U.S. patent application number 16/735143 was filed with the patent office on 2020-05-07 for tenofovir granules.
This patent application is currently assigned to STEERLIFE INDIA PRIVATE LIMITED. The applicant listed for this patent is STEERLIFE INDIA PRIVATE LIMITED. Invention is credited to Indu BHUSHAN, Radhika GHIKE, Vinay RAO.
Application Number | 20200138719 16/735143 |
Document ID | / |
Family ID | 62977406 |
Filed Date | 2020-05-07 |
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United States Patent
Application |
20200138719 |
Kind Code |
A1 |
BHUSHAN; Indu ; et
al. |
May 7, 2020 |
TENOFOVIR GRANULES
Abstract
The present invention relates to a granular composition
comprising essentially Tenofovir, wherein the composition is devoid
of an excipient. Tenofovir granules of the present invention are
prepared in twin-screw processor such that the content of total
impurities in the prepared granules is less than 2.0%.
Inventors: |
BHUSHAN; Indu; (Bengaluru,
IN) ; RAO; Vinay; (Bengaluru, IN) ; GHIKE;
Radhika; (Bengaluru, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
STEERLIFE INDIA PRIVATE LIMITED |
Bengaluru |
|
IN |
|
|
Assignee: |
STEERLIFE INDIA PRIVATE
LIMITED
Bengaluru
IN
|
Family ID: |
62977406 |
Appl. No.: |
16/735143 |
Filed: |
January 6, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
15881413 |
Jan 26, 2018 |
10561614 |
|
|
16735143 |
|
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/1688 20130101;
A61K 31/683 20130101; A61K 9/2009 20130101; A61K 9/2013 20130101;
A61P 1/16 20180101; A61K 31/675 20130101; A61K 9/2054 20130101 |
International
Class: |
A61K 9/16 20060101
A61K009/16; A61K 31/675 20060101 A61K031/675; A61K 9/20 20060101
A61K009/20; A61K 31/683 20060101 A61K031/683 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 27, 2017 |
IN |
201741003161 |
Claims
1. A process for preparing a granular composition consisting
essentially of Tenofovir devoid of an excipient and with content of
total impurities not more than 2.0% in twin screw processor
comprising the steps of: a. feeding Tenofovir into the intake zone
of the twin screw processor; b. conveying Tenofovir towards the
kneading zone and processing it in the kneading zone; c. conveying
Tenofovir from the kneading zone towards the exit; d. collecting
the Tenofovir granules.
2. The process for preparing granular composition of Tenofovir as
claimed in claim 1 wherein the temperature of the barrel in the
twin screw processor is between 25.degree. C. and 60.degree. C.
3. The process for preparing granular composition of Tenofovir as
claimed in claim 2 wherein the content of Tenofovir isoproxil
monoester is not more than 1%; and wherein the content of Tenofovir
disoproxil dimer is not more than 0.15%.
4. The process for preparing granular composition of Tenofovir as
claimed in claim 2 wherein the content of adenine is not more than
0.15%, the content of Tenofovir isoproxil monoester is not more
than 1%, the content of Tenofovir disoproxil ethyl ester is not
more than 0.15%, the content of Tenofovir isopropyl isoproxil is
not more than 0.3%, the content of Tenofovir disoproxil carbamate
is not more than 0.15% and the content of Tenofovir disoproxil
dimer is not more than 0.15%.
5. The process for preparing granular composition of Tenofovir as
claimed in claim 1 wherein the said composition is stable after
storage at 40.degree. C. and 75% Relative Humidity for a period of
at least 3 months.
6. The process for preparing granular composition of Tenofovir as
claimed in claim 1 wherein the said composition is stable after
storage at 25.degree. C. and 60% Relative Humidity for a period of
at least 3 months.
7. The process for preparing granular composition of Tenofovir as
claimed in claim 1 wherein the said composition is stable after
storage at 2.degree. C. to 8.degree. C. for a period of at least 3
months.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 15/881,413, filed Jan. 26, 2018, which claims benefit of Serial
No. 201741003161, filed 27 Jan. 2017 in India and is incorporated
herein by reference. To the extent appropriate, a claim of priority
is made to the above disclosed application.
FIELD OF THE INVENTION
[0002] The present invention relates to a granular composition
consisting essentially of Tenofovir, wherein the composition is
devoid of an excipient.
BACKGROUND OF THE INVENTION
[0003] Tenofovir, is chemically, 9-[2-(R)-(phosphonomethoxy)
propyl] adenine (PMPA). Tenofovir disoproxil is a pro-drug of
Tenofovir. It has increased oral bioavailability compared to
Tenofovir. Tenofovir is approved for commercial use as in the form
of Tenofovir disoproxil fumarate (TDF), chemically known as
9-[(R)-2-[[bis[[(isopropoxycarbonyl)oxy]-methoxy]phosphinyl]
methoxy] propyl] adenine fumarate (1:1).
[0004] Tenofovir Disoproxil Fumarate 300 mg Tablets are indicated
in combination with other anti-retrovirals for the treatment of
HIV-1 infection in adults and adolescents aged over 12 years.
Tenofovir Disoproxil Fumarate 300 mg Tablets are indicated for the
treatment of chronic hepatitis B in adults and adolescents aged
over 12 years with compensated liver disease, with evidence of
active viral replication, persistently elevated serum alanine
aminotransferase (ALT) levels and histological evidence of active
inflammation and/or fibrosis.
[0005] Tenofovir disoproxil fumarate (TDF) is observed to have poor
flow properties, therefore aqueous or non-aqueous wet granulation
is a preferred processing step in the formulation of the TDF
tablets, by most pharmaceutical manufacturers. Also, as per
International Journal of Drug Development & Research, 2012,
Volume 4, Issue 1, Pages 247-256; for Emtricitabine and Tenofovir
disoproxil fumarate film coated tablets, wet granulation with
pregelatinized starch as binder was found to be the best method of
choice for formulation of these tablets, as compared to direct
compression.
[0006] Literature is also available on non-wet granulation
techniques for compounding Tenofovir. For example--EP 2389929A1
discloses compositions of Tenofovir with pregelatinized starch
(5-15%) by weight prepared by direct compression. IN 2621/CHE/2013
discloses a hot-melt extruded Tenofovir disoproxil composition
having a binder. 843/CHE/2013 discloses an extrusion-spheronization
process for preparation of oral multi-particulate compositions
composed of Tenofovir coated with ethyl cellulose or methacrylic
acid co-polymers. CN103330683 B discloses hot-melt extrusion of
Tenofovir disoproxil fumarate with sweetener and polymer
Kollidon.RTM. VA64, Kollicoat.RTM. IR andSoluplus.RTM. to prepare
fine granules. European Patent Document EP1890681 B1 describes a
method comprising dry granulating a composition comprising a
pharmaceutically acceptable excipient, emtricitabine and tenofovir
DF to produce dry granules.
[0007] However, none of the references suggest or disclose free
flowing directly compressible Tenofovir granules devoid of an
excipient, or a process for preparation of such granules. Such
granules would be specifically more advantageous in case of unit
dose antiretroviral oral fixed dose combinations where there is a
larger percentage of API in the finished dosage form. For
example--Atripla.RTM. tablets, Complera.RTM. tablets, Stribild.RTM.
tablets, Emtricitabine200 mg/Tenofovir disoproxil fumarate 300
mg+Nevirapine 200 mg tablets, etc. Besides, since TDF is sensitive
towards hydrolytic degradation. It would be highly desirable to
process TDF in conditions which can prevent or minimize such
hydrolytic degradation. Further, it would be most desirable to
prepare free flowing directly compressible Tenofovir granules
devoid of an excipient which can remain stable at 40.degree. C. and
75% relative humidity for three months.
[0008] As per, Authorized USP Pending Monograph Version 1;
following are the impurities known for Tenofovir Disoproxil
Fumarate-- [0009] Tenofovir isoproxil
monoester--({[(R)-1-(6-Amino-9H-purin-9-yl) propan-2-yloxy] methyl}
(hydroxy) phosphoryloxy) methyl isopropyl carbonate [0010]
Tenofovir isopropyl
isoproxil--O-(Isopropoxycarbonyloxymethyl)-O-isopropyl-{(R)-[1-(6-amino-9-
H-purin-9-yl) propan-2-yloxy]}methylphosphonate [0011] Tenofovir
disoproxil ethyl
ester--O-(Ethoxycarbonyloxymethyl)-O-(isopropoxycarbonyloxymethyl)-{(R)-[-
1-(6-amino-9H-purin-9-yl) propan-2-yloxy]}methylphosphonate [0012]
Tenofovir disoproxil carbamate--O, O-Bis (isopropoxycarbonyl
oxymethyl){(R)-1-[(6-isopropoxycarbonylamino)-9H-purin-9yl]
propan-2-yloxy]}methylphosphonate and [0013] Tenofovir disoproxil
dimer--Tetra(isopropoxycarbonyloxymethyl)
(2S)-1,1'-[6,6'-methylenebis(azanediyl)bis(9H-purine-9,6-diyl)]bis(propan-
e-2,1-diyl)bis(oxy)bis(methylene)diphosphonate.
[0014] In view of increasing demand for Tenofovir products, sources
of quality-assured Tenofovir are constantly needed for the
production of good-quality finished dosage forms. Also, TDF API
(Active Pharmaceutical Ingredient) or dosage forms, with tighter
specifications for impurities would be highly desirable.
OBJECTS OF THE INVENTION
[0015] It is an object of the invention to provide a granular
composition consisting essentially of Tenofovir, wherein the
composition is devoid of an excipient.
[0016] It is an object of the invention to provide a granular
composition consisting essentially of Tenofovir, wherein the total
impurities are not more than 2.0%.
[0017] It is another object of the invention to provide a process
for preparation of a granular composition consisting of Tenofovir,
devoid of an excipient, using a twin-screw processor.
[0018] It is another object of the invention to provide a tablet
comprising i) the granular composition of Tenofovir prepared in
twin screw processor having a content of total impurities of not
more than 2.0% and ii) one or more pharmaceutically acceptable
excipients.
SUMMARY OF THE INVENTION
[0019] According to an aspect of the present invention, there is
provided a process for preparing a granular composition of
Tenofovir in a twin screw processor comprising the steps of [0020]
a. feeding Tenofovir into the intake zone of the twin screw
processor; [0021] b. conveying Tenofovir towards the kneading zone
and processing it in the kneading zone; [0022] c. conveying
Tenofovir from the kneading zone towards the exit; [0023] d.
collecting the Tenofovir granules; and wherein the temperature of
the barrel is between 25.degree. C. and 60.degree. C., [0024]
wherein the granules are devoid of an excipient.
[0025] According to another aspect of the present invention, there
is provided a granular composition consisting essentially of
Tenofovir, wherein the composition is devoid of an excipient and
the content of total impurities is not more than 2.0%.
[0026] According to yet another aspect of the present invention
there is provided a tablet comprising a) the granular composition
of Tenofovir prepared in a twin screw processor having a content of
total impurities of not more than 2.0% and b) one or more
pharmaceutically acceptable excipients.
BRIEF DESCRIPTION OF FIGURES
[0027] FIG. 1: DSC thermogram for TDF granules as per Example
5.
[0028] FIG. 2: DSC of TDF API before feeding into twin screw
processor.
DETAILED DESCRIPTION OF THE INVENTION
[0029] The present invention relates to a process for preparing a
granular composition consisting essentially of Tenofovir, wherein
the composition is devoid of an excipient.
[0030] Unless otherwise mentioned, the term "Tenofovir" as used
herein, includes Tenofovir and pharmaceutically acceptable salts,
esters, prodrugs or derivatives; or salts of said esters or
prodrugs or derivatives, thereof. Tenofovir disoproxil fumarate is
the preferred salt, which is the reason for describing the
invention with reference to Tenofovir disoproxil fumarate, although
it must not be considered to be limited only to the use of
Tenofovir disoproxil fumarate.
[0031] The term "excipient" as used herein means substances used to
formulate Tenofovir into pharmaceutical compositions. It also
includes diluents, disintegrants, solubilizers, stabilizers,
surfactants, binders, polymers, flow promoters, granulation aids
and lubricants.
[0032] Unless otherwise mentioned, the term "consisting of" when
used in connection with tenofovir means tenofovir inclusive of the
known and unknown impurities as described in this
specification.
[0033] In accordance with an embodiment, the present invention
provides a granular composition consisting essentially of
Tenofovir, wherein the composition is devoid of an excipient.
[0034] Such a composition can be directly compressed after mixing
with one or more, pharmaceutically acceptable excipients, and is
suitable for preparation of oral solid dosage forms, such as
tablets. An excipient such as pregelatinized starch is not required
as a pharmaceutically acceptable excipient for direct compression.
The granular Tenofovir composition devoid of an excipient, itself
has good compressibility and flow properties. Particularly, no
additional excipients are required to prepare Tenofovir granules.
This has more significance, in case of fixed dose combinations of
Tenofovir with other anti-retrovirals, as unit dosage forms,
wherein it can aid reduction in size of the unit dosage form. Some
of the examples of other anti-retroviral active moieties or their
pharmaceutically acceptable derivatives/analogues or other active
pharmaceutical ingredient/s, that can be incorporated into such a
fixed dose combination with Tenofovir are-Efavirenz, Emtricitabine,
Rilpivirine, Lamivudine, Nevirapine, Elvitegravir, Dolutegravir and
Cobicistat.
[0035] In accordance with a further embodiment, the granular
Tenofovir composition devoid of an excipient, has a compressibility
index of less than 30.
[0036] In accordance with an embodiment, the granular composition
consisting essentially of Tenofovir can be prepared by twin screw
granulation. Twin screw granulation refers to the process of
granulation carried out in a twin-screw processor.
[0037] In accordance with an embodiment, the present invention
provides a process for preparation of a granular composition
consisting of Tenofovir, devoid of an excipient, using a twin-screw
processor.
[0038] A co-rotating twin screw processor is used in one of the
embodiments, to prepare the said granular composition of Tenofovir.
The co-rotating twin-screw processor has two co-rotating screws
inside a processor barrel. The processor barrel has barrel sections
which are provided with temperature control means. These screws are
open length wise, and closed cross wise. The co-rotating twin screw
processor has a modular design for barrels and screws. Segmented
screws convey and shear the materials in channels bound by screw
flights and barrel walls, with short mass transfer distances. Each
individual screw section is designed to perform specific functions
such as conveying, mixing, shearing, or pressure building, thus
allowing precise control of conditions along the screw length. The
screw elements differ in pitch, pitch direction, length, and angle
of offset. Pitch, length, and location of such screw elements on
the shaft define a screw profile that influences the product
characteristics. Due to variable screw configuration, the twin
screw processor provides greater flexibility of operations to
control characteristics of product by monitoring and regulating
residence time, product temperature, pressure, and shear.
[0039] Alternatively, suitable extruders can also be used without a
die at the exit. The barrel temperatures would depend on the kind
of extruder or the kind of screw configuration within the extruder
that is used.
[0040] During twin screw granulation process of Tenofovir
disoproxil fumarate, in the co-rotating twin screw processor, the
barrel temperature/s, screw speed and feed rate are adjusted such,
that the following impurities or related substances known for
Tenofovir disoproxil fumarate, viz.-- [0041] Tenofovir isoproxil
monoester--({[(R)-1-(6-Amino-9H-purin-9-yl) propan-2-yloxy] methyl}
(hydroxy) phosphoryloxy) methyl isopropyl carbonate, [0042]
Tenofovir isopropyl
isoproxil--O-(Isopropoxycarbonyloxymethyl)-O-isopropyl-{(R)-[1--
(6-amino-9H-purin-9-yl) propan-2-yloxy]}methylphosphonate, [0043]
Tenofovir disoproxil ethyl
ester-O-(Ethoxycarbonyloxymethyl)-O-(isopropoxycarbonyloxymethyl)-{(R)-[1-
-(6-amino-9H-purin-9-yl) propan-2-yloxy]}methylphosphonate, [0044]
Tenofovir disoproxil carbamate--O, O-Bis (isopropoxycarbonyl
oxymethyl){(R)-1-[(6-isopropoxycarbonylamino)-9H-purin-9yl]
propan-2-yloxy]}methylphosphonate, and [0045] Tenofovir disoproxil
dimer--Tetra(isopropoxycarbonyloxymethyl)
(2S)-1,1'-[6,6'-methylenebis(azanediyl)bis(9H-purine-9,6-diyl)]bis(propan-
e-2,1-diyl)bis(oxy)bis(methylene)diphosphonate,
[0046] are not increased, or increase minimally, after granulating
TDF through the twin screw processor.
[0047] Such a process is simple and involves feeding of TDF into
the co-rotating twin screw processor and collection of free flowing
directly compressible (DC) TDF granules. The TDF API was fed into a
barrel section and was transferred forward along the screw length
through the other barrel sections towards the exit port where the
TDF granules were collected. The barrel temperature profile can be
maintained using the temperature control means provided separately
to different barrel sections. The temperatures can be as low as
about 25.degree. C. and as high as about 60.degree. C. All the
barrel sections can also be maintained at the same temperature, if
desired. However, the barrel temperatures to be maintained depend
on the residence time of TDF in the processor, which in turn
depends on the screw speed. These variables can be adjusted to
obtain desired quality of TDF granules. The granules can be fed
into the twin screw processor by means of specially designed
feeders to increase the feed rate.
[0048] The twin screw processor enables to prepare a product with
even tighter specifications for impurity levels and with an
improvement in the compressibility of Tenofovir API.
[0049] The twin screw processor enables to prepare a product with
minimal increase in impurity levels as compared to the input API.
The product so obtained is granular and remains stable even under
accelerated stability conditions. The granular compositions of
Tenofovir packed in aluminium pouches of 20 micron thickness were
found to remain stable.
[0050] In accordance with a further embodiment, there is provided a
granular Tenofovir composition devoid of an excipient comprising
Tenofovir, not more than 1% Tenofovir isoproxil monoester and not
more than 0.15% Tenofovir disoproxil dimer.
[0051] In accordance with a further embodiment, there is provided a
granular Tenofovir composition comprising Tenofovir, not more than
1% Tenofovir isoproxil monoester and not more than 0.15% Tenofovir
disoproxil dimer after storage at 40.degree. C. and 75% Relative
Humidity for a period of at least 3 months; wherein the composition
is devoid of an excipient.
[0052] In accordance with a further embodiment, there is provided a
granular Tenofovir composition comprising Tenofovir, not more than
1% Tenofovir isoproxil monoester and not more than 0.15% Tenofovir
disoproxil dimer after storage at 25.degree. C. and 60% Relative
Humidity for a period of at least 3 months; wherein the composition
is devoid of an excipient.
[0053] In accordance with a further embodiment, there is provided a
granular Tenofovir composition comprising Tenofovir, not more than
1% Tenofovir isoproxil monoester and not more than 0.15% Tenofovir
disoproxil dimer after storage at 2-8.degree. C. for a period of at
least 3 months; wherein the composition is devoid of an
excipient.
[0054] In accordance with a further embodiment, there is provided a
granular Tenofovir composition comprising Tenofovir, not more than
0.15% adenine, not more than 1% Tenofovir isoproxil monoester, not
more than 0.15% Tenofovir disoproxil ethylester, not more than 0.3%
Tenofovir isopropyl isoproxil, not more than 0.15% Tenofovir
disoproxil carbamate, not more than 0.15% Tenofovir disoproxil
dimer, not more than 0.10% of any individual unspecified impurity
and not more than 2.0% of total impurities; wherein the composition
is devoid of an excipient.
[0055] In accordance with a further embodiment, there is provided a
granular Tenofovir composition comprising Tenofovir, not more than
1% Tenofovir isoproxil monoester and not more than 0.15% Tenofovir
disoproxil dimer, prepared by a twin-screw granulation process;
wherein the composition is devoid of an excipient.
[0056] In accordance with a further embodiment, there is provided a
granular Tenofovir composition comprising Tenofovir, not more than
0.15% adenine, not more than 1% Tenofovir isoproxil monoester, not
more than 0.15% Tenofovir disoproxil ethyl ester, not more than
0.3% Tenofovir isopropyl isoproxil, not more than 0.15% Tenofovir
disoproxil carbamate, not more than 0.15% Tenofovir disoproxil
dimer, not more than 0.10% of any individual unspecified impurity
and not more than 2.0% of total impurities, prepared by a twin
screw granulation process; wherein the composition is devoid of an
excipient.
[0057] In accordance with the primary embodiment of the present
invention, there is provided a process for preparing granular
composition of Tenofovir in twin screw processor comprising the
steps of [0058] a. feeding Tenofovir into the intake zone of the
twin screw processor; [0059] b. conveying Tenofovir towards the
kneading zone and processing it in the kneading zone; [0060] c.
conveying Tenofovir from the kneading zone towards the exit; [0061]
d. collecting the Tenofovir granules; and wherein the temperature
of the barrel is between 25.degree. C. and 60.degree. C., [0062]
wherein the granules are devoid of an excipient.
[0063] In accordance with another embodiment, of the present
invention, there is provided a process for preparing tablets
comprising Tenofovir, the process comprising the steps of: (a) twin
screw granulation of Tenofovir without an excipient to form
granules; (b) optionally, sieving the Tenofovir granules; (c)
optionally, adding one or more excipients to the mixture; (e)
compressing the resulting mixture into tablets.
[0064] In accordance with an embodiment of the present invention,
the content of Tenofovir in solid oral composition is 200 to 400
mg, more preferably 300 mg. In an embodiment of the present, there
is provided a tablet comprising a) the granular composition of
Tenofovir prepared in the twin screw processor having content of
total impurities of not more than 2.0% and b) one or more
pharmaceutically acceptable excipients.
[0065] Similarly, the Tenofovir granules can be formulated with
other anti-retrovirals or other active pharmaceutical ingredient/s
in the form of granules or powders or tablets.
[0066] The invention is described by the following non-limiting
examples.
EXAMPLES
Example 1
[0067] Granules of Tenofovir Disoproxil Fumarate
[0068] Tenofovir disoproxil fumarate (TDF) was fed into an OMICRON
10P processor in barrel section B1, STEER ENGINEERING PVT. LTD.,
Do/Di=1.71 and processed at Screw Speed300 rpm, Barrel Temperature
25.degree. C. and feed rate of 5.0 g/minute.
[0069] The screw configuration was as follows:
TABLE-US-00001 TABLE 1 Screw configuration for OMICRON 10P RSE RSE
RSE RKB NKB RSE RSE Elements 10/10 20/20 10/10 45/5/10 90/5/10
20/20 10/10 Number 1 3 5 2 2 3 2
onsB1/B2/B3/B4 were kept at 25.degree. C. TDF Granules were
collected after exiting barrel section B4.
[0070] Following were the granule properties:
TABLE-US-00002 TABLE 2 Granule properties for TDF granules of
Example 1 Mesh No. % Cumulative wt. retained #20 (850 .mu.m) 13.03
#40 (450 .mu.m) 40.56 #60 (250 .mu.m) 61.21 #100 (150 .mu.m) 73.58
Mean Particle Diameter 350 .mu.m
[0071] Bulk Density (g/cc)--0.542, Tapped Density (g/cc)--0.766,
Compressibility Index (%)--29.268, Hausner Ratio-1.414
Analytical Testing
Organic Impurities for Tenofovir Granules
[0072] The test of organic impurities of Tenofovir Disoproxil
Fumarate granules carried out by HPLC (Make-Agilent 1260 Infinity
series).
[0073] The Tenofovir Disoproxil Fumarate granules sample was
analyzed for organic impurities as per method based on Organic
impurities, procedure 1 of USP Pending Monographs of Tenofovir
Disoproxil Fumarate v.1 Authorized Sep. 1, 2011.
[0074] The standard, Tenofovir Disoproxil Fumarate (TDF) was
prepared in solution A. concentration 0.502 .mu.g/mL in solution.
The sample i.e., TDF granules of the present invention was prepared
in solution A, concentration 520.05 .mu.g/mL.
[0075] The standard and sample solution was injected in
chromatographic system and following impurity results are
reported.
TABLE-US-00003 TABLE 3 Comparative results of analytical testing
for TDF granules of Example 1: Unprocessed Example 1 Acceptance
Impurity TDF API (%) (%) criteria (%) Adenine Not Not NMT 0.15
detected detected Tenofovirisoproxil 0.48 0.50 NMT 1.0 monoester
Tenofovirdisoproxil 0.03 0.03 NMT 0.15 ethyl ester Tenofovir
isopropyl 0.17 0.18 NMT 0.30 isoproxil Tenofovirdisoproxil Not Not
NMT 0.15 carbamate detected detected Tenofovirdisoproxil 0.04 0.07
NMT 0.15 dimer Any individual 0.02 0.02 NMT 0.10 unspecified
impurity Total impurities 0.84 0.90 NMT 2.0 NMT = Not More Than
Observation
[0076] From above impurity data, it is apparent that after
granulation of TDF, the impurity Tenofovir isoproxil monoester is
less than 1.00% and impurity Tenofovir disoproxil dimer is less
than 0.15%. Also, the total impurities are less than 1.0%
Preparation of Tablets from Granules of Example 1
[0077] The TDF granules of example 1 were compressed using 11 mm
standard die punch set.
Quantitative Composition for Unit Dose Tablet
TABLE-US-00004 [0078] TABLE 4 Quantitative composition for
Tenofovir tablet Ingredients Quantity (mg) Tenofovir disoproxil
fumarate 300 mg granules of Example 1 Microcrystalline cellulose
125 mg Croscarmellose Sodium 15 mg Magnesium Stearate 5 mg Fumed
silica 5 mg Total weight 450 mg
Tablet Characteristics--
[0079] Hardness--7-9 kp, Thickness--5.55 mm, % Friability--0.322,
Disintegration time--25-30 seconds
Examples 2 to 4: Granules of Tenofovir Disoproxil Fumarate
[0080] Tenofovir disoproxil fumarate was fed into an OMICRON 10P
processor in barrel section B1, STEER ENGINEERING PVT. LTD.,
Do/Di=1.71 and processed at the following processing conditions
TABLE-US-00005 TABLE 5 Processing conditions for Examples 2-4:
Barrel temperature Screw Feed profile (.degree. C.) Examples speed
RPM rate g/min B1/B2/B3/B4 Example 2 300 5.0 25/40/25/25 Example3
300 5.0 25/40/40/25 Example4 300 5.0 25/60/25/25
[0081] The screw configuration was same as that for Example 1. TDF
Granules were collected after exiting barrel section B4.
[0082] Tenofovir granules of Examples 2, 3 and 4 were given for
analysis: The results are as follows:
TABLE-US-00006 TABLE 6 Comparative results of analytical testing
for TDF granules of Examples 2-4 Unprocessed Acceptance Impurities
TDF API Example2 Example3 Example 4 criteriain % Adenine Not Not
Not Not NMT 0.15 detected detected detected detected Tenofovir
isoproxil 0.48 0.52 0.51 0.49 NMT 1.0 monoester Tenofovir 0.03 0.03
0.03 0.03 NMT 0.15 disoproxil ethylester Tenofovir 0.17 0.17 0.17
0.17 NMT 0.30 isopropylisoproxyl Tenofovir Not Not Not Not NMT 0.15
disoproxil detected detected detected detected carbamate Tenofovir
0.04 0.08 0.11 0.07 NMT 0.15 disoproxil dimer Any individual 0.02
0.03 0.03 0.02 NMT 0.10 Unspecified impurity Total 0.84 0.92 0.94
0.92 NMT 2.0 impurities
Example 5
[0083] Tenofovir disoproxil fumarate (TDF) was fed into an OMICRON
10P processor in barrel section B1, STEER ENGINEERING PVT. LTD.,
Do/Di=1.71 and processed at Screw Speed300 rpm, Barrel Temperature
25.degree. C. and feed rate of 5.0 g/minute. The screw
configuration was same as that for Example 1.
[0084] All barrel sections B1/B2/B3/B4 were kept at 25.degree.
C.TDF Granules were collected after exiting barrel section B4.
Thermal Analysis:
[0085] After granulating, the TDF granules were analyzed using DSC.
The melting properties obtained from DSC thermogram, were recorded
with a DSC instrument (DSC Q200, TA instrument). The DSC Q200
instrument was calibrated for temperature and enthalpy with indium
as a certified reference material (m.p.=156.6.degree. C.; Enthalpy
of fusion=3.296 (kJ/mol)2. Samples of TDF granules were sealed in
standard aluminium pans and heated in the DSC from 25.degree. C. to
250.degree. C., at a heating rate of 5.degree. C./minute. Dry
N.sub.2 gas, at a flow rate of 50 ml/min, was used to purge the DSC
equipment during measurement. The melting point of TDF granules as
per example 5 was 117.65.degree. C.
Example 6
[0086] Tenofovir disoproxil fumarate was fed into an OMICRON 10P
processor, STEER ENGINEERING PVT. LTD., Do/Di=1.71 and processed at
Screw Speed 300 rpm, Barrel Temperature 25.degree. C. and feed rate
same as Example 1.
[0087] The screw configuration was the same as Example 1:
TABLE-US-00007 TABLE 7 Screw configuration for OMICRON 10P RSE RSE
RSE RKB NKB RSE RSE Elements 10/10 20/20 10/10 45/5/10 90/5/10
20/20 10/10 Number 1 3 5 2 2 3 2 Zones Feeding and Kneading zone
Conveying metering zone zone
All barrels B1/B2/B3/B4 were kept at 25.degree. C. as in Example 1.
TDF Granules were collected after exiting barrel section B4.
[0088] Following were the granule properties:
TABLE-US-00008 TABLE 8 Granule properties for TDF granules of
Example 6 Mesh No. % Cumulative wt. retained #20 (850 .mu.m) 10.58
#40 (450 .mu.m) 38.12 #60 (250 .mu.m) 56.45 #100 (150 .mu.m) 70.49
Mean Particle Diameter 300
[0089] Bulk Density (g/cc)--0.550, Tapped Density (g/cc)--0.748,
Compressibility Index (%)--26.47, Hausner's Ratio--1.36
Stability Testing:
[0090] The granules were loaded for stability at the following
stability conditions for up to 3 months. [0091] 1. 2-8.degree. C.
[0092] 2. 25.degree. C. and 60% Relative Humidity [0093] 3.
40.degree. C. and 75% Relative Humidity
[0094] Samples were withdrawn at each month and Impurity testing
(for related substances) was performed.
Analytical Testing
Organic Impurities for Tenofovir Granules
[0095] The test of organic impurities of Tenofovir Disoproxil
Fumarate granules carried out by HPLC (Agilent 1260 Infinity
series).
[0096] The Tenofovir Disoproxil Fumarate granules sample were
analyzed for organic impurities as per Organic impurities,
procedure 1 of USP Pending Monographs of Tenofovir Disoproxil
Fumarate v.1 Authorized Sep. 1, 2011.
[0097] The standard [Tenofovir Disoproxil Fumarate (TDF)] was
prepared in solution A. concentration 0.502 .mu.g/mL in
solution.
[0098] The sample [TDF granules of the present invention] was
prepared in solution A, concentration 520.05 .mu.g/mL.
[0099] The standard and sample solution was injected in
chromatographic system and following impurity results are
reported.
TABLE-US-00009 TABLE 9 Comparative results of analytical testing
for TDF granules of Example 6 Acceptance Level (%) of the Present
Criteria Invention (NMT %) Tenofovir Stability data USP DC (3M)
Pending Grade 25.degree. C./ 40.degree. C./ Monograph Unprocessed
Granules 2- 60% 75% Name of Impurity API Tablets (API) initial
(Initial) 8.degree. C. RH RH (R)-9-(2- 0.15 0.2 BDL BDL BDL BDL BDL
Phosphono- methoxypropyl) adenine Adenine 0.15 0.2 BDL BDL BDL BDL
BDL Tenofovirisoproxil 1.0 3.0 0.321 0.355 0.420 0.555 0.766
monoester Tenofovirdisoproxil 0.15 -- ND ND ND ND ND ethyl ester
Tenofovir isopropyl 0.3 -- 0.118 0.120 0.132 0.126 0.123 isoproxil
Tenofovir 0.25 -- ND ND ND ND ND disoproxil Carbamate
Tenofovirdisoproxil 0.15 0.75 ND ND ND ND ND dimer Any individual
0.1 0.2 0.015 0.036 0.055 0.068 0.263 unknown impurity Total
impurity 2.0 4.0 0.490 0.584 0.661 0.874 1.555
List of Abbreviations
[0100] NMT--Not More Than
[0101] BDL--Below Detection Limit
[0102] ND--Not Detected
[0103] RH--Relative Humidity
[0104] Observation
[0105] From above impurity data, it is apparent that after
granulation of TDF, the impurity Tenofovir isoproxil monoester is
less than 1.00%. Also, the total impurities are less than 2.0%.
[0106] It is to be understood that the present invention is
susceptible to modifications, changes and adaptation by those
skilled in the art. Such modifications changes and adaptations are
intended to be within the scope of the present invention.
* * * * *