U.S. patent application number 14/131282 was filed with the patent office on 2014-05-22 for darunavir combination formulations.
This patent application is currently assigned to Janssen R&D Ireland. The applicant listed for this patent is Urbain Alfons C Delaet, Philip Erna H. Heyns, Eugeen Maria Jozef Jans, Roel Jos M. Mertens, Geert Van Der Avoort. Invention is credited to Urbain Alfons C Delaet, Philip Erna H. Heyns, Eugeen Maria Jozef Jans, Roel Jos M. Mertens, Geert Van Der Avoort.
Application Number | 20140142070 14/131282 |
Document ID | / |
Family ID | 46551505 |
Filed Date | 2014-05-22 |
United States Patent
Application |
20140142070 |
Kind Code |
A1 |
Delaet; Urbain Alfons C ; et
al. |
May 22, 2014 |
DARUNAVIR COMBINATION FORMULATIONS
Abstract
This invention relates to solid oral dosage forms of the HIV
inhibitor Darunavir and/or a pharmaceutically acceptable salt or
solvate thereof, and combination formulations thereof.
Inventors: |
Delaet; Urbain Alfons C;
(Balen, BE) ; Heyns; Philip Erna H.; (Vosselaar,
BE) ; Jans; Eugeen Maria Jozef; (Meerhout, BE)
; Mertens; Roel Jos M.; (Balen, BE) ; Van Der
Avoort; Geert; (Retie, BE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Delaet; Urbain Alfons C
Heyns; Philip Erna H.
Jans; Eugeen Maria Jozef
Mertens; Roel Jos M.
Van Der Avoort; Geert |
Balen
Vosselaar
Meerhout
Balen
Retie |
|
BE
BE
BE
BE
BE |
|
|
Assignee: |
Janssen R&D Ireland
Little Island, Co Cork
IE
|
Family ID: |
46551505 |
Appl. No.: |
14/131282 |
Filed: |
July 6, 2012 |
PCT Filed: |
July 6, 2012 |
PCT NO: |
PCT/EP2012/063249 |
371 Date: |
January 7, 2014 |
Current U.S.
Class: |
514/158 ;
264/129 |
Current CPC
Class: |
A61K 9/2054 20130101;
A61K 31/635 20130101; A61K 9/1652 20130101; A61K 9/2009 20130101;
A61K 9/2095 20130101; A61K 31/5377 20130101; A61P 31/18 20180101;
A61P 37/04 20180101; A61K 31/5377 20130101; A61P 31/00 20180101;
A61K 31/635 20130101; A61K 9/28 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101 |
Class at
Publication: |
514/158 ;
264/129 |
International
Class: |
A61K 31/635 20060101
A61K031/635; A61K 9/20 20060101 A61K009/20; A61K 9/28 20060101
A61K009/28 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 7, 2011 |
EP |
11173067.7 |
Claims
1. An oral dosage form comprising about 0.4 to 0.6% by weight (w/w)
of a lubricant, about 3% by weight (w/w) of a disintegrant, 17 to
20% by weight (w/w) of silicon dioxide loaded with GS-9350
corresponding to a total amount of about 150 mg free form
equivalent of GS-9350 and about 50 to 60% by weight (w/w) of
darunavir granulate, said darunavir granulate consisting of
darunavir and/or a pharmaceutically acceptable salt or solvate
thereof, Hypromellose and any residual water from the
granulation.
2. An oral dosage form according to claim 1, wherein the silicon
dioxide loaded with GS-9350 is colloidal silicon dioxide.
3. An oral dosage form according to claim 1, wherein the
Hypromellose is Hypromellose 2910 15 mPas.
4. An oral dosage form according to claim 1, comprising about 0.5%
by weight (w/w) of a lubricant
5. An oral dosage form according to claim 1, wherein the
desintegrant is polyplasdone XL-10 and the lubricant is magnesium
stearate
6. An oral dosage form according to claim 1, comprising about 800
mg free form equivalent of Darunavir.
7. A process for preparing an oral dosage form as claimed in claim
1 which comprises the steps of: Providing granulated darunavir by;
mixing water and Hypromellose, spraying this first mixture on a
powder of darunavir and/or a pharmaceutically acceptable salt or
solvate thereof, and drying the so obtained darunavir granulate
Providing a second mixture comprising microcrystalline cellulose,
silicon dioxide loaded with GS-9350, a disintegrant, Adding
granulated darunavir to the mixture and subsequent dry-blending
Adding a lubricant and mixing until homogeneous, Compressing the
mixture to provide the oral dosage form, said oral dosage form then
being optionally film-coated.
8. A process for preparing an oral dosage form according to claim
7, wherein the silicon dioxide loaded with GS-9350 is colloidal
silicon dioxide.
9. An oral dosage form as claimed in claim 1 for use in
medicine.
10. An oral dosage form as claimed in claim 1 for use in the
treatment of HIV infection.
11. A method for the treatment of an HIV infection in a subject
which comprises administering to the subject an effective amount of
an oral dosage form as claimed in claim 1.
Description
FIELD OF THE INVENTION
[0001] This invention relates to solid oral dosage forms of the HIV
inhibitor darunavir and combination formulations thereof.
BACKGROUND OF THE INVENTION
[0002] The treatment of Human Immunodeficiency Virus (HIV)
infection, known as cause of the acquired immunodeficiency syndrome
(AIDS), remains a major medical challenge. HIV is able to evade
immunological pressure, to adapt to a variety of cell types and
growth conditions and to develop resistance against currently
available drug therapies. The latter include nucleoside reverse
transcriptase inhibitors (NRTIs), non-nucleoside reverse
transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase
inhibitors (NtRTIs), HIV-protease inhibitors (PIs) and the more
recent fusion inhibitors.
[0003] Although effective in suppressing HIV, each of these drugs,
when used alone, is confronted with the emergence of resistant
mutants. This led to the introduction of combination therapy of
several anti-HIV agents usually having a different activity
profile. In particular the introduction of "HAART" (Highly Active
Anti-Retroviral Therapy) resulted in a remarkable improvement in
anti-HIV therapy, leading to a large reduction in HIV-associated
morbidity and mortality. Current guidelines for antiretroviral
therapy recommend such triple combination therapy regimen even for
initial treatment. However, none of the currently available drug
therapies is capable of completely eradicating HIV. Even HAART may
face the emergence of resistance, often due to non-adherence and
non-persistence with antiretroviral therapy. In these cases HAART
can be made effective again by replacing one of its components by
one of another class. If applied correctly, treatment with HAART
combinations can suppress the virus for many years, up to decades,
to a level where it no longer can cause the outbreak of AIDS.
[0004] Because of their pharmacokinetic properties and the need to
keep plasma levels above a minimum level, currently used anti-HIV
drugs require frequent administration of relatively high doses. The
number and/or volume of dosage forms that need to be administered
are commonly referred to as the "pill burden". A high pill burden
is undesirable for many reasons, such as the frequency of intake,
often combined with the inconvenience of having to swallow large
dosage forms, as well as the need to store and transport a large
number or volume of pills. A high pill burden increases the risk of
patients not taking their entire dose, thereby failing to comply
with the prescribed dosage regimen. As well as reducing the
effectiveness of the treatment, this also leads to the emergence of
viral resistance. The problems associated with a high pill burden
are multiplied where a patient must take a combination of different
anti-HIV agents or agents in combination with a so called booster
to improve pharmacokinetic properties.
[0005] Providing high dosage forms that have a relatively small
size contributes to the convenience of intake and therefore also
helps to overcome problems of pill burden.
[0006] Therefore, it would be desirable to provide HIV inhibitory
therapy that reduces pill burden in that it involves the
administration of dosage forms of a practical size and additionally
does not require frequent dosing.
[0007] One class of HIV drugs that is used in HAART is that of the
PIs amongst which is darunavir (TMC114), approved in the U.S., the
E.U. and a number of other countries and available under the trade
name Prezista.TM.. Darunavir, currently marketed in the form of
darunavir monoethanolate, has the following chemical name:
[(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(-
phenylmethyl)-propyl]-carbamic acid
(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester monoethanolate.
Its molecular formula is
C.sub.27H.sub.37N.sub.3O.sub.7S.C.sub.2H.sub.5OH, with a molecular
weight of 593.73, and the following chemical structure:
##STR00001##
[0008] Darunavir as well as processes for its preparation are
disclosed in EP 715618, WO99/67417, U.S. Pat. No. 6,248,775, and in
Bioorganic and Chemistry Letters, Vol. 8, pp. 687-690, 1998,
"Potent HIV protease inhibitors incorporating high-affinity
P.sub.2-ligands and (R) (hydroxyethylamino)sulfonamide isostere",
all incorporated herein by reference.
[0009] Improved combination formulations of darunavir with
pharmacokinetic boosters, e.g. cytochrome P.sub.450 inhibitors, are
disclosed in WO03/049746.
[0010] An example of a suitable cytochrome P.sub.450 inhibitor is
GS-9350, also known under the name Cobicistat. GS-9350 is loaded on
silicon dioxide, preferably colloidal silicon dioxide, and has the
following chemical name:
12-methyl-13-[2-(1-methylethyl)-4-thiazolyl]-9-[2-(4-morpholinyl)ethyl]-8-
,11-dioxo-3,6-bis(phenylmethyl)-, 5-thiazolylmethyl ester,
(3R,6R,9S)--. Its molecular formula is
C.sub.40H.sub.53N.sub.7O.sub.5S.sub.2, with a molecular weight of
776.023 g/mol, and the following chemical structure:
##STR00002##
GS-9350 as well as processes for its preparation are disclosed in
WO2008/010921, WO2008/103949 and WO2009/135179, all incorporated
herein by reference.
[0011] Because high darunavir dosage forms are inevitably large in
size, higher dose or combination dosage forms would take a size
that surpasses the convenience barrier. In order to reduce
pill-burden it would be desirable to achieve a dosage form with an
increased weight % of darunavir per dosage form. This would
facilitate either the generation of a higher dose tablet, or a
reduction in size of the present dose tablets. It would be
additionally desirable to combine darunavir, especially high
dosages of darunavir, and a pharmacokinetic booster agent e.g.
GS-9350 in one dosage form.
[0012] A darunavir tablet containing 600 mg of active ingredient
and having a total weight of 1250 mg per tablet is disclosed in
WO/2009/013356. The oral dosage forms are formed by direct
compression of the ingredients.
[0013] Higher dose darunavir formulations, dose-proportionally
derived from the currently marketed 600-mg tablet, were not deemed
desirable for use by patients because of their large size.
[0014] Furthermore, the direct compression method led to inferior
results when increasing the percentage of darunavir in the
formulation. Inferior results are obtained due to limited gliding
and flowing capacity of such a formulation. This is also the case
when other actives are added to the formulation.
[0015] The present invention is based on the unexpected finding
that a high weight % load of darunavir per dosage form is
facilitated by the granulation of darunavir before formulation.
[0016] Granulation of darunavir according to the present invention
thus facilitates a high loading of darunavir in a single dosage
form (>80% (w/w)) or the combination of darunavir with other
active ingredients and still having an acceptable size of the
dosage form.
[0017] The present invention thus provides anti-HIV therapy
involving the administration of darunavir dosage forms of
acceptable size, potentially as a combination formulation, thereby
requiring less frequent dosing. Hence, present dosage forms are
beneficial in terms of pill burden and drug compliance of the
patient.
SUMMARY OF THE INVENTION
[0018] In one aspect the invention relates to an oral dosage form
comprising about 0.4 to 0.6% by weight (w/w) of a lubricant, about
3% by weight (w/w) of a disintegrant, 17 to 20% by weight (w/w) of
silicon dioxide, preferably colloidal silicon dioxide, loaded with
GS-9350 corresponding to a total amount of about 150 mg free form
equivalent of GS-9350 and about 50 to 60% by weight (w/w) of
darunavir granulate, said darunavir granulate consisting of
darunavir and/or a pharmaceutically acceptable salt or solvate
thereof, Hypromellose and any residual water from the
granulation.
[0019] Preferably, the Hypromellose is Hypromellose 2910 15
mPas.
[0020] In yet another aspect, the invention relates to a process
for preparing an oral dosage form according to the invention
comprising the steps of: [0021] Providing granulated darunavir by;
mixing water and Hypromellose, spraying this first mixture on a
powder of darunavir and/or a pharmaceutically acceptable salt or
solvate thereof, and drying the so obtained darunavir granulate
[0022] Providing a second mixture comprising microcrystalline
cellulose, silicon dioxide, preferably colloidal silicon dioxide
loaded with GS-9350, a disintegrant, [0023] Adding granulated
darunavir to the mixture and subsequent dry-blending [0024] Adding
a lubricant and mixing until homogeneous, [0025] Compressing the
mixture to provide the oral dosage form, said oral dosage form then
being optionally film-coated.
[0026] In yet another aspect, the present invention relates to an
oral dosage form according to the invention for use in medicine,
more specifically for use in the treatment of HIV infections
[0027] In yet another aspect, the invention relates to a method for
the treatment of an HIV infection in a subject which comprises
administering to the subject an effective amount of an oral dosage
form according to the invention.
DESCRIPTION OF THE INVENTION
[0028] The present invention provides an oral dosage form of
darunavir and GS-9350 that is manufactured by using a darunavir
granulate.
[0029] By making use of this granulate, the weight percentage
darunavir can be increased per dosage form, thus generating oral
dosage forms with a high dose of free from equivalent of darunavir
(e.g. 800 mg). Additionally, the size and weight of existing dosage
forms (e.g. 400 or 600 mg) can be reduced by about 25%.
[0030] Advantageously, the solid oral dosage forms can comprise
additional active ingredients such as pharmacokinetic boosters,
e.g. GS-9350 and still be of an acceptable size. The size of the
dosage forms of the invention, i.e. the total weight of the dosage
forms, should be below a limit of convenience which is below the
size at which a number of patients starts having difficulty taking
in the dosage form. The total weight of the dosage forms of the
invention preferably is below about 1700 mg, and in particular
below about 1650 mg.
[0031] The oral dosage forms of the present invention preferably
are tablets.
[0032] As used herein, the term "darunavir" is meant to comprise
the base form, any pharmaceutically acceptable acid addition salt
thereof, as well as any pharmaceutically acceptable solvate
thereof. The pharmaceutically acceptable addition salts as
mentioned hereinabove the therapeutically active non-toxic acid
addition salt forms, which darunavir is able to form. In one
embodiment the term "darunavir" is meant to comprise the base form,
as well as any pharmaceutically acceptable solvate thereof.
[0033] The term pharmaceutically acceptable solvate comprises the
hydrates and the solvent addition forms that darunavir can form.
Examples of such forms are e.g. hydrates, alcoholates, e.g.
methanolates, ethanolates and propanolates, and the like.
[0034] Particular solvates are the ethanolate, e.g. the
monoethanolate.
[0035] As used herein the term "free-form equivalent" refers to
that quantity of darunavir or GS-9350, whether present in free form
(or base form), or as salt or solvate, that corresponds to a given
quantity of free form darunavir or GS-9350. For example 650 mg of
darunavir monoethanolate corresponds to 600 mg of free-form
equivalent darunavir.
[0036] For application in adults, high quantities of the active
ingredients may be used. In such instance, the dosage forms of the
invention contain from about 500 to about 900 mg, in particular
from about 600 mg to about 800 mg, for example about 800 mg, of
free-form equivalent darunavir per unit of the dosage form.
[0037] The darunavir in the dosage forms of the invention is added
to the formulation process in the form of a darunavir granulate
composition consisting of Darunavir or a pharmaceutically
acceptable salt or solvate thereof, Hypromellose and any residual
water from the granulation.
[0038] Preferably, the Darunavir is present in the form of its
ethanolate and the Hypromellose is Hypromellose 2910 15 mPas.
[0039] The amount of darunavir in the granulate composition may be
in the range from about 95% to about 100%, in particular about 97%
to about 99.9%, or about 98% to about 99%, by weight relative to
the total weight of the granulate composition comprising darunavir
and Hypromellose 2910 15 mPas. The granulate composition may
additionally contain residual water that is not completely removed
during processing.
[0040] The average particle size of the granulate is between 100
and 500 .mu.m, more preferably from 150 to 400 .mu.m and even more
preferably about 300 .mu.m.
[0041] As used herein, the term average particle size has its
conventional meaning as known to the person skilled in the art and
can be measured by art-known particle size measuring techniques
such as, for example, sedimentation field flow fractionation,
photon correlation spectroscopy, laser diffraction or disk
centrifugation. The average particle sizes mentioned herein may be
related to weight distributions of the particles. In that instance,
by "an average particle size of about 150 .mu.m" it is meant that
at least 50% of the weight of the particles have a particle size of
less than average of 150 .mu.m, and the same applies to the other
particle sizes mentioned. In a similar manner, the average particle
sizes may be related to volume distributions of the particles but
usually this will result in the same or about the same value for
the average effective particle size.
[0042] Granulation of darunavir preferably is performed in a
fluid-bed granulator. Preferably, darunavir is granulated by using
Hypromellose. More preferably, Hypromellose 2910 15 mPas is used.
According to the present invention, darunavir is granulated without
any filler or other excipients before formulation of the tablet
core.
[0043] Preferably, the oral dosage forms according to the present
invention will comprise a pharmacokinetic booster such as a
cytochrome P.sub.450 inhibitor. A preferred example of a cytochrome
P.sub.450 inhibitor is GS-9350. GS-9350 is provided as loaded on
silicon dioxide, preferably colloidal silicon dioxide. A suitable
process for the preparation of silicon dioxide, preferably
colloidal silicon dioxide, loaded with GS-9350 is described in WO
2009/135179, as incorporated herein by reference. The dosage forms
of the invention comprise about 150 mg of free-form equivalent
GS-9350 per unit of the dosage form.
[0044] GS-9350 can be used in base form or as a pharmaceutically
acceptable addition salt form, in particular as an acid addition
salt form, or as a pharmaceutically acceptable solvate. The
pharmaceutically acceptable addition salts are meant to comprise
the therapeutically active non-toxic salt forms.
[0045] The weight/weight ratio darunavir:GS-9350 may vary, but in
one embodiment it is in the range from about 10:1 to about 4:5, in
particular said ratio may be about 5:1.
[0046] Oral dosage forms according to the present invention will
preferably comprise pharmaceutically acceptable carriers and
excipients. Such inactive ingredients are added to help hold the
tablet together and give it strength, among others binders, fillers
disintegrant glidants and lubricants.
[0047] A wide variety of binders may be used, some common ones
including lactose, dibasic calcium phosphate, sucrose, corn (maize)
starch, microcrystalline cellulose and modified cellulose (for
example hydroxymethyl cellulose). Other such materials are silicon
dioxide, titanium dioxide, alumina, talc, kaolin, powdered
cellulose, as well as soluble materials such as mannitol, urea,
sucrose, lactose, dextrose, sodium chloride, and sorbitol. Such
agents may sometimes also be referred to as "fillers".
[0048] Microcrystalline cellulose that can be used comprises the
Avicel.TM. series of products available from FMC BioPolymer, in
particular Avicel PH 105.RTM. (20 .mu.m), Avicel PH 101.RTM. (50
.mu.m), Avicel PH 301.RTM. (50 .mu.m);
the microcrystalline cellulose products available from JRS Pharma,
in particular Vivapur.RTM. 105 (20 .mu.m), Vivapur.RTM. 101 (50
.mu.m), Emcocel.RTM. SP 15 (15 .mu.m), Emcocel.RTM. 50M 105 (50
.mu.m), Prosolv.RTM. SMCC 50 (50 .mu.m); the microcrystalline
cellulose products available from DMV, in particular
Pharmacel.RTM.105 (20 .mu.m), Pharmacel.RTM.101 (50 .mu.m); the
microcrystalline cellulose products available from Blanver, in
particular Tabulose (Microcel).RTM.101 (50 .mu.m), Tabulose
(Microcel).RTM.103 (50 .mu.m);
[0049] the microcrystalline cellulose products available from Asahi
Kasei Corporation, such as Ceolus.RTM. PH-F20JP (20 .mu.m),
Ceolus.RTM. PH-101 (50 .mu.m), Ceolus.RTM. PH-301 (50 .mu.m),
Ceolus.RTM. KG-802 (50 .mu.m).
[0050] A particularly preferred microcrystalline cellulose is
Ceolus.RTM. KG-802, average particle size (50 .mu.m). Additional
characteristics of Ceolus.RTM. KG-802 are a bulk density of about
0.2 (g/cm.sup.3) and an angle of repose of about 49.degree..
[0051] The average particle size of the Microcrystalline cellulose
may be in the range of from 5 .mu.m to 60 .mu.m, in particular from
10 .mu.m to 50 .mu.m, e.g. about 20 .mu.m.
[0052] In addition to the presence of any of the above indicated
ingredients, the tablet formulation according to the invention
contains a lubricant. This provides a formulation which avoids
manufacturing problems such as tablet sticking when the drug
product blend is compressed into tablets.
[0053] The lubricant is preferably magnesium stearate and is
generally present in an amount of 0.4 to 0.6% w/w, particularly
about 0.5% w/w.
[0054] The tablet formulation also contains a disintegrant to aid
disintegration and dissolution of the formulation upon
administration to the patients. The preferred disintegrant is
crospovidone, namely a synthetic homopolymer of cross-linked
N-vinyl-2-pyrrolidone available commercially as Polyplasdone XL-10
and is preferably present in an amount of 1 to 4% w/w, especially
about 3% w/w. Other disintegrants which may be used include
croscarmellose sodium (sodium salt of cross-linked
carboxymethylcellulose), available commercially as Acdisol.
[0055] The above tablet formulations can be used to make tablet
cores in conventional manner for example by initially dry blending
the ingredients, that preferably having been sieved. Subsequently,
the lubricant is added to the dry-blended mixture for final
dry-blending of the total tablet core blend, which is then
compressed into tablets having the desired size and weight.
[0056] For taste-masking and cosmetic reasons the tablet cores
according to the invention are generally provided with a film
coating for example an Opadry film-coating, which is generally used
in an amount of about 4% w/w based on the tablet core. Different
coloring agents may be used in the film coating in order to
differentiate between tablet strengths.
[0057] The coating can be applied to the core in coating suspension
for example in purified water, followed by drying of the coated
cores.
[0058] The administration of a dosage form in accordance with the
present invention may suffice to treat HIV infection although it
may be recommendable to co-administer other HIV inhibitors. The
latter preferably include HIV inhibitors of other classes, in
particular an NRTI, or NNRTI, but also a fusion inhibitor can be
added. HIV inhibitors that may be co-administered by preference are
those used in HAART combinations.
[0059] In certain instances, the treatment of HIV infection may be
limited to only the dosage form of the invention, without
co-administration of further HIV inhibitors. This option may be
recommended, for example, where the viral load is relatively low,
e.g. where the viral load (represented as the number of copies of
viral RNA in a specified volume of serum) is below about 200
copies/ml, in particular below about 100 copies/ml, more in
particular below 50 copies/ml, specifically below the detection
limit of the virus. This type of monotherapy may be applied after
initial treatment with a combination of HIV drugs, such as any of
the HAART combinations during a certain period of time until the
viral load in blood plasma reaches the afore mentioned low viral
level.
[0060] In a further aspect the present invention relates to the use
of a dosage form in accordance with the invention, for the
manufacture of a medicament for maintenance therapy of a subject
infected with HIV. The present invention also relates to the use of
a dosage form in accordance with the invention, for the manufacture
of a medicament for treating a subject infected with HIV, wherein
the dosage form is combined with two different NRTIs or NNRTIs.
[0061] As used herein the term "treatment of HIV infection" relates
to a situation of the treatment of a subject being infected with
HIV. The term "subject" in particular relates to a human being.
[0062] The doses of darunavir and GS-9350 in the dosage forms of
the invention are selected so as to keep the blood plasma
concentration of darunavir above the minimum blood plasma level
between two administrations. The term "minimum blood plasma level"
in this context refers to the lowest efficacious blood plasma
level, the latter being that blood plasma level of active that
provides effective treatment of HIV. The plasma levels of anti-HIV
compounds should be kept above these threshold blood plasma levels
because at lower levels the drugs may no longer be effective
thereby increasing the risk of mutations.
[0063] The dosage forms of the present invention provide effective
treatment of HIV infection in that the viral load is reduced while
keeping viral replication suppressed. The limited number of drug
administrations adds to the patients' compliance with the
prescribed therapy.
[0064] As used herein, the word "substantially" does not exclude
"completely" e.g. a composition which is "substantially free" from
Y may be completely free from Y. Where necessary, the word
"substantially" may be omitted from the definition of the
invention. The term "about" in connection with a numerical value is
meant to have its usual meaning in the context of the numerical
value. Where necessary the word "about" may be replaced by the
numerical value .+-.10%, or .+-.5%, or .+-.2%, or .+-.1%. All
documents cited herein are incorporated by reference in their
entirety.
EXAMPLES
General
[0065] Excipients used throughout the examples are listed in Table
1.
TABLE-US-00001 TABLE 1 Excipients Excipient Reference name PROSOLV
.RTM. SMCC HD90 HD90 Hypromellose 2910 15 mPa.s Methocel E15LV
premium Colloidal Anhydrous Silic.sup.a Cab-O-Sil M5P.sup.b
Crospovidone Polyplasdone XL-10 Magnesium Stearate Vegetal, type
5712 Coating powder brick red Opadry II brick red 85F250001
.sup.aColloidal Anhydrous Silica is alternately known as Colloidal
Silicon Dioxide .sup.bAlternative is Aerosil 200 from Degussa
[0066] The film coating, combined with debossing and differences in
tablet size, aids in the differentiation of the tablet strengths. A
secondary function of the film coating is taste masking.
[0067] The excipients used in Opadry II red 85F250001 are listed in
Table 2.
TABLE-US-00002 TABLE 2 Composition for Coating powder brick red
(Opadry II red 85F250001) Component Composition (w/w) Polyvinyl
alcohol 40.00 Polyethylylene glycol 3350 20.20 Talc 14.80 Titanium
dioxide 3.26 Iron Oxide Red 20.01 Iron Oxide Yellow 1.21 Iron Oxide
Black 0.52
Example 1
Darunavir Granulation
1: Granulation
[0068] A high dose formulation, e.g. 800-mg darunavir formulation,
dose-proportionally derived from the currently marketed 600-mg
tablet, was not perceived as suitable for use by patients because
of its large size. Furthermore, direct compression of an 800 mg
formulation proved not possible due to severely limited gliding and
flowing capacity. The formulations studied are shown in Table
3.
TABLE-US-00003 TABLE 3 Formulations used in concept feasibility
testing A B C Ingredients mg/tab % mg/tab % mg/tab % darunavir
867.28 69.38 867.28 72.27 867.28 72.27 MCC.sup.a -- -- 287.12 23.93
-- -- HPMC 2910 -- -- -- -- 24.00 2.00 15 mPa s Purified
water.sup.b -- -- 1043 .mu.l -- 600 .mu.l -- Prosolv HD90 337.08
26.97 -- 266.72 22.23 Crospolyvidone 25.01 2.00 36.00 3.00 36.00
3.00 Colloidal 11.38 0.91 3.60 0.30 -- -- anhydrous silica
Magnesium 9.25 0.74 6.00 0.50 6.00 0.50 stearate Total 1250 100
1200 100 1200 100 .sup.aMCC = Microcrystalline Cellulose (Avicel
PH101) .sup.bPurified water does not appear in the final
product
Direct Compression Formulation A:
[0069] All ingredients, except magnesium stearate, were sieved over
a stainless steel screen of 0.95 mm and blended for 10 minutes
using a lab-scale planetary mixer. In a second blending step, the
magnesium stearate was sieved and mixed for 5 minutes. The blend
was not compressed, because of the bad flowability (angle of
repose).
Wet Granulation Formulation B:
[0070] The powders of the internal phase (API/MCC) were sieved over
a stainless steel screen with 0.95 mm sieve openings and
transferred into the granulation insert of the fluid bed granulator
GPCG1.
[0071] The purified water (without binder) was sprayed on the
powder mixture. The process conditions for the granulation are
reported in the table below.
TABLE-US-00004 TABLE 4 Granulation conditions (B) Mixing/heating
Granulation Drying Air flow 63 > 64 m.sup.3/h 64 <> 112
m.sup.3/h 108 > 65 m.sup.3/h Spray rate -- 13 -> 23 g/min. --
Atomizing air flow 1.0 bar 1.0 bar 1.0 bar Inlet air temperature
60.degree. C. (set) 45.degree. C. (set) 60 > 70.degree. C. (set)
60 > 45.degree. C. (actual) 45 <> 77.degree. C. (actual)
Outlet air temperature 24 > 30.degree. C. 29 > 24.degree. C.
23 > 38.degree. C.
[0072] The dried granules and the excipients of the external phase
were sieved (0.95 mm) and blended for 10 min. In a second step, the
magnesium stearate was sieved, added and blended for 5 min. The
granulate after sieving was tested for granulometrics and LOD.
[0073] This final mixture was compressed at different compression
forces (750.fwdarw.2000 kg), using a single punch tablet press. The
obtained tablets (nom. weight 1200 mg, punch AC27/42: 20
mm.times.9.5 mm, radius 3 mm, oblong shape) were analyzed for
hardness, disintegration time and dissolution.
Wet Granulation Formulation C:
[0074] The API was sieved over a stainless steel screen with 0.95
mm sieve openings and transferred into the granulation insert of
the fluid bed granulator GPCG1.
[0075] The binder solution (HPMC 15 cps 4% solution in water) was
sprayed on the powder mixture. The process conditions for the
granulation are reported in the table below.
TABLE-US-00005 TABLE 5 Granulation conditions GPCG1 (C)
Mixing/heating Granulation Drying Air flow 60 m.sup.3/h 60 <>
113 m.sup.3/h 93 > 90 m.sup.3/h Spray rate -- 20 g/min --
Atomizing air 1.0 bar 1.0 bar 1.0 bar flow Inlet air 60.degree. C.
(set) 45 <> 55.degree. C. (set) 60.degree. C. (set)
temperature 51 <> 56.degree. C. 57 <> 68.degree. C.
(actual) (actual) Outlet air 24 > 31.degree. C. 31 >
24.degree. C. 25 > 38.degree. C. temperature
[0076] The dried granules and the excipients of the external phase
were sieved (0.95 mm) and blended for 10 min. In a second step, the
magnesium stearate was sieved, added and blended for 5 min.
[0077] Tablet characteristics of the compression mixtures (B and C
are shown in Table 6. The Direct Compression concept A was not
compressed, because of insufficient flowability (high angle of
repose) of the blend. Tablet hardness was measured according to
industry standard.
TABLE-US-00006 TABLE 6 Compression data and tablet characteristics
Comp. force 750 kg 1000 kg 1250 kg 1500 kg 1750 kg 2000 kg B Blend
Flow Tendency towardsrat holing in hopper Aspect Tablet splitting -
lackof binding OK Hardness - daN NE.sup.1 18.0 Disint. time -
NE.sup. 134 sec C Blend Flow Good flow (out of hopper) Aspect OK
(no defects) Hardness - daN 8.8 11.9 14.6 15.6 19.4 19.0 Disint.
time - ' 2'11'' 3'13'' 6'18'' 15'34'' 21'29'' 23'23'' '' .sup.1NE =
not executed
[0078] Concept (C), in which the darunavir is granulated solely
with an aqueous HPMC 15 mPas binder solution and Prosolv HD90
filler material is added extra-granularly (i.e., in the final dry
mixture), provided a superior process.
2: Darunavir 800 Mg Representative Formulation
[0079] Based on the superior process including granulation, a
representative oral dosage form comprising 800 mg free from
equivalent of darunavir was formulated. The qualitative and
quantitative composition of such a representative oral dosage form
is provided in Table 7.
TABLE-US-00007 TABLE 7 Representative darunavir (TMC114) 800-mg
Tablet 800 mg Component (mg/tablet) (% wt) Core Tablet darunavir
Ethanolate 867.28.sup.a 78.84 Hypromellose 2910 15 mPa s 13.20 1.20
Purified water.sup.b 330.00 .mu.L 0.00 Silicified Mycrocrystalline
177.72 16.16 Cellulose.sup.c Crospovidone 33.00 3.00 Colloidal
Anhydrous Silica 3.30 0.30 Magnesium Stearate 5.50 0.50 Core Tablet
Weight 1100.00 100.00 Film Coating Coating powder brick red 44.00
4.00 Purified Water.sup.b 176.00 .mu.L 0.00 Total Tablet Weight
1144.00 104.00 .sup.aQuantity of darunavir ethanolate equivalent to
800 mg of darunavir. .sup.bPurified Water does not appear in the
final product. .sup.cA commercially available (`Prosolv HD90`),
spray-dried mixture consisting of 98% (w/w) microcrystalline
cellulose and 2% (w/w) colloidal silicon dioxide, individually
meeting compendial requirements.
3: Large Scale Manufacturing Process According to the Present
Invention
[0080] Several large scale badges were produced according to the
specifications below.
Preparation of the 4% Binder Solution:
[0081] 1/3 of total quantity of purified water was warm up until
75-85.degree. C. [0082] Hypromellose 2910 15 mPas was added while
mixing with strong vortex. [0083] After mixing for 10-20 min, the
rest of (cold) purified water was added, while mixing with vortex
for 5-10 minutes. The creation of foam was avoided by pouring the
water slowly along the wall of the vessel. [0084] The solution was
cooled and de-aerated until is clear and the temperature was = or
<30.degree. C. [0085] Gentle mixing was applied for 1-2 min
before the start of the granulation.
Wet Granulation Conditions (on GPCG-30 Granulator)
[0086] Darunavir was transferred into the granulation insert of the
fluid bed granulator GPCG-30 and pre-warmed. The binder solution
(HPMC 15 cps 4% solution in water) was sprayed on the powder
mixture and finally the granulate was dried. The GPCG-30 fluid-bed
parameters used for the batches granulated at target, dry and wet
condition, respectively, are listed in the tables below.
TABLE-US-00008 TABLE 8 Granulation conditions on GPCG-30, target
condition, D Pre-warming Granulation Drying Air flow 500 m.sup.3/h
700 > 950 m.sup.3/h 950 > 700 m.sup.3/h Spray rate -- 200
> 250 g/min -- Atomizing -- 3.2 bar -- air flow Inlet air
60.degree. C. 50.degree. C. 60.degree. C. temperature Outlet air
36.degree. C. (end) 24.3.degree. C. (end) 37.degree. C. (end)
temperature
TABLE-US-00009 TABLE 9 Granulation conditions on GPCG-30, target
condition, E Pre-warming Granulation Drying Air flow 500 m.sup.3/h
700 > 950 m.sup.3/h 950 > 700 m.sup.3/h Spray rate -- 200
> 250 g/min -- Atomizing -- 3.2 bar -- air flow Inlet air
60.degree. C. 50.degree. C. 65.degree. C. temperature Outlet air
36.degree. C. (end) 24.9.degree. C. (end) 37.degree. C. (end)
temperature
TABLE-US-00010 TABLE 10 Granulation conditions on GPCG-30, dry
condition, F Pre-warming Granulation Drying Air flow 500 m.sup.3/h
700 > 800 m.sup.3/h 800 m.sup.3/h Spray rate -- 180 g/min --
Atomizing -- 3.2 bar -- air flow Inlet air 60.degree. C. 55.degree.
C. 65.degree. C. temperature Outlet air 36.degree. C. (end)
25.7.degree. C. (end) 37.degree. C. (end) temperature
TABLE-US-00011 TABLE 11 Granulation conditions on GPCG-30, wet
condition, G Pre-warming Granulation Drying Air flow 500 m.sup.3/h
750 > 1300 m.sup.3/h 1050 > 850 m.sup.3/h Spray rate -- 220
g/min -- Atomizing air flow -- 3.2 bar -- Inlet air temperature
55.degree. C. 45.degree. C. 65.degree. C. Outlet air temperature
35.degree. C. (end) 22.6.degree. C. (end) 37.degree. C. (end)
Blending and Compression Conditions
[0087] The dried granules were sieved through a hand sieve size
with 0.95 mm openings and subsequently blended with external phase
excipients (sieved through to 0.95 mm hand sieve) in a Gallay bin
blender for 10 min at 9 rpm. In a second step, the magnesium
stearate was sieved, added and blended for 5 min.
[0088] Physical characteristics of the granulates and the final
blends (compression mixtures) are listed in the tables below.
TABLE-US-00012 TABLE 12 Physical characteristics of the granulate E
F G D target dry wet target cond. cond. cond. cond. before after
before before before sieving sieving sieving sieving sieving Loose
bulk volume 2.16 2.18 2.20 2.24 2.08 (ml/g) Tapped bulk volume 1.98
1.98 1.99 2.00 1.91 (ml/g) Hausner index 1.09 1.10 1.11 1.12 1.09
Carr index 8.33 9.17 9.55 10.71 8.17 Angle of repose 37.degree.40'
39.degree.30' 39.degree.40' 44.degree.20' 36.degree.40' d50 (.mu.)
318 313 302 265 393 d84 (.mu.) 184 198 196 162 256 d84/d50 0.58
0.63 0.65 0.61 0.65 Fraction <75.mu. (%) 0.4 0.2 0.2 0.2 0.0
TABLE-US-00013 TABLE 13 Physical characteristics of the final blend
D target cond. E F G formula w/o target cond. dry cond. wet cond.
aerosil final formula final formula final formula Loose bulk 2.06
2.08 2.11 1.98 volume (ml/g) Tapped bulk 1.80 1.84 1.88 1.78 volume
(ml/g) Hausner index 1.14 1.13 1.12 1.11 Carr index 12.62 11.54
10.90 10.10 Angle of 43.degree.20' 36.degree.20' 37.degree.40'
35.degree.40' repose (36.degree.50').sup.1 d50 (.mu.) 318 263 244
332 d84 (.mu.) 179 146 139 198 d84/d50 0.56 0.55 0.57 0.60 Fraction
3.9 5.9 6.8 5.4 <75.mu. (%)
Compression Results
[0089] The final blend of the batches was compressed at nominal
weight (1100 mg) at different compression forces and speeds on a
Courtoy module S high-speed rotary tablet press (10-16 punches)
using a demo punch (oval shape) set with dimension 19.times.9.5 mm.
The obtained tablets were analyzed for weight, hardness, thickness,
aspect, disintegration time and friability. During compression the
compression settings, incl. ejection force were monitored.
[0090] The tablet cores compressed at target compression force
(13N) were also coated on a lab-scale coater according to the final
formulation composition (with Opadry II red at 4% level).
[0091] Despite the reasonably broad variation in GPCG-30 fluid-bed
granulation conditions used, acceptable physical characteristics of
the granulate and final blends are obtained in all cases (tables 12
and 13). As expected, a finer and less dense granulate is obtained
when dryer thermodynamic conditions are used. Blend flowability
improves with the addition of aerosil [(37.degree. 40' vs
43.degree. 20' for batches E (with aerosil) and batches D (without
aerosil), respectively], confirming the functionality of the
aerosil glidant material. The addition of the external phase
excipients has a beneficial effect on material flowability.
[0092] Very similar physical characteristics are obtained for the
granulates of batches D and E manufactured under (almost) identical
granulation conditions, confirming the reproducibility of the
fluid-bed granulation process.
[0093] Drying of the granulate until an outlet-air temperature of
37.degree. C. is reached results in a narrow LOD result range
within 5.2 to 6.0% for the granulate and within 5.6 to 6.1% for the
final blend, confirming the reproducibility of the drying process
regardless of the granulation (thermodynamic) condition used.
Example 2
Darunavir GS-9350 Co-Formulation
2.1 Preparation of Darunavir Granulate
[0094] A binder solution was prepared analogous to wet granulation
form C.
[0095] The quantitative and qualitative composition of 1000 mg
representative darunavir granulate as obtained by the described
process is provided in Table 14.
TABLE-US-00014 TABLE 14 Quantitative and Qualitative Composition of
darunavir granules Component Quantity (mg) darunavir ethanolate
985.00 Hypromellose 2910 15 mPa s 15.00 Purified water.sup.a 374.79
Total 1,000 .sup.aRemoved during processing
2.2 Oral Dosage Forms Comprising Darunavir and GS-9350
2.2.1 For Darunavir/GS-9350 Eq. 800/150-mg Oral Film Coated Tablets
(I):
[0096] 1. 14.97 kg of the dried darunavir granules was sieved
through an appropriate screen together with 4.896 kg GS-9350 loaded
on colloidal silicon dioxide, 2.846 kg silicified microcrystalline
cellulose, 1.897 kg microcrystalline cellulose and 765 g
crospovidone [0097] 2. Mixture was collected in a suitable blender
and mixed until homogeneous [0098] 3. 127.5 g of magnesium stearate
was sieved through an appropriate screen and add to the content of
the blender [0099] 4. Mixed until homogeneous [0100] 5. Compressed
into tablets on a suitable tablets press
2.2.2 For Darunavir/GS-9350 Eq. 800/150-mg Oral Film Coated Tablets
(II):
[0100] [0101] 1. 14.09 kg of the dried darunavir granules was
sieved through an appropriate screen together with 4.608 kg GS-9350
loaded on colloidal silicon dioxide, 6.008 kg silicified
microcrystalline cellulose and 768 g crospovidone [0102] 2. Mixture
was collected in a suitable blender and mix until homogeneous
[0103] 3.128 g of the magnesium stearate was sieved through an
appropriate screen and add to the content of the blender [0104] 4.
Mixed until homogeneous [0105] 5. Compressed into tablets on a
suitable tablets press
2.3 Coating
[0106] The tablet cores were transferred into a suitable coating
apparatus where the tablet cores were warmed up by supplying warm
air. Subsequently the spraying of a coating suspension on the
tablets was started and the coated tabled were dried in the coating
apparatus.
2.4. Results
[0107] 2.4.1
[0108] The quantitative and qualitative composition of 800/150-mg
oral film coated tablet (I) is provided in Table 15.
TABLE-US-00015 TABLE 15 Quantitative and Qualitative Composition of
the 800/150-mg oral film coated tablets (I) Quantity per tablet
(mg) Component GS-9350 loaded on colloidal silicon 288.00 dioxide
darunavir 908.6 mg/g granules 880.48 Silicified microcrystalline
cellulose 167.41 Microcrystalline cellulose (Ceolus 111.61 KG802)
Crospovidone 45.00 Magnesium stearate.sup.a 7.50 Core tablet weight
1500.00 Film coating Coating powder white 45.00 Purified
water.sup.b 180.00 Total tablet weight 1545.00 .sup.aVegetable
grade .sup.bRemoved during processing
2.4.2
[0109] The quantitative and qualitative composition of 800/150-mg
oral film coated tablet (II) is provided in Table 16.
TABLE-US-00016 TABLE 16 Quantitative and Qualitative Composition of
800/150-mg oral film coated tablets (II) Quantity per tablet (mg)
Component GS-9350 loaded on colloidal silicon dioxide 288.00
darunavir 908.6 mg/g granules 880.48 Silicified microcrystalline
cellulose 375.52 Crospovidone 48.00 Magnesium stearate.sup.a 8.00
Core tablet weight 1600.00 Film coating Coating powder white 48.00
Purified water.sup.b 192.00 Total tablet weight 1648.00
.sup.aVegetable grade .sup.bRemoved during processing
[0110] As can be observed, the addition of Microcrystalline
cellulose (Keolus KG802) even further reduces the oral dosage form
weight.
* * * * *