol L-
3000 series
HPLC).
[00237]PAMPA permeabilities of complex Ivacaftor formulation and complex
Lumacaftor
formulation were measured in FaSSIF and FeSSIF media and were found to be
above 0.5*10-6
cm/s for Ivacaftor and 2*10-6 cm/s for Lumacaftor measured by UV-VIS (Figure
5).
[00238]PAMPA permeabilities of pharmaceutical combination composition prepared
by powder
blending was measured in water; FaSSIF and FeSSIF media and were found to be
above 0.5*10-6
cm/s for Ivacaftor and 2*10-6 cm/s for Lumacaftor measured by UV-VIS (Figure
6).
[00239]PAMPA permeabilities of pharmaceutical combination composition prepared
by spray-
drying in combination was measured in water; FaSSIF and FeSSIF media and were
found to be
above 0.2*10-6 cm/s for Ivacaftor and 1.5*10-6 cm/s for Lumacaftor measured by
HPLC (Figure
7).
Stability of the solid complex formulations
[00240]Physical stability of the complex Ivacaftor, complex Lumacaftor
formulations and
pharmaceutical composition of the present invention was monitored using PAMPA
assays.
PAMPA permeability was measured in FaSSIF and FeSSIF media after storage of
the samples at
different conditions. 6 month storage at RT or 40 C/75% relative humidity
showed no
significant decrease in the measured PAMPA permeability of complex Ivacaftor
and complex
Lumacaftor under any of the tested condition measured by RP-HPLC (Figure 8).
Pharmaceutical
combinations showed stability over 2 months when stored at 40 C/75% relative
humidity
(Figure 9).
Structural analysis
[00241]Morphology of complex Ivacaftor formulation and complex Lumacaftor
formulation was
investigated using FEI Quanta 3D scanning electron microscope. Complex
Ivacaftor formulation
comprises spherical particles with particle size less than 50 nm, while
spherical particles of
complex Lumacaftor formulation have particle size in the range of less than
100 nm (Figure 10).
[00242]Structural analysis was performed by using Vertex 70 FT-IR with ATR and
HORIBA
jobinYvon LabRAM HR UV¨NUS¨NM instruments.
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43
[00243]Complex Ivacaftor formulation used in the present invention is
characterized by the
Raman spectrum shown in Figure 11 and ATR spectrum shown in Figure 12.
[00244] Complex Ivacaftor formulation used in the present invention is
characterized by
Raman shifts at 552 cm-1, 648 cm-1, 826 cm-1, 845 cm-1, 888 cm-1, 932 cm-
1,1026 cm-1, 1062 cm-1,
.. 1082 cm-1, 1129 cm-1, 1140 cm-1, 1208 cm-1, 1233 cm-1, 1262 cm-1, 1284 cm-
1, 1295 cm-1, 1361 cm
1, 1450 cm-1, 1528 cm-1, 1573 cm-1, 1618 cm-1, 1677 cm-1, 1738 cm-1, 746 cm-1,
2884 cm-1 and 2936
_
cm'.
[00245]Complex Ivacaftor formulation used in the present invention is
characterized by Raman
shifts at 1082 cm-1, 1233 cm-1, 1284 cm-1, 1361 cm-1, 1528 cm-1, 1618 cm-1-
and 1738 cm-1.
[00246]Complex Ivacaftor formulation used in the present invention is
characterized by infrared
(ATR) spectrum having characteristic peaks at 588 cm-1, 628 cm-1, 767 cm-1,
842 cm', 962 cm-1,
1019 cm-1, 1108 cm-1, 1148 cm-1, 1240 cm-1, 1343 cm-1, 1370 cm-1, 1425 cm-1,
1465 cm-1, 1525 cm
1, 1567 cm-1, 1666 cm-1- and 1732 cm-1.
[00247]Complex Ivacaftor formulation used in the present invention is
characterized by ATR
spectrum having characteristic peaks at 628 cm-1, 767 cm-1, 1108 cm-1, 1370 cm-
1, 1465 cm-1- and
1666 cm-1.
[00248] Complex Lumacaftor formulation used in the present invention
is characterized
by characteristic Raman shifts at 553 cm-1, 602 cm-1, 635 cm-1, 654 cm-1, 747
cm-1, 841 cm-1, 899
cm-1, 934 cm-1, 1002 cm-1, 1021 cm-1, 1117 cm-1, 1205 cm-1, 1232 cm-1, 1310 cm-
1, 1352 cm-1, 1372
cm-1, 1428 cm-1, 1444 cm-1, 1497 cm-1, 1592 cm-1, 1609 cm-1- and 1677 cm-1-
shown in Figure 13.
[00249] Complex Lumacaftor formulation used in the present invention
is characterized
by characteristic Raman shifts at 553 cm-1, 654 cm-1, 747 cm-1, 841 cm-1, 899
cm-1, 1117 cm-1, 1205
cm-1, 1310 cm-1, 1372 cm-1, 1428 cm-1, 1677 cm-1- and 1737 cm-1.
[00250] Complex Lumacaftor formulation used in the present invention
is characterized
by characteristic infrared (ATR) peaks at 635 cm-1, 703 cm-1, 747 cm-1- , 837
cm-1, 1021 cm-1, 1165
cm-1, 1231 cm-1, 1288 cm', 1369 cm-1, 1423 cm-1, 1462 cm-1, 1494 cm-1, 1667 cm-
1- and 1731 cm-1-
shown in Figure 14.
[00251]Complex Lumacaftor formulation used in the present invention is
characterized by
characteristic infrared (ATR) peaks at 703 cm-1, 837 cm-1, 1231 cm-1, 1369 cm-
1- and 1667 cm-1.
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[00252] The structure of the complex Ivacaftor, complex Lumacaftor
formulation and the
pharmaceutical combination compositions were investigated by powder X-ray
diffraction (XRD)
analysis (Philips PW1050/1870 RTG powder-diffractometer). The measurements
showed that
both the Ivacaftor and Lumacaftor in the complex and in the combination
formulations were
XRD amorphous (Figure 15). Characteristic reflections on the diffractograms at
43 and 44
2Theta could be attributed to sample holder.
Comparative formulation study
[00253]Ivacaftor is marketed in its solid dispersion form under the trade name
of
KALYDECOO. Manufacturing of solid dispersion of Ivacaftor is described in US
20140221424
Al patent application. Using the manufacturing method described in the patent
application, solid
dispersion of Ivacaftor was prepared for comparative analytical assays. A
solvent system of
methyl ethyl ketone (MEK) and water in the ratio of 90 wt `)/0 MEK : 10 wt
`)/0 water was heated
to 20-30 C in a reaction vessel equipped with a magnetic stirrer and thermal
circuit. Into this
solvent system, hypromellose acetate succinate polymer (HPMCAS), sodium-lauryl-
sulfate and
Ivacaftor were added in the ratio of 19.5 wt `)/0 hypromellose acetate
succinate : 0.5 wt `)/0 SLS:80
wt `)/0 Ivacaftor. The resulting mixture was solid formulated by spray-drying
method.
[00254]Comparative analytical assays were used to investigate the
physicochemical properties of
the formulation prepared by solid dispersion technology and continuous flow
mixing of the
present invention.
[00255] PAMPA permeability of the solid dispersion could not be detected in
water FaSSIF, while
it was 70 `)/0 of the permeability of the complex Ivacaftor formulation of the
present invention in
FeSSIF condition (Figure 16).
[00256]Comparative apparent solubility measurements showed that the apparent
solubility of
complex Ivacaftor formulation was at least 0.99 mg/mL, while apparent
solubility of crystalline
Ivacaftor, Ivacaftor in physical mixture, amorphous Ivacaftor in aqueous
sodium-lauryl-sulfate
solution and solid dispersion was below 0.1 mg/mL (Figure 17).
[00257]Comparative dissolution tests performed in water showed that the
dissolution of
Ivacaftor from the granulated complex formulation was instantaneous, within 10
minutes 90 %
of the Ivacaftor dissolved from the complex Ivacaftor formulation, while 0
`)/0 Ivacaftor dissolved
from the solid dispersion in 60 minutes (Figure 18).
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[00258]Ivacaftor was ball milled in the presence of the excipients used for
the preparation of
solid dispersion. Crystalline Lumacaftor was ball milled in the absence of
complexation agent
(Luviscol VA64) and pharmaceutically acceptable excipient (SDS) and in the
presence of them.
Ball milling parameters were the following:
5 Speed: 500 rpm
Milling time: 1 hour
Number of the balls: 25 pcs with 10 mm diameter
Milling vessel's material: Si2N3
Quantity of the milled samples: 100 mg API equivalent mass in 12 mL Milli-Q
water
10 [00259] After the milling, the vessel was washed out with 5 mL
Milli-Q water. The
products were frozen on salted ice and then it was lyophilized using a freeze-
drier equipped with
-110 C ice condenser, with a vacuum pump. The material and in-vitro properties
of the resulted
formulations were compared to the complex Lumacaftor and Ivacaftor
formulations of the
present invention.
15 [00260]Particle size of the formulations was measured by DLS technique
in reconstituted
dispersion/solution. The results are summarized in Figure 19. Ball milled
crystalline Lumacaftor
was hardly redispersible in purified water resulting in a suspension with
visible particles, the
particle size could not be determined.
[00261]Apparent solubility of complex Lumacaftor formulation was 14.913 mg/mL
when 20 mg
20 Lumacaftor equivalent formulation was redispersed (Figure 20).
[00262]PAMPA permeability of the formulations was measured in FaSSIF
biorelevant media and
compared. PAMPA permeability of the complex Lumacaftor formulation was 4.651,
while it was
0.288 for the ball milled crystalline Lumacaftor (Figure 21).
[00263] GI simulated dissolution of the powder mixture of complex Ivacaftor
and Lumacaftor
25 .. formulations shows completely eliminated food effect both for Ivacaftor
and Lumacaftor in in-
vitro. Based the dissolution data, significantly increased or full absorption
is expected in in-vitn9
studies. Dissolution of Ivacaftor and Lumacaftor from the powder blend was
above 80 `)/0 within
5 minutes (Figure 22 and Figure 23).
[00264]In comparison, dissolution of Ivacaftor from the solid dispersion of
Ivacaftor showed 5-
30 fold increase in FessiF condition indicating significant difference in
its absorption in fed state in-
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46
vivo. The increase in the dissolution was 3-fold and 1.5 fold for the ball
milled solid dispersion of
Ivacaftor and ball milled Ivacaftor with Luviskol VA 64 Pluronic F108 and SDS,
respectively.
Dissolution of Lumacaftor from the crystalline material was below 10 `)/0 both
in FaSSIF and
FeSSIF media. The dissolution of Lumacaftor increased when the particle size
was decreased,
however it did not exceed 40 A in any of the tested condition. 2-fold
difference in the dissolution
was observed in FeSSIF medium compared to the FaSSIF condition (Figure 22 and
Figure 23).
[00265]PAMPA permeability of different compositions were measured and
compared. PAMPA
permeability of complex Ivacaftor and complex Lumacaftor formulation in the
pharmaceutical
composition of the present invention outperformed the in-vitro performance of
the tested
formulations (Figure 24).
Pharmacokinetics
In-vitro assays
[00266] Based on in-vitro data (Figure 2, Figure 3, Figure 19 and
Figure 20) which shows
fast and full dissolution and increased permeability in fasted and fed state
simulation it is
expected that the complex Lumacaftor formula delivers full absorption and the
elimination of the
food effect.
In-vivo PK test in large animals
[00267]A beagle dog study using the granulated complex Ivacaftor formulation
of the present
invention at a dose of 3 mg/kg was performed in the fasted and fed state. The
granulated
complex formulation was administered to the animals orally as reconstituted
dispersion. Food
effect was only 1.1-fold (food effect in humans is 2-4-fold higher in the fed
state, that is why the
drug has to be taken after a high fat meal). Exposure was 1.25-times higher
than the reference
exposure. Cm ax was somewhat lower for the complex Ivacaftor formulation,
however, for the
more important parameter, C,,m, the complex Ivacaftor was 1.4-times higher
(Figure 25 and
Figure 26).
[00268] From the foregoing description, one skilled in the art can easily
ascertain the essential
characteristics of this invention, and without departing from the spirit and
scope thereof, can
make various changes and modifications of the invention to adapt it to various
usages and
conditions.
