U.S. patent application number 12/941127 was filed with the patent office on 2011-05-12 for novel process for the manufacture of pharmaceutical preparations.
Invention is credited to Ralph Diodone, Stephan Lauper, Hans-Juergen Mair, Johannes Pudewell, Frank Wierschem.
Application Number | 20110112136 12/941127 |
Document ID | / |
Family ID | 42352265 |
Filed Date | 2011-05-12 |
United States Patent
Application |
20110112136 |
Kind Code |
A1 |
Diodone; Ralph ; et
al. |
May 12, 2011 |
NOVEL PROCESS FOR THE MANUFACTURE OF PHARMACEUTICAL
PREPARATIONS
Abstract
The present invention is related to an improved method for the
manufacture of Micro-precipitated Bulk Powder (MBP) containing the
active pharmaceutical ingredient Propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide and Hydroxypropylmethylcellulose Acetate Succinate
(HPMCAS). The invention is further directed to pharmaceutical
compositions containing said MBP, as well as its use in the
manufacture of medicaments for the treatment of cancer.
Inventors: |
Diodone; Ralph; (Breisach,
DE) ; Lauper; Stephan; (Kaiseraugst, CH) ;
Mair; Hans-Juergen; (Loerrach, DE) ; Pudewell;
Johannes; (Oberwil, CH) ; Wierschem; Frank;
(Rheinfelden, CH) |
Family ID: |
42352265 |
Appl. No.: |
12/941127 |
Filed: |
November 8, 2010 |
Current U.S.
Class: |
514/300 |
Current CPC
Class: |
A61K 9/0014 20130101;
A61K 9/1635 20130101; C07B 2200/13 20130101; A61K 9/1652 20130101;
A61K 31/437 20130101; A61P 35/00 20180101; A61K 9/10 20130101; A61P
21/00 20180101; A61K 9/0019 20130101; A61P 25/16 20180101; A61P
35/04 20180101; C07D 471/04 20130101; A61P 25/04 20180101; A61P
25/00 20180101; A61P 43/00 20180101; A61P 25/28 20180101; A61P
29/00 20180101; A61P 35/02 20180101 |
Class at
Publication: |
514/300 |
International
Class: |
A61K 31/437 20060101
A61K031/437; A61P 35/00 20060101 A61P035/00 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 11, 2009 |
EP |
09175665.0 |
Claims
1. A method for manufacturing a solid dispersion containing the
amorphous form of the compound of formula 1 ##STR00002## and
HPMCAS, comprising the following steps: (a) dissolving the compound
of formula 1 and HPMCAS in the same organic solvent to give one
single organic phase; (b) continuously adding the organic phase
obtained under (a) into an aqueous phase which is present in a
mixing chamber, said mixing chamber being equipped with a high
shear mixing unit and two additional openings which connect said
mixing chamber to a closed loop wherein said aqueous phase is
circulated and passes through the mixing chamber; (c) precipitating
a mixture consisting of the amorphous form of the compound of
formula 1 and HPMCAS out of the aqueous phase mentioned under (b),
while the high shear mixer is operating and said aqueous phase is
passed through the mixing chamber in a closed loop, resulting in
the formation of an aqueous suspension of the precipitate; (d)
continuously circulating the aqueous suspension through the mixing
chamber while the high shear mixing unit is operating and after the
organic solution prepared under (a) has been completely added to
the aqueous phase until a defined particle size and/or particle
size distribution is obtained; (e) isolating the solid phase from
the suspension; (f) washing of the isolated solid phase with 0.01 N
HCl and/or water; and (g) delumping and drying the solid phase.
2. The method according to claim 1, wherein the organic phase in
(a) is a 10 to 40% solution of the compound of formula 1 and HPMCAS
in DMA, the ratio of said compound to HPMCAS being from about 10 to
90% (w/w) to about 60 to 40% (w/w); and the continuous adding in
step (b) is achieved via an injector nozzle which is oriented in an
angle between 40 and 50.degree. to the longitudinal axis of the
high shear mixer and has a distance of about 1 to about 10 mm from
the rotor of said high shear mixer which is operating with a tip
speed of about 15 to about 25 m/sec.
3. The method according to claim 2, wherein the organic phase in
(a) is a 35% solution of the compound of formula 1 and HPMCAS in
DMA, the ratio of said compound to HPMCAS being 30% to 70%
(w/w).
4. The method according to claim 1, wherein the organic phase in
(a) comprises DMA, the compound of formula 1 and HPMCAS-L, and step
(b) comprises adding said organic phase into aqueous (0.01 N) HCl
at a mass flow ratio in the range of about 80/1 to 200/1 (aqueous
phase/organic phase) while said aqueous HCl is kept at a
temperature of about 2-8.degree. C.
5. The solid dispersion produced by the method according to claim
1.
6. The solid dispersion according to claim 5, characterized in that
it is a microprecipitated bulk powder (MBP) wherein the compound of
formula 1 is predominantly present in its amorphous form.
7. A pharmaceutical preparation containing the solid dispersion as
obtainable according to the method of claim 1, optionally together
with additional pharmaceutically acceptable adjuvants.
Description
PRIORITY TO RELATED APPLICATION(S)
[0001] This application claims the benefit of European Patent
Application No. 09175665.0, filed Nov. 11, 2009, which is hereby
incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention is related to an improved method for
the manufacture of solid dispersions, in particular
Micro-precipitated Bulk Powder (MBP), containing the compound
Propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide (formula 1) and Hydroxypropylmethylcellulose
Acetate Succinate (HPMCAS).
##STR00001##
[0003] The compound of formula 1, methods of synthesizing it as
well as conventional pharmaceutical formulations containing that
compound have been disclosed in WO 2007002433 and WO 2007002325.
The compound of formula 1 shows valuable pharmaceutical properties
as potential medicament for the inhibition of cancer proliferation,
in particular solid tumor growth.
BACKGROUND OF THE INVENTION
[0004] Compounds that have low solubility in water (for example,
certain compounds in crystalline form), have a low dissolution rate
and as a result can exhibit poor bioavailability. Poorly
bioavailable compounds can present problems for therapeutic
administration to a patient, often due to unpredictability in
dose/therapy effects caused by erratic absorption of the compound
by the patient. For example, the intake of food may affect the
ability of the patient to absorb such poorly bioavailable
compounds, thus potentially requiring dosing regimens to take into
account the effect of food. In addition, when dosing, a large
safety margin may be required for the dose as a result of the
unpredictable dose effects. Further, due to poor bioavailability, a
large dose of the compound may be required to achieve a desired
therapeutic effect, thus potentially resulting in undesired side
effects.
[0005] The amorphous form of Compound 1 has improved solubility in
water as compared to the crystalline form, but is unstable as it
has a tendency to crystallize. Thus it is desired to formulate
Compound I so that it may exist stably primarily in amorphous
form.
[0006] HPMCAS is a polymer that has been used for the manufacture
of solid dispersions (SD) of drugs (see for example H. Konno, L. S.
Taylor, Journal of Pharmaceutical Sciences, Vol. 95, No. 12, 2006,
2692-2705).
[0007] EP 0 901 786 B1 discloses a composition comprising a
spray-dried solid dispersion of a poorly water soluble drug and
HPMCAS. Disclosed drugs are glycogen phosphorylase inhibitors and
5-lipoxygenase inhibitors as disclosed in WO 96/39385 and WO
95/05360 respectively.
[0008] EP 1 368 001 B1 discloses a pharmaceutical formulation
comprising the drug bicalutamide and an enteric polymer, like
HPMCAS. Disclosed methods for evaporating the solvent include
rotary evaporation, spray drying, lyophilisation and thin film
evaporation. It is further disclosed that other techniques may be
used such as solvent controlled precipitation, pH controlled
precipitation, spray congealing and supercritical fluid technology
(eg, the Solution Enhanced Dispersion by Supercritical Fluid (SEDS)
technique).
[0009] EP 0 344 603 B1 discloses formulating HPMCAS with a drug
designated as NZ-105. The patent discloses formulations prepared by
dissolving NZ-105 and HPMCAS in an organic solvent and removing the
solvent by means of vacuum-drying, spray-drying, freeze-drying, or
the like. More specifically, dispersions of HPMCAS and NZ-105 are
formed by (1) fluidized bed granulation by coating either calcium
hydrogen phosphate particles or lactose crystals or 2) vacuum
drying with lactose to form a solid cake that is then pulverized to
form a powdery material. Particle sizes are described to be in the
range of 100 to 400 mesh (0.037 mm to 0.149 mm).
[0010] EP 0 580 860 discloses a process for the preparation of a
solid dispersion of drug dissolved in a polymer, which polymer is
inter alia HPMCAS. The claimed process is characterized by the use
of a twin-screw extruder being equipped with paddle means.
[0011] F. Tanno et. al. disclose the use of HPMCAS as a carrier in
solid dispersions. The specific drug used as a model substance in
the study is Nifedipine. The solid dispersions were obtained by
spraying a mixture of HPMCAS and the drug in an organic solvent on
a Teflon.TM. sheet, evaporating the solvent and removing an milling
the resulting film (in Drug Development and Industrial Pharmacy,
Vol. 30, No. 1, 2004, 9-17). Molecular Pharmaceutics, Vol. 5, No.
6, 2008, 1003-1019 also discloses HPMCAS spray-dried dispersions
using several poorly water soluble drugs.
[0012] Bruno C. Hancock, George Zografi, Journal of Pharmaceutical
Sciences, Vol 86, No. 1, 1997, 1-12 discloses methods for removing
solvents when making solid dispersions using the so called solvent
method, including for example spray-drying, vacuum-drying,
freeze-drying or precipitation.
SUMMARY OF THE INVENTION
[0013] In certain aspects and embodiments there are provided
methods of preparing solid dispersions comprising HPMCAS and the
compound of formula 1. In many embodiments the methods may use a
lower amount of organic solvents as compared to other methods and
as such may be more environmentally friendly; are safe when used on
an industrial scale; and/or show improved properties such as
stability against re-crystallization. In many aspects and
embodiments the methods involve micro-precipitation of a mixture of
HPMCAS and the compound of formula 1 within an aqueous phase using
the conditions and process parameters as described herein.
[0014] In one embodiment there is provided a method for
manufacturing a solid dispersion containing the amorphous form of
the compound of formula 1 and HPMCAS, wherein the solid dispersion
is obtained by introducing a solution of the compound of formula 1
and HPMCAS in the same organic solvent within an aqueous phase, and
subsequent precipitation and isolation of said solid dispersion
from said aqueous phase.
[0015] In certain more specific embodiments, the above method
includes the following steps,
(a) dissolving the compound of formula 1 and HPMCAS in the same
organic solvent to give one single organic phase; (b) continuously
adding the organic phase obtained under (a) into an aqueous phase
which is present in a mixing chamber, said mixing chamber being
equipped with a high shear mixing unit and two additional openings
which connect said mixing chamber to a closed loop wherein said
aqueous phase is circulated and passes through the mixing chamber;
(c) precipitating a mixture consisting of the amorphous form of the
compound of formula 1 and HPMCAS out of the aqueous phase mentioned
under (b), while the high shear mixer is operating and said aqueous
phase is passed through the mixing chamber in a closed loop,
resulting in the formation of an aqueous suspension of the
precipitate; (d) continuously circulating the aqueous suspension
through the mixing chamber while the high shear mixing unit is
operating and after the organic solution prepared under (a) has
been completely added to the aqueous phase until a defined particle
size and/or particle size distribution is obtained; (e) isolating
the solid phase from the suspension; (f) washing of the isolated
solid phase with 0.01 N HCl and/or water; and (g) delumping and
drying the solid phase.
[0016] In still more specific embodiments the present methods
include the steps, wherein [0017] the organic phase in step (a)
above is a 10 to 40% solution of the compound of formula 1 and
HPMCAS in DMA, the ratio of said compound to HPMCAS being from
about 10 to 90% (w/w) to about 60 to 40% (w/w); and [0018] the
continuous adding in step (b) above is achieved via an injector
nozzle which is oriented in an angle between 40 and 50.degree. to
the longitudinal axis of the high shear mixer and has a distance of
about 1 to about 10 mm from the rotor of said high shear mixer
which is operating with a tip speed of about 15 to about 25
m/sec.
[0019] In still more specific embodiments the present methods
include the step, wherein [0020] the continuous adding in step (b)
above is achieved via an injector nozzle which is oriented in an
angle of about 45.degree. to the longitudinal axis of the high
shear mixer and has a distance of about 2 to about 4 mm from the
rotor of said high shear mixer which is operating with a tip speed
of about 25 m/sec.
[0021] In other specific embodiments the present methods include
the step, wherein [0022] the drying in step (g) above is achieved
via fluidized bed drying.
[0023] In yet another particularly preferred embodiment, the
organic phase in (a) comprises DMA, the compound of formula 1 and
HPMCAS-L, and step (b) comprises adding said organic phase into
aqueous (0.01 N) HCl at a mass flow ratio in the range of about
80/1 to 200/1 (aqueous phase/organic phase) while said aqueous HCl
is kept at a temperature of about 2-8.degree. C.
[0024] In a further embodiment there are provided the solid
dispersions obtained by the above-mentioned method.
[0025] The dried precipitate can be further processed into any type
of solid pharmaceutical preparations or dosage forms, which are
known to the person of skill in the art. Particularly preferred are
oral dosage forms such as tablets, capsules, pills, powders,
suspensions, pasts and the like. Detailed descriptions of suitable
excipients as well as methods for making such pharmaceutical
preparations can for example be found in: Raymond C. Rowe et al,
Handbook of Pharmaceutical Excipients, 6.sup.th edition, 2009,
Pharmaceutical Press (Publ.); ISBN-10: 0853697922.
[0026] Consequently, so obtained pharmaceutical preparations form
further embodiments provided herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] FIG. 1 shows a schematic drawing of the setup for the
manufacturing of solid dispersion (MBP) according to the present
invention. The setup provides two reservoirs (vessels) with
temperature control means, one for providing the aqueous phase at a
controlled temperature (1), the other for providing the organic
phase at a controlled temperature (2). Both vessels are further
equipped with automatic stirrers (3). The aqueous phase is
circulated in a closed loop (4) using a pump (5), while passing a
high shear mixing unit (6). The organic phase is added into the
aqueous phase within the high shear mixing unit with the aid of a
dosing pump (7) and via an injector nozzle which is shown in more
detail in FIG. 2.
[0028] FIG. 2 shows are more detailed schematic drawing of the high
shear mixing unit ((6) of FIG. 1). The nozzle (8) is placed within
the aqueous phase inside the high shear mixing unit. The nozzle can
be oriented within different angles (.alpha.) with respect to the
rotor (9) of the high shear mixing unit, and within defined
distances (d) of the rotor tip.
[0029] FIG. 3 shows the comparison of X-ray diffractograms obtained
from two lots of solid dispersions (MBP's), manufactured via high
shear mixer precipitation according to the present invention (3a)
and via conventional spray precipitation (3b). The results
presented in this figure demonstrate that the spray precipitated
MBP is less stable against re-crystallization than the high shear
precipitated MBP as evidenced by the early occurrence of sharp
signals in the diffractograms of (b), which can be allocated to the
crystalline form of the compound of formula (1). Bottom line in
each picture represents the initial sample, the following lines
bottom up after 14 h, 41 h, 96 h, 6 d respective 13 d storage in a
clime chamber (50.degree. C. 90% RH).
DETAILED DESCRIPTION OF THE INVENTION
[0030] The compound of formula 1, which is an active pharmaceutical
ingredient (API), and the excipient Hydroxypropylmethylcellulose
Acetate Succinate (HPMCAS) is dissolved in an organic, water
miscible solvent in a feed hopper. In a second vessel an aqueous
phase of defined temperature is pumped in a loop outside of the
vessel, while passing through a high shear mixer (HSM, rotor/stator
unit). A schematic drawing of the process can be seen in FIG. 1.
The temperature of both solutions was controlled during the
complete manufacturing process. The solution with the API and
excipient (organic phase) is dosed with a defined flow rate into
the mixing chamber, containing the rotor/stator tools, while the
high shear unit (dispersing unit) is operating. During the mixing
of the two liquids (aqueous- and organic phase) an almost water
insoluble precipitate, which is a mixture of amorphous API and
HPMCAS with a defined ratio, is formed, leading to a suspension of
micro precipitated bulk powder (MBP) in the outer phase (mixture of
water and organic solvent). After complete addition of the organic
phase the suspension was forced a number of passes through the
dispersing unit in order to adjust the particle size. Subsequently
the suspension was centrifuged and washed with a water phase
several times in order to remove the organic solvent and finally
was washed additionally with pure water. The obtained wet MBP was
delumped and dried to a water content below 2% by weight (w/w). The
MBP was obtained as a white, free flowing powder.
[0031] The compound of formula 1 can be synthesized according to
methods disclosed in WO 2007002433 or WO 2007002325.
[0032] The term "HPMCAS" means Hydroxypropylmethylcellulose Acetate
Succinate (trade name: AQOAT, available from Shin-Etsu Chemical
Industry Co., Ltd., Japan or appointed distributors), which is
available in the following grades: AS-LF, AS-MF, AS-HF, AS-LG,
AS-MG and AS-HG. The solubility of the different HPMCAS grades as
well as their drug release behaviour depends on the pH-value of the
environment. Accordingly, the release behaviour of a drug can be
tailored in the range of about pH5.2 to about pH6.5 by the choice
of the appropriate HPMCAS grade (see product information brochure
for AQOAT). Therefore, in one embodiment, the compound of formula 1
is in a solid dispersion with at least one polymer selected from
HPMCAS grades AS-L, AS-M, AS-H. It is, however, contemplated that a
mixture of two or more of the various HPMCAS grades can also be
used in accordance with the present invention.
[0033] The term "solid dispersion" as used herein means a solid
state material formed by a high molecular weight compound, such as
a polymer, preferably HPMCAS, wherein a low molecular weight
compound, such as the compound of formula 1, is molecularly
dispersed. Preferably the solid dispersion exists as a one phase
system. An especially preferred solid dispersion according to the
present invention is a microprecipitated bulk powder (MBP)
essentially consisting of HPMCAS and the compound of formula 1
which is predominantly in its amorphous form.
[0034] The "organic solvent" mentioned under step (a) means any
organic solvent wherein both the compound of formula 1 and HPMCAS
are miscible. Preferred organic solvents are N-Methylpyrrolidone,
Dimethylformamide, Dimethylsulfoxide, Dimethylacetamide (DMA), with
DMA being the most preferred. The combined amount of the compound
of formula 1 and HPMCAS together in the organic phase can be within
the range of about 10 to 40 weight %, preferably about 15 to 40
weight %, more preferably about 25 to 40, most preferably about 35
weight %. The weight ratio of the compound of formula 1/HPMCAS
within the organic solvent is from about 10/90 to about 60/40
weight %, more preferably from about 30/70 to about 60/40 weight %,
and most preferably about 30/70 weight %, respectively. Preferably,
the temperature of the organic solvent is adjusted between 50 and
110.degree. C., preferably 60 and 90.degree. C., most preferred at
about 70.degree. C. prior to its addition to the mixing chamber as
mentioned under step (b). The mixture of the compound of formula 1
and HPMCAS in the organic solvent is also designated herein as the
"organic phase" or "DMA phase".
[0035] The "aqueous phase" mentioned under step (b) preferably
consists of acidic water (pH<7), most preferably of 0.01 N
hydrochloric acid (HCl). The aqueous phase is kept at a temperature
between about 2 and about 60.degree. C., preferably between about 5
and about 20.degree. C., most preferably about 5.degree. C. The
aqueous phase circulates out of the bottom valve of its reservoir
((1) of FIG. 1) due to the stream created by the high shear mixer
or with an auxiliary pump, preferably a rotary lobe pump, then
passes through the high shear mixer, back into the reservoir.
Preferably, the outlet of the loop is placed under the fluid level
maintained in the reservoir, in order to prevent foaming.
[0036] The addition of the organic phase to the mixing chamber as
mentioned in step (b) above is achieved via an injector nozzle
which directly points into the aqueous phase. Any conventional
nozzle known to the person of skill in the art can be used.
Preferred injector nozzles show central or acentric geometry are
isolated and have a diameter of about 1 to 10 mm. The acentric (not
centered) geometry and a diameter of 5 mm are especially preferred.
The injector nozzle may point to the rotor of the high shear mixing
unit in an angle between 0 and 90.degree., preferably between 40
and 50.degree., most preferably at 45.degree. (.alpha., FIG. 2).
During the process according to the present invention, the distance
between the point of the injector nozzle and the tip of the rotor
of the high shear mixing unit is about 1 to 10 mm, preferably about
2 to 4 mm and most preferably about 2.6 mm. The addition of the
organic phase is preferably carried out at dosing rates of about
60/1 to about 300/1 (i.e. mass flow ratio of aqueous phase/organic
phase during precipitation), preferably about 70/1 to about 120/1
and most preferably at about 100/1. Final ratio of aqueous
phase/organic phase after precipitation is in the range of about
5/1-12/1 preferably 7/1-10/1 and most preferably at 8.5/1.
[0037] While the organic phase is added (injected) into the aqueous
phase of the mixing chamber, the high shear mixing unit is
operating. Any conventional high shear mixing unit (rotor/stator
unit) known to the person of skill in the art can be applied.
Especially preferred are toothed disk dispersing units. The
preferred rotor geometry according to the present invention uses a
rotor/stator unit with a radial single teeth row or double teeth
row or combination thereof. Rotors with conical teeth rows can also
be applied. The tip speed of the rotor is from about 15 to about 25
m/sec., preferably 25 m/sec.
[0038] Subsequent to the complete addition of the organic phase
into the aqueous phase, the obtained suspension, thus the
precipitate consisting of the amorphous compound of formula 1 and
HPMCAS in the aqueous phase, is further circulated in the closed
loop containing the high shear mixing unit. Outside of the high
shear mixing unit the circulation must be carried out with the aid
of an auxiliary pump, preferred a rotary lobe pump. The suspension
passes the high shear mixing unit several times, up to the moment
where a desired particle size and/or particle size distribution is
obtained. Usually the suspension passes the high shear mixing unit
about 1 to 60 times, most preferably 6 times. The particle size
and/or particle size distribution can be controlled by standard
techniques, well known to the person of skill in the art, such as
for example dynamic light scattering. The preferred particle size
according to the present invention is with in the range of
D50=80-230 .mu.m preferably D50=80-160 .mu.m.
[0039] Isolation of the solid dispersion (MBP) according to step
(e) above can be carried out by using conventional filter
techniques or centrifuges. Prior to isolation, the suspension is
preferably adjusted to about 5 to 10.degree. C. Subsequently, the
isolated solid dispersion is washed with acidic water; preferably
0.01 N HCl followed by further washing with pure water in order to
substantially remove the organic solvent (step (f)). The isolated
(wet) solid dispersion (MBP) usually shows a water content between
60 and 70% (w/w), which requires drying before any further
processing. The drying can be carried out using any standard
techniques known to the person of skill in the art, for example
using a cabinet dryer at temperatures between 30 and 50.degree. C.,
preferably at about 40.degree. C. and at reduced pressure,
preferably below 20 mbar. Several drying procedures can be combined
or used sequentially, whereby the use of fluidized bed drying is
especially preferred as the final drying step according to the
present invention.
[0040] The stability of the solid dispersion (MBP) according to the
present invention was compared with the stability of an MBP
obtained via conventional spray precipitation. "Conventional spray
precipitation" means that the organic phase was sprayed onto the
aqueous phase via a nozzle which is placed outside the aqueous
phase, above its surface like it is the case for many conventional
spray-precipitation techniques. All further process parameters are
the same for both methods. The stability, thus the inhibition of
re-crystallization of the compound of formula 1, is determined by
x-ray diffraction measurements, using a conventional wide angle
X-ray scattering setup as it is well known to the skilled artisan.
Sample preparation was identical for both MBP's. The samples were
treated in a climate chamber (50.degree. C. and 90% humidity (RH))
for several hours respective days (0 h, 14 h, 41 h, 4 d, 6 d, 13 d)
prior to X-ray measurements. The results are shown in FIG. 3 (a)
for the MBP obtained according to the present invention, and (b)
for the MBP obtained by the conventional method. The earliest X-ray
curves of both MBP's show a broad halo in the wide angle region
with the absence of sharp signals, thereby clearly evidencing that
both materials are in an amorphous state. Within several days,
sharp signals occur in the X-ray curves obtained from the MBP
manufactured by the conventional method ((b) in FIG. 3), but not in
the X-ray curves obtained from the MBP prepared using the method as
disclosed herein ((a) in FIG. 3).
[0041] The novel processes as provided herein can preferably be
carried out using a setup as shown in the accompanying FIG. 1.
[0042] The solid dispersion, in particular the MBP obtainable
according to the methods provided can be used in a wide variety of
forms for administration of drugs such as the compound of formula
1, including drugs that are poorly water soluble, and in particular
for oral dosage forms. Exemplary dosage forms include powders or
granules that can be taken orally either dry or reconstituted by
addition of water to form a paste, slurry, suspension or solution;
tablets, capsules, or pills. Various additives can be mixed, ground
or granulated with the solid dispersion as described herein to form
a material suitable for the above dosage forms. Potentially
beneficial additives may fall generally into the following classes:
other matrix materials or diluents, surface active agents, drug
complexing agents or solubilizers, fillers, disintegrants, binders,
lubricants, and pH modifiers (e.g., acids, bases, or buffers).
Examples of other matrix materials, fillers, or diluents include
lactose, mannitol, xylitol, microcrystalline cellulose, calcium
diphosphate, and starch. Examples of surface active agents include
sodium lauryl sulfate and polysorbate 80. Examples of drug
complexing agents or solubilizers include the polyethylene glycols,
caffeine, xanthene, gentisic acid and cyclodextrins. Examples of
disintegrants include sodium starch gycolate, sodium alginate,
carboxymethyl cellulose sodium, methyl cellulose, and
croscarmellose sodium. Examples of binders include methyl
cellulose, microcrystalline cellulose, starch, and gums such as
guar gum, and tragacanth. Examples of lubricants include magnesium
stearate and calcium stearate. Examples of pH modifiers include
acids such as citric acid, acetic acid, ascorbic acid, lactic acid,
aspartic acid, succinic acid, phosphoric acid, and the like; bases
such as sodium acetate, potassium acetate, calcium oxide, magnesium
oxide, trisodium phosphate, sodium hydroxide, calcium hydroxide,
aluminum hydroxide, and the like, and buffers generally comprising
mixtures of acids and the salts of said acids. At least one
function of inclusion of such pH modifiers is to control the
dissolution rate of the drug, matrix polymer, or both, thereby
controlling the local drug concentration during dissolution.
[0043] As was stated earlier, additives may be incorporated into
the solid amorphous dispersion during or after its formation. In
addition to the above additives or excipients, use of any
conventional materials and procedures for formulation and
preparation of oral dosage forms using the compositions disclosed
herein known by those skilled in the art are potentially
useful.
[0044] Consequently, a further embodiment includes a pharmaceutical
preparation containing the solid dispersion as obtained by a method
as described herein. The preparation may optionally also contain
additional pharmaceutically acceptable adjuvants.
[0045] In one embodiment, the solid dispersion may be processed
into a film-coated tablet containing up to 92% of the MBP
obtainable according to the process disclosed herein, and wherein
the MBP consists of about 30% compound of formula (1) and about 70%
HPMCAS. The remaining part of the tablet consists of a mixture of
conventional disintegrants such as for example croscarmellose
sodium; glidant such as for example colloidal anhydrous silica;
binders such as for example hydroxypropylcellulose; lubricants such
as for example Magnesium stearate; and a film coat. Any
conventional film coating mixture known to the skilled person can
be applied, e.g. Opadry II pink 85F14411. A representative mixture
for a film-coated tablet is given in Example 6.
[0046] In still another embodiment, there is provided a solid
dispersion as obtained according to the present process for use as
a medicament.
[0047] In yet another embodiment there is provided the use of the
solid dispersion obtainable by the present process in the
manufacture of medicaments for the treatment of cancer, in
particular solid tumors, and more particularly malignant
melanomas.
[0048] In still another embodiment, there is provided the solid
dispersion as obtained according to the present process for use as
a medicament for the treatment of cancer, in particular solid
tumors, and more particularly malignant (metastatic) melanoma.
EXAMPLES
[0049] The invention will become apparent by the following examples
which are given for illustration of the invention rather than
limiting its intended scope.
Example 1
Preparation of the DMA Phase
[0050] The concentration of the compound of formula 1 and HPMCAS in
the organic solvent was 35% (w/w), while the ratio of the compound
of formula 1 and HPMCAS is 30 to 70: The temperature of the
solution was adjusted to 70.degree. C.
[0051] In a 250 ml double jacked glass flask reactor 21 g of the
compound of formula 1 were dissolved in 130 g Dimethylacetamide
(DMA) at 20-25.degree. C. Under stirring, 48.9 g of HPMC-AS were
added to the solution. The mixture was heated up to 70.degree. C. A
clear solution was obtained.
Example 2
Preparation of the Aqueous Phase
[0052] In a double jacketed 2.0 liter reactor 1210 g of 0.01 N HCl
was tempered to 5.degree. C. Out of the bottom valve of the reactor
the water phase was circulated by the high shear mixer or with an
auxiliary pump, preferred a rotary lobe pump, and then followed by
the high shear mixer, back to the top of the reactor. The inlet of
the recirculation into the reactor was under the fluid level in
order to prevent foaming (see FIG. 1).
Example 3
Precipitation
High Shear Mixer
[0053] The tip speed of the rotor in the high shear mixer was set
25 m/sec. A rotor/stator combination with one teeth row, each for
rotor and stator was used.
Dosing of the DMA Solution
[0054] The DMA solution tempered at 70.degree. C. was dosed with a
gear pump via an injector nozzle, which was pointing into the
mixing chamber of the high shear mixer, into the circulating
aqueous phase.
Dosing Rate of the DMA Solution
[0055] The DMA solution was dosed into the aqueous phase resulting
in a ratio of HCl/DMA, in the mixing chamber of the high shear
mixer of 100/1.
Example 4
Additional Dispersing in the HSM (after Precipitation), Isolation
and Washing
[0056] After addition of the DMA solution the obtained MBP
suspension was dispersed for an additional time, corresponding to
equivalents of the batch passing the high shear mixer. The time was
corresponding to a turnover in calculated recirculation times of
the batch of 6 times. The obtained suspension, hold at 5-10.degree.
C. was separated from the solid MBP. This was be done by using a
suction filter. The isolated MBP was washed with 0.01 N HCl (15 kg
0.01 N HCl/kg MBP) followed by a washing with water (5 kg water/kg
MBP) in order to remove the DMA. The isolated (wet) MBP had a water
content between 60 and 70%.
Example 5
Delumping and Drying
[0057] Prior to drying the (wet) MBP was delumped by using a sieve
mill. The (wet) MBP was dried in a cabinet dryer. During the drying
process of the MBP the temperature of the product was below
40.degree. C. in order to avoid recrystallization of the API. The
pressure inside the cabinet dryer was below 20 mbar. The water
content of the MBP after drying was below 2.0% and was signed
amorphous in the XRPD pattern.
Example 6
Film Coated Tablet
TABLE-US-00001 [0058] Component Quantity (mg/tablet) MBP (30%
compound (1), 800.00 70% HPMCAS) Croscarmellose sodium 29.40
Colloidal anhydrous silica 10.40 Hydroxypropylcellulose 4.25
Magnesium stearate 5.95
[0059] The above mentioned ingredients were mixed and pressed into
tablets by conventional means. The film coat consists of Poly(vinyl
alcohol) (8.00 mg), Titanium dioxide (4.98 mg), Macrogol 3350 (4.04
mg), Talc (2.96 mg) and Iron oxide red (0.02 mg). Any other
conventional film coat mixture, like e.g. Opadry II pink 85F14411,
may also be used.
* * * * *