U.S. patent application number 15/370588 was filed with the patent office on 2017-03-23 for unitary pharmaceutical dosage form.
The applicant listed for this patent is BRISTOL-MYERS SQUIBB & GILEAD SCIENCES, LLC. Invention is credited to Terrence C. DAHL, Munir A. HUSSAIN, Robert L. JERZEWSKI, Robert A. LIPPER, Mark M. MENNING, Reza OLIYAI, Taiyin YANG.
Application Number | 20170079999 15/370588 |
Document ID | / |
Family ID | 37532913 |
Filed Date | 2017-03-23 |
United States Patent
Application |
20170079999 |
Kind Code |
A1 |
DAHL; Terrence C. ; et
al. |
March 23, 2017 |
UNITARY PHARMACEUTICAL DOSAGE FORM
Abstract
In accordance with this invention a novel pharmaceutical product
containing efavirenz, emtricitabine and tenofovir DF are provided
as a multicomponent unitary oral dosage form, component 1
comprising tenofovir DF (and, optionally, emtricitabine) and
component 2 comprising efavirenz, wherein components 1 and 2 are in
a stabilizing configuration. In preferred embodiments component 1
is made by dry granulation.
Inventors: |
DAHL; Terrence C.;
(Sunnyvale, CA) ; HUSSAIN; Munir A.; (Belle Mead,
NJ) ; LIPPER; Robert A.; (Pennington, NJ) ;
JERZEWSKI; Robert L.; (Belle Mead, NJ) ; MENNING;
Mark M.; (San Francisco, CA) ; OLIYAI; Reza;
(Burlingame, CA) ; YANG; Taiyin; (Monte Sereno,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BRISTOL-MYERS SQUIBB & GILEAD SCIENCES, LLC |
Foster City |
CA |
US |
|
|
Family ID: |
37532913 |
Appl. No.: |
15/370588 |
Filed: |
December 6, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14640825 |
Mar 6, 2015 |
9545414 |
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15370588 |
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14050714 |
Oct 10, 2013 |
9018192 |
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14640825 |
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11453122 |
Jun 13, 2006 |
8598185 |
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14050714 |
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60771279 |
Feb 7, 2006 |
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60690010 |
Jun 13, 2005 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/513 20130101;
A61P 31/00 20180101; A61K 31/535 20130101; A61K 31/675 20130101;
A61K 31/536 20130101; A61P 31/12 20180101; A61K 9/2054 20130101;
A61K 9/209 20130101; A61P 31/18 20180101; A61K 31/551 20130101;
A61K 31/522 20130101; A61K 31/683 20130101; A61K 9/2077
20130101 |
International
Class: |
A61K 31/683 20060101
A61K031/683 |
Claims
1. A composition comprising tenofovir DF and a surfactant whereby
the surfactant is in a stabilizing configuration with the tenofovir
DF.
2-30. (canceled)
Description
BACKGROUND OF THE INVENTION
[0001] This application relates to products for the treatment of
viral infections, in particular HIV infections, using the known
antiviral compounds efavirenz (tradename Sustiva, also known as
EFV), emtricitabine (tradename Emtriva, also known as FTC) and
tenofovir DF (disoproxil fumarate, also known as TDF) (tradename
Viread, sold in combination with emtricitabine under the tradename
Truvada).
[0002] The Truvada product is produced by wet granulation of
emtricitabine and tenofovir DF (WO 04/64845), which under the
circumstances produces a chemically stable dosage form. This
product does not contain efavirenz.
[0003] HIV therapy using efavirenz as well as emtricitabine and
tenofovir DF has been considered desirable (hereafter "triple
combination"; see WO 04/64845). Manufacturing a commercially viable
triple combination product, however, would require that the final
product meet stringent FDA requirements for bioequivalence to the
commercial products, Viread (tenofovir disoproxil fumarate),
Emtriva (emtricitabine), and Sustiva (efavirenz), and that the
tablet be of suitable size for patients to easily swallow.
[0004] Initial efforts to simply combine the three drugs (active
pharmaceutical intermediates, or APIs) into a unitary, essentially
homogeneous composition manufactured by wet granulation failed to
produce a chemically stable tablet. The tenofovir DF in this
combination tablet was highly unstable and rapidly degraded in
stability studies. The efavirenz formulation was unexpectedly
incompatible with tenofovir DF, a result now attributed to the
surfactant (sodium lauryl sulfate) found in the efavirenz portion
of the formulation.
[0005] Another attempt was made to produce the triple combination,
this time using a dry granulation of the three part combination and
omitting the surfactant. This resulted in a tablet that failed to
achieve bioequivalence with respect to efavirenz in human clinical
trials. The peak efavirenz concentration in the blood stream and
total drug exposure (Cmax and AUC) were both below the parameters
determined for the commercial comparator, Sustiva (efavirenz)
tablets. The inventors concluded that at least the surfactant in
the triple combination (efavirenz/emtricitabine/tenofovir
disoproxil fumarate) tablets was necessary to achieve
bioequivalence to Sustiva.
[0006] Next, combination tablets were manufactured by wet
granulating the efavirenz component with the surfactant and other
excipients, separately manufacturing the Truvada component using
dry granulation, mixing the granulates together, compressing the
mixture into tablets, and then film-coating the tablets.
Unexpectedly, this approach also failed to produce the desired
bioequivalence in between the commercial product, Sustiva
(efavirenz), and clinical trial material (i.e., proposed commercial
triple combination product). A novel and inventive step was needed
to overcome the shortcomings of more straight-forward approaches to
a triple combination dosage form.
[0007] Copending U.S. Ser. No. 60/771,353 (filed of even date and
expressly incorporated herein by reference) is directed to solving
another obstacle encountered in the preparation of the triple
combination dosage form, that of reducing the size of the combined
product. While the prior art reports the successful manufacture of
chemically stable Truvada preparations (WO04/64845), these
preparations contain relatively low proportions of excipient to
API. Increasing the proportion of excipients and wet granulating
the three API combination unexpectedly resulted in a preparation in
which the tenofovir DF was highly unstable. As reported in U.S.
Ser. No. 60/771,353, it was believed that use of sufficient water
to accomplish the wet granulation of efavirenz (which has
relatively low solubility in comparison to emtricitabine and
tenofovir DF) caused the latter two APIs to dissolve into a
eutectic mixture. The eutectic mixture dried during granulation to
form a glassy or amorphous product in which the tenofovir DF is
chemically unstable in comparison to the crystalline API. Supplying
enough excipient to ameliorate the effect of the excess water was
not consistent with the objective of obtaining a triple combination
oral dosage form of manageable proportions.
[0008] As described further in U.S. Ser. No. 60/771,353, this
obstacle was overcome by dry granulating the emtricitabine and
tenofovir DF composition, i.e., granulating the composition without
contacting same with a destabilizing amount of liquid water.
Omitting water (particularly, liquid water) or reducing the
presence of water to an insubstantial amount eliminates the
disadvantages formation of a eutectic mixture and enhances the
stability of the resulting pharmaceutical product.
[0009] Despite the advantages conferred by dry granulation of the
emtricitabine/tenofovir DF component, it was still necessary to
overcome the unexpected incompatibility of tenofovir DF and the
surfactant used in the Sustiva formulation.
SUMMARY OF THE INVENTION
[0010] In accordance with this invention, the stability and
bioequivalence objective for the triple combination product have
been achieved by providing a multicomponent dosage form, one
component comprising tenofovir DF and, optionally, emtricitabine,
and the other comprising at least efavirenz. Another embodiment of
the invention is a dosage form comprising a tenofovir DF component
and a surfactant component not in destabilizing contact with the
tenofovir DF component.
DETAILED DESCRIPTION OF THE INVENTION
[0011] The dosage form of this invention comprises efavirenz,
emtricitabine and tenofovir DF. As noted, tenofovir DF and
efavirenz are in separate components, Emtricitabine generally is
included in the tenofovir DF component, but in other embodiments
the emtricitabine is present in its own component, or is mixed with
the efavirenz component. Its disposition is not critical to the
practice of this invention. All that is necessary is that
emtricitabine be present in the dosage form and that the tenofovir
DF component be substantially separated from the surfactant in the
efavirenz component. Any method, additive, process feature or
configuration that suitably minimizes the contact of surfactant
with tenofovir DF is suitable in the practice of this
invention.
[0012] The term "component" means a physically discrete unit or
compartment which is associated physically with and in contact with
other components. This does not mean that the units or compartments
are physically not in contact. In fact, it generally is preferred
that they are in physical contact and form a unitary device,
article or composition. The degree of association is only that
which is needed to facilitate the oral consumption of the
composition as a single dosage form. This invention does not
include, for example, patient packs with the Sustiva and Truvada
products in separate wells or containers, or other associations
which are essentially packaging solutions alone (although, of
course, the compositions at this invention optionally are packed or
packaged in any conventional fashion suitable under the
circumstances).
[0013] Typically, the components of the dosage form of this
invention conveniently are organized in multiple layers, ordinarily
a bilayer as shown in the exemplified embodiment. However, if
emtricitabine is present in its own component then the dosage form
will constitute at least a trilayer structure. There need not be a
single component for each drug (for example, the dosage forms
optionally include 2 layers for each of the components, for a total
of 6). Thus, the dosage unit includes laminates of many components.
There do not need to be equal numbers of each component, e.g.,
layers, for each drug or drug combination so long as the total
dosage of all components in sum is the desired amount.
[0014] Other means for spatially organizing components are suitable
so long as the desired degree of separation of tenofovir DF and
surfactant is accomplished. For example, rather than forming planar
layers along the axis of a tablet, the components optionally are
organized in an annular fashion, with each ring or cylinder
containing a separate component. Another alternative is to employ a
press coating process to associate the components.
[0015] The components generally are in direct contact with one
another, i.e., no barrier or protective layer is present between
them. In other embodiments, a barrier is introduced between the
incompatible components. A suitable example of this embodiment of
the invention would be a multi-compartment capsule in which the
incompatible components are distributed into separate compartments.
Alternatively, a tablet is optionally provided that contains one
encapsulated component disbursed or distributed within the
incompatible component. In general, intimate, direct admixture of
the incompatible components is undesirable unless means are
provided to protect the tenofovir DF component from surfactant.
[0016] In typical embodiments the components of the dosage form of
this invention are spatially organized so as to not place the
tenofovir DF component into destabilizing contact with the
surfactant in the efavirenz component. "Destabilizing" means any
contact between tenofovir DF and the surfactant that is capable
causing pharmaceutically unacceptable degradation of tenofovir DF.
A stabilizing configuration is any spatial organization of the
tenofovir DF and efavirenz components that does not result in the
generation of a "pharmaceutically unacceptable amount" of any one
of the following degradation products. A destabilizing contact is a
spatial organization that results in the generation of any of the
following degradation products in a "pharmaceutically unacceptable
amount".
[0017] The spatial geometry and conditions of the permitted contact
between tenofovir DF and surfactant-containing component are
essentially unlimited. This spatial geometry is termed a
"stabilizing configuration" or, stated differently, is a
configuration that does not contain a "destabilizing contact" as
defined below. There are many ways in which the central observation
of this invention (that is, that sodium lauryl sulfate destabilizes
tenofovir DF) can be harnessed to prevent the generation of
pharmaceutically unacceptable levels of degradation of tenofovir
DF.
[0018] In addition, when emtricitabine is present in the tenofovir
DF component, the permitted contact also that which does not
produce pharmaceutically unacceptable amounts of emtricitabine
degradation product.
[0019] "Degradation" of tenofovir DF is the generation--in
pharmaceutically unacceptable amounts--of at least one of the
degradation products mono-POC PMPA, dimer or mixed dimer.
"Degradation" of FTC is defined as the generation--in
pharmaceutically unacceptable amounts, of FTU. These degradation
products are shown below.
Mono-POC PMPA
##STR00001##
[0020] Dimeric Degradation Products
[0021] Dimer
##STR00002##
[0022] Mixed Dimmer
##STR00003##
[0023] FTU has the structure
##STR00004##
[0024] A "pharmaceutically unacceptable amount" is defined as the
following amounts of each degradation product. Degradation products
optionally are assayed in either an absolute or incremental amount.
This absolute or total amount of degradation product is simple the
amount found in the test article. The incremental amount is the
additional amount of degradation product appearing in the product
over that which was present (if any) in the API starting material.
Moreover, the amount of degradation product optionally is measured
at two points in time. One is at the time of release into the
marketplace. The other is after exposure to storage conditions
under the conditions described below, i.e., the shelf life as set
forth below.
Total Amounts at Release (First Commercial Sale)
[0025] No more than about 3%, ordinarily about 1.5%, of mono-POC
PMPA.
[0026] No more than about 1%, ordinarily about 0.5of Dimer.
[0027] No more than about 0.5%, ordinarily about 0.25% of Mixed
Dimer.
[0028] Less than about 0.5%, ordinarily about 0.2% of FTU.
Total Amounts at Shelf Life (Storage at 25.degree. C./60% RH for 24
mo.)
[0029] No more than about 10%, ordinarily about 5% of mono-POC
PMPA.
[0030] No more than about 2%, ordinarily about 1% of Dimer.
[0031] No more than about 2%, ordinarily about 1% of Mixed
Dimer.
[0032] No more than about 4%, ordinarily about 2% of FTU.
Incremental Amounts at Release (First Commercial Sale)
[0033] No more than about 2%, ordinarily about 0.5%, of mono-POC
PMPA.
[0034] No more than about 0.6%, ordinarily about 0.1% of Dimer.
[0035] No more than about 0.3%, ordinarily about 0.05% of Mixed
Dimer.
[0036] Less than about 0.4%, ordinarily about 0.1% of FTU
Incremental Amounts at Shelf Life (Storage at 25.degree. C./60% RH
for 24 mo.)
[0037] No more than about 9%, ordinarily about 4% of mono-POC
PMPA.
[0038] No more than about 1.6%. ordinarily about 0.6% of Dimer.
[0039] No more than about 1.8%, ordinarily about 0.8% of Mixed
Dimer.
[0040] No more than about 3.9%, ordinarily about 1.9% of FTU.
[0041] The percentage of degradation products is the amount of
degradation product as measured by HPLC retention time comparison.
In the HPLC retention time comparison, the retention time of the
main peaks observed in the tablets is required to be within 2% of
the retention time of the main peaks in the a reference standard
preparation containing efavirenz, emtricitabine, and tenofovir DF
in an assay which has been shown to be specific for efavirenz,
emtricitabine, and tenofovir DF. The percentage is determined be
dividing the total amount of tenofovir DF plus the three
degradation products into the amount of individual degradation
product as determined by the HPLC assay.
[0042] These parameters are employed to evaluate whether a test
composition has met the requirements of a stabilizing contact. For
example, a triple combination dosage form optionally is designed as
a shaped article comprising slugs of compressed granules of the
tenofovir DF component dispensed within a matrix of the efavirenz
component. A variety of slug sizes might be used in making the
composition. This constellation of potential products then would be
tested, or stored under the conditions above and then tested, to
assay the generation of tenofovir DF and/or FTC degradation
products. If the resulting product upon release did not contain
more than the specified approximate limits of any one or more of
the 4 containments listed under any of the 4 assay paradigms above,
then the contact would be considered stabilizing. Of course, the
artisan may adopt more stringent standards, but this will be a
matter of choice and shall not limit the scope of this
invention.
[0043] In preferred embodiments the emtricitabine and tenofovir DF
are combined and this component is prepared by dry granulation
(U.S. Ser. No. 60/771,353). In preferred embodiments, a composition
comprising dry granulated tenofovir DF and emtricitabine is
employed in one component of the dosage forms of this
invention.
[0044] Dry granulation is a well-known pharmaceutical manufacturing
process per se. In general, API is combined with excipients and
lubricant excipient and then compressed to form a mass. This mass
typically is then comminuted or milled, then sieved to obtain the
desired size of particle. The granular product is compressed into
tablets, filled into capsules or otherwise formed into a unitary
dosage form in conventional fashion.
[0045] Compression into a mass is accomplished by conventional
equipment. Typically, the API and excipients are passed through a
roller apparatus for compaction. However, other means for
compacting the API mixture, e.g., compaction into slugs (or
"slugging"), optionally are used.
[0046] A dry granulation process is one in which a dry composition
of the API and selected excipient(s) is compressed to form a mass,
which is comminuted or milled if necessary, and then optionally
sieved to produce the desired size granules. Compression into a
mass is accomplished by conventional equipment. Typically, the API
and excipients are passed through a roller apparatus for
compaction. However, other means for compacting the API mixture,
e.g., compaction into slugs (or "slugging"), can be used.
[0047] A composition comprising dry granulated emtricitabine and
tenofovir DF is the product of a dry granulation process. This
composition essentially retains the crystalline APIs and is
substantially free of dried eutectic emtricitabine/tenofovir DF. It
typically will contain less than about 15% by weight dried eutectic
mixture, ordinarily less than about 10% and generally less than
about 5%.
[0048] The dry granulation process is conducted in the absence of a
destabilizing amount of water, "destabilizing" being that amount of
liquid water that is capable causing pharmaceutically unacceptable
degradation of tenofovir DF and/or FTC as defined herein. If the
dosage form of this invention includes a dry granulated
emtricitabine/tenofovir DF component, then the amount of permitted
degradation product in the final dosage form is still the same as
that which is set forth above, i.e., the amount of water exposure
and contact, together or alone, are not to result in degradation
products failing to meet the standards described above. It is an
option, of course, to test the dry granulates for their level of
degradation product first, and if they pass, then to formulate them
into the dosage form of this invention and then determine if the
contact results in any increase in degradation products that takes
the resulting dosage form outside the parameters established.
[0049] Bound, entrained or absorbed water are commonly present in
excipients. This water will not significantly adversely affect the
stability of tenofovir DF and thus is not excluded from the dry
granulates optionally used in the dosage form of this invention. In
general, liquid water (added or generated in situ) from any source,
e.g., chemical reactions, condensation, entrained ice, or the like
is to be excluded from the granulation. However, minor amounts of
liquid water optionally are added during granulation. These amounts
typically would be less than about 5% by weight, ordinarily less
than about 1% by weight, however the water is generated or
supplied. Water is present in the final granulation product up to
about 10% by weight (Karl Fischer), but preferably is less, as low
as 0.1% by weight. However, permitted quantities of water may vary
depending upon other factors in the granulation, e.g., excipient
type, temperature and so forth. For example, if a hygroscopic
excipient is included this will convert added water into a bound
form. All that is necessary is that the water not result in
degradation of tenofovir DF and/or emtricitabine in the final
product. In general, water is excluded both from the pregranulation
stage (preparation of the composition to be used directly in the
granulation) as well as during the granulation process itself.
[0050] Absence of water or "dry" does not mean the absence of
liquid. Granulations with organic solvents are also feasible
provided that destabilizing amounts of water are excluded.
[0051] Dry granulation results in a product that contains minimal
amounts of water. The amount of water in the product granulate or
dosage forms made therefrom are measured by loss on drying (LOD) or
by the Karl Fischer method. The LOD of compositions of this
invention are about 15%, about 10%, about 5% or typically less than
about 3% by weight. The Karl Fischer water is about from 0.1 to 10%
by weight, usually less than about 5% by weight, or less than about
2%. The amount of water in the final preparations, as opposed to
the granulates, is a function of granulate water as well as minor
amounts of water used during subsequent process steps such as
coating. These amounts of water added in later steps than
granulation generally will not affect the stability of the
emtricitabine/tenofovir DF APIs, and therefore are subject to
considerable permitted variation.
[0052] The manufacturing process described below is directed to the
preparation of a triple combination tablet containing efavirenz,
emtricitabine and tenofovir DF. In this particular embodiment the
last two drugs are emplaced in a portion of the tablet which is
separate from, but in contact with, the portion of the tablet
containing efavirenz. It will be understood, however, that the
emtricitabine and tenofovir DF component of the tablet, which is an
embodiment of this invention, optionally is manufactured as a
stand-alone product and not necessarily in assembly with an
efavirenz component. In this option, the emtricitabine/tenofovir DF
dry granulation intermediate described below is simple compressed
into tablets or conventionally processed into other conventional
unitary dosage forms such as capsules, cachets, suppositories, or
the like.
[0053] The dosage forms of this invention are stored in containers,
preferably under desiccant such as silica gel in amounts generally
sufficient to maintain the RH over the dosage forms at under about
10%, preferably under about 5%.
Materials
[0054] The quantitative compositions of the efavirenz powder blend,
FTC/TDF powder blend, and film-coated bi-layer EFV/FTC/TDF tablets
are listed in Table 1, Table 2, and Table 3. respectively. The
quantities of efavirenz, emtricitabine, and tenofovir DF were
adjusted for drug content factors (DCF) if the value was less than
0.99 with a concomitant reduction to the quantity of
microcrystalline cellulose in each granulation.
TABLE-US-00001 TABLE 1 Quantitative composition of efavirenz powder
blend % w/w Unit Formula Ingredient of Total (mg/tablet) Efavirenz
38.71 600.0 Microcrystalline Cellulose, NF/EP 11.52 178.6
Hydroxypropyl cellulose, NF/EP 2.48 38.4 Sodium Lauryl Sulfate,
USP/EP 0.77 12.0 Croscarmellose Sodium, NF/EP 3.87 48.0 Magnesium
Stearate, NF/EP 0.58 9.6 Total for Tablet Core 57.94 898.0
TABLE-US-00002 TABLE 2 Quantitative composition of FTC/TDF powder
blend % w/w Unit Formula Ingredient of Total (mg/tablet)
Emtricitabine 12.90 200.0 Tenofovir Disoproxil Fumarate 19.35 300.0
Microcrystalline Cellulose, NF/EP 5.77 89.5 Croscarmellose Sodium,
NF/EP.sup.a 3.10 48.0 Magnesium Stearate, NF/EP.sup.a 0.94 14.5
Total for Tablet Core 42.06 652.0 .sup.aTo be incorporated into
both the intragranular and extragranular portions of the
formulation during the manufacturing process.
TABLE-US-00003 TABLE 3 Quantitative composition of film-coated
bi-layer EFV/FTC/TDF Tablets % w/w Unit Formula Ingredient of Total
(mg/tablet) Efavirenz Powder Blend 57.94 898.0 FTC/TDF Powder Blend
42.06 652.0 Total for Tablet Cores 100.00 1550.0 Opadry II Pink
3.00 46.5 Purified Water, USP/EP.sup.a Total for Film-Coated
Tablets 1596.5 .sup.aWater removed during film-coating process.
[0055] The excipients were all compendial grade materials.
Efavirenz Wet Granulation
[0056] Efavirenz was wet granulated using a Niro-Fielder PMA-400
equipment train. Efavirenz, microcrystalline cellulose and sodium
lauryl sulfate (Table 1) were added to the PMA-400 and blended for
3 minutes. Croscarmellose sodium and hydroxyl propyl cellulose
(Table 1) were added to the pre-mix and blended for an additional 2
minutes. Purified water was added to form a suitable granulation
followed by additional wet massing after water addition. Table 4
lists the summary of granulation parameters used for two
representative lots and sub parts. All sub parts used a water to
efavirenz ratio of 1.30 except for AB509 Mix C which used a 1.25
ratio of water to efavirenz.
TABLE-US-00004 TABLE 4 Efavirenz wet granulation process parameter
summary AB507 AB509 Mix Mix Mix Mix Mix Mix Process Parameter A B C
A B C Granula- Total Water 33.57 33.56 33.56 33.56 33.56 32.18 tion
Added (kg) Ratio of 1.30 1.30 1.30 1.30 1.30 1.25 Water:EFV Total
Addition 9:36 9:29 9:24 9:17 9:32 9:02 Time (Min:Sec) Final
Impeller 10.4 9.8 8.5 11.3 11.3 9.9 Power (% Load) Wet Total Time
4:00 3:00 3:00 2:00 1:15 2:00 Massing (Min:Sec) Final Impeller 11.6
12.0 11.7 18.0 17.7 10.5 Power (% Load) Drying.sup.a Inlet
Temperature 70 70 (.degree. C.) Time (Hr:Min) 1:45 1:51 Final
Outlet 50 50 Temp. (.degree. C.) Final LOD 0.3 0.8 (%) .sup.aMixes
A, B, and C for each lot were combined before drying.
[0057] In general, the wet granules were milled, then dried to an
LOD less than or equal to 1.5%. The dried granules were milled and
blended with magnesium stearate (Table 1).
[0058] The bulk density, particle size, and moisture content by LOD
of the efavirenz granulations are listed in the first three lines
of Table 5 (the B lot numbers are efavirenz products, the C lot
numbers are emtricitabine/tenofovir DF). Particle size was
determined by sitting 10-gram samples through 3-inch diameter
screens using a sonic sifter (Model L3P, ATM Corporation,
Milwaukee, Wis., USA). This following US Standard Mesh sizes
(openings) were used: #20 (850 .mu.m), #30 (600 .mu.m), #40 (425
.mu.m), #60 (250 .mu.m), #80 (180 .mu.m), and #250 (63 .mu.m). The
agitation and pulse were set at 7 and the sifting time was 5
minutes. The amount of powder retained on the sieves and the fines
collector was determined by calculating the difference in weight
before and after sifting. The geometric mean particle size was
calculated by logarithmic weighting of the sieved distribution.
[0059] Bulk density was determined by filling a 100-mL graduated
cylinder with sample and calculating the difference in weight
between the empty and full graduated cylinder per unit volume.
[0060] Moisture content measurements by loss on drying (LOD) were
performed by heating a 2.5 g sample at 85.degree. C. for 15 minutes
using a heat lamp/balance system (Model LP16/PM400, Mettler-Toledo,
Columbus, Ohio, USA).
[0061] The granulations had similar bulk densities (0.54 to 0.56
g/mL) and similar geometric mean particle size distributions (215
to 268 .mu.m). The LOD value of the final blend were consistent
from 0.98 to 1.80%. The individual sieve distributions for the
efavirenz granulations are listed in Table 6.
TABLE-US-00005 TABLE 5 Summary of efavirenz powder blend and
emtricitabine/tenofovir DF powder blend physical properties
Geometric Mean Diameter Gilead Particle Size Bulk Density LOD Lot
Number (.mu.m) (g/mL) (%) AB507 247 0.56 1.80 AB508 215 0.55 1.08
AB509 268 0.54 0.98 AC507 330 0.60 0.91 AC508 344 0.60 1.02 AC509
343 0.59 0.99
TABLE-US-00006 TABLE 6 Particle size distribution for efavirenz and
FTC/TDF powder blends % Weight Retained on Screen.sup.a US Standard
Screen Size (mesh opening) Gilead 20 30 40 60 80 230 pan Lot
(>850 (600 (425 (250 (180 (63 (<63 Number .mu.m) .mu.m)
.mu.m) .mu.m) .mu.m) .mu.m) .mu.m) AB507 5.9 10.9 16.2 22.2 11.4
22.6 10.9 AB508 6.1 10.4 15.8 20.0 9.0 20.8 17.9 AB509 9.6 13.3
17.4 20.1 8.9 17.2 13.3 AC507 22.0 19.8 15.2 11.2 4.6 10.5 16.6
AC508 22.1 20.1 15.4 11.6 5.1 10.6 14.9 AC509 22.4 19.7 15.3 11.7
4.8 11.1 14.8
Emtricitabine/Tenofovir DF Dry Granulation
[0062] Emtricitabine, microcrystalline cellulose, tenofovir DF, and
croscarmellose (Table 2) were blended in a 650 L tote bin using a
Gallay blender for 10 minutes. Magnesium stearate (Table 2) was
added and blended for an additional 5 minutes. This pre-blend was
then transferred to a 320-L Matcon bin fitted with a cone valve
discharging station to assist with material transfer into the
roller compactor hopper.
[0063] The pre-blend was roller compacted using a Gerteis
Macro-Pactor model 250/25/3 with 250 mm diameter by 50 mm wide
smooth rolls. The roll gap thickness (2 mm), roll spread (10 rpm),
compaction force (4 kN/cm), oscillating mill speed (75 rpm
clockwise and counterclockwise), and oscillating mill screen
opening (1.25 mm) were kept constant for all batches. The
oscillating mill angle of rotation was also the same for all lots
at 150.degree. clockwise and 140.degree. counterclockwise.
[0064] There was no material handling issues among all three
batches while feeding into the roller compactor. The entire roller
compaction process proceeded without any apparent sign of heat
accumulation of the equipment, product build-up, or melting. The
granulations then were blended with extragranular croscarmellose
sodium (34% of total amount) and magnesium stearate (47% of total
amount).
[0065] The particle size, bulk density, and LOD of the
emtricitabine/tenofovir DF dry granulations were all similar for
the three batches and are listed in Table 5 (bottom 3
compartments). The geometric particle sizes were very similar at
from 330 to 344 .mu.m. Bulk densities ranged from 0.59 to 0.60
g/mL. The final blend LOD values were consistent from 0.91 to
1.02%. The final powder blends have remarkably consistent physical
properties.
[0066] The efavirenz and tenofovir DF granulations each have
geometric mean particle sizes that optionally range from 100 to 600
.mu.m, bulk densities optionally ranging about from 0.1 to 1 g/mL
and LOD values optionally ranging about from 0.1 to 10% by
weight.
Final Blends
[0067] The mass of efavirenz granulation and extragranular
magnesium stearate were adjusted appropriately based on the yield
of emtricitabine/tenofovir DF dry granulation. Efavirenz
granulation and emtricitabine/tenofovir DF dry granulation were
blended in a 3 cubic foot V-blender for 10 minutes. Magnesium
stearate was added and blended an additional 5 minutes. Samples of
the final powder blend were taken from 10 different locations after
blending and analyzed for blend uniformity. The efavirenz and
emtricitabine/tenofovir DF final powder blends showed acceptable
blend uniformity and homogeneity for all three active ingredients
indicating the robustness of the formulation regardless of the
particle size or bulk density of emtricitabine/tenofovir DF dry
granulations and efavirenz granulations. The granulations and
blending procedure would be satisfactory for the formulation of a
larger scale.
Tablet Core Compression
[0068] Efavirenz/emtricitabine/tenofovir DF final powder blend was
compressed into table cores using a Stokes Genesis Model 757, 41
station bilayer tablet press equipped plain-faced upper/embossed
"123" lower, capsule-shaped (20.0 mm.times.10.4 mm) punches. The
target mass of the tablet cores was 1550 mg. Samples of the core
tablets were taken from a minimum of 20 equally spaced locations
during the compression run and analyzed for content uniformity. In
general, all powder blends compressed satisfactory on the rotary
tablet press with respect to tablet hardness, friability, tablet
thickness, tablet appearance, and tablet weight variation. The
compression operation was performed at a rate of approximately 500
tablets/minute (12 rpm press speed) or approximately 0.8 kg/minute
to deliver satisfactory tablet weight uniformity.
Tablet Film-Coating
[0069] Suitable film coatings are selected by routine screening of
commercially available preparations. This activity is well within
the skill of the ordinary artisan. Each lot of tablet cores was
divided into two coating sub-lots that were film coated in a
48-inch Thomas Engineering COMPU-LAB coating pan using a
dual-nozzle spraying system. All the tablet cores were film-coated
using a 15% w/w aqueous coating suspension Opadry II Pink, which
was used within 24 hours of preparation. All tablets cores were
coated to a target weight gain of 3.0% using a target spray rate of
180 g/min, which corresponds to a normalized spray rate of 1.5 to
2.3 g/min/kg tablets.
HPLC Assay for Degradation Products
[0070] Efavirenz/emtricitabine/tenofovir DF tablets (EFV/FTC/TDF
tablets) are assayed by HPLC for EFV, FTC, and TDF using external
reference standards. The degradation products of EFV, FTC, and TDF
are determined by area normalization with the application of
relative response factors, as appropriate. The identity of EFV,
FTC, and TDF are confirmed by comparison of their retention times
with those of the reference standards.
Standard and Sample Solution Preparation
Standard and Sample Solvent
25 mM Phosphate Buffer, pH 3
[0071] Weigh and transfer 3.4 g of potassium phosphate monobasic,
anhydrous into a 1 L volumetric flask. Add about 800 mL of water
and mix until dissolved.
[0072] Adjust the pH to 3.0.+-.0.1 with phosphoric acid, then
dilute to volume with water.
Sample Solvent (40:30:30: 25 mM Phosphate Buffer, pH
3:Acetonitrile:Methanol)
[0073] Combine 400 mL of 25 mM Phosphate Buffer, pH 300 mL of
acetonitrile, and 300 mL of methanol and mix. Allow to equilibrate
to ambient temperature.
50:50 Acetonitrile:Methanol
[0074] Combine 500 mL of acetonitrile and 500 mL of methanol and
mix. Allow to equilibrate to ambient temperature.
Standard Solution
[0075] Accurately weigh approximately 60 mg of EFV reference
standard 20 mg of FTC reference standard, and 30 mg of TDF
reference standard and transfer into a 100 mL volumetric flask. Add
approximately 80 mL of sample solvent (40:30:30) to the flask and
mix or sonicate until dissolved. Dilute to volume with sample
solvent (40:30:30) and mix well. The final concentration of each
component is approximately 0.6 mg/mL of EFV, 0.2 mg/mL of FTC, and
0.3 mg/mL of 100.
System Suitability Test Solutions
Sensitivity Check Standard
[0076] Prepare a 10 .mu.g/mL FTU stock solution by accurately
weighing out approximately 10 mg of the FTU authentic substance
into a 100 mL volumetric flask. Add sample solvent (40:30:30) to
approximately 80% of volume and mix or sonicate until dissolved.
Dilute to volume with sample solvent (40:30:30) and mix well. Pipet
10 mL of this solution into a 100 mL volumetric flask. Dilute to
volume with sample solvent (40:30:30) and mix well.
[0077] Prepare the sensitivity check standard containing 0.2 mg/mL
of FTC and 0.2 .mu.g/mL of FTU (0.10% relative to FTC). Accurately
weigh out 20 mg FTC into a 100 mL volumetric flask. Using a Class A
pipet, transfer 2.0 mL of the FTU stock solution into the same
flask. Add additional sample solvent (40:30:30) to the flask and
mix or sonicate until dissolved. Dilute to volume with sample
solvent (40:30:30) and mix well. Alternatively, 2.0 mL of the 10
.mu.g/mL FTU stock solution may be added to the standard solution
prior to diluting to volume.
Sample Preparation for EFV/FTC/TDF Tablets
[0078] The strength and degradation product content of EFV/FTC/TDF
tablets is determined by the analysis of a composite solution
prepared from ten tablets.
[0079] The final concentration of each component in the sample
solution is approximately 0.6 mg/mL of EFV, 0.2 mg/mL of FTC, and
0.3 mg/mL of TDF. [0080] a) Place ten tablets into a 1 L volumetric
flask and add 400 mL 25 mM phosphate buffer, pH 3 to the volumetric
flask. [0081] b) Mix by stirring vigorously for about 75 minutes.
[0082] c) Add 50:50 acetonitrile:methanol to the flask to
approximately 2 cm below the volume mark. [0083] d) Equilibrate the
solution to ambient temperature by mixing for an hour. Dilute to
volume with 50:50 acetonitrile:methanol. Mix well by inverting the
flask or stirring with a magnetic stir bar. [0084] e) Using a 0.45
.mu.m syringe filter with a syringe, filter approximately 10 mL of
step (d) for the next dilution. Discard the first 2 mL of filtrate.
[0085] f) Using a Class A pipet, transfer 5.0 mL of the filtrate
from step (e) into a 50 mL volumetric flask and dilute to volume
with sample solvent (40:30:30). Mix well.
Chromatography
[0086] 1. An HPLC equipped with a UV detector and an electronic
data acquisition system is used.
[0087] 2. An HPLC column, 4.6 mm i.d. by 250 mm long, packed with
C12 reversed phase, 4 .mu.m particle size, 80 .ANG. pore size
material is used.
[0088] 3. Mobile phase buffer: Prepare a 20 mM ammonium acetate
buffer, pH 4.6; adjust pH with acetic acid as needed.
[0089] 4. Mobile phase gradient: Elute with Mobile Phase
Buffer:acetonitrile from 99:1 to 1:99 over 67 minutes.
[0090] 5. Peak detection: UV at 262 nm
[0091] 6. Injection volume: 10 .mu.L
[0092] Under the stated chromatographic conditions, the retention
times of the FTC, TDF and EFV peaks are typically 11, 33, and 50
minutes, respectively.
Injection Sequence
[0093] Inject the sample solvent at least twice as a blank to
ensure that the column is equilibrated and to identity any
potential artifact peaks.
[0094] Inject the sensitivity check standard or standard solution
containing approximately 0.10% FTU to measure the sensitivity of
detection.
[0095] Inject five replicates of standard solution 1 (R1), followed
by a single injection of standard solution 2 (R2). Calculate the
theoretical plates and tailing factors from the standard solution
injections.
[0096] For identity, strength, and degradation products
determination, perform duplicate injections of the sample
solution.
[0097] All sample solutions must be bracketed by standard solution
injections. Generally, not more than ten sample solution injections
between bracketing standard injections is recommended.
System Suitability
Theoretical Plates and Tailing Factor
[0098] Calculate the number of theoretical plates (N) and the
tailing factors (T) for the EFV, FTC, and TDF peaks from the
Standard Solution Chromatogram. The formulas for N and T
determination are defined in the current United States
Pharmacopeia. The values of these parameters must conform to the
criteria :N.ltoreq.40,000 and 0.8.ltoreq.T.gtoreq.2.0.
Sensitivity Check
[0099] The sensitivity check will utilize the FTU peak in the
sensitivity check standard present at approximately 0.10%.
Calculate the area percent of the FTU peak with the appropriate RRF
(listed in Table 2) applied for the sensitivity check standard
using the calculation for percent individual degradation product.
Compare this result to the theoretical percent of FTU for the
sensitivity check standard as follows:
Sensitivity = FTU Determined FTU Theoretical ##EQU00001##
Where
[0100] FTU.sub.Determined=area percent of FTU determined for the
sensitivity check standard or standard solution [0101]
FTU.sub.Theoretical=theoretical area percent of FTU for the
sensitivity check standard or standard solution
[0102] The sensitivity must be between 0.70-1.30.
Evaluation and Calculations
Identification of Degradation Products
[0103] Employ the appropriate detection parameters (such as peak
threshold, minimum peak area, etc.) to allow detection of peaks
present at 0.05% or less. Identify the impurities and degradation
products of EFV, FTC, and TDF present in the chromatograms of the
sample solution injections by noting the relative retention times
(RRT) of the observed secondary peaks, discounting any peaks not
related to the sample. Only degradation products are quantified.
Calculate the average of the results from all sample solutions
injections to the nearest 0.01%. In cases where the degradation
product was not detected or was below the threshold of integration
in one injection and/or sample, use only the quantified results in
the recalculation (i.e., do not treat as a zero value).
RRT = retention time of the secondary peak retention time of the
tenofovir disoproxil peak ##EQU00002##
[0104] The RRTs and the relative response factor (RRF) values of
the potential impurities and degradation products for EFV are shown
in Table 1, and the degradation products are shown in bold-face.
The impurities and degradation products for FTC are shown in Table
2, and the degradation products are in bold-face. The impurities
and degradation products for TDF are shown in Table 3, and the
degradation products are in bold face.
[0105] As the RRT may vary, the identity of impurities and
degradation products may be confirmed by comparison to authentic
substances (or to impurity and degradation product peaks in the
reference standard), if required.
Degradation Product Content Determination
Quantification of FTC Degradation Products
[0106] Determine the level of each degradation product of FTC
observed in the chromatograms of the sample solution injections
using the following formula:
Degradation Product ( % ) = 1 TPA .times. RRF .times. 100
##EQU00003##
Where:
[0107] I=Area of the degradation product peak [0108] TPA=Total peak
area (area of FTC and all related degradation products, excluding
impurities and artifacts), corrected by RRF. [0109] RRF=Relative
response factor with respect to FTC
8.4.3 Quantification of TDF Degradation Products
[0110] Determine the level of each degradation product of TDF
observed in the chromatograms of the sample solution injections
using the following formula:
Degradation Product ( % ) = 1 TPA .times. RRF .times. 100
##EQU00004##
Where
[0111] I=Area of the degradation product peak or unassigned peak
[0112] TPA=Total peak area (area of the TDF main peak, all related
degradation products, and all unassigned peaks, excluding
impurities and artifacts), corrected by RRF [0113] RRF=Relative
response factor with respect to TDF
Results and Reporting
Degradation Products Content
[0114] Report individually the average of the results for each
degradation product observed to the nearest 0.01%. Report the total
degradation product content of EFV, FTC, and TDF respectively to
the nearest 0.1%, as the sum of the average levels of all
degradation product peak observed. For degradation products found
at levels less than 0.05%, report their levels as trace and do not
include their levels in the calculation of total degradation
product content.
REFERENCES
[0115] United State Pharmacopeia <621>
[0116] Pharmacopeial Forum 26(4) 2000
TABLE-US-00007 TABLE 1 EFV related impurities and degradation
products EFV Related Approximate Compound RRT.sup.a RRF.sup.b
SD-573.sup.c 1.46 0.5 SR-695.sup.d 1.50 EFV 1.50 SP-234 1.57 SW-965
1.60 SE-563 1.73 SM-097.sup.c 1.83 0.5 .sup.aApproximate RRTs, and
the values are relative to the TDF peak .sup.bRRFs for EFV related
degradation products are relative to EFV .sup.cEFV related
degradation products .sup.dSR-695 elutes before EFV (approximately
0.1 min separation) Degradation products are marked in bold
face
TABLE-US-00008 TABLE 2 FTC related degradation product FTC Related
Approximate Compound RRT.sup.a RRF.sup.b FTC 0.33 FTU.sup.c 0.38
0.7 .sup.aApproximate RRTs, and the values are relative to the TDF
peak .sup.bRFs for FTC related degradation products are relative to
FTC .sup.cFTC related degradation products
TABLE-US-00009 TABLE 3 Tenofovir DF related degradation products
TDF Related Approximate Compound RRT.sup.a RRF.sup.b mono-POC
PMPA.sup.c 0.47 0.6 Mixed Dimer.sup.c 0.98 1.0 TDF 1.00 Dimer.sup.c
1.34 0.9 .sup.aApproximate RRTs, and the values are relative to the
TDF peak .sup.bRRFs for TDF related degradation products are
relative to TDF .sup.cTDF related degradation products
* * * * *