U.S. patent application number 17/550253 was filed with the patent office on 2022-03-31 for levothyroxine liquid formulations.
This patent application is currently assigned to Fresenius Kabi USA, LLC. The applicant listed for this patent is Fresenius Kabi USA, LLC. Invention is credited to Basma M. IBRAHIM, Arunya USAYAPANT.
Application Number | 20220096414 17/550253 |
Document ID | / |
Family ID | 1000006026044 |
Filed Date | 2022-03-31 |
United States Patent
Application |
20220096414 |
Kind Code |
A1 |
USAYAPANT; Arunya ; et
al. |
March 31, 2022 |
LEVOTHYROXINE LIQUID FORMULATIONS
Abstract
The present invention is directed to a pharmaceutical product
which includes a liquid formulation comprising levothyroxine or a
pharmaceutically acceptable salt thereof. The formulation of the
present invention includes a cyclodextrin, water, and an amine, and
has a pH above the buffering range of the amine. The liquid
formulation of the invention is stable and ready-to-use.
Inventors: |
USAYAPANT; Arunya;
(Mundelein, IL) ; IBRAHIM; Basma M.;
(Lincolnshire, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Fresenius Kabi USA, LLC |
Lake Zurich |
IL |
US |
|
|
Assignee: |
Fresenius Kabi USA, LLC
Lake Zurich
IL
|
Family ID: |
1000006026044 |
Appl. No.: |
17/550253 |
Filed: |
December 14, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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17306504 |
May 3, 2021 |
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17550253 |
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16511220 |
Jul 15, 2019 |
11135190 |
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17306504 |
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15700258 |
Sep 11, 2017 |
10398669 |
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16511220 |
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15366864 |
Dec 1, 2016 |
9782376 |
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15700258 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/08 20130101; A61K
31/198 20130101; A61K 9/0019 20130101; A61K 47/18 20130101; A61K
47/02 20130101; A61K 33/18 20130101 |
International
Class: |
A61K 31/198 20060101
A61K031/198; A61K 9/08 20060101 A61K009/08; A61K 47/18 20060101
A61K047/18; A61K 47/02 20060101 A61K047/02; A61K 9/00 20060101
A61K009/00; A61K 33/18 20060101 A61K033/18 |
Claims
1. A pharmaceutical product comprising an aqueous formulation for
parenteral administration, the formulation comprising levothyroxine
sodium at a concentration of from about 5 mcg/mL to about 100
mcg/mL and sulfobutylether .beta.-cyclodextrin, wherein the
formulation comprises an amine capable of stabilizing the
levothyroxine in the formulation and has a pH above the buffering
range of the amine, wherein, following storage for one week at
55.degree. C., the formulation contains not more than 2.0%
liothyronine (T3) and not more than about 5% total impurities.
2. The pharmaceutical product of claim 1, wherein the formulation
contains not more than 2.0% liothyronine (T3).
3. The pharmaceutical product of claim 1, wherein the total
impurities are determined after storage for two months at
40.degree. C.
4. The pharmaceutical product of claim 1, wherein the formulation
retains at least about 95% of the initial concentration of
levothyroxine or pharmaceutically acceptable salt thereof after
storage for at least 12 months at room temperature.
5. The pharmaceutical product of claim 1, wherein the formulation
is contained within a clear glass vial.
6. The pharmaceutical product of claim 1, wherein the amounts of T3
and total impurities are determined by a peak area percent method
using high-performance liquid chromatography (HPLC).
7. The pharmaceutical product of claim 1, wherein the formulation
comprises levothyroxine sodium at a concentration of about 100
mcg/mL.
8. A pharmaceutical product comprising an aqueous formulation for
parenteral administration, the formulation comprising levothyroxine
sodium at a concentration of about 100 mcg/mL and sulfobutylether
.beta.-cyclodextrin, wherein the formulation comprises an amine
capable of stabilizing the levothyroxine in the formulation, has a
pH above the buffering range of the amine, is contained within a
clear glass vial, and wherein, following storage for one week at
55.degree. C., the formulation contains not more than 2.0%
liothyronine (T3) and not more than about 5% total impurities.
9. The pharmaceutical product of claim 8, wherein the total
impurities are determined after storage for two months at
40.degree. C.
10. The pharmaceutical product of claim 8, wherein the formulation
retains at least about 95% of the initial concentration of
levothyroxine or pharmaceutically acceptable salt thereof after
storage for at least 12 months at room temperature.
11. The pharmaceutical product of claim 8, wherein the amounts of
T3 and total impurities are determined by a peak area percent
method using high-performance liquid chromatography (HPLC).
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This patent application is a continuation of co-pending U.S.
patent application Ser. No. 17/306,504, filed on May 3, 2021, which
is a continuation of U.S. patent application Ser. No. 16/511,220,
filed Jul. 15, 2019, now U.S. Pat. No. 11,135,190, which is a
continuation of U.S. patent application Ser. No. 15/700,258, filed
Sep. 11, 2017, now U.S. Pat. No. 10,398,669, which is a
continuation of U.S. patent application Ser. No. 15/366,864, filed
Dec. 1, 2016, now U.S. Pat. No. 9,782,376, the disclosures of which
are incorporated herein by reference in their entireties for all
purposes.
BACKGROUND OF THE INVENTION
[0002] Levothyroxine sodium for injection is a sterile lyophilized
product for parenteral administration of levothyroxine sodium for
thyroid replacement therapy. Levothyroxine sodium for injection is
particularly useful when thyroid replacement is needed on an urgent
basis, for short term thyroid replacement, and/or when oral
administration is not possible, such as for a patient in a state of
myxedema coma.
[0003] Full chemical names for levothyroxine sodium include
4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodo-L-phenylalanine sodium,
and L-tyrosine-O-(4-hydroxy-3,5-diiodophenyl)-3,5-diiodo-monosodium
salt. Levothyroxine sodium has a molecular weight of approximately
798.85 and the following chemical structure:
##STR00001##
[0004] Conventional formulations of levothyroxine sodium for
injection are preservative-free lyophilized powders containing
levothyroxine sodium and the excipients mannitol, sodium phosphate
buffer, and sodium hydroxide. Administration of the conventional
formulations involve reconstitution of the lyophilized powder in
0.9% sodium chloride injection (USP) to provide an injectable
solution.
[0005] However, use of the conventional lyophilized formulations
requires reconstitution or dilution by healthcare practitioners
prior to use. Once reconstituted, the levothyroxine sodium
solutions have a limited stability, and must be used within a few
hours of reconstitution. In addition, contaminants may be
introduced into the solutions during the reconstitution process,
thereby compromising patient safety.
[0006] It has been shown that levothyroxine in oral tablets and in
aqueous solutions undergoes degradation. Major degradation products
of levothyroxine are known to include 3,3',5-triiodothyronine (T3)
3,5-diiodothyronine (T2) 3,3',5,5'-tetraiodothyroacetic acid
(TTAA4) 3,3',5-triiodothyroacetic acid (TTAA3) and
3,5-diiodothyroacetic acid (TTAA2) (Kannamkumarath et al., J. Anal.
At. Spectrom., 2004, 19: 107-113 and Patel et al., Int. J. Pharm.,
2003, 264: 35-43)). 3,3',5-triiodothyronine, known as liothyronine
or T3, is a major degradant. Aqueous solutions of levothyroxine
sodium have been shown to be more stable at basic pH than at acidic
pH, but significant degradation of levothyroxine sodium also has
been shown to occur at basic pH (Patel et al., Int. J. Pharm.,
2003, 264: 35-43).
[0007] Thus, there remains a need in the art for a ready-to-use
injectable formulation of levothyroxine sodium that exhibits
storage stability.
BRIEF SUMMARY OF THE INVENTION
[0008] The invention provides a liquid formulation comprising
levothyroxine or a pharmaceutically acceptable salt thereof,
tromethamine, sodium iodide, and water, wherein the formulation has
a pH of about 9.0 to about 11.5.
[0009] The invention also provides a liquid formulation comprising
(a) levothyroxine or a pharmaceutically acceptable salt thereof in
a concentration of about 20 mcg/mL to about 100 mcg/mL, (b)
tromethamine in a concentration of about 5 mg/mL to about 20 mg/mL,
(c) sodium iodide in a concentration of about 100 mcg/mL to about
300 mcg/mL, (d) sodium chloride, and (e) water, wherein the
formulation has a pH of about 9.8 to about 10.8.
DETAILED DESCRIPTION OF THE INVENTION
[0010] The invention provides a liquid formulation comprising
levothyroxine or a pharmaceutically acceptable salt thereof,
tromethamine, sodium iodide, and water, wherein the formulation has
a pH of about 9.0 to about 11.5. The liquid formulation according
to the invention is stable and ready-to-use.
[0011] As used herein, a "ready-to-use" formulation is a sterile,
injectable formulation that is not reconstituted from a solid by a
healthcare provider prior to use. Rather, a ready-to-use
formulation is supplied by a pharmaceutical manufacturer in a
suitable container (e.g., vial, syringe, bag, container) in liquid
form. In some embodiments, a ready-to-use formulation is an
injectable formulation that is administered to a subject without
dilution. In other embodiments, a ready-to-use formulation is a
concentrated, liquid solution that must be diluted prior to
administration to a subject. Thus, in some embodiments, the
formulation of the present invention can be further diluted in an
appropriate diluent such as, for example, WFI (water for
injection), 0.9% sodium chloride, or 5% dextrose to a lower
levothyroxine concentration.
[0012] The formulation according to the present invention is
stable. As used herein, the terms "stable" and "stability"
encompass any characteristic of the formulation which may be
affected by storage conditions including, without limitation,
potency, total impurities, levothyroxine degradation products,
specific optical rotation, optical purity, water content,
appearance, viscosity, sterility, and color and clarity. The
storage conditions which may affect stability include, for example,
duration of storage, temperature, humidity, and/or light
exposure.
[0013] In certain embodiments, a stable levothyroxine formulation
refers to a formulation that retains at least about 90%, or about
least about 95%, or at least about 96%, or at least about 98%, of
the labeled concentration of levothyroxine or pharmaceutically
acceptable salt thereof after storage under typical and/or
accelerated conditions. In further embodiments, a stable
levothyroxine formulation refers to less than about 15% (area
percent), or less than about 10% (area percent), or less than about
7% (area percent), or less than about 5% (area percent), or less
than about 2% (area percent) of levothyroxine-related impurities
are present after storage under typical and/or accelerated
conditions.
[0014] In some embodiments, the liquid formulation of the invention
is stable for at least 12 months, at least 18 months, at least 24
months, or at least 36 months at refrigerated temperature (e.g., at
5.+-.2.degree. C.). In other embodiments, the liquid formulation of
the invention is stable for at least 12 months, at least 18 months,
at least 24 months, or at least 36 months at room temperature
(e.g., at 25.+-.2.degree. C.).
[0015] Methods for determining the stability of a formulation of
the invention with respect to a given parameter are well-known to
those of skill in the art. For example, individual impurities and
total impurities can be assessed by high-performance liquid
chromatography (HPLC) or thin layer chromatography (TLC). Unless
otherwise indicated to the contrary, a percentage amount of
liothyronine, other individual impurities, or total impurities
reported herein in the formulation is determined by a peak area
percent method using HPLC.
[0016] The formulation comprises levothyroxine or any
pharmaceutically acceptable salt thereof. Preferably, the
formulation comprises levothyroxine sodium. In an embodiment, the
levothyroxine sodium is levothyroxine sodium pentahydrate, which is
the sodium salt of the levo-isomer of thyroxine, an active
physiological substance found in the thyroid gland.
[0017] When the formulation comprises levothyroxine sodium, the
levothyroxine sodium can be present in the formulation in any
suitable concentration. Typically, levothyroxine sodium can be
present in the formulation at a concentration of about 5 mcg/mL
(micrograms/milliliter) or more, for example, about 10 mcg/mL or
more, about 15 mcg/mL or more, about 20 mcg/mL or more, about 25
mcg/mL or more, about 30 mcg/mL or more, about 35 mcg/mL or more,
about 40 mcg/mL or more, or about 45 mcg/mL or more.
[0018] Alternatively, levothyroxine sodium can be present in the
formulation at a concentration of about 500 mcg/mL or less, for
example, about 450 mcg/mL or less, about 400 mcg/mL or less, about
350 mcg/mL or less, about 300 mcg/mL or less, about 250 mcg/mL or
less, about 200 mcg/mL or less, or about 150 mcg/mL or less.
[0019] Levothyroxine sodium can be present in the formulation in a
concentration bounded by any two of the aforementioned endpoints.
For example, levothyroxine sodium can be present in the formulation
in a concentration of about 5 mcg/mL to about 500 mcg/mL, for
example, about 10 mcg/mL to about 450 mcg/mL, about 15 mcg/mL to
about 400 mcg/mL, about 20 mcg/mL to about 350 mcg/mL, about 25
mcg/mL to about 300 mcg/mL, about 30 mcg/mL to about 300 mcg/mL,
about 35 mcg/mL to about 300 mcg/mL, about 40 mcg/mL to about 300
mcg/mL, about 45 mcg/mL to about 300 mcg/mL, or about 50 mcg/mL to
about 250 mcg/mL, or about 20 mcg/mL to about 100 mcg/mL.
[0020] In a preferred embodiment, levothyroxine sodium is present
at a concentration of about 20 mcg/mL. In another preferred
embodiment, levothyroxine sodium is present at a concentration of
about 40 mcg/mL. In yet another preferred embodiment, levothyroxine
sodium is present at a concentration of about 100 mcg/mL.
[0021] The formulation can be provided in any suitable volume. In
some embodiments, the volume of the formulation is about 0.5 mL or
more, e.g., about 1 mL or more, about 3 mL or more, about 5 mL or
more, about 8 mL or more, about 10 mL or more, about 20 mL or more,
or about 50 mL or more. In other embodiments, the volume of the
formulation is about 200 mL or less, e.g., about 150 mL or less,
about 100 mL or less, about 50 mL or less, about 30 mL or less,
about 15 mL or less, about 10 mL or less, or about 5 mL or less.
The formulation can be provided in a volume bounded by any two of
the aforementioned endpoints. For example, the formulation can be
provided in a volume of about 1 mL to about 200 mL, about 1 mL to
about 50 mL, about 3 mL to about 30 mL, about 5 mL to about 100 mL,
or about 3 mL to about 10 mL. In certain preferred embodiments, the
volume of the formulation is about 5 mL. One of ordinary skill in
the art can readily select an appropriate container based upon the
volume of the formulation.
[0022] The formulation comprises at least one stabilizing agent.
The stabilizing agent serves to stabilize levothyroxine or a
pharmaceutically acceptable salt thereof in the liquid
formulation.
[0023] In some embodiments, the stabilizing agent is an amine.
Non-limiting examples of suitable amines include tromethamine
(i.e., 2-amino-2-hydroxymethyl-propane-1,3-diol or Tris),
bis(2-hydroxyethyl)-imino-tris(hydroxymethyl)methane (Bis-tris or
Bis-tris methane), monoethanolamine, diethanolamine,
triethanolamine, 2-amino-2-methyl-1,3-propanediol,
2-dimethylamino-2-methyl-1-propanediol, 2-amino-2-ethylpropanol,
2-amino-1-butanol, and 2-amino-2-methyl-1-propanol. Preferably, the
amine is tromethamine.
[0024] The amine can be present in the formulation in any suitable
concentration. Typically, the amine can be present in the
formulation at a concentration of about 1 mg/mL
(milligram/milliliter) or more, for example, about 5 mg/mL or more,
about 10 mg/mL or more, about 15 mg/mL or more, or about 20 mg/mL
or more. Alternatively, the amine can be present in the formulation
at a concentration of about 50 mg/mL or less, for example, about 45
mg/mL or less, about 40 mg/mL or less, about 35 mg/mL or less,
about 30 mg/mL or less, about 25 mg/mL or less, or about 20 mg/mL
or less.
[0025] Thus, the amine can be present in the formulation in a
concentration bounded by any two of the aforementioned endpoints.
For example, the amine can be present in the formulation in a
concentration of about 1 mg/mL to about 50 mg/mL, for example,
about 1 mg/mL to about 50 mg/mL, about 5 mg/mL to about 45 mg/mL,
about 5 mg/mL to about 40 mg/mL, about 5 mg/mL to about 35 mg/mL,
about 5 mg/mL to about 30 mg/mL, about 5 mg/mL to about 25 mg/mL,
or about 5 mg/mL to about 20 mg/mL. In a preferred embodiment, the
amine is tromethamine present at a concentration of about 20 mg/mL.
In another preferred embodiment, the amine is tromethamine present
at a concentration of about 10 mg/mL.
[0026] In some embodiments, the stabilizing agent is a salt of
iodine, such as sodium iodide or potassium iodide. In some
embodiments, the formulation comprises sodium iodide at a
concentration of about 10 mcg/mL or more, e.g., 25 mcg/mL or more,
50 mcg/mL or more, 75 mcg/mL or more, 100 mcg/mL or more, 125
mcg/mL or more, 150 mcg/mL or more, 175 mcg/mL or more, or 200
mcg/mL or more. In other embodiments, the formulation comprises
sodium iodide at a concentration of about 500 mcg/mL or less, e.g.,
450 mcg/mL or less, 400 mcg/mL or less, 350 mcg/mL or less, 300
mcg/mL or less, 250 mcg/mL or less, 200 mcg/mL or less, 175 mcg/mL
or less, or 150 mcg/mL or less.
[0027] Thus, the sodium iodide can be present in the formulation in
a concentration bounded by any two of the aforementioned endpoints.
For example, the sodium iodide can be present in the formulation in
a concentration of about 10 mcg/mL to about 500 mcg/mL, for
example, about 50 mcg/mL to about 400 mcg/mL, about 100 mcg/mL to
about 300 mcg/mL, about 125 mcg/mL to about 300 mcg/mL, about 125
mcg/mL to about 250 mcg/mL, about 125 mcg/mL to about 200 mcg/mL,
about 125 mcg/mL to about 175 mcg/mL, or about 125 mcg/mL to about
150 mcg/mL. In a preferred embodiment, the sodium iodide is present
at a concentration of about 140 mcg/mL.
[0028] The formulation can comprise one, two, or three or more
stabilizing agents. In certain embodiments, the formulation
comprises an amine and a salt of iodine, preferably tromethamine
and sodium iodide. In some embodiments, the formulation comprises
about 10 mg/mL tromethamine and about 140 mcg/mL sodium iodide.
[0029] The formulation comprises an isotonicity adjuster.
Non-limiting examples of suitable isotonicity adjusters include
sodium chloride, potassium chloride, dextrose, glycerin, and
mannitol. In a preferred embodiment, the isotonicity adjuster is
sodium chloride.
[0030] The isotonicity adjuster can be present at any suitable
concentration. In some embodiments, the isotonicity adjuster is
present at a concentration that renders the formulation isotonic or
approximately isotonic with cells (e.g., red blood cells) and/or
isotonic or approximately isotonic to blood plasma.
[0031] The formulation optionally comprises a pH adjuster. The pH
adjuster can be any suitable pH adjuster, for example, the pH
adjuster can be sodium hydroxide, potassium hydroxide, hydrochloric
acid, or combinations thereof. In a preferred embodiment, the pH
adjuster is sodium hydroxide, hydrochloric acid, or a combination
thereof.
[0032] The formulation can have any suitable pH. Typically, the
formulation can have a pH of about 9.0 or more including, for
example, about 9.0 or more, about 9.2 or more, about 9.4 or more,
about 9.6 or more, about 9.8 or more, about 10.0 or more, or about
10.2 or more. Alternatively, the formulation can have a pH of about
11.5 or less including, for example, about 11.3 or less, about 11.1
or less, about 11.0 or less, about 10.9 or less, about 10.8 or
less, about 10.7 or less, about 10.6 or less, or about 10.5 or
less.
[0033] The formulation can have a pH bounded by any two of the
above endpoints recited for the formulation. For example the
formulation can have a pH of about 9.0 to about 11.5 including, for
example, about 9.0 to about 11.0, about 9.2 to about 10.8, about
9.2 to about 10.8, about 9.4 to about 10.8, about 9.6 to about
10.8, about 9.8 to about 10.8, about 10.0 to about 10.8, about 10.0
to about 10.7, about 10.0 to about 10.5, or about 10.2 to about
10.6.
[0034] Tromethamine has a buffering range of about 7 to about 9. In
a preferred embodiment, the pH of the formulation is about 9.8 to
about 10.8, which is above the buffering range of tromethamine.
While not wishing to be bound by any particular theory, it is
believed that tromethamine exerts a stabilizing effect on
levothyroxine by a mechanism unrelated to buffering of the
formulation.
[0035] In a preferred embodiment, the formulation comprises (a)
levothyroxine or a pharmaceutically acceptable salt thereof in a
concentration of about 20 mcg/mL to about 100 mcg/mL, (b)
tromethamine in a concentration of about 5 mg/mL to about 20 mg/mL,
(c) sodium iodide in a concentration of about 100 mcg/mL to about
300 mcg/mL, (d) sodium chloride, and (e) water, wherein the
formulation has a pH of about 9.8 to about 10.8.
[0036] The formulation that comprises levothyroxine or a
pharmaceutically acceptable salt thereof, tromethamine, sodium
iodide, sodium chloride, and water may further include one or more
other substances. Non-limiting examples of other substances include
diluents, salts, buffers, stabilizers, solubilizers, and
preservatives. In certain embodiments, the other substance is a
cyclodextrin, such as hydroxypropyl-.beta.-cyclodextrin or
sulfobutylether .beta.-cyclodextrin.
[0037] A formulation comprising levothyroxine or a pharmaceutically
acceptable salt thereof, tromethamine, sodium iodide, sodium
chloride, and water can be prepared by using any suitable
technique, many of which are known to those skilled in the art. The
formulation can be prepared in a batch or continuous process.
Generally, the formulation can be prepared by combining the
components thereof in any order. The term "component" as used
herein includes individual ingredients (e.g., levothyroxine sodium,
tromethamine, sodium iodide, sodium chloride, optional pH adjuster,
etc.) as well as any combination of ingredients (e.g.,
levothyroxine sodium, tromethamine, sodium iodide, sodium chloride,
optional pH adjuster, etc.). In some embodiments, the formulation
is formed by combining the components together in a vessel. The
components can be combined in any order.
[0038] In some embodiments, the water is added to a suitable
vessel, then the tromethamine, sodium iodide, and sodium chloride
are added, either sequentially or together, and the mixture is
stirred. Next, the pH is adjusted to the desired value.
Subsequently, the levothyroxine sodium is added, and the mixture is
stirred until the levothyroxine sodium is dissolved. In some
embodiments, the water and sodium chloride are combined and stirred
until the sodium chloride is dissolved to provide an aqueous
solution of sodium chloride. Subsequently, the levothyroxine
sodium, tromethamine, and sodium iodide are added, either
sequentially or together, and the mixture is stirred. Next, the pH
is adjusted to the desired value. Optional ingredients, such as
diluents, salts, buffers, stabilizers, solubilizers, and
preservatives, can be provided to the formulation at any stage in
its preparation.
[0039] In some embodiments, the formulation is filtered through one
or more filters prior to filling the composition into one or more
suitable containers, such as a vial, an ampoule, a cartridge, a
syringe, or a bag. Preferably, one or more of the filtration steps
and the filling step are performed under aseptic conditions in
order to provide a sterile container comprising a sterile
formulation. A sterile formulation of the invention is preferably
one in which substantially all forms of microbial life have been
destroyed by an appreciable amount to meet the sterilization
criteria set forth in the U.S. Pharmacopeia. See U.S. Pharmacopeia
32, NF 27, 1 (2009) 80-86.
[0040] The invention also provides a container comprising a
formulation comprising levothyroxine sodium, tromethamine, sodium
iodide, sodium chloride, optional pH adjustor, and any other
optional components. In certain embodiments, the container is a
vial, an ampoule, a bag, a bottle, a cartridge, or a syringe. In
some embodiments, the container, the composition, or both the
container and the composition are sterile. Preferably, the
container is sealed by way of a closure, such as a stopper,
plunger, and/or tip-cap.
[0041] The container and closure can be made of glass, plastic,
and/or rubber. One or more surfaces of the container and/or closure
can be treated with a compound to limit reactivity with one or more
components of the formulation. In some embodiments, the container
and/or closure are treated with silicon. In other embodiments, the
container is treated with ammonium sulfate
((NH.sub.4).sub.2SO.sub.4). The container can be clear or opaque,
and can be any color. In some embodiments, the container is flint
colored. In other embodiments, the container is amber colored.
[0042] In certain embodiments, the invention provides a pre-filled
syringe containing a formulation of the invention described herein.
In certain embodiments, a syringe according to the invention is a
component of an autoinjector.
[0043] In some embodiments, the liquid formulation of the invention
contains not more than 1.5% liothyronine (T3). In other
embodiments, the liquid formulation contains not more than 1.25%
liothyronine, e.g., not more than 1.0% liothyronine, not more than
0.9% liothyronine, not more than 0.8% liothyronine, not more than
0.7% liothyronine, not more than 0.6% liothyronine, not more than
0.5% liothyronine, not more than 0.4% liothyronine, not more than
0.35% liothyronine, not more than 0.30% liothyronine, not more than
0.25% liothyronine, not more than 0.2% liothyronine, or any range
therein. For example, in certain embodiments, the liquid
formulation contains 0.2%-1.5% liothyronine, 0.25%-1.25%
liothyronine, 0.25%-1.0% liothyronine, 0.3%-0.9% liothyronine,
0.2%-0.4% liothyronine, 0.25%-0.4% liothyronine, or 0.25%-0.35%
liothyronine.
[0044] In some embodiments, the liquid formulation contains not
more than a specified amount of liothyronine as measured after
storage of the formulation at a predetermined temperature for a
predetermined time period. In certain embodiments, the liquid
formulation contains not more than 1.0% liothyronine, e.g., not
more than 0.8% liothyronine, not more than 0.6% liothyronine, not
more than 0.5% liothyronine, not more than 0.4% liothyronine, not
more than 0.30% liothyronine, not more than 0.2% liothyronine, or
any range therein as measured after storage of the formulation at
25.+-.2.degree. C. for a period of four months. In other
embodiments, the liquid formulation contains not more than 1.5%
liothyronine, e.g., not more than 1.25%, not more than 1.0%, not
more than 0.8%, not more than 0.6%, not more than 0.5%, not more
than 0.4%, or any range therein as measured after storage of the
formulation at 40.+-.2.degree. C. for a period of four months.
[0045] In some embodiments, the liquid formulation of the invention
contains not more than 5.0% total impurities. In other embodiments,
the liquid formulation contains not more than 4.0% total
impurities, e.g., not more than 3.5% total impurities, not more
than 3.0% total impurities, not more than 2.5% total impurities,
not more than 2.0% total impurities, not more than 1.5% total
impurities, not more than 1.25% total impurities, not more than
1.0% total impurities, not more than 0.9% total impurities, not
more than 0.8% total impurities, not more than 0.7% total
impurities, or any range therein. For example, in certain
embodiments, the liquid formulation contains 1.0%-5.0% total
impurities, 1.5%-3.5% total impurities, 0.8%-3.0% total impurities,
0.7%-2.0% total impurities, 1.25%-4.0% total impurities, 0.8%-1.5%
total impurities, or 0.9%-1.25% total impurities.
[0046] In some embodiments, the liquid formulation contains not
more than a specified amount of total impurities as measured after
storage of the formulation at a predetermined temperature for a
predetermined time period. In certain embodiments, the liquid
formulation contains not more than 2.0% total impurities, e.g., not
more than 1.5% total impurities, not more than 1.25% total
impurities, not more than 1.0% total impurities, not more than 0.9%
total impurities, not more than 0.8% total impurities, not more
than 0.7% total impurities, or any range therein as measured after
storage of the formulation at 25.+-.2.degree. C. for a period of
four months. In other embodiments, the liquid formulation contains
not more than 5.0% total impurities, e.g., not more than 4.0% total
impurities, not more than 3.5% total impurities, not more than 3.0%
total impurities, not more than 2.5% total impurities, not more
than 2.0% total impurities, not more than 1.5% total impurities, or
any range therein as measured after storage of the formulation at
40.+-.2.degree. C. for a period of four months.
[0047] The invention also provides a method of stabilizing a
levothyroxine formulation by forming a mixture comprising
levothyroxine or a pharmaceutically acceptable salt thereof,
tromethamine, sodium iodide, sodium chloride, and water, thereby
stabilizing the formulation. The identity and amounts of
levothyroxine or pharmaceutically acceptable salt thereof,
tromethamine, sodium iodide, and sodium chloride present in the
mixture as well as the pH can be the same as the identity and
amounts of these components and the pH described herein with
respect to a formulation of the invention. The formulation formed
by the method of stabilizing a levothyroxine formulation can have
the same stability characteristics as the stability characteristics
described herein with respect to a formulation of the invention,
particularly with regard to total impurities and liothyronine.
[0048] The formulation according to the invention is suitable for
administration to a subject to treat or prevent a disease or
condition. Preferably, the subject is a mammal. More preferably,
the mammal is a human. Preferably, the disease or condition is a
disease or condition that is treatable by the administration of
levothyroxine or a pharmaceutically acceptable salt thereof, such
as hypothyroidism. In some embodiments, the condition is myxedema
coma.
[0049] The following examples further illustrate the invention but,
of course, should not be construed as in any way limiting its
scope.
Example 1
[0050] This example demonstrates the stability of exemplary
formulations comprising levothyroxine sodium, tromethamine, and
water as a function of the pH of the formulation.
[0051] Separate samples containing levothyroxine sodium at a
concentration of 20 mcg/mL, tromethamine at a concentration of 10
mg/mL in normal saline (0.9% NaCl in water) were adjusted to
various pH levels. One sample additionally contained hydroxypropyl
(HP) .beta.-cyclodextrin at a concentration of 10 mg/mL. 5 mL of
each sample was filled into 10 cc amber tubing vials, and the vials
were stoppered with 20 mm stoppers under nitrogen. The samples were
stored at temperatures of 25.degree. C., 40.degree. C. and
55.degree. C. The samples stored at 55.degree. C. were analyzed by
HPLC at 1 and 4 weeks (W) of storage. The samples stored at
40.degree. C. were analyzed by HPLC at 4 W and 3 months (M) of
storage. The samples stored at 25.degree. C. were analyzed by HPLC
at 3 M of storage.
[0052] The HPLC conditions were as follows:
Column: Waters SYMMETRY.TM. C8 (5 .mu.m, 4.6.times.150 mm) HPLC
column Mobile Phase A: Sodium
heptanesulfonate/Acetonitrile/Water/Methanol/H.sub.3PO.sub.4 (4.023
g/800 mL/1600 mL/1600 mL/4 mL) Mobile Phase B: Sodium
heptanesulfonate/Acetonitrile/Water/Methanol/H.sub.3PO.sub.4 (2.013
g/1000 mL/100 mL/900 mL/2 mL)
Diluent: 0.01 N NaOH
[0053] Column temperature: 25.degree. C. Flow rate: 1.5 mL/min
Injection volume: 40-200 Autosampler temperature: 5.degree. C.
Detection: UV at 225 nm
[0054] Separation mode: Gradient Gradient program:
TABLE-US-00001 Time % Mobile Phase (minutes) A B 25 100 0 40 10 90
50 10 90 51 100 0 60 100 0
The relative response time (RRT) for liothyronine to levothyroxine
was approximately 0.73.
[0055] The results for liothyronine, largest unknown impurity, and
total impurities as determined by peak area percent are set forth
in Table 1.
TABLE-US-00002 TABLE 1 Levothyroxine Na (mcg/mL) 20 Tromethamine
(mg/mL) 10 HP-.beta.-cyclodextrin (mg/mL) -- -- -- -- 10 Solvent
Normal saline pH 8 9 9.5 10 9 55.degree. C., % Liothyronine 15.2
2.7 1.2 0.6 2.7 1 W % largest unknown impurity 1.59 0.67 0.50 0.27
0.86 % total impurities 17.5 3.6 2.2 1.5 4.0 55.degree. C., %
Liothyronine nt nt 1.7 3.1 nt 4 W % largest unknown impurity nt nt
0.09 0.55 nt % total impurities nt nt 2.1 4.2 nt 40.degree. C., %
Liothyronine nt nt 0.9 0.4 nt 4 W % largest unknown impurity nt nt
0.12 0.12 nt % total impurities nt nt 1.7 0.6 nt 25.degree. C., %
Liothyronine nt nt 0.6 0.35 nt 3M % largest unknown impurity nt nt
0.46 0.11 nt % total impurities nt nt 1.51 0.71 nt 40.degree. C., %
Liothyronine nt nt 1.56 0.87 nt 3M % largest unknown impurity nt nt
0.48 0.16 nt % total impurities nt nt 2.66 1.35 nt nt = not
tested
[0056] The results described in Table 1 demonstrate reduced
liothyronine and total impurities were detected in levothyroxine
formulations having a pH of 9-10 as compared to pH 8.
[0057] The effect of pH on levothyroxine stability was further
tested in samples having a pH 9.5-11.5. Separate samples containing
levothyroxine sodium at a concentration of 20 mcg/mL or 100 mcg/mL,
tromethamine at a concentration of 10 mg/mL in normal saline were
adjusted to various pH levels. 5 mL of each sample was filled into
10 cc amber tubing vials, and the vials were stoppered with 20 mm
stoppers under nitrogen. The samples were stored at temperatures of
25.degree. C., 40.degree. C., and 55.degree. C. The samples stored
at 55.degree. C. were analyzed by HPLC at 1 W and 2 W of storage.
The samples stored at 25.degree. C. and 40.degree. C. were analyzed
by HPLC at 2 M of storage using the HPLC conditions described
hereinabove.
[0058] The results for liothyronine, largest unknown impurity, and
total impurities as determined by peak area percent are set forth
in Table 2.
TABLE-US-00003 TABLE 2 Levothyroxine Na (mcg/mL) 20 20 100 20
Tromethamine (mg/mL) 10 Solvent Normal saline pH 9.5 10.4 10.4 11.5
55.degree. C., 1 W % Liothyronine 0.9 0.2 0.3 0.1 % largest unknown
0.09 0.09 0.11 0.08 impurity % total impurities 1.2 0.5 0.7 0.4
55.degree. C., 2 W % Liothyronine 1.9 0.4 0.8 0.2 % largest unknown
0.1 0.1 0.11 0.1 impurity % total impurities 2.0 0.9 1.1 0.4
25.degree. C., 2M % Liothyronine 0.34 0.17 0.23 0.34 % largest
unknown 0.11 0.20 0.11 15.4 impurity % total impurities 0.7 0.6 0.6
19.6 40.degree. C., 2M % Liothyronine 1.00 0.38 0.49 0.31 % largest
unknown 0.14 0.22 0.10 9.2 impurity % total impurities 1.44 0.88
0.8 12.1
[0059] The results described in Table 2 demonstrate that reduced
liothyronine and/or total impurities were detected in levothyroxine
formulations having a pH of 10.4 as compared to pH 9.5 or 11.5
following storage at 25.degree. C. or 40.degree. C. for 2 M.
Example 2
[0060] This example demonstrates the stability of exemplary
formulations comprising levothyroxine sodium, sodium iodide, and
tromethamine as a function of sodium iodide concentration and pH of
the formulation.
[0061] Separate samples containing 20 mcg/mL levothyroxine sodium,
10 mg/mL tromethamine, 5.4 mg/mL sodium chloride, and sodium iodide
at a concentration of 280 mcg/mL, 140 mcg/mL, or 6 mcg/mL in water
were adjusted to various pH levels. 5 mL of each sample was filled
into 10 cc flint molded vials, and the vials were stoppered with 20
mm stoppers under nitrogen. The samples were stored at temperatures
of 25.degree. C. or 55.degree. C. for 4 W prior to analysis by
HPLC.
[0062] The HPLC conditions were as follows:
Column: ACE Excel 3 C18-PFP, 4.6.times.150 mm HPLC column Mobile
Phase A: Sodium
heptanesulfonate/Acetonitrile/Water/Methanol/H.sub.3PO.sub.4 (4.0
g/800 mL/1600 mL/1600 mL/4.0 mL) Mobile Phase B: Sodium
heptanesulfonate/Acetonitrile/Water/Methanol/H.sub.3PO.sub.4 (4.0
g/2000 mL/200 mL/1800 mL/4.0 mL)
Diluent: 0.01 N NaOH
[0063] Column temperature: 25.degree. C. Flow rate: 1.5 mL/min
Injection volume: 80 Autosampler temperature: 5.degree. C.
Detection: UV at 225 nm
[0064] Separation mode: Gradient Gradient program:
TABLE-US-00004 Time % Mobile Phase (minutes) A B 0 100 0 25 100 0
40 10 90 50 10 90 51 100 0 60 100 0
The relative response time (RRT) for liothyronine to levothyroxine
was approximately 0.71.
[0065] The results for liothyronine, largest any other individual
impurity (AOII), and total impurities as determined by peak area
percent are set forth in Table 3.
TABLE-US-00005 TABLE 3 Levothyroxine Na (mcg/mL) 20 Tromethamine
(mg/mL) 10 Solvent 5.4 mg/mL sodium chloride in water NaI (mcg/mL)
280 140 6 pH 9.5 10 10.5 9.5 10 10.5 10.5 25.degree. C., 4 W %
Liothyronine 0.28 0.26 0.26 0.28 0.27 0.26 0.25 % AOII 0.56 0.55
0.57 0.52 0.55 0.6 0.33 % total impurities 1.58 1.61 1.66 1.51 1.64
1.75 1.9 55.degree. C., 4 W % Liothyronine 1.63 1.06 0.71 1.74 1.06
0.74 0.87 % AOII 0.53 0.54 0.53 0.59 0.61 0.53 0.99 % total
impurities 3.24 2.76 2.43 3.6 2.86 2.49 3.5
[0066] The samples also were stored at temperatures of 25.degree.
C. or 40.degree. C. for 2 M or 4 M prior to analysis by HPLC.
[0067] The HPLC conditions were as follows:
Column: Phenomenex Kinetex 2.6 .mu.m C18, 4.6.times.150 mm HPLC
column
Mobile Phase A: 0.05 M Sulfamic Acid, pH 2.0
Mobile Phase B: Acetonitrile
Diluent: 10% Mobile Phase A in Methanol:Acetonitrile:Mobile Phase A
(1000 mL:300 mL:700 mL)
[0068] Column temperature: 27.degree. C. Flow rate: 1.2 mL/min
Injection volume: 50 Autosampler temperature: 25.degree. C.
Detection: UV at 225 nm
[0069] Separation mode: Gradient Gradient program:
TABLE-US-00006 Time % Mobile Phase (minutes) A B 0 70 30 5 70 30 33
32 68 35 32 68 36 70 30 50 70 30
The relative response time (RRT) for liothyronine to levothyroxine
was approximately 0.62.
[0070] The results for liothyronine, largest any other individual
impurity (AOII), and total impurities as determined by peak area
percent are set forth in Table 4.
TABLE-US-00007 TABLE 4 Levothyroxine Na (mcg/mL) 20 Tromethamine
(mg/mL) 10 Solvent 5.4 mg/mL sodium chloride in water NaI (mcg/mL)
280 140 6 pH 9.5 10 10.5 9.5 10 10.5 10.5 25.degree. C., 2M %
Liothyronine 0.28 0.24 0.23 0.29 0.25 0.24 0.26 % AOII 0.11 0.12
0.11 0.09 0.10 0.12 0.46 % total impurities 0.81 0.8 0.85 0.76 0.77
0.88 1.85 40.degree. C., 2M % Liothyronine 0.9 0.55 0.39 0.88 0.55
0.41 0.43 % AOII 0.13 0.13 0.17 0.14 0.14 0.15 0.91 % total
impurities 1.56 1.2 1.07 1.42 1.18 1.09 2.5 25.degree. C., 4M %
Liothyronine 0.35 0.28 0.25 0.35 0.28 0.26 0.25 % AOII 2.14 0.17
0.11 0.18 0.17 0.17 1.21 % total impurities 3.26 0.93 1.04 1.00
0.93 0.94 2.81 40.degree. C., 4M % Liothyronine 1.23 0.84 0.58 1.3
0.86 0.59 0.6 % AOII 0.52 1.38 1.07 0.72 0.92 0.69 1.45 % total
impurities 2.76 3.23 2.72 2.84 2.73 2.14 3.51
[0071] The results described in Tables 3 and 4 demonstrate that
levels of liothyronine in formulations comprising 140 mcg/mL or 280
mcg/mL sodium iodide were decreased as the pH was increased from
9.5 to 10 and from 10 to 10.5 following storage at 55.degree. C.
for 4 W or at 40.degree. C. for 2 M or 4 M. The levels of total
impurities in formulations comprising 140 mcg/mL sodium iodide also
were decreased as the pH was increased from 9.5 to 10 and from 10
to 10.5 following storage at 55.degree. C. for 4 W or at 40.degree.
C. for 2 M or 4 M. Lower levels of AOII and total impurities were
detected in formulations comprising 140 mcg/mL or 280 mcg/mL sodium
iodide at pH 10.5 as compared to formulations comprising 6 mcg/mL
sodium iodide at pH 10.5 following storage at 55.degree. C..degree.
for 4 W or at 40.degree. C. for 2 M or 4 M.
Example 4
[0072] This example demonstrates the stability of exemplary
formulations comprising levothyroxine sodium, sodium iodide, and
tromethamine as a function of vial type.
[0073] An aqueous solution containing 20 mcg/mL levothyroxine
sodium, 10 mg/mL tromethamine, 5.4 mg/mL sodium chloride, and 6
mcg/mL sodium iodide was adjusted to pH 10.5. 5 mL of the solution
was filled into each of the vials described in Table 5, and the
vials were stoppered under nitrogen.
TABLE-US-00008 TABLE 5 Glass vial Inner surface Type Size Color
preparation treatment Vial 1 Glass 10 cc Flint Molded No Vial 2
Glass 10 cc Amber Molded (NH.sub.4).sub.2SO.sub.4 Vial 3 Glass 5 cc
Amber Tubing (NH.sub.4).sub.2SO.sub.4 Vial 4 Glass 6 cc Flint
Molded No Vial 5 Plastic.sup.1 10 cc Opaque N/A N/A Vial 6
Plastic.sup.2 10 cc Opaque N/A N/A Vial 7 Plastic.sup.3 10 cc Clear
N/A N/A Vial 8 Plastic.sup.3 10 cc Amber N/A N/A Vial 9
Plastic.sup.4 10 cc Clear N/A Silicon Vial 10 Plastic.sup.4 10 cc
Amber N/A Silicon .sup.1polypropylene copolymer-ExxonMobil PP9122
.sup.2polypropylene copolymer-Flint Hills Resources 23M2A
.sup.3cyclic olefin polymer-Daikyo CRYSTAL ZENITH .TM. .sup.4cyclic
olefin polymer-SiO.sub.2 Medical Products
[0074] The vials were stored at a temperature of 25.degree. C. or
55.degree. C. for 4 W prior to analysis by HPLC. The HPLC
conditions were the same as described hereinabove for the data of
Table 3. The results for liothyronine (T3), largest any other
individual impurity (AOII), and total impurities as determined by
peak area percent are set forth in Table 6.
[0075] The results described in Table 6 demonstrate that vial
material, size, color, and/or treatment can affect the stability of
formulations comprising levothyroxine sodium, sodium iodide, and
tromethamine.
Example 5
[0076] This example demonstrates the stability of comparative
formulations comprising levothyroxine sodium, glycerol, sodium
chloride, and water as a function of the pH of the formulation.
[0077] Separate samples containing levothyroxine sodium at a
concentration of 20 mcg/mL and glycerol at a concentration of 100
mg/mL in normal saline were adjusted to pH levels of 7, 8, and 9. 5
mL of each sample was filled into 10 cc amber tubing vials, and the
vials were stoppered with 20 mm stoppers under nitrogen. The
samples were stored at a temperature of 55.degree. C. The samples
were analyzed by HPLC at 1 week of storage using the HPLC
conditions described in Example 1. The results for liothyronine,
largest unknown impurity, and total impurities as determined by
peak area percent are set forth in Table 7.
TABLE-US-00009 TABLE 7 Levothyroxine Na (mcg/mL) 20 Glycerol
(mg/mL) 100 Solvent Normal saline pH 7 8 9 55.degree. C., 1 W %
Liothyronine 3.6 3.4 2.4 % largest unknown 1.16 1.30 0.82 impurity
% total impurities 5.3 5.4 3.8
[0078] The results described in Table 7 demonstrate that high
levels of impurities are formed in levothyroxine formulations
containing glycerol over the pH range 7-9 following storage at
55.degree. C. for one week.
Example 6
[0079] This example demonstrates a method for preparing an
exemplary formulation of the invention.
[0080] The composition of an exemplary formulation containing 100
mcg levothyroxine in 5 mL volume is as described in Table 8.
TABLE-US-00010 TABLE 8 Component Quantity per mL Levothyroxine
sodium, USP 20 mcg Sodium chloride 6.48 mg Sodium iodide 0.14 mg
Tromethamine, USP 10 mg Sodium hydroxide (1N) As needed to adjust
pH Hydrochloric acid (1N) to 10-10.5 (target 10.3) Purified water
q.s.
[0081] The compositions for exemplary formulations containing 200
mcg or 500 mcg levothyroxine in 5 mL volume are the same as
described in Table 8, except that the concentrations of
levothyroxine sodium are 40 mcg/mL and 100 mcg/mL,
respectively.
[0082] An exemplary formulation is prepared by filling purified
water in an amount of approximately 80% of a predetermined final
batch volume into a suitable container. The entire amounts of
sodium chloride, sodium iodide, and tromethamine are added in
succession, with mixing until dissolution of each ingredient prior
to addition of the next ingredient. The pH is determined, and then
adjusted to pH 10.3 (range of 10.0 to 10.5) with sodium hydroxide
and/or hydrochloric acid. The entire amount of levothyroxine sodium
is added to the container, and the solution is mixed until
dissolution. The pH is determined, and then adjusted to pH 10.3
(range of 10.0 to 10.5) with sodium hydroxide and/or hydrochloric
acid. Purified water is added in an amount sufficient to reach the
predetermined batch volume with continued mixing to ensure complete
dissolution of all ingredients. The formulation can be bubbled with
nitrogen or other suitable gas throughout the compounding to limit
the dissolved oxygen in the formulation. Under aseptic conditions,
the solution is filtered through a 0.22 .mu.m filter, and then 5 mL
of the filtered solution is filled into containers (e.g. vials)
under nitrogen. The containers are then sealed (e.g., stoppered)
under nitrogen.
[0083] All references, including publications, patent applications,
and patents, cited herein are hereby incorporated by reference to
the same extent as if each reference were individually and
specifically indicated to be incorporated by reference and were set
forth in its entirety herein.
[0084] The use of the terms "a" and "an" and "the" and "at least
one" and similar referents in the context of describing the
invention (especially in the context of the following claims) are
to be construed to cover both the singular and the plural, unless
otherwise indicated herein or clearly contradicted by context. The
use of the term "at least one" followed by a list of one or more
items (for example, "at least one of A and B") is to be construed
to mean one item selected from the listed items (A or B) or any
combination of two or more of the listed items (A and B), unless
otherwise indicated herein or clearly contradicted by context. The
terms "comprising," "having," "including," and "containing" are to
be construed as open-ended terms (i.e., meaning "including, but not
limited to,") unless otherwise noted. Recitation of ranges of
values herein are merely intended to serve as a shorthand method of
referring individually to each separate value falling within the
range, unless otherwise indicated herein, and each separate value
is incorporated into the specification as if it were individually
recited herein. All methods described herein can be performed in
any suitable order unless otherwise indicated herein or otherwise
clearly contradicted by context. The use of any and all examples,
or exemplary language (e.g., "such as") provided herein, is
intended merely to better illuminate the invention and does not
pose a limitation on the scope of the invention unless otherwise
claimed. No language in the specification should be construed as
indicating any non-claimed element as essential to the practice of
the invention.
[0085] Preferred embodiments of this invention are described
herein, including the best mode known to the inventors for carrying
out the invention. Variations of those preferred embodiments may
become apparent to those of ordinary skill in the art upon reading
the foregoing description. The inventors expect skilled artisans to
employ such variations as appropriate, and the inventors intend for
the invention to be practiced otherwise than as specifically
described herein. Accordingly, this invention includes all
modifications and equivalents of the subject matter recited in the
claims appended hereto as permitted by applicable law. Moreover,
any combination of the above-described elements in all possible
variations thereof is encompassed by the invention unless otherwise
indicated herein or otherwise clearly contradicted by context.
* * * * *