U.S. patent application number 15/063821 was filed with the patent office on 2016-09-01 for amorphous salt of a macrocyclic inhibitor of hcv.
This patent application is currently assigned to Janssen Pharmaceuticals, Inc.. The applicant listed for this patent is Janssen Pharmaceuticals, Inc.. Invention is credited to Herman De Kock, Peter Jozef Maria Van Remoortere, Roger Petrus Gerebern Vandecruys.
Application Number | 20160251345 15/063821 |
Document ID | / |
Family ID | 40756982 |
Filed Date | 2016-09-01 |
United States Patent
Application |
20160251345 |
Kind Code |
A1 |
Van Remoortere; Peter Jozef Maria ;
et al. |
September 1, 2016 |
Amorphous Salt of a Macrocyclic Inhibitor of HCV
Abstract
The amorphous form of the sodium salt of the macrocyclic
inhibitor of HCV of formula: ##STR00001## as well as processes for
manufacturing this salt.
Inventors: |
Van Remoortere; Peter Jozef
Maria; (Princeton, NJ) ; Vandecruys; Roger Petrus
Gerebern; (Westerlo, BE) ; De Kock; Herman;
(Arendonk, BE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Janssen Pharmaceuticals, Inc. |
Titusville |
NJ |
US |
|
|
Assignee: |
Janssen Pharmaceuticals,
Inc.
Titusville
NJ
|
Family ID: |
40756982 |
Appl. No.: |
15/063821 |
Filed: |
March 8, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13202166 |
Aug 18, 2011 |
9321758 |
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PCT/EP2010/001197 |
Feb 26, 2010 |
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15063821 |
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Current U.S.
Class: |
514/312 |
Current CPC
Class: |
A61P 31/00 20180101;
C07D 417/14 20130101; A61K 9/14 20130101; C07D 417/04 20130101;
A61P 43/00 20180101; A61P 31/14 20180101; A61K 31/4725
20130101 |
International
Class: |
C07D 417/14 20060101
C07D417/14 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 27, 2009 |
EP |
09153964.3 |
Claims
1. The sodium salt of the compound of formula I: ##STR00003## in
solid amorphous form.
2-7. (canceled)
8. A pharmaceutical composition comprising the sodium salt of the
compound claim 1, and a pharmaceutically acceptable carrier.
9-10. (canceled)
Description
FIELD OF THE INVENTION
[0001] The present invention relates to the sodium salt of a
macrocyclic inhibitor of HCV in amorphous form and to a process for
preparing this amorphous sodium salt.
BACKGROUND OF THE INVENTION
[0002] Infection with the Hepatitis C Virus (HCV) is generally
recognized as a major healthcare problem worldwide. HCV infection
can progress to liver fibrosis, which can lead to liver cirrhosis,
end-stage liver disease, and HCC (hepatocellular carcinoma), making
it the leading cause of liver transplantations. Current standard of
care in HCV treatment involves the administration of Pegylated
interferon-alpha-2a or Pegylated interferon-alpha-2b in combination
with ribavirin during 24 or 48 weeks. Current therapy has its
limitations in that only part of the patients is treated
successfully, in that it faces significant side effects, is often
poorly tolerated, and by its long duration. Hence there is a need
for HCV inhibitors that overcome these disadvantages.
[0003] Replication of the genome of HCV is mediated by a number of
enzymes, amongst which is HCV NS3 serine protease. Various agents
have been described that inhibit this enzyme. WO 05/073216
discloses linear and macrocyclic NS3 serine protease inhibitors
with a central cyclopentane moiety. WO 2007/014926 discloses a
series of macrocyclic NS3 serine protease inhibitors, including
salt-forms of these compounds. Amongst these, the compound of
formula I with the chemical structure depicted hereinafter, is of
particular interest. This compound, with its full chemical name
(1R,4R,6S,15R,17R)-cis-N-[17-[2-(4-isopropylthiazol-2-yl)-7-methoxy-8-met-
hylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0.sup.-
4,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide or
(1R,4R,6S,7Z,15R,17R)-N-[17-[2-(4-isopropylthiazol-2-yl)-7-methoxy-8-meth-
ylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0.sup.4-
,6]octadec-7-ene-4-carbonyl](cyclopropyl)-sulfonamide, is also
referred to as "TMC435". TMC 435 can be prepared by the synthesis
procedures described in Example 5 of WO 2007/014926. As used
herein, the terms "compound of formula I" and "TMC435" refer to the
same chemical entity.
[0004] TMC435 not only shows pronounced activity against HCV but
also has an attractive pharmacokinetic profile. Clinical
investigations show that this compound is well-tolerated in
patients and confirm its potential to effectively suppress HCV.
##STR00002##
[0005] TMC435 is poorly water-soluble and improving its solubility
as well as its concomitant bioavailability are desirable targets
for drug development. Administering higher doses of poorly soluble
drugs could overcome bioavailability problems, but this leads to
larger and therefore less practicable dosage forms. Desired are
dosage forms that are compact and easy to manufacture.
[0006] It is known that bioavailability of poorly soluble active
agents can be improved by converting these in amorphous form.
Typically, the more crystalline the pharmaceutical agent, the lower
is its bioavailability or vice versa, reducing the degree of
crystallinity has a positive effect on bioavailability. Amorphous
materials generally offer interesting properties such as a higher
dissolution rate and solubility than crystalline forms, typically
resulting in improved bioavailability. Generating and stabilizing
this state typically proves out to be difficult because for many
substances the amorphous form is unstable, quickly converting
partially or completely to the more stable crystalline form. This
conversion is influenced by external factors such as temperature,
humidity, traces of crystalline material in the environment, etc.
Even amorphous forms that seem stable for long periods of time can
convert partially or completely to crystalline forms, sometimes for
reasons that are not immediately clear.
[0007] The amorphous and crystalline forms not only show
differences in bioavailability, but also in their processing
properties, such as hygroscopicity, flowability, compaction, and
the like. If during the clinical development and manufacture of
solid dosage forms the solid form of the drug substance is not
stable, the exact amount of the desired form used or studied may
vary from one lot to another causing undesired variability not only
in therapeutic efficacy but also in manufacturing conditions.
Hence, a drug taken into development will almost always be
converted into its crystalline form because of its stability in the
manufacture and storage of pharmaceutical dosage forms. Very few
drugs therefore are available in the amorphous state.
[0008] It is an object of the present invention to provide a solid
form of the compound of formula I that is stable and has beneficial
properties in terms of one or more of the following: its
bioavailability, pharmacokinetic properties such as, release rate,
area under the curve, and the like; as well as its ability to be
formulated, stored and administered as to effectively exert its
antiviral properties.
[0009] It now has been found that the sodium salt of the compound
of formula I can be converted into its amorphous form, which form
is surprisingly stable and can advantageously be used as active
ingredient in anti-HCV therapy. This form can be converted into
pharmaceutical compositions and dosage forms that are compact and
easy to manufacture. It further has been found that this form can
conveniently be prepared by spray-drying as manufacturing
procedure.
DESCRIPTION OF THE FIGURES
[0010] FIG. 1 is an Infrared spectrum (microATR) of the amorphous
Na salt of TMC435
[0011] FIG. 2 is a Powder XRD (X-ray diffraction) pattern of the
amorphous Na salt of TMC435
[0012] FIG. 3 is a DSC (differential scanning calorimetry) curve of
the amorphous Na salt of TMC435
[0013] FIG. 4 is an MDSC (modulated differential scanning
calorimetry) overlay of the amorphous Na salt of TMC435
[0014] FIG. 5 is a TGA (thermogravimetric analysis) curve of the
amorphous Na salt of TMC435
[0015] FIG. 6 is a DVS (dynamic vapor sorption) of the amorphous Na
salt of TMC435
[0016] FIG. 7 is a Powder XRD pattern of the amorphous Na salt of
TMC435 stored during 1 year 8 months and 23 days
DESCRIPTION OF THE INVENTION
[0017] The present invention relates to the sodium salt of the
compound of formula I in amorphous form. The present invention
further also to a process for preparing the amorphous form of the
sodium salt of the compound of formula I.
[0018] In one embodiment, the invention concerns the sodium salt of
the compound of formula I in amorphous form, as specified herein,
substantially free from impurities. In a particular embodiment, the
sodium salt of the compound of formula I in amorphous form contains
no more than about 5% of impurities, or no more than about 2% of
impurities, or no more than about 1% of impurities, or no more than
about 0.5% of impurities, or no more than about 0.1% of impurities.
The impurities may be compounds other than the compound of formula
I, or may be any of the other solid forms of the compound of
formula I, in particular crystalline forms. Purity may be tested by
standard spectroscopic techniques, for example with X-ray
diffraction.
[0019] The present invention also relates to a process for
preparing the sodium salt of the compound of formula I in amorphous
form, which process comprises the steps of: [0020] a) preparing a
mixture of the compound of formula I in a pharmaceutically
acceptable non-aqueous solvent and aqueous sodium hydroxide; and
[0021] b) spray-drying the mixture of step a) in a spray-drying
apparatus.
[0022] In one embodiment, step a) comprises mixing a sodium
hydroxide solution with the said solvent and subsequently adding
the compound of formula I, preferably in its free form, i.e.
non-salt form. In a particular embodiment a sodium hydroxide
solution in water is added to the solvent, and subsequently, the
compound of formula I is added. The procedures of step a) are
preferably conducted under stirring. Also preferred is that in step
a) the compound of formula I is allowed to form a solution and that
this solution is subsequently spray-dried.
[0023] The mixture or solution resulting from step a) is then
sprayed through the nozzle of a spray-dryer whereby the solvent
from the resulting droplets is evaporated, usually at elevated
temperatures, e.g. by the introduction of hot air.
[0024] In one embodiment, the aqueous sodium hydroxide is a
concentrated solution of sodium hydroxide in an aqueous medium, in
particular in water, for example a NaOH solution that is in the
range of about 1N to about 12.5N, or of about 5N to about 12.5N, or
of about 7.5N to about 12.5N, for example is about 10 N.
[0025] Solvents that can be used in this process are those that are
accepted for use in the preparation of pharmaceutical compositions
and are both volatile enough for use in spray-drying (with a
boiling point below e.g. 150.degree. C., or below e.g. 100.degree.
C.) and can sufficiently dissolve TMC435 (having a TMC435
solubility of e.g. >10 g/l, or e.g. >50 g/l). Suitable
solvents comprise halogenated hydrocarbons, such as chloroform or
preferably, dichloromethane; or ethers such as diethylether or
tetrahydrofuran. The drying gas may be any gas. Preferably, the gas
is air or an inert gas such as nitrogen, nitrogen-enriched air or
argon. The temperature of the drying gas at the gas inlet of the
spray-drying chamber can be from about 25.degree. C. to about
300.degree. C., or from about 60.degree. C. to about 300.degree.
C., or from about 60.degree. C. to about 150.degree. C.
[0026] The spray-drying is conducted in a conventional spray-drying
apparatus comprising a spray-drying chamber, atomizing means for
introducing the feed mixture into the spray-drying chamber in the
form of droplets, a source of heated drying gas that flows into the
spray-drying chamber through an inlet, and an outlet for the heated
drying gas. The spray-drying apparatus also comprises a means for
collecting the solid pharmaceutical powder that is produced. The
atomizing means can be a rotary atomizer, a pneumatic nozzle, an
ultrasonic nozzle or, preferably, a high-pressure nozzle.
[0027] Suitable rotary atomizers include those having an air
turbine drive operating from a high pressure compressed air source,
for example a 6 bar compressed air source, which supplies power to
an atomization wheel for atomizing the feed mixture. The
atomization wheel may be vaned. Preferably, the rotary atomizer is
located in the upper part of the spray-drying chamber, for example
in the chamber roof, so that the droplets produced dry and fall to
the lower part of the chamber. Typically, rotary atomizers produce
droplets that have a size in the range of from about 20 to about
225 .mu.m, in particular from about 40 to about 120 .mu.m, the
droplet size depending upon the wheel peripheral velocity.
[0028] Suitable pneumatic nozzles (including two-fluid nozzles)
comprise those that are located in the upper part of the
spray-drying chamber, for example in the chamber roof, and operate
in so-called "co-current mode". Atomization takes place using
compressed air such that the air-liquid ratio is in the range of
about 0.5-1.0:1 to about 5:1, in particular from about 1:1 to about
3:1. The feed mixture and the atomizing gas are passed separately
to the nozzle head, where the atomization takes place. The size of
the droplets produced by pneumatic nozzles depends on the operating
parameters and can be in the range e.g. from about 5 to 125 .mu.m,
or from about 20 to 50 .mu.m.
[0029] Two-fluid nozzles that operate in so-called "counter-current
mode" may also be used. These nozzles operate in a similar way to
two-fluid nozzles in co-current modes except that they are located
in a lower part of the drying chamber and spray droplets
upwards.
[0030] Typically, counter-current two-fluid nozzles generate
droplets, which, when dried, produce particles having a size in the
ranging from about 15 to about 80 .mu.m.
[0031] Suitable ultrasonic atomizer nozzles convert low viscosity
liquids into ultra fine sprays. As liquids are pumped through the
center of the probe, the liquids are mechanically pulverized into
droplets from the vibrating tip. These droplets are larger with low
frequency probes and smaller with higher frequency probes.
[0032] A preferred atomizer type for use in the invention is the
high-pressure nozzle where liquid feed is pumped to the nozzle
under pressure. Pressure energy is converted to kinetic energy, and
feed issues from the nozzle orifice as a high-speed film that
readily disintegrates into a spray as the film is unstable. The
feed is made to rotate within the nozzle using a swirl insert or
swirl chamber resulting in cone-shaped spray patterns emerging from
the nozzle orifice. Swirl insert, swirl chamber and orifice
dimensions together with variation of pressure gives control over
feed rate and spray characteristics. The size of the droplets
produced by high-pressure nozzles depends on the operating
parameters and can be in the range from about 5 to 125 mm, e.g.
from about 20 to about 50 mm.
[0033] Suitable atomizing means may be selected depending on the
desired droplet size, which depends on a number of factors, such as
the viscosity and temperature of the feed mixture, the desired flow
rate and the maximum acceptable pressure to pump the feed mixture,
have on droplet size. After selecting the atomizing means so that
the desired average droplet size is obtained for a feed mixture
having a particular viscosity, the mixture is admitted to the
spray-drying chamber at a particular flow rate.
[0034] The powder obtained after the spray-drying step may further
be dried, for example at increased temperature, or at reduced
pressure, or both.
[0035] The processes described herein provide convenient procedures
to prepare the amorphous sodium salt of TMC435 in very high yield
and with a high degree of purity (both close to 100%, such as for
example the yield and being >95%, or >99%, these percentages
in the instance of purity being w/w, i.e. weight/weight). Small
amounts of water can be present in the obtained product after
drying, for example from about 5% to about 1%, w/w. When brought
into contact with humidity, up to about 13% (in particular about
13.1%) can be absorbed. Even when water is absorbed, the product
remains stable.
[0036] The resulting powder, after addition of the required
excipients, can be processed directly into solid dosage forms such
as tablets or capsules.
[0037] In still a further aspect, the invention provides the
amorphous form of the sodium salt of the compound of formula I,
obtained or obtainable by a spray-drying process as described
herein.
[0038] The present invention also relates to the sodium salt of the
compound of formula I in amorphous form for use as a medicament.
This invention also relates to the sodium salt of the compound of
formula I in amorphous form for use as a HCV inhibitor, or for use
for the treatment of HCV-related conditions. The invention also
relates to the use of the sodium salt of the compound of formula I
in amorphous form in the manufacture of a medicament for inhibiting
HCV, or for the treatment of HCV-related conditions.
[0039] The present invention also concerns a method of treating a
mammal, in particular a human, suffering from HCV infection, or
suffering from conditions associated with HCV infection, said
method comprising administering the amorphous sodium salt of the
compound of formula I to a mammal in need thereof.
[0040] HCV-related conditions include those pathologic conditions
brought on by HCV, including progressive liver fibrosis,
inflammation and necrosis leading to cirrhosis, end-stage liver
disease, and HCC. The amount to be administered in particular is an
effective amount, this referring to an amount that is effective in
suppressing or reducing HCV infection, or suppressing or reducing
the conditions associated with HCV infection. Preferably, said
amount is selected such that the viral load drops significantly,
e.g. the viral load drops at least two orders of magnitude, or the
viral load drops at least three orders of magnitude, or the viral
load drops at least four orders of magnitude, or the viral load
drops below the detection limit of HCV.
[0041] In addition, the invention provides a pharmaceutical
composition comprising the sodium salt of the compound of formula I
in amorphous form and a pharmaceutically acceptable carrier. The
said sodium salt of the compound of formula I in amorphous form
preferably is present in the said pharmaceutical composition in an
effective amount, i.e. an amount as specified above.
[0042] The pharmaceutically acceptable carrier present in the
pharmaceutical compositions of the invention may comprise one or
more pharmaceutically acceptable excipients. The said
pharmaceutical compositions preferably are in solid form but may
also be in liquid or semi-liquid form, in which case the compound
of formula I in amorphous form is present as a suspension.
Pharmaceutically acceptable excipients comprise solid carriers such
as binders, fillers, starches, diluents, lubricants, binders,
disintegrants, and the like. Binders comprise starches, gelatin,
cellulose and its derivatives, natural and synthetic gums such as
guar gum, gum Arabic, etc. Fillers comprise talc, calcium
carbonate, microcrystalline cellulose, powdered cellulose, kaolin,
mannitol, sorbitol, starch, etc. Disintegrants comprise agar-agar,
alginic acid, calcium carbonate, microcrystalline cellulose,
croscarmellose sodium, crospovidone, pre-gelatinized starch, etc.
Lubricants comprise oils, e.g. vegetable or animal oils, such as
sunflower oil or cod liver oil, magnesium stearate, zinc stearate,
mannitol, sorbitol, searic acid, sodium lauryl sulfate, talc, agar,
etc.
[0043] Pharmaceutical compositions may be prepared as dosage forms
to be administered orally, which is preferred, or parenterally
(including subcutaneously, intramuscularly, and intravenously),
rectally, transdermally, bucally, or nasally. Suitable forms for
oral administration include powders, granulates, aggregates,
tablets, caplets, compressed or coated pills, dragees, sachets,
hard or gelatin capsules, and suspensions. Suitable forms for
parenteral administration include various aqueous or non-aqueous
suspensions. In this instance the particles that are suspended are
of sufficient small size as to allow parenteral administration. For
nasal delivery there are provided suitable art-known aerosol
delivery systems. The compositions may be conveniently presented in
unit dosage form, in particular tablets and capsules.
Alternatively, the dosage forms may be presented as one, two,
three, four, or more subdoses administered at appropriate intervals
throughout the day.
[0044] The sodium salt of the compound of formula I in amorphous
form, either as such or in the form of a pharmaceutical composition
or, preferably, as unit dosage form, is preferably administered
once daily (q.d.). Other dosage regimens may also be applied, for
example twice or three times daily. A suitable daily dosage of the
sodium salt of the compound of formula I in amorphous form,
expressed as amounts of the free form of the compound of formula I,
per day, is from about 1 mg to about 1000 mg of the compound of
formula I, or from about 5 to about 800 mg, or from about 5 to
about 400 mg, or from about 10 to about 300 mg, or from about 20 to
about 250 mg, or from about 50 to about 200 mg, for example about
25 mg, or about 75 mg, or about 100 mg, or about 150 mg, or about
200 mg. To calculate the daily amount of the amorphous sodium salt
to be administered, each of the cited values has to be multiplied
by 1.029, or by 1.0293.
[0045] The unitary dosage forms as described herein will contain
amounts of the sodium salt of the compound of formula I in
amorphous form that are equal to the amounts mentioned above.
[0046] In addition to the ingredients mentioned above, the
pharmaceutical compositions of the present invention may include
other agents conventional in the art having regard to the type of
composition in question, for example those suitable for oral
administration may include flavoring agents or taste masking
agents.
[0047] The invention also relates to a combination of the sodium
salt of the compound of formula I in amorphous form and another
antiviral compound, in particular another anti-HCV compound. The
term "combination" may relate to a product containing (a) the
sodium salt of the compound of formula I in amorphous form, as
specified herein, and (b) optionally another anti-HCV compound, as
a combined preparation for simultaneous, separate or sequential use
in treatment of HCV infections.
[0048] Anti-HCV compounds that can be used in such combinations
include HCV polymerase inhibitors, HCV protease inhibitors,
inhibitors of other targets in the HCV life cycle, and an
immunomodulatory agents, and combinations thereof. HCV polymerase
inhibitors include, NM283 (valopicitabine), R803, JTK-109, JTK-003,
HCV-371, HCV-086, HCV-796 and R-1479, R-7128, MK-0608, VCH-759,
PF-868554, GS9190, XTL-2125, NM-107, GSK625433, R-1626, BILB-1941,
ANA-598, IDX-184, IDX-375, MK-3281, MK-1220, ABT-333, PSI-7851,
PSI-6130, VCH-916, Inhibitors of HCV proteases include BILN-2061,
VX-950 (telaprevir), GS-9132 (ACH-806), SCH-503034 (boceprevir),
ITMN-191, MK-7009, BI-12202, BILN-2065, BI-201335, BMS-605339,
R-7227, VX-500, BMS650032, VBY-376, VX-813, SCH-6, PHX-1766,
ACH-1625, IDX-136, IDX-316. An example of an HCV NS5A inhibitor is
BMS790052, A-831, A-689, NIM-811 and DEBIO-025 are examples of NS5B
cyclophilin inhibitors.
[0049] Inhibitors of other targets in the HCV life cycle, including
NS3 helicase; metallo-protease inhibitors; antisense
oligonucleotide inhibitors, such as ISIS-14803 and AVI-4065;
siRNA's such as SIRPLEX-140-N; vector-encoded short hairpin RNA
(shRNA); DNAzymes; HCV specific ribozymes such as heptazyme, RPI,
13919; entry inhibitors such as HepeX-C, HuMax-HepC; alpha
glucosidase inhibitors such as celgosivir, UT-231B and the like;
KPE-02003002; and BIVN 401.
[0050] Immunomodulatory agents include, natural and recombinant
interferon isoform compounds, including .alpha.-interferon,
.beta.-interferon, .gamma.-interferon, and .omega.-interferon, such
as Intron A.RTM., Roferon-A.RTM., Canferon-A300.RTM.,
Advaferon.RTM., Infergen.RTM., Humoferon.RTM., Sumiferon MP.RTM.,
Alfaferone.RTM., IFN-Beta.RTM., and Feron.RTM.; polyethylene glycol
derivatized (pegylated) interferon compounds, such as PEG
interferon-.alpha.-2a (Pegasys.RTM.), PEG interferon-.alpha.-2b
(PEG-Intron.RTM.), and pegylated IFN-.alpha.-con1; long acting
formulations and derivatizations of interferon compounds such as
the albumin-fused interferon albuferon .alpha.; compounds that
stimulate the synthesis of interferon in cells, such as resiquimod;
interleukins; compounds that enhance the development of type 1
helper T cell response, such as SCV-07; TOLL-like receptor agonists
such as CpG-10101 (actilon), and isatoribine; thymosin .alpha.-1;
ANA-245; ANA-246; histamine dihydrochloride; propagermanium;
tetrachlorodecaoxide; ampligen; IMP-321; KRN-7000; antibodies, such
as civacir and XTL-6865; and prophylactic and therapeutic vaccines
such as InnoVac C and HCV E1E2/MF59.
[0051] Other antiviral agents include, ribavirin, amantadine,
viramidine, nitazoxanide; telbivudine; NOV-205; taribavirin;
inhibitors of internal ribosome entry; broad-spectrum viral
inhibitors, such as IMPDH inhibitors, and mycophenolic acid and
derivatives thereof, and including, but not limited to, VX-497
(merimepodib), VX-148, and/or VX-944); or combinations of any of
the above.
[0052] Particular agents for use in said combinations include
interferon-.alpha. (IFN-.alpha.), pegylated interferon-.alpha. (in
particular pegylated interferon-.alpha.-2a and -.alpha.-2b), and
ribavirin, as well as therapeutics based on antibodies targeted
against HCV epitopes, small interfering RNA (Si RNA), ribozymes,
DNAzymes, antisense RNA.
[0053] In another aspect there are provided combinations of the
sodium salt of the compound of formula I in amorphous form as
specified herein and an anti-HIV compound. The latter preferably
are those HIV inhibitors that have a positive effect on drug
metabolism and/or pharmacokinetics that improve bioavailability. An
example of such an HIV inhibitor is ritonavir.
[0054] The said combinations may find use in the manufacture of a
medicament for treating HCV infection in a mammal infected
therewith, said combination in particular comprising the sodium
salt of the compound of formula I in amorphous form, as specified
above and interferon-.alpha. (IFN-.alpha.), pegylated
interferon-.alpha. (in particular pegylated interferon-.alpha.-2a
and -.alpha.-2b), or ribavirin. Or the invention provides a method
of treating a mammal, in particular a human, infected with HCV
comprising the administration to said mammal of an effective amount
of a combination as specified herein. In particular, said treating
comprises the systemic administration of the said combination, and
an effective amount is such amount that is effective in treating
the clinical conditions associated with HCV infection.
[0055] In one embodiment the above-mentioned combinations are
formulated in the form of a pharmaceutical composition that
includes the active ingredients described above and a carrier, as
described above. Each of the active ingredients may be formulated
separately and the compositions may be co-administered, or one
composition containing both, and if desired further, active
ingredients may be provided. In the former instance, the
combinations may also be formulated as a combined preparation for
simultaneous, separate or sequential use in HCV therapy. The said
composition may take any of the forms described above. In one
embodiment, both ingredients are formulated in one dosage form such
as a fixed dosage combination. In a particular embodiment, the
present invention provides a pharmaceutical composition comprising
(a) a therapeutically effective amount of the sodium salt of the
compound of formula I in amorphous form, (b) a therapeutically
effective amount of another HCV inhibitor, such as those mentioned
above, and (c) a carrier. The carrier may comprises any of the
ingredients mentioned above.
[0056] The individual components of the combinations of the present
invention can be administered separately at different times during
the course of therapy or concurrently in divided or single
combination forms. The present invention is meant to embrace all
such regimes of simultaneous or alternating treatment and the term
"administering" is to be interpreted accordingly. In a preferred
embodiment, the separate dosage forms are administered
simultaneously.
[0057] The amorphous sodium salt of TMC435 is stable during long
periods of time, i.e. periods exceeding 11/2 years, as can be
demonstrated by comparing the XRD spectra taken shortly after its
preparation and after a long period of time. FIG. 7 shows the
Powder XRD pattern of the amorphous Na salt of TMC435 after storing
during 1 year, 8 months and 23 days. This pattern remained
essentially unchanged as compared to the pattern obtained shortly
after the preparation of TMC435 Na salt, as represented in FIG. 2.
This means that the amorphous Na salt of TMC435 allows stable
storage during a normal shelf life period.
[0058] As used herein, the term "about" has its conventional
meaning. In certain embodiments when in relation to a numerical
value, it may be interpreted to mean the numerical value .+-.10%,
or .+-.5%, or .+-.2%, or .+-.1%, or .+-.0.5%, or .+-.0.1%. In other
embodiments, the word "about" is left out so as to indicate that
the precise value is meant.
EXAMPLES
[0059] The following examples are intended to illustrate the
present invention and not to limit it thereto.
Example 1
Preparation of the Sodium Salt of TMC435 in Amorphous Form
[0060] Sodium hydroxide 10 N solution, prepared by dissolving 24.00
g sodium hydroxide in 55.80 g purified water, was added to 5949.00
g vigorously stirred methylene chloride. TMC435 (450.00 g) was
added to this mixture under moderate stirring, and stirring was
continued until the resulting mixture was visually clear. The thus
obtained mixture was spray dried in a standard spray dryer under
N.sub.2 conditions. The spray dried product was collected and dried
in a vacuum oven. The resulting powder being the amorphous sodium
salt of TMC435, contained the free form of the active ingredient
TMC435 in an amount of 971.53 mg/g powder.
Example 2
Preparation of TMC435 Oral Capsules
[0061] The spray dried powder (72.05 g) obtained in example 1,
sodium laurylsulfate (1.19 g), anhydrous colloidal silica (1.19 g)
and lactose monohydrate (158.83 g) were sieved and blended in a
suitable recipient for 10 minutes. Sieved magnesium stearate (1.19
g) was added to this mixture and the resulting mixture was blended
for 5 more minutes. The resulting composition was filled into hard
gelatin capsules.
TABLE-US-00001 TABLE 1 presents the batch formula for a typical
batch size of 700 capsules in the manufacturing of amorphous TMC435
sodium salt oral capsules. Quantity (mg) Quantity (g) per Batch
Component per capsule Size of 700 capsules amorphous TMC435 sodium
salt 102.93 mg 72.05 g Sodium lauryl sulphate 1.7 mg 1.19 g
Magnesium stearate 1.7 mg 1 19 g Silica colloidal anhydrous 1.7 mg
1.19 g Lactose monohydrate 226.9 mg 158.83 g Hard gelatin
capsule-size 0- 1 pc 700 pcs cap red5/body red5
TABLE-US-00002 TABLE 2 presents the batch formula for a typical
batch size of 600 capsules in the manufacturing of amorphous TMC435
sodium salt 25 mg oral capsules. Quantity (mg) Quantity (g) per
Batch Component per capsule Size of 600 capsules amorphous TMC435
sodium 25.73 mg 15.44 g salt Sodium lauryl sulphate 0.4 mg 0.24 g
Magnesium stearate 0.4 mg 0.24 g Silica colloidal anhydrous 0.4 mg
0.24 g Lactose monohydrate 51.8 mg 31.08 g Hard gelatin
capsule-size 4- 1 pc 600 pcs cap red5/body red 5
Example 3
Characterization of the Amorphous Sodium Salt Prepared According to
Example 1
[0062] Amorphous [0063] Showed a glass transition at 192.5.degree.
C. [0064] Contained solvent (water) [0065] DSC showed an
endothermic signal at 81.1.degree. C. (78 J/g) [0066] TGA showed a
weight loss of 3.7% (25-245.degree. C.) [0067] Hygroscopic Infrared
spectrometry (IR) Micro Attenuated Total Reflectance (microATR)
[0068] The sample was analyzed using a suitable microATR
accessory.
number of scans: 32 resolution: 1 cm.sup.-1 wavelength range: 4000
to 400 cm.sup.-1 apparatus: Thermo Nexus 670 FTIR spectrophotometer
baseline correction: yes detector: DTGS with KBr windows
beamsplitter: Ge on KBr micro ATR accessory: Harrick Split Pea with
Si crystal
[0069] The IR spectrum of TMC435 Na salt contained solvent (water)
and reflects the vibrational modes of the molecular structure of
the sodium salt of TMC435.
[0070] IR spectrum See FIG. 1
Powder XRD
[0071] X-ray powder diffraction (XRPD) analysis was carried out on
a Philips X'PertPRO MPD diffractometer PW3050/60 with generator
PW3040. The instrument was equipped with a Cu LFF X-ray tube
PW3373/10. The compound was spread on a zero background sample
holder.
Instrument Parameters
[0072] generator voltage: 45 kV generator amperage: 40 mA geometry:
Bragg-Brentano stage: spinner stage
Measurement Conditions
[0073] scan mode: continuous scan range: 3 to 50.degree. 2.theta.
step size: 0.0167.degree./step counting time: 29.845 sec/step
spinner revolution time: 1 sec radiation type: CuK.alpha. radiation
wavelength: 1.5406 .ANG.
Incident Beam Path Diffracted Beam Path
[0074] program divergence slit: 15 mm long anti scatter shield: +
Soller slit: 0.04 rad Soller slit: 0.04 rad beam mask: 15 mm Ni
filter: + anti scatter slit: 1.degree. detector: X'Celerator beam
knife: +
[0075] The X-ray powder diffraction pattern of the amorphous TMC435
sodium salt showed only the presence of a halo, indicating that
this compound was present as an amorphous product.
[0076] XRD pattern See FIG. 2
Differential Scanning Calorimetry (DSC)
[0077] About 3 mg of the compound was transferred into a standard
aluminum TA-Instrument sample pan. The sample pan was closed with a
cover and the DSC curve was recorded on a TA-Instruments Q1000
MTDSC equipped with a RCS cooling unit.
Parameters
[0078] initial temperature: 25.degree. C. heating rate: 10.degree.
C./min final temperature: 300.degree. C. nitrogen flow: 50
ml/min
[0079] The DSC curve of TMC435 sodium salt showed an endothermic
signal at 81.1.degree. C. (77 J/g) due to solvent evaporation.
[0080] A second event was observed at .+-.199.4.degree. C. and is
probably related to the glass transition (Tg), the relaxation
energy and/or to the evaporation of solvent.
[0081] DSC curve See FIG. 3
Modulated Differential Scanning Calorimetry (MDSC)
[0082] About 3 mg of amorphous TMC435 sodium salt was transferred
into a standard aluminum TA-Instrument sample pan. The sample pan
was closed with a cover and the DSC curve was recorded on a
TA-Instruments Q1000 MTDSC equipped with a RCS cooling unit.
Parameters
Mode: T4P
[0083] nitrogen flow: 50 ml/min equilibrate at: -60.degree. C.
modulate: heat only 60 s ramp: 2.degree. C./min Final temperature:
225.degree. C.
[0084] An MDSC experiment was conducted to determine the glass
transition (Tg) (shift in specific heat) of the sample. In general,
MDSC experiments can separate the evaporation of solvent and the
relaxation energy, which are kinetic processes (non-reversing heat
flow signal) from the change in heat capacity (reversing heat flow
signal). The (total) heat flow is comparable to a standard DSC
signal. If a non-hermetic sample pan was used for the amorphous
TMC435 sodium salt, the MDSC curve showed the evaporation of the
solvent present at .+-.46.9.degree. C. clearly separated from the
glass transition at .+-.192.5.degree. C.
[0085] MDSC overlay See FIG. 4.
Thermogravimetry (TGA)
[0086] Amorphous TMC435 was transferred into an aluminum sample
pan. The TG curve was recorded on a TA Instruments Q500
thermogravimeter.
Parameters
[0087] initial temperature: room temperature heating rate:
20.degree. C./min resolution factor: 4 final condition: 300.degree.
C. or <80[(w/w) %]
[0088] For amorphous TMC435 sodium salt, a weight loss of .+-.3.7%
was registered in the temperature region from room temperature up
to 245.degree. C. and was due to the evaporation of solvent (water)
present in the sample. The loss of weight above 250.degree. C. was
due to the decomposition of the product.
[0089] TGA curve See FIG. 5
Adsorption-Desorption (DVS)
[0090] Amorphous TMC435 (19 mg) was transferred into a SMS (Surface
Measurement Systems Ltd.) dynamic vapor sorption model DVS-1 and
the weight change was recorded with respect to the atmospheric
humidity at 25.degree. C.
Parameters
[0091] drying: 60 min under dry nitrogen equilibrium: <0.01%/min
for minimal 15 min and maximal 60 min. data interval: 0.05% or 2.0
min Measurements were made at the following relative humidity (RH
(%)) levels: first set:
5,10,20,30,40,50,60,70,80,90,95,90,80,70,60,50,40,30,20,10,5 second
set:
5,10,20,30,40,50,60,70,80,90,95,90,80,70,60,50,40,30,20,10,5,0
[0092] During the initial drying step, a weight loss of 2.03% was
registered for the sodium salt of compound I. The obtained dried
product was hygroscopic and adsorbed up to 13.1% water at high
relative humidity. During the desorption cycle 1.61% moisture
remained on the product.
[0093] The obtained product after DVS was investigated with IR and
XRD and remained amorphous.
[0094] ADS/DES curve See FIG. 6.
* * * * *