Title of Invention

FORMULATION OF A THIENOPYRIDINE PLATELET AGGREGATION INHIBITOR

Abstract A formulation of a compound of formula (I), packaged in a air and moisture impervious nitrogen-inerted bilster pack alongwith pharmaceutically accepted inactive ingredients such as excipients/diluents.
Full Text Field of the Invention
The invention relates to a novel formulation of Prasugrel.
Background of the Invention
Thienopyridines such as Ticlopidine and Clopidogrel (sold as Plavix ®.
registered trademark of Sanofi-Aventis S.A) have been used for the treatment of
thrombosis and related diseases. Clopidogrel in particular has found widespread use
compared to the older ticlopidine.
Prasugrel is a next generation thienopyridine currently undergoing clinical
development for the treatment of thrombosis and/or related diseases including as an
adjunct to percutaneous coronary intervention procedures.
US Patent 5,288,726 discloses and claims tetrahydrothienopyridine derivatives
including 2-Acetoxy-5-(a-cycloprpylcarbonyl-2-fluorobenzyl)-4,5,6,7-
tetrahydrothieno [3,2-c] pyridine.
US patent 6, 693,115 B2 discloses and claims the hydrochloric acid and maleic
acid salts of 2-Acetoxy-5-(α-cycloprpylcarbonyl-2-fluorobenzyl)-4,5,6,7-
tetrahydrothieno[3,2-c]pyridine. The HC1 and maleate salt forms provide unexpected
and unobvious improvements in their efficacy and stability profiles compared to Other
salts and also compared to the free base molecule. The HC1 salt of 2-Acetoxy-5-(α-
cycloprpylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine is also
known as Prasugrel. Prolonged exposure of the HC1 salt (prasugrel) to air and
moisture results in some degradation.
Therefore, there is a need for further improvements in the stability, shelf life
and therefore long term efficacy of individual doses of prasugrel.
Summary of the Invention
The present invention provides a formulation comprising a therapeutically
effective amount of the compound of formula I


packaged in an air and moisture impervious gas-inerted blister pack.
The present invention further provides a formulation of compound I comprising a
tablet, caplet, capsule or other solid formulation of the compound of formula 1 packaged
in an air and moisture impervious gas-inerted blister pack.
The present invention provides an improved formulation of the compound of
formula I comprising a therapeutically effective amount of a tablet, caplet, capsule or
other solid formulation of the compound of formula I packaged in an air and moisture
impervious gas-inerted blister pack.
The present invention relates to a method of improving the stability and shelf life
of the compound of formula I comprising packaging tablet(s), caplet(s) or capsule(s) or
other solid formulation of the compound of formula I in gas inerted aluminum foil blister
pack(s).
The present invention relates to the use of a formulation of the compound of
formula 1 comprising administering a therapeutically effective amount of a tablet, caplet,
capsule or other solid formulation of the compound of formula I which has been packaged
in an air and moisture impervious gas-inerted blister pack for the treatment and/or
prevention of thrombosis, acute coronary syndrome, ACS-MM, stroke, cerebrovascular
aneurysyms, and high risk vascular diseases.
The present invention relates to the use of a pharmaceutical formulation of a
compound of formula 1 which has been packaged in a nitrogen-inerted aluminum foil
blister pack in combination with other cardio protective agents for the treatment of
Cardiovascular Diseases.
The present invention relates to a method for improving the stability and shelf life
of a pharmaceutical composition comprising a compound of formula I wherein individual

tablet(s), caplet(s) or capsule(s) of the compound of formula I is/are packaged in nitrogen-
inerted aluminum foil blister packs.
The present invention provides a formulation of a compound for formula 1
comprising a therapeutically effective amount of the compound of formula 1 from about
5 mg to about 60 mg base equivalent packaged in a gas-inerted aluminum foil blister
pack.
The present invention provides a process for the manufacture of a compound of
formula I comprising the steps of:
a. preparing tablets, caplets or capsules of the compound of formula I, and
b. packaging said tablets, caplets or capsules of the compound of formula 1 in
gas inerted aluminum foil blister packs.
The present invention provides an article of manufacture comprising a compound
of formula I packaged in an air and moisture impervious gas-inerted blister pack.
The present invention relates to a method of treating Cardiovascular Diseases
comprising administering to a patient in need thereof a formulation of the compound of
formula I comprising a therapeutically effective amount of a tablet, caplet, capsule or
other solid formulation of the compound of formula I which has been packaged in an air
and moisture impervious gas-inerted blister pack.
The present invention relates to a method for the manufacture of a medicament
comprising packaging a compound of formula I in an air and moisture impervious blister
pack containing a predominance of an inert gas for use independently or in combination
with other cardioprotective agents for the treatment, prevention and/or amelioration of
Cardiovascular Diseases.
Detailed Description
As used herein the term "Prasugrel" means the compound of formula I as
shown. While the compound is also named CS-747HC1, and Prasugrel HC1 here and
elsewhere, these terms mean one and the same thing, the compound of formula I as
shown.

The term, "Cardiovascular Diseases" refers to diseases treatable, preventable,
or able to be ameliorated by treatment with a compound of formula I and/or by
performance of cardiac interventional procedures including coronary (PCI) and non-
coronary interventions. Examples of cardiovascular diseases encompassed by the
invention include coronary occlusion, restenosis, stroke, acute coronary syndrome
(ACS), ACS with medical management (ACS-MM), high risk vascular diseases
(HRVD), cerebro vascular aneurysm (CVA). congestive heart failure, cardiac
alternation, ventricular aneurysm, neural aneurysm, myocardial infarction, cardiac
arrest, cardiac dysrhythmia including atrial fibrillation, cardiac edema, cardiac dyspnea,
cardiac failure, tachycardia, cardiac hemoptysis, cardiac incompetence, cardiac
murmur, cardiac syncope, cardiac tamponade, cerebrovascular disease and/or
peripheral artery disease.
"Administering" as used herein refers to an oral administration of the
compound of formula I including buccal, sublingual and other forms of oral
administration, which allow for the compound of formula I to perform its intended
function of treating and/or preventing the occurrence or recurrence of Cardiovascular
Diseases independently or as part of a combination therapy (treatment) with an
interventional procedure such as a PCI procedure or as part of a combination treatment
with other cardioprotective agents. Such administration by virtue of the combination
treatment includes the performance of a PCI procedure e.g. the implantation of stent, or
performance of balloon angioplasty.
The term "treatment" as used herein refers to the amelioration, inhibition,
prevention of occurrence or recurrence, reduction in severity or effect of cardiovascular
diseases including but not limited to restenosis, acute coronary syndromes (ACS)
including medically managed ACS, myocardial infarction, cerebro vascular aneurysm,
and high risk vascular diseases by the use of a compound of formula I singly or in
combination with other cardio-protective agents or as an adjunct to an interventional
procedure such as PCI or other interventional procedure.
The term "therapeutically effective amount" as used herein refers to the amount
of a compound of formula I necessary or sufficient in single or multiple units to treat
the particular Cardiovascular Disease in a treatment regimen comprised of a compound

of formula I as prescribed by a qualified treating physician or as approved by
applicable regulatory authorities.
The therapeutically effective amount may vary depending on factors known to
one of skill in the art (a qualified prescriber) including for example, the optional
combination of compound I with aspirin or other cardioprotective agent or
interventional procedure such as PCI, the use of drug coated stents, mode and regimen
of administration, the size of the subject, genetic or behavioral predisposition to
Cardiovascular Diseases or the severity and recurrence thereof. One of skill in the art
would be able to consider these and related factors to make the appropriate
determination regarding the therapeutically effective amount for a particular patient.
The phrase "other cardio protective agents" as used herein refers to therapeutic
agents that have been proven and approved to provide beneficial effects (treatment
anaVor prevention of occurrence or recurrence) to a patient afflicted with or susceptible
to Cardiovascular Diseases. Examples of cardioprotective agents include but are not
limited to aspirin, effective GPIIb/IIIa inhibitors, effective statins such as HMG-CoA
reductase inhibitors, super statins, acyl CoA-cholesterol O-acyltransferase (ACAT)
inhibitors, effective anticoagulants, effective thienopyridines, and other effective lipid
modifying agents.
The phrase "pharmaceutically acceptable carrier" refers to any substance or
medium co-formulated with the compound of formula 1 and which allows the
compound to perform its intended function. Examples of such carriers include
solutions, solvents, dispersion media, delay agents, emulsions, microparticles and the
like for combination therapies.
The phrases "combination therapy," "combination treatment," "in conjunction
with," "combination of a compound of formula I and stent," and "in conjunction with a
PCI procedure" if and as used herein are synonymous and indicate that a patient who is
a candidate for a PCI procedure or other interventional procedure is administered a
therapeutically effective dose(s) of a compound of formula I or a pharmaceutically
acceptable salt, prodrug, active metabolite, racemate or enantiomer thereof, optionally
in combination with aspirin at a reasonable period of time prior to and/or after PCI or
other interventional procedure. A reasonable period of time for administering the

compound of formula 1, optionally wich aspirin, prior to PCI or other interventional
procedure may be up to about sixty days prior and may include no prior administration.
The purpose of the prior administration is to achieve an on-going beneficial effect plus
a rapid onset of an effect on platelet function prior to the intervention procedure, and
over and above the rapid onset characteristic of a compound of formula I, without prior
treatment (loading dose), thereby maximizing the potential benefit to the patient. The
dosing of a compound of formula I prior to an interventional procedure such as
stenting or balloon angioplasty may not be practical or necessary in emergency
situations. For the purpose of this invention a reasonable period after PCI or other
interventional procedure, for conjunctive treatment with a compound of formula I, may
be a period of from about 5 days to about 700 days and preferably from about 30 days
to about 365 days. Ultimately, the precise period of therapy according to this invention
is a determination to be made by the treating or attending physician and tailored to the
particular patient.
The phrase "air and moisture impervious" as used herein means materials of
appropriate thickness known to one of skill in the art or ascertainable with minimal
experimentation that when sealed within specifications are likely to substantially and
significantly prevent air and moisture entry and egress. One of skill in the art is aware
that absolute imperviousness may be difficult to achieve and that the inventors believe
that the phrase "air and moisture impervious" material or blister pack is used
comparatively based on the knowledge of one skilled in the art that some materials are
less impervious to air and moisture than others and that absolute imperviousness is
difficult to attain. A material that is both air and moisture impervious is preferred.
Examples of air and moisture impervious materials include aluminum, PCTFE
(Aclar®) and Aclar®-EVOH. Aluminum foil blister packs are most preferred.
The phrase "gas-inerted" as used herein means that a gas that is inert to the
tablet, capsule, caplet or other solid formulation surrounds the available cavity or space
other than that occupied by the tablet, caplet, or capsule in a blister pack. The gas may
be an inert gas or other gas that does not adversely affect (react with) the tablet, caplet
or capsule. Examples of gases useful as inciting gases include CO2, argon, nitrogen,
neon, krypton, and CO (m non-lethal pharmaceutically acceptable quantities). More

preferred as a gas useful for the practice of the invention is nitrogen or argon. Most
preferred is nitrogen.
The phrases "predominantly," and "predominance of an inert gas" as used
herein are synonymous and are intended to mean that the volume of space surrounding
the tablet, caplct or capsule in the blister pack cavity is essentially or nearly or as much
as practically possible completely filled with nitrogen or other inert gas. The effect of
said "predominance of an inert gas" is mat oxygen content is reduced to about less than
2% to 4%.
The term "base equivalent" as used herein conveys its ordinary meaning, i.e.
amount of the compound of formula I (the HC1 salt) that is equivalent to the base form.
One of skill in the art is able to make the conversion, and sample equivalent amounts
are shown in the examples.
The term "other solid formulation" as used herein include fast disintegrating,
fast dissolving, quick release or other approved or approvable solid presention of a
drug known to one of skill in the art.
The term "formulation" as used herein includes its ordinary meaning and also
includes the pharmaceutically prepared compound of formula I and the packaging of
said compound of formula I according to the present invention. Thus a compound of
formula I formulated eimer as the tablet, caplet. capsule, slow release or fast
disintegrating (dissolving) form or other solid form packaged in a gas-inerted
aluminum foil blister pack is a formulation for the purpose of the present invention.
Likewise, a compound of formula I formulated either as the tablet, caplet, capsule,
slow release or fast disintegrating (dissolving) form or other solid form packaged in a
gas-inerted aluminum foil blister pack is an article of manufacture for the purpose of
the present invention.
Preferred Embodiments of the Invention
One embodiment of the present invention is the provision of a pharmaceutical
formulation comprising a compound of formula I wherein individual tablets, caplets or
capsules of said compound are packaged in an air and moisture impervious material
containing an inert gas for the purpose of improving the stability and/or extending shelf
life.

In a preferred embodiment the present invention provides a formulation of the
compound of formula 1 wherein tablets, caplets or capsules containing the compound of
formula I are packaged in aluminum foil blister packs in an atmosphere comprised
predominantly of an inert gas.
In another preferred embodiment the tablets, caplets or capsules of the compound
of formula I are packaged in a blister pack(s) containing a gas selected from the group
consisting of nitrogen, helium, neon, argon, carbon dioxide, and carbon monoxide.
In a more preferred embodiment the tablets, caplets or capsules of the compound
of formula I are packaged in blister pack(s) inerted with a gas selected from the group
consisting of nitrogen, helium, and argon. In a most preferred embodiment, the tablets,
caplets or capsules of the compound of formula I are packaged in nitrogen-inerted blister
pack(s). Thus a most preferred formulation comprises tablets, caplets or capsules of the
compound of formula I packaged in nitrogen-inerted aluminum foil blister pack(s).
In another preferred embodiment, the compound of formula I packaged in an air
and moisture impervious nitrogen inerted aluminum blister pack is adapted for use in
treating ACS, ACS with medical management (ACS-MM), Stroke, and HRVD singly or
in combination with other cardio-protective agents or as an adjunct to an interventional
procedure such as PCI or other interventional procedure.
The compound of formula I, analogs, salts, solvates, and enantiomer thereof may
be prepared by a variety of methods, including methods described in portions or all of the
disclosures of U.S. Patent Nos. 5,288,726 and 6,693,115B2 the entire contents of which
are incorporated herein by reference. In particular, US patent 6,693,115 B2 discloses and
claims the hydrochloric acid salt of 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-
4,5,6,7-tetrahydrothieno[3,2-c]pyridine), the compound of formula I, also known as
Prasugrel.
A solid oral dosage form can be prepared using a variety of pharmaceutically
acceptable excipients, well known to one skilled in the art. Normally, one or more
excipients would be selected from each of the following categories;
(a) Diluents such as but not limited to mannitol, lactose monohydrate,
pregelatinized starch or microcrystalline cellulose.

(b) Disintegrates such as but not limited to croscarmellose sodium, low substituted
hydroxypropyl cellulose or sodium starch glycolate.
(c) Binders including but not limited to hydroxypropyl mcthylcellulose and
hydroxypropyl cellulose. For tablet applications, a lubricant would also be recommended
such as but not limited to magnesium stearate, stearic acid, and glyceryl behcnate.
If a tablet is produced, it is often desirable to film coat the resulting tablet to
provide a pharmaceutically acceptable appearance and to make said tablet easier to
swallow. Commercial suppliers such as, for example, Colorcon Inc.(USA), produce a
variety of film coating systems containing polymers, plasticizcrs and pigments that can be
mixed with water and sprayed onto the tablets in a side vented coating pan. A particularly
preferred system is marketed as Opadry II® and this film coating system (containing the
additive lactose monohydrate) is especially useful in film coating debossed tablets.
Conceivably, prasugrel could be blended with one or more excipients described
above and filled into capsules or compressed into tablets. In order to improve the flow
properties, it might be desirable to pass these blends through a roller compactor or other
equipment to produce a more flowable material.
Because of the stability properties of prasugrel (susceptibility to hydrolysis and
oxidation), certain excipients- most notably povidone and crospovidone (usually
containing trace peroxides) and manufacturing processes (e.g. wet granulation) would not
be recommended. Gas inerted aluminum foil blister packaging is an advantageous and
attractive solution to the problem. To further enhance product stability once
manufactured, unit dose blister packaging, in particular, gas inerted aluminum foil blister
packaging is an advantageous solution to the problem.
Unit dose blister packaging is a convenient presentation for patients and health
care providers and these cavities and packages can be prepared from a number of film
forming materials. Most commonly, blisters are prepared from films comprised of PVC,
PCTFE, and other additives designed to allow the cavity to be formed by heating and
tooling designed to create a cavity lo hold the finished solid oral dosage form (capsule,
gelcap or tablet). After the dosage form is filled into the formed cavities, a foil backing
composite is applied to the top of the cavities and the backing is sealed to the blister film
by the application of appropriate amount of heat. One of skill in the art is able to effect

the above procedure including determining the appropriate amount of heat with minimal
experimentation.
Another type of unit dose blister packaging consists of cold form aluminum
blisters. In these cases, a heavier gauge of foil with appropriate additives is formed
without the application of heat into a cavity to hold the solid oral dosage form. After the
dosage form is filled into the formed cavities, a foil backing composite is applied to the
top of the cavities and the backing is sealed to the cavities by the application of
appropriate heat. One significant advantage of this type of blister is that the aluminum
foil is virtually impervious to moisture and oxygen and thus may be particularly suited to
packaging dosage forms of Prasugrel (compound of formula I) requiring greater
protection from moisture and air. An air and moisture impervious gas-inerted blister pack
having aluminum cavity and aluminum foil covering is most preferred.
The introduction of an inert atmosphere into the blister cavity can be
accomplished by various means. In one instance, a vacuum may be used to evacuate the
air from the formed cavities and the tablets then filled into the cavities in a chamber
constructed over the blistering machine such that the atmosphere can be controlled by
introduction of an inert gas thereby effectively minimizing the oxygen content.
Alternatively, a gas purging station could be placed on the blistering machine to
introduce pressurized inert gases into the cavities containing tablets just prior to the
sealing station. By controlling the pressure of the gas purging station, the atmosphere
containing oxygen can be forced out of the cavity, effectively reducing the oxygen content
of the cavity containing the dosage form by predominantly filling the cavity with inert gas.
Alternatively, gas-inerting may be accomplished by injecting a controlled amount
of a liquified inert gas into the blister cavity just prior to the sealing station. As the gas
heats up and expands, oxygen may be effectively reduced by displacement.
Demonstration of the Invention
The stability of tablets, capsules or caplets of the compound of formula I is
affected by factors including age (length of storage), and storage conditions, such as for
example, temperature and relative humidity. The proper storage conditions ensure an
extended shelf life during which the potency of the tablets, caplets or capsules is more
likely to be within recommended and/or approved specification limits thereby ensuring

the chemical and pharmacodynamic integrity of the tablets, caplets or capsules
administered to patients. Studies have shown that despite the improvements associated
with the HCI salt of CS-747 vis-a-vis stability, etc (see U.S. Patent 6,693,115B2) there
remains room for improvement. Specifically, it is now known that stored tablets
containing the compound of formula 1 degrade by both hydrolytic and oxidative
pathways. It is also believed that there are crossovers between these degradation
pathways wherein intermediates or products of certain steps in one pathway may inter-
convert or be kinetically accelerated or hindered by the concentration of product (or
intermediate), air or moisture from the environment or the other pathway. A proposed
schematic of degradation pathways as currently postulated is shown below in Schemes
1 and 2.


The inventors have been able to individually track hydrolytic degradation
products OXTP1 and OXTP2, along with the oxidative degradation products Diketone
and HYTP. As shown in Scheme 2. two primary degradation products, OXTP

tautomer and iminium, are believed to react with each other to give a mixture of
dimeric isomers. These dimeric isomers then can react further resulting in a complex
mixture of products that have been termed "late eluting impurities" or LEIs. The level
of any individual LEI is insignificant; however, when measured collectively, the
amount of degradation represented by the LEIs is significant. The inventors have
discovered an improved formulation by tracking the amounts of these degradation
products over time under controlled temperature and humidity conditions using
different packaging methods. The ideal formulation would result in minimizing the
amount of all degradation products over a longer time period. However, because of the
interplay of pathways of degradation and inter-conversion between degradation
produces and pathways, the next best possibility is to discover a packaging or
formulation that affords the least change in potency. In other words, a preferred
objective is to discover a formulation that affords a composite reduction over time in
most of the degradation products thereby satisfying a hitherto unmet need. Also
preferred is a formulation of prasugrel comprising a packaging method/process that
harnesses the potential advantage of "controlling" the mix of degradation products to
produce a more favorable distribution. For example, it may be desirable to have less
LEI's and more OXTP 1 and 2. OXTP 1 and 2 are (1) better "known" entities, (2)
have been qualified by toxicological studies, (3) have specification limits, and (4) can
be quantitated in the related substances method. The inventors have achieved the first
objective of a general reduction in impurity profiles allowing for improved stability
and longer shelf life. Invention have also achieved the additional objective of
"controlling" the mix of degradation products to favor reduction in the amounts of
LEI's which are less well-defined or unknown, largely uncharacterized, and for which
specified limits have not been set.
The inventors compared the effect of packaging materials and methods on the
stability of a drug product containing the compound of formula I. The materials and
methods compared include (1) nitrogen inerted blisterpacks comprised of 2.0 mil
PCTFE (polychlorotrifluoroethylene) containing blister material and aluminum foil
lidding; (2) nitrogen inerted blister packs comprised of 2.0 mil PCTFE/ethyl vinyl
alcohol (EVOH) combination blister material and aluminum foil lidding; (3) non-

inerted blister packs comprised of cold form aluminum foil blister material with
aluminum foil lidding; (4) nitrogen-inerted blister packs comprised of cold form
aluminum foil blister material with aluminum foil lidding; and (5) a 50 count, 75-mL
bottle with a combination silica gel and carbon desiccant pack. A general packaging
description and results for each described package configuration are described below.
A tablet formulation containing 12.5 mg of the compound of formula T was
provided for packaging into 4 separate unit dose blister pack configurations, as
described above. The blister-packed tablets were then placed into controlled
environment chambers having the following conditions: 25 °C at 60% relative
humidity, 30 °C at 65% relative humidity, and 40 °C at 75% relative humidity.
Samples were removed from these controlled chambers at various elapsed times from
their initial placement in the controlled environments. The samples were submitted for
chemical analysis to assess changes in potency, total related substances (TRS),
OXTP1, OXTP2, Diketone, HYTP and Late Eluting Impurities (LED- Data from the
various blister packed materials along with data for the same lot of tablets packaged in
an HDPE bottle with desiccant are presented below.


packages that were incapable of preserving a low oxygen environment or which were
packaged under normal atmospheric conditioas. This was true for each of the storage
conditions (25 °C, 60%RH and 30 °C, 65%RH). This trend was true at 10 and 12
months.
Late Eluting Impurities is a combination of peaks the identities of which have
not been determined. Advantageously and unexpectedly, the present invention
(particularly, the use of cold form nitrogen inerted aluminum foil blister packs) results
in a significant reduction of the percentage of these combined late eluting impurities
(LEI's) or degradation products. The LEI's in tablets stored in nitrogen inerted cold
form aluminum foil blisters were substantially lower than for tablets stored in the other
packages that were incapable of maintaining a low oxygen environment or which were
packaged under normal atmospheric conditions. This was true for each of the storage
conditions (25 °C, 60%RH, 30 °C, 65%RH and 40 °C, 75%RH (not shown)).
During the execution of this study, empty blisters were produced with nitrogen inerting
using the three blister materials; 2.0 mil PCTFE, EVOH/PCTFE and cold form
aluminum blisters. At representative intervals, the oxygen content of these empty
blisters was measured to determine the impact of storage time and conditions on this
parameter. Representative results are presented below in figure 1:
Figure 1: Oxygen Content Analyses of Blister Packs


Based on the inability of the two clear blister films (2.0 mil PCTFE and
EVOH/PCTFE) to maintain a low oxygen environment, these blisters (2,0 mil PCTFE
and EVOH/PCTFE) were not assayed at some of the later timepoints in this study.
This study showed that the cold form nitrogen inerted aluminum foil blister packs at 25
p.si, 30 oC, and 65% RH contained the least amount of oxygen over time.
In a subsequent formulation stability study, a tablet formulation containing 12.5
mg of the compound of formula I was provided for packaging into foil pouches that
were inerted with gases containing known concentrations of oxygen in nitrogen to
further elucidate the impact of oxygen concentration on the formation of impurities in
the formulation. The results of this study referred to herein as Multi-Vac study are
presented in the following Table 2:

As shown in Table 2, the potency of tablets stored in low oxygen environments
such as those achieved with the cold form nitrogen-inerted aluminum foil blister packs
was consistently higher than the potency for tablets packaged under normal
atmospheric conditions or at higher oxygen environments (as shown in table above).
This was true for each of the stability (tested) conditions (25 °C, 60%RH, 30 °C,
65%RH and 40 °C, 75%RH).
The LEI results for tablets stored in low oxygen content foil pouches (blister
packs) were consistently lower than for tablets stored in packages containing normal

atmospheric conditions or at higher oxygen environments. This was true for each of
the stability conditions (25 °C, 60%RH, 30 °C, 65%RH and 40 °C, 75%RH).
To examine the impact of moisture content on resultant tablet stability in
nitrogen inerted or normal atmosphere blisters, tablets of formulation 2 (infra) were
stored at different relative humidities and then packaged into cold form blisters, with or
without nitrogen inertiug. The results are presented in the Table 3.

As shown in Table 3, the potency of tablets exposed to lower humidities prior
to packaging and then nitrogen inerted when placed into cold form aluminum blisters
was consistently higher than for tablets exposed to higher humidities and then
packaged under normal atmospheric conditions. This was true for each of the stability
conditions (25 °C, 60%RH, 30 °C, 65%RH and 40 °C, 75%RH).
Also as shown in Table 3, the LEI's in tablets exposed to lower humidities prior
to packaging and then nitrogen inerted when placed into cold form aluminum blisters
were consistently lower than for tablets exposed to higher humidities and then
packaged under normal atmospheric conditions. This was true for each of the stability
conditions (25 °C, 60%RH, 30 °C, 65%RH and 40 °C, 75%RH).
Diketone Peak
With respect to the assayed level of the diketone related substance peak, the
invention also demonstrates a significant, unexpected and advantageous improvement
over other forms of formulation. Each study (tables 1-3) illustrated that the formation
of this impurity was related to oxygen concentrations. Packages such as the cold form
nitrogen inerted aluminum foil blister packs containing and maintaining lower oxygen
environments tended to minimize the formation of this impurity.

HYTP Peak
With respect to the amount of the HYTP peak, the invention demonstrates a
significant, unexpected and advantageous improvement over other forms of
formulation/packaging. Each study (Tables 1-3) illustrated that the formation of this
impurity was related to oxygen concentrations. Packages such as cold form nitrogen
inerted aluminum foil blister packs containing and maintaining lower oxygen content
tended to minimize the formation of this impurity. In addition, as this impurity is
derived from hydrolysis products (OXTP)- exposure to lower relative humidities
and/or packages containing a desiccant also helped to lessen the formation of this
impurity.
Thus, applicants have also provided a method of advantageously controlling the
distribution of impurities. The use of nitrogen-inerted blister packs reduces the
amounts of impurities as discussed above, importantly, it also has the effect of shifting
the distribution of impurities by particularly minimizing the amount of LEI's.
Applicants by operation of the present invention have achieved control of water
activity to levels from about 0.2 to about 0.4. Also applicants have achieved
reductions in oxygen content in the head space of the blister pack to about less than 2%
to 4%,
Method of Using the Invention
The method of using the invention involves preparing and administering a
pharmaceutical formulation comprising tablets, caplets or capsules of the compound of
formula I packaged in nitrogen-inerted aluminum blister packs. The blister packs may be
individual units or a pallet of multiple blister packs joined at appropriate perforation
points for ease of dispensing or packaging for sale as appropriate or approved. The
method of the invention involves formulation of the active ingredient into a tablet, caplet
or capsule including slow release capsule or fast disintegrating tablets packaged in gas-
inerted blister packs preferably aluminum foil blister packs. The improved formulation as
defined herein includes the packaging of the tablet, caplet or capsule into a nitrogen
inerted blister pack, preferably aluminum foil blister packs. Typically, the tablet, caplet or
capsule may contain from about 1 to about 60 mg of the compound of formula I.
Preferably the tablet caplet or capsule may contain from about 5 mg to about 60 mg base

equivalents of the compound of formula I. Most preferably, the tablet, caplet or capsule
contains about 5 mg, 10 mg, 15 mg, 30 mg, or 60 mg base equivalents of the compound
of formula I.
The following procedures of making the tablet, caplet or capsule useful for the
practice of the invention are illustrative only and are not intended to limit che scope of the
invention in any way. It is understood that the tablets, caplets or capsules so made are then
packaged in nitrogen-inerted aluminum foil blister packs the preparation of which is
described in the examples and elsewhere in this document. "Active ingredient", refers to
a compound according to formula (I) or a pharmaceutically acceptable salt, solvate, active
metabolite, enantiomer, racemate or prodrug thereof with or without other cardio
protective agent(s) which is/are to be administered to a patient in need thereof, optionally
in combination with aspirm or as an adjunct to a stent or PCI procedure.
Examples
The following per tablet, caplet or capsule formulation examples, and reference
examples are intended to further illustrate the present invention and are not intended to
limit the scope of this invention.
Formulation 1
CS-747 HC1 (13.72 mg equivalent to 12.5 mg base), mannitol, hydioxypiopyl
methylcellulose, croscarmellose sodium, microcrystalline cellulose and magnesium
stearate are blended and then roller compacted to produce a granulation. To the resulting
granulation, additional croscarmellose sodium, microcrystalline cellulose and magnesium
stearate are added and the material is blended and compressed to form tablets weighing
250 mg. An Opadry® II beige film coating mixture is added to water and then sprayed
onto these tablets in a side vented coating pan.
The tablet is then packaged in an aluminum foil blister pack, inerted or filled with a gas
such as nitrogen and then sealed using procedures known to one of skill in tiie art.
Formulation 2
CS-747 HCl (10.98 mg equivalent to 10.00 mg base) mannitol, hydroxypropyl
methylcellulose, croscarmellose sodium, microcrystalline cellulose and magnesium
stearate are blended and then roller compacted to produce a granulation. To the resulting
granulation, additional croscarmellose sodium, microcrystalline cellulose and magnesium

stearate are added and the material is blended and compressed to form tablets weighing
250 mg. An Opadry II® beige film coating mixture is added to water and then sprayed
onto these tablets in a side vented coating pan.
Solid compositions of formula I may be prepared using the ingredients below per
tablet, capsule or caplet:
Formulation 3
CS-747 HCl (5.49 mg equivalent to 5.0 mg base), mannitol, hydroxypropyl
methylcellulose, croscarmellosc sodium, microcrystalline cellulose and magnesium
stearate are blended and then roller compacted to produce a granulation(s). To the
resulting granulation(s), additional croscarmellose sodium, microcrystalline cellulose and
magnesium stearate are added and the material is blended and compressed to form tablets
weighing from 125-250 mg. An Opadry® II beige film coating mixture is added to water
and then sprayed onto these tablets in a side vented coating pan.
The resulting tablet(s), caplet(s), or capsule(s) are then packaged in a nitrogen-
inerted blister pack(s) using procedures disclosed herein and/or known to one of skill in
the art or attained with minimal experimentation by one of skill in the art. The tabiet(s),
caplet(s), or capsule(s) are then placed in boxes for storage and/or shipping.
Formulation 4
CS-747 HCl (8.24 mg equivalent to 7.5 mg base), mannitol, hydroxypropyl
methylcellulose, croscarmellose sodium, microcrystalline cellulose and magnesium
stearate arc blended and then roller compacted to produce a granulation(s). To the
resulting granulation(s), additional croscarmellose sodium, microcrystalline cellulose and
magnesium stearate are added and the material is blended and compressed to form tablets
weighing from 125-250 mg. An Opadry II® beige film coating mixture is added to water
and then sprayed onto these tablets in a side vented coating pan. The resulting tablets),
caplet(s), or capsule(s) are then packaged in a nitrogen-inerted blister pack(s) using
procedures disclosed herein and/or known to one of skill in the art or attained with
minimal experimentation by one of skill in the art. The tablct(s), caplet(s), or capsule(s)
are then placed in boxes for storage and/or shipping.

Formulation 5
CS-747 HCl (16.47 mg equivalent to 15.00 mg base), mannitol, hydroxypropyl
methylcellulose, croscarmellose sodium, microcrystalline cellulose and magnesium
stearate are blended and then roller compacted to produce a granulation(s). To the
resulting granulation(s), additional croscarmellose sodium, microcrystalline cellulose and
magnesium stearate are added and the material is blended and compressed to form tablets
weighing from 125-250 mg. An Opadry II® beige film coating mixture is added to water
and then sprayed onto these tablets in a side vented coating pan.
The resulting tablet(s), caplet(s), or capsule(s) arc then packaged in a nitrogen-inerted
blister pack(s) using procedures disclosed herein and/or known to one of skill in the art or
attained with minimal experimentation by one of skill in the art. The tablet(s), caplet(s),
or capsule(s) are then placed in boxes for storage and/or shipping.
Formulation 6
CS-747 HCl (32.94 mg equivalent to 30 mg base), mannitol, hydroxypropyl
methylcellulose, croscarmellose sodium, microcrystalline cellulose and magnesium
stearate are blended and then roller compacted to produce a granulation(s). To the
resulting granulation(s), additional croscarmellose sodium, microcrystalline cellulose and
magnesium stearate are added and the material is blended and compressed to form tablets
weighing from 125-250 mg. An Opadry II® beige film coating mixture is added to water
and then sprayed onto these tablets in a side vented coating pan.
The resulting tablct(s), caplet(s), or capsule(s) are then packaged in a nitrogen-inerted
blister pack(s) using procedures disclosed herein and/or known to one of skill in the art or
attained with minimal experimentation by one of skill in the art. The tablet(s), caplet(s),
or capsule(s) are then placed in boxes for storage and/or shipping.
One of skill in the art is aware that other doses of the compound of formula I such
as, for example 60 mg dose may be prepared following the procedures outlined above for
given doses with appropriate adjustments as necessary.

We Claim:
1. A formulation comprising a therapeutically effective amount of the compound of
formula I

packaged in an air and moisture impervious nitrogen-inerted blister pack
alongwith pharmaceutically accepted inactive ingredients such as
excipients/diluents.
2. A formulation as claimed in claim 1 wherein the therapeutically effective amount
of the compound of formula I is from 5 mg to 60 mg base equivalent.
3. A formulation as claimed in claim 1 wherein the therapeutically effective amount
of the compound of formula I is 5 mg base equivalent.
4. A formulation as claimed in claim 1 wherein the therapeutically effective amount
of the compound of formula I is 10 mg base equivalent.
5. A formulation as claimed in claim 1 wherein the therapeutically effective amount
of the compound of formula I is 15 mg base equivalent.
6. A formulation as claimed in claim 1 wherein the therapeutically effective amount
of the compound of formula I is 60 mg base equivalent.
7. A formulation as claimed in claim 1 wherein the blister pack is an aluminum foil
blister pack.
8. A formulation as claimed in claim 1 wherein the compound of Claim 1 is a tablet,
caplet or capsule comprising a compound of formula I
9. A process of producing a formulation as claimed in claim 1, comprising the steps
of:
(a) preparing tablets, caplets or capsules of the compound of formula I, and

(b) packaging said tablets, caplets, capsules or other solid formulation of the
compound of formula I in nitrogen-inerted blister packs, wherein oxygen
content in the head space of the blister pack is reduced to about less than
2% to 4.0 %, and the water activity in the tablets, caplets or capsules of the
compound of formula I is controlled to less than about 0.2 to 0.4.
11. An article of manufacture comprising a compound of formula I packaged in an air
and moisture impervious nitrogen-inerted blister pack.
12. A method for the manufacture of a medicament comprising a compound of
formula I packaged in an impervious material containing nitrogen.


A formulation of a compound of formula (I), packaged in a air and moisture impervious
nitrogen-inerted bilster pack alongwith pharmaceutically accepted inactive ingredients
such as excipients/diluents.


Documents:

04769-kolnp-2007-abstract.pdf

04769-kolnp-2007-assignment.pdf

04769-kolnp-2007-claims.pdf

04769-kolnp-2007-correspondence others.pdf

04769-kolnp-2007-description complete.pdf

04769-kolnp-2007-form 1.pdf

04769-kolnp-2007-form 13.pdf

04769-kolnp-2007-form 2.pdf

04769-kolnp-2007-form 3.pdf

04769-kolnp-2007-form 5.pdf

04769-kolnp-2007-gpa.pdf

04769-kolnp-2007-international exm report.pdf

04769-kolnp-2007-international publication.pdf

04769-kolnp-2007-international search report.pdf

04769-kolnp-2007-others.pdf

04769-kolnp-2007-pct priority document notification.pdf

04769-kolnp-2007-pct request form.pdf

4769-KOLNP-2007-ABSTRACT.pdf

4769-KOLNP-2007-AMANDED CLAIMS.pdf

4769-kolnp-2007-assignment.pdf

4769-kolnp-2007-correspondence.pdf

4769-KOLNP-2007-DESCRIPTION (COMPLETE).pdf

4769-KOLNP-2007-EXAMINATION REPORT REPLY RECIEVED.pdf

4769-kolnp-2007-examination report.pdf

4769-KOLNP-2007-FORM 1.pdf

4769-kolnp-2007-form 13.pdf

4769-kolnp-2007-form 18.1.pdf

4769-kolnp-2007-FORM 18.pdf

4769-KOLNP-2007-FORM 2.pdf

4769-kolnp-2007-form 26.pdf

4769-kolnp-2007-form 3.1.pdf

4769-KOLNP-2007-FORM 3.pdf

4769-kolnp-2007-form 5.1.pdf

4769-KOLNP-2007-FORM 5.pdf

4769-kolnp-2007-granted-abstract.pdf

4769-kolnp-2007-granted-claims.pdf

4769-kolnp-2007-granted-description (complete).pdf

4769-kolnp-2007-granted-form 1.pdf

4769-kolnp-2007-granted-form 2.pdf

4769-kolnp-2007-granted-specification.pdf

4769-KOLNP-2007-OTHERS.pdf

4769-kolnp-2007-reply to examination report.pdf

abstract-04769-kolnp-2007.jpg


Patent Number 251944
Indian Patent Application Number 4769/KOLNP/2007
PG Journal Number 16/2012
Publication Date 20-Apr-2012
Grant Date 18-Apr-2012
Date of Filing 10-Dec-2007
Name of Patentee ELI LILLY AND COMPANY
Applicant Address LILLY CORPORATE CENTER, CITY OF INDIANAPOLIS, STATE OF INDIANA
Inventors:
# Inventor's Name Inventor's Address
1 TAMARA, BETH EDELMAN 19012 WINSTON COURT, NOBLESVILLE, INDIANA 46060
2 DAVID, BRIAN DZIENNIK 13994 EAST 113TH STREET, FORTVILLE, INDIANA 46040
3 OREN, PETER, LLOYD 6358 MANCHESTER DRIVE, FISHERS, INDIANA 46038
4 TERNIK, ROBERT, LOUIS 10090 WALTHAN WAY, FISHERS, INDIANA 46038
PCT International Classification Number A61K 31/4365
PCT International Application Number PCT/US2006/021860
PCT International Filing date 2006-06-06
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/689,183 2005-06-10 U.S.A.