U.S. patent application number 12/436990 was filed with the patent office on 2009-11-12 for compositions of peptides and processes of preparation thereof.
This patent application is currently assigned to Merrion Research III Limited. Invention is credited to Thomas W. Leonard.
Application Number | 20090280169 12/436990 |
Document ID | / |
Family ID | 40801968 |
Filed Date | 2009-11-12 |
United States Patent
Application |
20090280169 |
Kind Code |
A1 |
Leonard; Thomas W. |
November 12, 2009 |
Compositions of peptides and processes of preparation thereof
Abstract
The present invention provides composition of comprising a
therapeutically effective amount of at least one peptide,
polypeptide, analog or derivative thereof and a sufficient amount
of at least one stabilizing agent to improve the stability of the
peptide, polypeptide, an analog or derivative thereof, wherein at
least one stabilizing agent is a medium chain fatty acid salt, an
ester, an ether, or a derivative of a medium chain fatty acid and
has a carbon chain length of from about 4 to about 20 carbon atoms
or is a surface active agent. The method for preparation of a
composition of a peptide, polypeptide, protein, an analog and/or
derivative thereof is also provided. The process comprises mixing
the peptide, polypeptide, protein, an analog or derivative thereof
with a sufficient amount of at least one stabilizing agents to
improve the stability of the peptide, polypeptide, protein, an
analog or derivative thereof, and the agent is a medium chain fatty
acid salt, an ester, an ether, or a derivative of a medium chain
fatty acid and has a carbon chain length of from about 4 to about
20 carbon atoms or is a surface active agent.
Inventors: |
Leonard; Thomas W.;
(Wilmington, NC) |
Correspondence
Address: |
MYERS BIGEL SIBLEY & SAJOVEC
PO BOX 37428
RALEIGH
NC
27627
US
|
Assignee: |
Merrion Research III
Limited
|
Family ID: |
40801968 |
Appl. No.: |
12/436990 |
Filed: |
May 7, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61051038 |
May 7, 2008 |
|
|
|
Current U.S.
Class: |
514/1.1 ;
424/482; 514/21.4 |
Current CPC
Class: |
A61P 15/18 20180101;
A61P 15/00 20180101; A61P 43/00 20180101; A61K 9/2846 20130101;
A61P 25/28 20180101; A61P 15/16 20180101; A61P 35/00 20180101; A61P
5/02 20180101; A61P 3/10 20180101; A61K 47/14 20130101; A61P 37/02
20180101; A61K 38/09 20130101; A61K 47/12 20130101; A61P 5/24
20180101; A61K 9/4891 20130101; C07K 7/06 20130101 |
Class at
Publication: |
424/463 ;
424/482; 514/2 |
International
Class: |
A61K 9/48 20060101
A61K009/48; A61K 9/32 20060101 A61K009/32; A61K 38/00 20060101
A61K038/00 |
Claims
1. A composition comprising a therapeutically effective amount of
at least one peptide, polypeptide, protein, an analog or derivative
thereof and a sufficient amount of at least one stabilizing agent
to improve the stability of the peptide, polypeptide, protein,
analog or derivative thereof, wherein at least one stabilizing
agent is a salt, an ester, an ether, or a derivative of a medium
chain fatty acid and having a carbon chain length of from about 4
to about 20 carbon atoms or is a surface active agent.
2. The composition of claim 1, wherein at least 90% of the peptide,
polypeptide, protein, analog or derivative thereof is retained
after the composition stands at 37.degree. C. for at least about 24
hours.
3. The composition of claim 1, wherein at least one peptide,
polypeptide, protein, analog or derivative thereof is insulin, or
an analog or derivative thereof.
4. The composition of claim 1, wherein at least one peptide,
polypeptide, protein, analogs or derivative thereof is
glucagon-Like Peptide (GLP), or an analog or derivative
thereof.
5. The composition of claim 4, wherein at least one GLPs is
selected from the group consisting of GLP-1, GLP-1 analogs and
derivatives thereof, GLP-2, GLP-2 analogs and derivatives thereof,
exendin-4, analogs and derivatives thereof.
6. The composition of claim 1, wherein at least one peptide,
polypeptide, protein, an analog or derivative thereof is selected
from the group consisting of GnRH agonists and antagonists,
somatostatin, ACTH, corticotropin-releasing factor, angiotensin,
calcitonin, gastric inhibitory peptide, growth hormone-releasing
factor, pituitary adenylate, exendin, exendin-3, cyclase activating
peptide, secretin, enterogastrin, somatostatin, somatotropin,
somatomedin, parathyroid hormone, thrombopoietin, erythropoietin,
hypothalamic releasing factors, prolactin, thyroid stimulating
hormones, endorphins, enkephalins, vasopressin, oxytocin, opioids
and analogues thereof, superoxide dismutase, interferon,
asparaginase, arginase, arginine deaminase, adenosine deaminase,
ribonuclease, FVII, FXIII, a mixture of FVII and FXIII, IL-20,
IL-21, IL-28a, IL-29, IL-31, and analogs and derivatives
thereof.
7. The composition of claim 1, which is solid at room
temperature.
8. The composition of claim 1, which is in a solid oral dosage
form.
9. The composition of claim 1, wherein the stabilizing agent is a
salt of a medium chain fatty acid and has a carbon chain length of
from about 8 to 14 carbon atoms.
10. The composition of claim 1, wherein the stabilizing agent is
selected from the group consisting of sodium caprylate, sodium
caprate and sodium laurate.
11. The composition of claim 1, wherein the concentration of the
stabilizing agent in the composition is equal to or above the
critical micelle concentration of the stabilizing agent in the
composition.
12. The composition of claim 1, wherein the dissolution rate of the
stabilizing agent and the peptide, polypeptide, protein, analogs or
derivatives thereof in the composition are substantially the
same.
13. The composition of claim 1, further comprising one or more
excipients selected from the group consisting of rate-controlling
polymeric materials, diluents, lubricants, disintegrants,
plasticizers, anti-tack agents, opacifying agents, pigments, and
flavorings.
14. The composition of claim 13, wherein at least one
rate-controlling polymer is a polymer derived from acrylic or
methacrylic acid, esters or copolymers derived from acrylic or
methacrylic acid.
15. The composition of claim 1, further comprising an enteric
coating.
16. The composition of claim 15, wherein the enteric coating
comprises at least one polymer selected from the group consisting
of poly(acrylic acid), polyacrylate, poly(methacrylic acid),
polymethacrylate, and mixtures thereof.
17. The composition of claim 15, wherein the enteric coated
composition is a tablet or capsule.
18. The composition of claim 1, wherein the composition is in a
form selected from the group consisting of a multiparticulate form,
a sustained-release form and an instant release form.
19. The composition of claim 1, further comprising at least one
diluent which is an inert filler chosen from microcrystalline
cellulose, lactose, dibasic calcium phosphate and saccharides.
20. The composition of claim 19, wherein the inert filler is at
least one lactose which is lactose monohydrate or lactose
anhydrous.
21. The composition of claim 20, wherein the inert filler is at
least one saccharide selected from the group consisting of
mannitol, starch, sorbitol, sucrose, and glucose.
22. The composition of claim 1, further comprising at least one
lubricant selected from the group consisting of colloidal silicon
dioxide, talc, magnesium stearate, calcium stearate, and stearic
acid.
23. The composition of claim 1, further compriseing at least one
disintegrant selected from the group consisting of lightly
crosslinked polyvinylpyrrolidone, corn starch, potato starch, maize
starch and modified starches, croscarmellose sodium, crospovidone,
and sodium starch glycolate.
24. A method for preparation of a composition of a peptide,
polypeptide, protein, an analog or derivative thereof, wherein the
process comprises mixing the peptide, polypeptide, protein analogs
or derivatives thereof with a sufficient amount of at least one
stabilizing agents to improve the stability of peptide,
polypeptide, protein, an analog or derivative thereof, and the
agent is a salt, an ester, an ether, or a derivative of a medium
chain fatty acid and having a carbon chain length of from about 4
to about 20 carbon atoms, or is a surface active agent.
25. The methods of claim 24, wherein at least 90% of the peptide,
polypeptide, protein, analog or derivative thereof is retained
after the composition stands at 37.degree. C. for at least about 24
hours.
26. The method of claim 24, wherein the stabilizing agent is a
medium chain fatty acid salt.
27. The method of claim 24, wherein the stabilizing agent is a
medium chain fatty acid salt having a carbon chain length of from
about 8 to about 14 carbon atoms.
28. The method of claim 24, wherein the concentration of the
stabilizing agent in the composition is equal or above the critical
micelle concentration of the stabilizing agent in the composition.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C.
.sctn.119(e) of U.S. Provisional Patent Application Ser. No.
61/051,038, filed May 7, 2008, the disclosures of which is
incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention generally relates to compositions of
peptides, polypeptides, proteins, analogues or derivatives thereof,
and the process of preparation thereof.
BACKGROUND OF THE INVENTION
[0003] A variety of biologically active peptides, polypeptides and
proteins have been widely used for medical treatment. For a
majority of medical treatments, there is a need to deliver a
sustained level of biologically active peptides or proteins to
animals or humans to provide a stable therapeutic effect.
Additionally, the biologically active peptides or proteins also
need to be stored for a prolonged period of time and still maintain
their activity. However, many naturally occurring and synthetic
peptides and proteins as well as their analogs have exhibited a
tendency to form gels, aggregates, fibrils, dimers, other polymers,
coagulates, etc. In some cases, the formed material may be able to
revert back to the active monomer form. In other cases, the altered
state may be permanent and represent a degraded state. Some
exemplary biologically active peptides include insulin,
glucagon-like peptide-1 (GLP-1) and Gonadotropin-releasing hormone
(GnRH) analogs. The instability of the peptides has become a
significant barrier for the preparation, process, storage and
delivery of these peptides.
[0004] To date, a few methods have been discovered that may be used
to stabilize solution of peptides or proteins. For example, U.S.
Pat. No. 6,124,261 describes a non aqueous polar aprotic peptide
formulation that may be used to stabilize the peptide. In another
example, a citrate buffering agent may be used to reduce the
gelation of fatty acid-acylated protein. See U.S. Pat. No.
5,631,347.
[0005] However, due to the diversity of biologically active
peptides and proteins, there is a continuing need to find new
compositions of peptides or proteins with improved stability and
processes of preparing compositions of peptides or proteins.
SUMMARY OF THE INVENTION
[0006] The present invention provides compositions comprising a
therapeutically effective amount of at least one peptide,
polypeptide, protein, an analog or derivative thereof and a
sufficient amount of at least one stabilizing agent to improve the
stability of the peptide, polypeptide, protein, analog or
derivative thereof in a solution, wherein at least one stabilizing
agent is a medium chain fatty acid salt, or an ester, an ether, or
a derivative of a medium chain fatty acid and has a carbon chain
length of from about 4 to about 20 carbon atoms or is a surface
active agent. In some embodiments, at least one peptide,
polypeptide, protein, an analog or derivative thereof is insulin,
or an analog or derivative thereof. In one embodiment, at least one
peptide, polypeptide, protein, analog or derivative thereof is
Glucagon-Like Peptide (GLP), or an analog or derivatives thereof.
In another embodiment, the stabilizing agent is selected from the
group consisting of sodium caprylate, sodium caprate and sodium
laurate.
[0007] According to another aspect of the present invention,
methods for preparation of a composition of at least one peptide,
polypeptide, protein, analog or derivative thereof are provided. In
some embodiments, the methods comprises mixing the peptide,
polypeptide, protein, analog or derivative thereof with a
sufficient amount of at least one stabilizing agent to improve the
stability of the peptide, polypeptide, protein, analog or
derivative thereof, and the stabilizing agent is a medium chain
fatty acid salt, or an ester, an ether, or a derivative of a medium
chain fatty acid and has a carbon chain length of from about 4 to
about 20 carbon atoms. In one embodiment, the stabilizing agent is
a medium chain fatty acid salt has a carbon chain length of from
about 8 to about 14 carbon atoms.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] The following drawings form part of the present
specification and are included to further demonstrate certain
aspects of the present invention. The invention may be better
understood by reference to one or more of these drawings in
combination with the detailed description of specific embodiments
presented herein.
[0009] FIG. 1 is a table describing the preparation of different
acyline batches.
[0010] FIG. 2 shows appearance of 9% and 16.7% acyline samples of
different acyline batches in propylene glycol.
[0011] FIG. 3 shows the appearance of 0.5% and 1% acyline samples
of different acyline batches in water.
[0012] FIG. 4(a) shows the appearance of 5 mg and 10 mg doses
acyline microemulsions of different acyline batches.
[0013] FIG. 4(b) shows the formulation of the microemulsion.
[0014] FIG. 5 graphically demonstrates the comparison results of
the gelation of 0.1 mg/mL acyline sample with 1% and 0% Tween
80.
[0015] FIG. 6 graphically demonstrates the comparison results of
the gelation of 0.1 mg/mL acyline sample having 5 mg/mL, 1 mg/mL,
0.1 mg/mL and 1% Tween 80.
[0016] FIG. 7 graphically demonstrates the comparison results of
the gelation of 0.1 and 0.01 mg/mL acyline sample having 1% and 1
mg/mL Tween 80.
[0017] FIG. 8 graphically demonstrates the comparison results of
the gelation of 0.01 mg/mL acyline sample having 0.1%, 0.5% and 1%
Tween 80.
[0018] FIG. 9 graphically demonstrates the correlation between the
concentration of sodium caprate and the gelation of acyline.
[0019] FIG. 10(a) illustrates the formulation of microemulsion
1--55% Capmul MCM. FIG. 10(b) illustrates the formulation of
microemulsion 2--45% Capmul PG-8. FIG. 10(c) illustrates the
formulation of microemulsion 3--55% Capmul MCM C10.
[0020] FIG. 11 graphically demonstrates the comparison results of
relative bioavailability of different formulations of acyline.
[0021] FIG. 12 graphically demonstrates the comparison results of
relative bioavailability of (1) enteric tablets 10 mg acyline
versus acyline sample with no surface active agent and (2) enteric
tablets 10 mg acyline versus 5 mg acyline with sodium caprate
sample.
[0022] FIG. 13(a) illustrates the correlation of % of recovery of
insulin for insulin formulations with or without sodium caprate.
FIG. 13(b) illustrates % of recovery of insulin from insulin
formulations with capric acid.
DETAILED DESCRIPTION
[0023] The foregoing and other aspects of the present invention
will now be described in more detail with respect to the
description and methodologies provided herein. It should be
appreciated that the invention can be embodied in different forms
and should not be construed as limited to the embodiments set forth
herein. Rather, these embodiments are provided so that this
disclosure will be thorough and complete, and will fully convey the
scope of the invention to those skilled in the art.
[0024] All patents, patent applications and publications referred
to herein are incorporated by reference in their entirety. In case
of a conflict in terminology, the present specification is
controlling.
[0025] The terminology used in the description of the invention
herein is for the purpose of describing particular embodiments only
and is not intended to be limiting of the invention. As used in the
description of the embodiments of the invention and the appended
claims, the singular forms "a", "an" and "the" are intended to
include the plural forms as well, unless the context clearly
indicates otherwise. Also, as used herein, "and/or" refers to and
encompasses any and all possible combinations of one or more of the
associated listed items. Furthermore, the term "about," as used
herein when referring to a measurable value such as an amount of a
compound, dose, time, temperature, and the like, is meant to
encompass variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the
specified amount. Unless otherwise defined, all terms, including
technical and scientific terms used in the description, have the
same meaning as commonly understood by one of ordinary skill in the
art to which this invention belongs.
[0026] As used herein, "alcohol" means an organic compound in which
one or more hydroxyl (OH) groups are attached to carbon (C) atoms
in place of hydrogen (H) atoms. In some embodiments, the alcohol
contains 1-6 carbon atoms. Yet, in other embodiments, the alcohol
contains 1-4 carbon atoms. Exemplary alcohols include, but are not
limited to, methanol, ethanol, n-propanol, iso-propanol, butanol,
tert-butanol, pentanol, hexanol.
[0027] As used herein, "gelation" means that a compound of interest
undergoes aggregation to form fibrils, dimers, longer polymers,
coagulates, or structures that may result in formation of a colloid
structure or gel. The viscosity of the mixture, used in the present
application, may be applied to a compound of interest in aqueous
solution or a solid mass.
[0028] "Gelation" may occur to varying extents, and may occur in
such a maimer as to be non-detectable by ordinary means. For
example, there may be no increased viscosity or changes in the flow
characteristics of the solution. However, the material formed from
the gelation (hereinafter "gel") may be removed by physical means
such as filtration and thus detected by analytical techniques known
to one skilled in the art. The presence of gels may cause
significant problems in the development of different administration
forms. For example, when the gelled system is processed to obtain
powders of the drug as part of drug substance manufacturing
techniques, a xerogel may be formed during the process. As used
herein, `xerogel` is a solid formed from the gel after the liquid
is removed from a gelled system. The powder obtained from the
gelled system containing xerogel may have substantially different
characteristics from powders obtained from solutions that contain
no gelled material. In some situations, obtained power loses the
biological activity. Therefore, the formation of gels may
potentially cause deleterious effects at either the drug substance
processing stage, or at the stage of preparing the dosage form or
storage stage.
[0029] The degree of agglomeration or coalescence which results in
the formation of the gel may be measured by various methods known
to one skilled in the art, for example micro or macro filtration
followed by assay of the filtrate, centrifugation followed by assay
of the supernatant, or various optical absorption or diffraction
methods including those utilizing visible or UV light methods, or
laser based methods. The methods of measuring physical
characteristics of the liquid may also be used such as surface
tension, freezing point depression, viscosity, or measurement of
other colligative properties. The degree of xerogel formation may
be measured by dispersing the material in water and using the
techniques described herein or by direct measurement on the powder
by methods known to one skilled in the art including x-ray powder
diffraction, IR spectroscopy, or other methods known to the art
that may be carried out on powdered materials.
[0030] As used herein, the term "reduce the gelation" means to
disrupt, retard or eliminate the gel formation of a compound. In
situation where the gelation is reversible, the term "reduce the
gelation" also means to reverse the gel back to monomeric form of
the compound, which maintains it biological activity. As used
herein, the term "anti-gelling agent" refers to an agent, a
compound, a composition or a combination thereof which may inhibit
the gelation of at least 50% of the compound of interest, when a
sufficient amount of the anti-gelling agent is used. In some
embodiments, the anti-gelling agent may inhibit the gelation of at
least 80% of the compound of interest, when a sufficient amount of
the anti-gelling agent is used. In some embodiments, the
anti-gelling may inhibit the gelation of at least 90% of the
compound of interest, when a sufficient amount of the anti-gelling
agent is used.
[0031] As used herein, a "therapeutically effective" or
"therapeutically acceptable" amount refers to an amount that will
elicit a therapeutically useful response in a subject. The
therapeutically useful response may provide some alleviation,
mitigation, or decrease in at least one clinical symptom in the
subject. Those skilled in the art will appreciate that the
therapeutic useful response need not be complete or curative, as
long as some benefit is provided to the subject. In some
embodiments, the subject is an animal. In some embodiments, the
subject is a human.
[0032] As used herein, the term "water miscible solvent" means a
solvent that can be mixed with water to form a solution. Water
miscible solvents may be used to create a hydrophilic phase.
[0033] The present invention provides compositions comprising,
consisting essentially of, or consisting of, a therapeutically
effective amount of at least one peptide, polypeptide, protein, an
analog or derivative thereof and a sufficient amount of at least
one stabilizing agents to improve the stability of the peptide,
polypeptide, protein, analog or derivative thereof. As used herein,
a "stabilizing agent" is an agent that improves the stability of a
peptide, polypeptide, protein, an analog or derivative thereof
described herein.
[0034] In some embodiments, at least one stabilizing agent is a
medium chain fatty acid salt, or an ester, an ether, or a
derivative of a medium chain fatty acid and has a carbon chain
length of from about 4 to about 20 carbon atoms. In some
embodiments, at least one stabilizing agent is a surface active
agent.
[0035] The present invention provides compositions that maintain
the stability of peptide, polypeptide, protein, an analog or
derivative thereof described herein for a sufficient time to be
stored, processed and/or administered for treatment. One way of
measuring the stability is measuring the percentage of peptide,
polypeptide, protein, an analog or derivative thereof is retained
under a specific condition. As used herein, the term "peptide,
polypeptide, protein, analog or derivative thereof is retained"
means that the peptide, polypeptide, protein, an analogs or
derivative thereof does not form gels, aggregates, fibrils, dimers,
other polymers, coagulates, rather it maintains as a monomer or its
biological activity after a period of time. In one embodiment, in
the composition of the present invention, at least about 50% of the
peptide, polypeptide protein, an analog or derivative thereof is
retained after the composition stands at about 37.degree. C. for at
least about 24 hours. In some embodiments, in the composition of
the present invention, at least about 80% of the peptide,
polypeptide protein, an analog or derivative thereof is retained
after the composition stands at about 37.degree. C. for at least
about 24 hours. In some embodiments, in the composition of the
present invention, at least about 90% of the peptide, polypeptide
protein, an analog or derivative thereof is retained after the
composition stands at about 37.degree. C. for at least about 24
hours. In some embodiments, in the composition of the present
invention, at least about 95% of the peptide, polypeptide protein,
an analog or derivative thereof is retained after the composition
stands at about 37.degree. C. for at least about 24 hours. In some
embodiments, the stability is improved when the gelation of
peptide, polypeptide, protein, an analog or derivative thereof is
reduced.
[0036] The compositions described herein may be used directly for
storage, processing or administration. Alternatively, the
composition may also be used to mix with a suitable medium (e.g. a
solvent, a microemulsion or a solid mass) for storage, processing
or administration. In the situations where a medium is used, the
stability of peptide, polypeptide, protein, analogues or
derivatives thereof in the medium is improved as described
herein.
[0037] In some embodiments, the stabilizing agent is an
anti-gelling agent. In one embodiment, the present invention
provides compositions comprising, a therapeutically effective
amount of one or more peptide, polypeptide, protein, an analog or
derivative thereof, and a sufficient amount of at least one
anti-gelling agents to reduce the gelation of the peptide,
polypeptide, protein, an analog or derivative thereof.
[0038] In one embodiment, the dissolution rate of the stabilizing
agent and the peptide, polypeptide, protein, analogs or derivatives
thereof in the composition are substantially the same.
I. Peptide, Polypeptide, Protein, an Analog and Derivative
Thereof
[0039] The present invention can be applied to any peptide,
polypeptide, protein, analog or derivative that has a tendency to
aggregates, dimerizes, polymerizes, coagulates, gels or
fibrillates. Analogs, derivatives, and pharmaceutically acceptable
salts of any of the peptides, polypeptides or proteins are included
in these terms. As used herein, the "tendency to to aggregates,
dimerize, polymerize, coagulate, gel or fibrillate" refers to that
at least 50% of a compound of interest undergoes aggregation to
form fibrils, dimers, polymers that coagulates, or structures that
may result in formation of a colloid structure or gel in a system
at a certain temperature (e.g. 37.degree. C.) after the system
stands for a period of time (e.g. at least about 24 hours).
[0040] In some embodiments, at least one peptide, polypeptide,
protein, an analog or derivative thereof is an insulin or an analog
or derivative thereof.
[0041] In one embodiment, at least one peptide, polypeptide,
protein, analogs or derivatives thereof is Glucagon-Like Peptide
(GLP), or an analog or derivative thereof. In another embodiment,
at least one GLP is selected from the group consisting of GLP-1,
GLP-1 analogs, derivatives thereof, GLP-2, GLP-2 analogs,
derivatives thereof, and exendin-4, analogs and derivatives
thereof.
[0042] More exemplary peptides, polypeptides, proteins, analogs or
derivatives thereof include, but are not limited to, GnRH agonists
and antagonists, somatostatin, ACTH, corticotropin-releasing
factor, angiotensin, calcitonin, gastric inhibitory peptide, growth
hormone, growth hormone-releasing factor, pituitary adenylate,
exendin, exendin-3, cyclase activating peptide, secretin,
enterogastrin, somatostatin, somatotropin, somatomedin, parathyroid
hormone, thrombopoietin, erythropoietin, hypothalamic releasing
factors, prolactin, thyroid stimulating hormones, endorphins,
enkephalins, vasopressin, oxytocin, opioids and analogues thereof,
superoxide dismutase, interferon, asparaginase, arginase, arginine
deaminase, adenosine deaminase, ribonuclease, FVII, FXIII, a
mixture of FVII and FXIII, IL-20, IL-21, IL-28a, IL-29, IL-31,
analogs and derivatives thereof.
[0043] In some embodiments, at least one peptide, polypeptide,
protein, analog or derivative comprises a variety of GnRH related
compounds which have a tendency of gelation. As used herein, the
"tendency of gelation" refers to that at least 50% of a compound
undergoes aggregation to form fibrils, dimers, polymers that
coagulates, or structures that may result in formation of a colloid
structure or gel in a system at a certain temperature (e.g.
37.degree. C.) after the system stands for a period of time (e.g.
at least about 2 hours). As used herein, GnRH related compounds
include both GnRH antagonists and GnRH agonists. In some
embodiments, the present invention may be applied to GnRH
antagonists. In some embodiments, the present invention include,
but is not limited to, the following GnRH antagonists, acyline
(Ac-D2Nal-D4Cpa-D3Pal-Ser4Aph(Ac)-D4Aph(Ac)-Leu-ILys-Pro-DAla-NH.sub.2),
Acetyl-.beta.-[2-Naphthyl]-D-Ala-D-p-Chloro-Phe-.beta.-[3-Pyridyl]-D-Ala--
Ser-N.epsilon.-[Nicotinoyl]-Lys-N.epsilon.-[Nicotinoyl]-D-Lys-Leu-N.epsilo-
n.-[Isopropyl]-Lys-Pro-D-Ala-NH.sub.2 (also referred to herein as
Antide), acetyl-D2Nal1, D4CIPhe2, D3Pal3, ARg5, Dglu6 (AA) (also
referred to herein as NalGlu),
acetyl-D2Nal-D4CIPhe-D3Pal-Ser-Aph(Ac)-D-Aph(Ac)-Leu-Lys(lpr)-Pro-D-Ala-N-
H.sub.2, Abarelix (Specialty European Pharma, Dusseldorf, Germany),
Nal-Lys, Synarel, (Searle Peapack, N.J.), Ganirelix
(Orgalutron/Antagon) (Organan, West Orange, N.J.), Cetrorelix I
(Aeterna Zentaris Inc, Frankfurt, Germany), Cetrotide, Azaline B,
new generation long-acting GnRH analogues incorporating
p-ureido-phenylalanines at positions 5 and 6 (such as Degarelix),
FE200486,
Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph(L-hydroorotyl)-D4Aph(carbarnoyl)-Leu-ILys-P-
ro-DAla-NH.sub.2 (the acetate salt of which is FE200486),
Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph(Atz)-D4Aph(Atz)-Leu-ILys-Pro-DAla-NH.sub.2
wherein Atz is 3'-amino-1H-1',2',4'-triazol-5'-yl, and the
antagonists described in U.S. Pat. Nos. 5,506,207, 5,821,230,
5,998,432, 6,156,772, 6,156,767, 6,150,522, 6,150,352, 6,147,088,
6,077,858, 6,077,847, 6,025,366, 6,017,944, 6,004,984, 6,214,798,
and 6,875,843. In some embodiments, the GnRH antagonists of the
present invention have a tendency of gelation in the presence of
ions. In some embodiments, at least one GnRH antagonist is selected
from the group consisting of acyline, abarelix, azaline B,
cetrorelix, ganirelix, teverelix, degarelix, antide, orntide and
GnRH antagonists described in U.S. Pat. No. 7,098,305.
[0044] In one embodiment, at least one GnRH antagonist is selected
from the group consisting of abarelix, cetrorelix, degarelix,
ganirelix, and a pharmaceutically acceptable salt thereof.
[0045] As used throughout this specification and claims, the term
"abarelix" refers to a compound having a structure of Formula I
##STR00001##
The IUPAC name of Formula I is
acetyl-D-.beta.-naphthylalanyl-D-4-chlorophenylalanyl-D-3-pyridylalanyl-L-
-seryl-L-N-methyl-tyrosyl-D-asparagyl-L-leucyl-L-N(e)-isopropyl-lysyl-L-pr-
olyl-D-alanyl-amide. The term "abarelix" includes the compound of
Formula I, pharmaceutically acceptable salts thereof, and
equilibrium mixtures of these. The term "abarelix" also includes
crystalline, hydrated or solvated crystalline, and amorphous forms
of the compound of Formula I and pharmaceutically acceptable salts
thereof.
[0046] As used throughout this specification and claims, the term
"cetrorelix" refers to a compound having a structure of Formula
II.
##STR00002##
The IUPAC name of Formula II is
Acetyl-D-3-(2'-naphtyl)-alanine-D-4-chlorophenylalanine-D-3-(3'-pyridyl)--
alanine-L-serine-L-tyrosine-D-citruline-L-leucine-L-arginine-L-proline-D-a-
lanine-amide. The term "cetrorelix" includes the compound of
Formula II, pharmaceutically acceptable salts thereof, and
equilibrium mixtures of these. The term "cetrorelix" also includes
crystalline, hydrated or solvated crystalline, and amorphous forms
of the compound of Formula II and pharmaceutically acceptable salts
thereof.
[0047] As used throughout this specification and claims, the term
"degarelix" refers to a compound having a structure of Formula
III.
##STR00003##
The IUPAC name of Formula III is
N-acetyl-3-(naphtalen-2-yl)-D-alanyl-4-chloro-D-phenylalanyl-3-(pyridin-3-
-yl)-D-alanyl-L-seryl-4-((((4S)-2,6-dioxohexahydropyrimidin-4-yl)carbonyl)-
amino)-L-phenylalanyl-4-(carbamoylamino)-D-phenylalanyl-L-leucyl-N6-(1-met-
hylethyl)-L-lysyl-L-prolyl-D-alaninamide. It is also known as
FE-200486. The term "degarelix" includes the compound of Formula
III, pharmaceutically acceptable salts thereof, and equilibrium
mixtures of these. The term "degarelix" also includes crystalline,
hydrated or solvated crystalline, and amorphous forms of the
compound of Formula III and pharmaceutically acceptable salts
thereof.
[0048] As used throughout this specification and claims, the term
"ganirelix" refers to a compound having a structure of Formula
IV.
##STR00004##
[0049] The IUPAC name of Formula IV is a
(2S)-1-[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2R)-2-[[(2S)-2-[[(2R)-2-[[(2R)-2-[[(2-
R)-2-acetamido-3-naphthalen-2-ylpropanoyl]amino]-3-(4-chlorophenyl)propano-
yl]amino]-3-pyridin-3-ylpropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(4-hy-
droxyphenyl)propanoyl]amino]-6-[bis(ethylamino)methylideneamino]hexanoyl]a-
mino]-4-methylpentanoyl]amino]-6-[bis(ethylamino)methylideneamino]hexanoyl-
]-N-[(2R)-1-amino-1-oxopropan-2-yl]pyrrolidine-2-carboxamide. The
term "ganirelix" includes the compound of Formula IV,
pharmaceutically acceptable salts thereof, and equilibrium mixtures
of these. The term "ganirelix" also includes crystalline, hydrated
or solvated crystalline, and amorphous forms of the compound of
Formula IV and pharmaceutically acceptable salts thereof.
[0050] In some embodiments, the present invention may be applied to
GnRH agonists that have a tendency of gelation. The exemplary GnRH
agonists include, but are not limited to, histerelin, leuprolide
and goserelin.
[0051] The terms "GnRH related compound", "GnRH antagonist" and
"GnRH agonist" include all forms thereof including stereoisomers,
enantiomers, diastereomers, racemic mixtures, and derivatives
thereof, for example, salts, acids, esters and the like. The
compound may be provided in any suitable phase state including as
solid, liquid, solution, suspension and the like. When provided in
a solid particulate form, the particles may be of any suitable size
or morphology and may assume one or more crystalline,
semi-crystalline and/or amorphous forms.
[0052] The peptide, polypeptide, protein, analogs or derivatives
there of used in the present invention may be present in any amount
which is sufficient to elicit a therapeutic effect and, where
applicable, may be present either substantially in the form of one
optically pure enantiomer or as a mixture, racemic or otherwise, of
enantiomers. As will be appreciated by those skilled in the art,
the actual amount of peptide, polypeptide, protein, analogs or
derivatives there of used in the composition will depend on the
potency of the selected compound in question.
[0053] The peptides, polypeptides, proteins, analogs or derivatives
described herein may be obtained through commercial resources or
may be prepared according to methods known to one skill in the art.
The GnRH antagonists applied in the present invention may be
prepared using a method known to one of ordinary skill in the art
or a process described in the present invention. For example,
acyline can be prepared according to the method described in U.S.
Pat. No. 5,506,207.
II. Stabilizing Agents
[0054] The amount of the stabilizing agent used in the present
invention can vary considerably. For example, the amount can be
dependent upon individual stabilizing agents, solvent systems and
other components in the composition. Generally, the amount of
stabilizing agent should be sufficient to improve the stability of
peptide, polypeptide, protein, analogs or derivatives thereof in a
system such that at least 50% of peptide, polypeptide, protein, an
analog or derivative thereof is retained when the composition
stands at 37.degree. C. for at least about 24 hours. In some
embodiments, the amount of stabilizing agent should be sufficient
to improve the stability of peptide, polypeptide, protein, analogs
or derivatives thereof in a system such that at least 80% of
peptide, polypeptide, protein, analog or derivative thereof is
retained when the composition stands at 37.degree. C. for at least
about 24 hours. In other embodiments, the amount of anti-gelling
agent should be sufficient to be sufficient to improve the
stability of peptide, polypeptide, protein, an analog or derivative
thereof in a system such that at least 90% of peptide, polypeptide,
protein, an analog or derivative thereof is retained when the
composition stands at 37.degree. C. for at least about 24 hours. In
some embodiments, the concentration of the stabilizing agent in the
composition is at least equal to or above the CMC (Critical Micelle
Concentration) of the stabilizing agent in the composition.
[0055] A. Medium Chain Fatty Acid and Derivatives Thereof
[0056] In some embodiments, at least one stabilizing agent is a
medium chain fatty acid salt, or ester, ether or a derivative of a
medium chain fatty acid and which has a carbon chain length of from
4 to 20 carbon atoms. In some embodiments, at least one stabilizing
agent is medium chain fatty acid salt, or ester, ether or a
derivative of a medium chain fatty acid and which has a carbon
chain length of from 6 to 20 carbon atoms. In some embodiments, the
carbon chain length is from 8 to 14. In some embodiments, at least
one stabilizing agent is a salt of medium chain fatty acid and has
a carbon chain length of from 8 to 14 carbon atoms. In some
embodiments, at least one stabilizing agent is a medium chain fatty
acid salt, or ester, ether or a derivative of a medium chain fatty
acid and which has a carbon chain length of from 6 to 20 carbon
atoms; with the provisos that (i) where the stabilizing agent is an
ester of a medium chain fatty acid, said chain length of from 6 to
20 carbon atoms relates to the chain length of the carboxylate
moiety, and (ii) where the stabilizing agent is an ether of a
medium chain fatty acid, at least one alkoxy group has a carbon
chain length of from 6 to 20 carbon atoms. In another embodiment,
at least one stabilizing agent is a medium chain fatty acid salt,
or ester, ether or a derivative of a medium chain fatty acid which
is solid at room temperature and which has a carbon chain length of
from 8 to 14 carbon atoms; with the provisos that (i) where the
stabilizing agent is an ester of a medium chain fatty acid, said
chain length of from 8 to 14 carbon atoms relates to the chain
length of the carboxylate moiety, and (ii) where the stabilizing
agent is an ether of a medium chain fatty acid, at least one alkoxy
group has a carbon chain length of from 8 to 14 carbon atoms. In
some embodiments, at least one stabilizing agent is a sodium salt
of a medium chain fatty acid, the medium chain fatty acid having a
carbon chain length of from 8 to 14 carbon atoms. In some
embodiments, the stabilizing agent is solid at room temperature. In
another embodiment, at least one stabilizing agent is selected from
the group consisting of sodium caprylate, sodium caprate, and
sodium laurate. In one embodiment, at least one stabilizing agent
is sodium caprate.
[0057] B. Surface Active Agents
[0058] In some embodiments, at least one stabilizing agent is a
surface active agent. As used herein, the term "surface active
agent" refers to an agent that lowers the surface tension of the
medium in which it is dissolved and/or the interfacial tension with
other phases, and, accordingly, is positively adsorbed at the
liquid/vapor and/or at other interfaces. The surface active agents
employed in the present invention include both ionic agents, i.e.,
cationic, anionic or zwitterionic, and non-ionic agents, or a
mixture thereof.
[0059] Examples of cationic surface active agents include, but are
not limited to, benzalkonium chloride, dicetyl ammonium chloride,
cetyldimethylethylammonium bromide, cetylpyridinium chloride and
salts of the above surface active agents.
[0060] Examples of anionic surface active agents include, but are
not limited to, sodium stearoyl lactylate, hydrogenated lecithin,
sodium lauryl sulfate, C.sub.8-32 fatty acids and salts thereof,
cholic acid and derivatives thereof such as deoxycholate, and its
salts, ursodeoxycholic acid, and taurocholic acid; C.sub.8-56
diesters of tartaric acid; phospholipids such as phosphatidic acid
and phosphatidyl serine; C.sub.5-29 monoesters of lactic acid;
C.sub.8-20 sulfonates, including alkyl-, olefin-, and alkylaryl
derivatives; tridecyl- and dodecylbenzene sulfonic acids; and
C.sub.5-33 sarcosine and betaine derivatives.
[0061] Examples of zwitterionic surface active agents include, but
are not limited to, phospholipids such as lecithin,
phosphatidylethanolamine, sphingomyelins, dodecyl betaine, dodecyl
dimethylamine oxide, cocamidopropyl betaine, and coco ampho
glycinate.
[0062] Examples of non-ionic surface active agents include, but are
not limited to, steareths; polyethylene glycol (PEGs); polysorbates
(e.g. Tween 80); cetearyl glucoside; various commercially available
sorbitans and their derivatives, for example, sorbitan hexastearate
ethoxylate EO 6 mole, sorbitan isostearate, sorbitan laurate,
sorbitan monoisostearate ethoxylate EO 20 mole, sorbitan
monolaurate ethoxylate EO 20 mole, sorbitan monooleate ethoxylate
EO 20 mole, sorbitan monopalmitate ethoxylate EO 20 mole, sorbitan
monostearate ethoxylate EO 20 mole, sorbitan monstearate ethoxylate
EO 6 mole, Sorbitan oleate, sorbitan palmitate, sorbitan
sesquioleate, sorbitan stearate, sorbitan tetraoleate ethoxylate EO
30 mole, sorbitan tetraoleate ethoxylate EO 40 mole, sorbitan
tetraoleate ethoxylate EO 6 mole, sorbitan tetrastearate ethoxylate
EO 60 mole, sorbitan trioleate ethoxylate EO 20 mole, sorbitan
trioleate, sorbitan tristearate ethoxylate EO 20 mole, and sorbitan
tristearate; ethoxylated castor oil, C.sub.5-29 mono-glycerides and
ethoxylated derivatives thereof; C.sub.15-60 diglycerides and
polyoxyethylene derivatives thereof having 1 to 90 POE groups;
C.sub.10-40 esters (10-40 carbon atoms in the alcohol) of long
chain fatty acids (fatty acids having 16 carbon atoms and above);
C.sub.10-40 alcohols; sterols such as cholesterol, ergosterol, and
C.sub.2-24 esters thereof; C.sub.8-96 ethoxylated fatty esters;
C.sub.14-130 sucrose fatty esters; and polyoxyethylene (POE)
derivatives thereof having 0 to 90 POE groups, e.g.,
polyoxyethylene sorbitan monooleate, sorbitol hexaoleate POE
(50).
[0063] In some embodiments, at least one surface active agent is
selected from the group consisting of sodium lauryl sulfate,
polysorbate surface active agents (such as polysorbate 20 (Tween
20), polysorbate 80 (Tween 80)), sorbitan surface active agents,
sorbitan monolaurate and polyethoxylated castor oil and a
combination thereof. In some embodiments, at least one surface
active agent comprises polysorbate.
III. Additional Excipients
[0064] According to some aspects of the present invention, the
composition of the present invention further comprises one or more
excipients. As will be appreciated by those skilled in the art, the
exact choice of excipients and their relative amounts will depend
to some extent on the final dosage form. In some embodiments, the
excipients are selected from the group consisting of
rate-controlling polymeric materials, diluents, lubricants,
disintegrants, plasticizers, anti-tack agents, opacifying agents,
pigments, and flavorings.
[0065] As used herein, the term "rate controlling polymer material"
comprises hydrophilic polymers, hydrophobic polymers and mixtures
of hydrophilic and/or hydrophobic polymers that are capable of
controlling or retarding the release of the drug compound such as a
GnRH related compound from a solid oral dosage form of the present
invention. Suitable rate controlling polymer materials include
those selected from the group consisting of hydroxyalkyl cellulose
such as hydroxypropyl cellulose and hydroxypropyl methyl cellulose;
poly(ethylene) oxide; alkyl cellulose such as ethyl cellulose and
methyl cellulose; carboxymethyl cellulose, hydrophilic cellulose
derivatives; polyethylene glycol; polyvinylpyrrolidone; cellulose
acetate; cellulose acetate butyrate; cellulose acetate phthalate;
cellulose acetate trimellitate; polyvinyl acetate phthalate;
hydroxypropylmethyl cellulose phthalate; hydroxypropylmethyl
cellulose acetate succinate; polyvinyl acetaldiethylamino acetate;
poly(alkylmethacrylate) and poly (vinyl acetate). Other suitable
hydrophobic polymers include polymers and/or copolymers derived
from acrylic or methacrylic acid and their respective esters, zein,
waxes, shellac and hydrogenated vegetable oils. In one embodiment,
the rate-controlling polymer comprises a polymer derived from
acrylic or methacrylic acid and their respective esters or
copolymers derived from acrylic or methacrylic acid and their
respective esters. In another embodiment, the rate-controlling
polymer comprises hydroxypropylmethylcellulose (HPMC).
[0066] In some embodiments, at least one rate controlling polymer
material is selected from the group consisting of poly acrylic
acid, poly acrylate, poly methacrylic acid and poly methacrylate
polymers such as those sold under the Eudragit.RTM. trade name
(Rohm GmbH, Darmstadt, Germany), for example, Eudragit.RTM. L,
Eudragit.RTM. S, Eudragit.RTM. RL, Eudragit.RTM. RS coating
materials and mixtures thereof. Some of these polymers can be used
as delayed release polymers to control the site where the drug is
released. In some embodiments, the rate controlling polymer include
polymethacrylate polymers such as those sold under the
Eudragit.RTM. trade name (Rohm GmbH, Darmstadt, Germany), for
example, Eudragit.RTM. L, Eudragit.RTM. S, Eudragit.RTM. RL,
Eudragit.RTM. RS coating materials and mixtures thereof.
[0067] In some embodiments, the present invention may further
comprise diluents. Any suitable diluent may be used in the present
invention. Exemplary diluents include, but are not limited to,
pharmaceutically acceptable inert fillers such as microcrystalline
cellulose, lactose, dibasic calcium phosphate, saccharides, and/or
mixtures thereof. Examples of diluents include microcrystalline
cellulose such as those sold under the Avicel trademark (FMC Corp.,
Philadelphia, Pa.), for example, Avicel.TM. pH101, Avicel.TM. pH102
and Avicel.TM. pH112; lactose such as lactose monohydrate, lactose
anhydrous and Pharmatose DCL21; dibasic calcium phosphate such as
Emeompress.RTM. (JRS Pharma, Patterson, N.Y.); mannitol; starch;
sorbitol; sucrose; and glucose. In some embodiments, the inert
filler comprises microcrystalline cellulose. In one embodiment, the
inert filler comprises a lactose selected from the group consisting
of lactose monohydrate and lactose anhydrous. In another
embodiment, the inert filler comprises a saccharide selected from
the group consisting of mannitol, starch, sorbitol, sucrose, and
glucose. In one embodiment, the saccharide is sorbitol.
[0068] In some embodiments, the composition of the present
invention may further comprise lubricants. Any suitable lubricant
may be used in the present invention. In some embodiments, the
lubricant comprises agents that act on the flowability of the
powder to be compressed. Exemplary lubricants include, but are not
limited to, colloidal silicon dioxide such as Aerosil.TM. 200,
talc, stearic acid, magnesium stearate, and calcium stearate. In
some embodiments, the lubricant is stearic acid.
[0069] In some embodiments, the composition of the present
invention may further comprise disintegrants. Any suitable
disintegrant may be used in the present invention. Exemplary
disintegrants include, but are not limited to, lightly cross-linked
polyvinyl pyrrolidone, corn starch, potato starch, maize starch and
modified starches, croscarmellose sodium, cross-povidone, sodium
starch glycolate and combinations and mixtures thereof. In some
embodiments, the disintegrant is chosen from crospovidone and
polyvinylpyrrolidone.
[0070] In some embodiments, the composition described above may
further comprise an enhancer. The enhancer can be any suitable
enhancer that is known to one of ordinary skill in the art.
Exemplary enhancers include, but are not limited to, a medium chain
fatty acid salt, ester, ether or a derivative of a medium chain
fatty acid which has a carbon chain length of from 4 to 20 carbon
atoms. In some embodiments, the enhancer is solid at room
temperature. In some embodiments, the enhancer is medium chain
fatty acid salt, ester, ether or a derivative of a medium chain
fatty acid and which has a carbon chain length of from 6 to 20
carbon atoms. In some embodiments, the carbon chain length is from
8 to 14. In some embodiments, the enhancers are S-Cyclodextrins,
vitamin E TPGS, gallic acid esters, crospovidones, sorbitan esters,
poloxamers, or olyoxyethylene glycolated natural or hydrogenated
castor oil (Cremophor.RTM., BASF). In some embodiments, the
enhancers are medium chain glycerides or a mixture of medium chain
glycerides. Exemplary enhancers are further described in U.S.
Patent Publication No. 2003/0091623, and U.S. Pat. No. 6,372,728
which are incorporated by reference in their entireties.
IV. Application of Co-Solvent System During the Preparation of a
GnRH Related Compound
[0071] The GnRH related compound described herein may be prepared
in the presence of a co-solvent system in a manner that the
gelation of the GnRH compound is reduced. In some embodiments, the
final step of the preparation of the GnRH related compound is
conducted in the presence of a co-solvent system. In some
embodiments, the final step is drying, using known techniques, such
as lyophilization, tray drying, spray drying, fluid bed drying, or
other similar techniques known to one skilled in the art.
[0072] In some embodiments, the co-solvent system comprises water
and at least one water-miscible solvent. The water miscible solvent
can be chosen from, but are not limited to, linear or branched
C.sub.1-6 alcohol, tetrahydrofuran, acetone, ethyl methyl ketone,
methyl isobutyl ketone, methyl isopropyl ketone, cyclohexanone,
diethyl ketone, pentan-3-one, cyclohexane, acetonitrile,
N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, alcohol,
ethylene glycol, diglyme, monoglyme, ethylene glycol monomethyl
ether, diethylene glycol, triethylene glycol, polyethylene glycol
and a mixture thereof. In certain embodiments, at least one water
miscible solvent is a linear or branched C.sub.1-6 alcohol.
Exemplary suitable alcohols include, but are not limited to,
methanol, ethanol, propanol, iso-propanol, butanol, sec-butanol,
iso-butanol, tert-butanol, 1-pentanol, 2-pentanol, and hexanol. In
some embodiments, at least one water miscible solvent is selected
from the group consisting of methanol, ethanol, n-propanol,
iso-propanol and tert-butanol. In some embodiments, at least one
water miscible solvent is selected from the group consisting of
methanol, ethanol, iso-propanol, tert-butanol, acetoniltrile and
methylene chloride. In some embodiments, the present invention may
be carried out with two or more water miscible solvents. In some
embodiments, the weight ratio of the water miscible solvent to
water is in the range of about 1/1000 to about 99/1. In some
embodiments, the weight ratio is about 3/97 to about 59/41.
[0073] In some embodiments, the process comprises further adding
acid during the preparation of the GnRH related compound. Acids
used in the present invention include, but are not limited to
acetic acid, sulfuric acid, hydrochloride acid, trifluoracetate,
citrate acid, tartaric acid, ascorbic acid, and boric acid, etc.
Generally, the concentration of the acid is sufficient to prepare a
salt of the GnRH related compound. In some embodiments, the
concentration of the acid depends on the molecular weight of the
GnRH related compound and the acid used herein. In some
embodiments, the concentration is in the range of about 0.5% to
about 20% of the solution.
V. Methods of Preparing the Compositions
[0074] According to some aspects of the present invention, methods
for preparation of a composition of a peptide, polypeptide,
protein, an analog or derivative thereof, are provided. In some
embodiments, the method comprises mixing the peptide, polypeptide,
protein, an analog or derivative thereof with a sufficient amount
of at least one stabilizing agents to improve the stability of
peptide, polypeptide, protein, an analog and/or derivative thereof.
In some embodiments, at least one stabilizing agent is a medium
chain fatty acid salt, an ester, an ether, or a derivative of a
medium chain fatty acid and has a carbon chain length of from about
4 to about 20 carbon atoms or is a surface active agent. As used
herein, the term "mixing" means contacting, combining, reacting,
and/or coating a peptide, polypeptide, protein, an analog and/or
derivative thereof, with one or more stabilizing agents. In one
embodiment, "mixing" means combining a peptide, polypeptide,
protein, an analog or derivative thereof with a stabilizing agent
in a composition. In one embodiment, the GnRH related compound is
prepared in the presence of a co-solvent system described herein.
In some embodiment, the concentration of the stabilizing agent in
the composition is equal to or above the critical micelle
concentration of the stabilizing agent.
VI. Pharmaceutical Compositions and Administration
[0075] In one embodiment, the present invention provides a
pharmaceutical composition comprising a therapeutically effective
amount of one or more peptide, polypeptide, protein, an analog or
derivative thereof, and a sufficient amount of at least one
stabilizing agents to improve the stability of the peptide,
polypeptide, protein, an analog or derivative thereof, wherein at
least one stabilizing agent is a medium chain fatty acid salt, an
ester, an ether, or a derivative of a medium chain fatty acid and
has a carbon chain length of from about 4 to about 20 carbon atoms
or is a surface active agent. In another embodiment, the
pharmaceutical composition further comprises a pharmaceutically
acceptable carrier. The term "pharmaceutically acceptable carrier"
as used herein refers to any substance, not itself a therapeutic
agent, used as a vehicle for delivery of a therapeutic agent to a
subject.
[0076] The compositions of the present invention may be suitable
for formulation for oral, parenteral, inhalation spray, topical,
rectal, nasal, sublingual, buccal, vaginal or implanted reservoir
administration, etc. In one embodiment, the compositions are
administered orally, topically, intraperitoneally or intravenously.
Sterile injectable forms of the compositions of this invention may
be aqueous or oleaginous suspension. These suspensions may be
formulated according to techniques known in the art using suitable
dispersing or wetting agents and suspending agents. The sterile
injectable preparation may also be a sterile injectable solution or
suspension in a nontoxic parenterally acceptable diluent or
solvent. Among the acceptable vehicles and solvents that may be
employed are water, Ringer's solution and isotonic sodium chloride
solution. In addition, sterile, fixed oils are conventionally
employed as a solvent or suspending medium.
[0077] In some embodiments, the composition used in the present
invention is in an oral dosage form. In some embodiments, the oral
dosage form is chosen from tablets, capsules, granules, powders,
capsules filled with granules or powders, capsules filled with
liquids or semi-solids, sachets filled with granules or powders,
liquid, emulsions, microemulsions, and any composition that capable
of forming emulsions. In one embodiment, the oral dosage form may
be a tablet, a multiparticulate, or a capsule. In one embodiment,
the medium chain fatty acid and derivatives thereof described
herein may also function as an enhancer.
[0078] In some embodiments, the oral dosage form is a delayed
release dosage form which minimizes the release of the peptide,
polypeptide, protein, an analog or derivative thereof and the
stabilizing agents and/or the enhancer in the stomach, and hence
the dilution of the local stabilizing agent or the concentration of
the enhancer therein, and releases the peptide, polypeptide,
protein, an analog or derivative thereof and the stabilizing agent
or the enhancer in the intestine. In some embodiments, the oral
dosage form is a delayed release rapid onset dosage form. Such a
dosage form minimizes the release of peptide, polypeptide, protein,
an analog or derivative thereof and stabilizing agent or enhancer
in the stomach, and hence the dilution of the local stabilizing
agent or enhancer concentration therein, but releases the peptide,
polypeptide, protein, an analog or derivative thereof and the
stabilizing agent or the enhancer rapidly once the appropriate site
in the intestine has been reached, maximizing the delivery of the
poorly permeable or soluble peptide, polypeptide, protein, an
analog or derivative thereof by maximizing the local concentration
of the peptide, polypeptide, protein, an analog or derivative
thereof and the stabilizing agent at the site of absorption.
[0079] In the case of any of the embodiments described herein, a
controlled release coating may be applied to the final dosage form
(capsule, tablet, multilayer tablet etc.). In one embodiment, the
controlled release coating may comprise a rate controlling polymer
material described herein. The dissolution characteristics of such
a coating material may be pH dependent or independent of pH.
[0080] In some embodiments, the composition of the present
invention may have an enteric coating thereon. In one embodiment,
the enteric coating comprises a polymer selected from the group
consisting of poly(acrylic acid), polyacrylate, poly(methacrylic
acid), polymethacrylate, and mixtures thereof. In some embodiments,
the enteric coated composition may be in the form of a tablet or
capsule.
[0081] The term "tablet" as used herein includes, but is not
limited to, immediate release (IR) tablets, sustained release (SR)
tablets, matrix tablets, multilayer tablets, multilayer matrix
tablets, extended release tablets, delayed release tablets and
pulsed release tablets any or all of which may optionally be coated
with one or more coating materials, including polymer coating
materials, such as enteric coatings, rate-controlling coatings,
semi-permeable coatings and the like. The term "tablet" also
includes osmotic delivery systems in which a drug compound is
combined with an osmagent (and optionally other excipients) and
coated with a semi-permeable membrane, the semi-permeable membrane
defining an orifice through which the drug compound may be
released. Tablet solid oral dosage forms may be useful in the
practice of the invention include those selected from the group
consisting of IR tablets, SR tablets, coated IR tablets, matrix
tablets, coated matrix tablets, multilayer tablets, coated
multilayer tablets, multilayer matrix tablets and coated multilayer
matrix tablets. In some embodiments, a tablet dosage form is an
enteric-coated tablet dosage form. In some embodiments, a tablet
dosage form is an enteric-coated rapid onset tablet dosage
form.
[0082] Capsule solid oral dosage forms may be useful in the
practice of the present invention include those selected from the
group consisting of instant release capsules, sustained release
capsules, coated instant release capsules, and coated sustained
release capsules including delayed release capsules. Capsules may
be filled with powders, granules, multi particulates, tablets,
semi-solids, or liquids. In some embodiments, a capsule dosage form
is an enteric-coated capsule dosage form. In some embodiments, a
capsule dosage form is an enteric-coated rapid onset capsule dosage
form. Capsules may be made of hard gelatin, soft gelatin, starch,
cellulose polymers, or other materials as known to the art.
[0083] The term "multiparticulate" as used herein means a plurality
of discrete particles, pellets, mini-tablets and mixtures or
combinations thereof. If the oral form is a multiparticulate
capsule, such hard or soft gelatin capsules can suitably be used to
contain the multiparticulate. In some embodiments, a sachet may
suitably be used to contain the multiparticulate. In some
embodiments, the multiparticulate may be coated with a layer
containing rate controlling polymer material. In some embodiments,
a multiparticulate oral dosage form according to the invention may
comprise a blend of two or more populations of particles, pellets,
or mini-tablets having different in vitro and/or in vivo release
characteristics. For example, a multiparticulate oral dosage form
may comprise a blend of an instant release component and a delayed
release component contained in a suitable capsule.
[0084] In some embodiments, the multiparticulate and one or more
auxiliary excipient materials can be compressed into tablet form
such as a multilayer tablet. In some embodiments, a multilayer
tablet may comprise two layers containing the same or different
levels of the same active ingredient having the same or different
release characteristics. In some embodiments, a multilayer tablet
may contain different active ingredient in each layer. Such a
tablet, either single layered or multilayered, can optionally be
coated with a controlled release polymer so as to provide
additional controlled release properties. In some embodiments,
multiparticulate dosage form comprises a capsule containing delayed
release rapid onset minitablets. In some embodiments, a
multiparticulate dosage form comprises a delayed release capsule
comprising instant release minitablets. In some embodiments, a
multiparticulate dosage form comprises a capsule comprising delayed
release granules. In some embodiments, a multiparticulate dosage
form comprises a delayed release capsule comprising instant release
granules.
[0085] The term "emulsion" used herein means a suspension or
dispersion of one liquid within a second immiscible liquid. In some
embodiments, the emulsion is an oil-in-water or
water-in-oil-in-water emulsion.
[0086] The term, "microemulsion" used herein means a solution in
which the hydrophobic (oil-like) phase and the hydrophilic
(water-like) phase and a surface active agent form micelle
structures. Such dispersions are clear and stable over time.
[0087] In addition, "emulsion" or "microemulsion", used herein
includes a hydrophilic or a hydrophobic liquid which, on dilution
with a hydrophobic or a hydrophilic liquid respectively, form an
emulsion or a microemulsion. In some embodiments, "emulsion", or
`microemulsion`, used herein may include solid or semi-solid
materials which may be liquid at higher temperatures. For example,
the material may be solid at room temperature. At about body
temperature (about 37.degree. C.), the material may be liquid.
[0088] Alternatively, pharmaceutically acceptable compositions of
this invention may be in the form of a suppository for rectal
administration. The suppositories can be prepared by mixing the
agent with a suitable non-irritating excipient that is solid at
room temperature but liquid at rectal temperature and therefore
will melt in the rectum to release the drug. Such materials include
cocoa butter, beeswax and polyethylene glycols.
[0089] Pharmaceutically acceptable compositions of the present
invention may be in the form of a topical solution, ointment, or
cream in which the active component is suspended or dissolved in
one or more carriers. Carriers for topical administration of the
compounds of this invention include, but are not limited to,
mineral oil, liquid petrolatum, white petrolatum, propylene glycol,
polyoxyethylene, polyoxypropylene compound, emulsifying wax and
water. Where the topical formulation is in the form of an ointment
or cream, suitable carriers include, but are not limited to,
mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters
wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and
water.
[0090] When the pharmaceutically acceptable composition is an
ophthalmic formulation, it may be a micronized suspension in
isotonic, pH adjusted sterile aqueous solution, or as a solution in
isotonic, pH adjusted sterile saline, either with or without a
preservative such as benzylalkonium chloride. Alternatively, for
ophthalmic uses, the pharmaceutically acceptable compositions may
be formulated in the form of an ointment.
[0091] The pharmaceutically acceptable compositions of this
invention may also be administered by nasal, aerosol or by
inhalation administration routes. Such compositions are prepared
according to techniques well-known in the art of pharmaceutical
formulation and may be prepared as solutions in saline, employing
benzyl alcohol or other suitable preservatives, absorption
promoters to enhance bioavailability, fluorocarbons, and/or other
conventional solubilizing or dispersing agents.
[0092] It should also be understood that a specific dosage and
treatment regimen for any particular patient will depend upon a
variety of factors, including the activity of the specific compound
employed, the age, body weight, general health, gender, diet, time
of administration, rate of excretion, drug combination, and the
judgment of the treating physician and the severity of the
particular disease being treated. The amount of a compound of the
present invention in the composition will also depend upon the
particular compound in the composition.
VII. Methods of Treatment and Use
[0093] Another aspect of the present invention provides a method of
treatment of a medical condition treatable by a peptide,
polypeptide, protein, an analog or derivative thereof comprising
administering to a patient suffering from said condition a
pharmaceutical composition as described in the present application.
As used herein, the medical condition includes, but is not limited
to, diabetes mellitus, Alzheimer, autoimmune diseases, colon
cancer, sex hormone dependent disease such as benign prostate
hyperplasia, prostate cancer, estrogen-dependent breast cancer,
endometrial cancer, ovarian cancer, endometriosis and precocious
puberty, and contraception in a human or animal subject
[0094] Yet, another embodiment provides use of pharmaceutical
composition as described in the present application in the
manufacture of a medicament for the treatment of a medical
condition treatable by said peptide, polypeptide, protein, analogs
and/or derivatives thereof.
[0095] It is understood that the combinations of all embodiments
described herein are also envisaged in the present invention.
[0096] The present invention will now be described in more detail
with reference to the following examples. However, these examples
are given for the purpose of illustration and are not to be
construed as limiting the scope of the invention.
EXAMPLES
1. Application of Co-Solvent During the Preparation of Acyline
(1) Preparation of Acyline Batches
[0097] The six different acyline batches are described in FIG. 1,
which summarizes the variations in the lyophilization procedure,
which is the last step of the preparation of acyline. For lots XF
173/315-125, XF 185/165-133 and XF 173/315-151A, a co-solvent
system is used in the lyophilization step. Water is used as a
solvent for other batches. The batches and the associated
lyophilization solvents are also illustrated in FIG. 1. The acyline
may be prepared according to methods known to one of skill in the
art, for example U.S. Pat. No. 6,747,125, or processes described in
the present application.
Example 1
[0098] The study of gelation for different acyline batches in
propylene glycol is carried out and the result is summarized in
FIG. 2. The 9% and 16.7% of acyline sampls are prepared by using
the acyline batches listed in FIG. 1. The 9% acyline sample of XF
173/315-125, XF 185/165-133 and XF 173/315-151A are prepared by
using acyline prepared via use of a co-solvent during the
lyophilization step. The acyline batches of XF 173/315-125, XF
185/165-133 and XF 173/315-151A appear clear and non-viscous after
2 hours. Other batches which are lyophilized by using water as a
solvent did not appear as clear and non-viscous solutions due to
the presence of gelled acyline.
Example 2
[0099] The gelation of different acyline drug batches in water is
investigated and the results are summarized in FIG. 3. The 0.5% and
1% acyline samples are prepared by using the acyline batches listed
in FIG. 1. The 0.5% and 1% of acyline samples of XF 173/315-125, XF
185/165-133 and XF 173/315-151A which are prepared by using
co-solvent during the lyophilization step appear clear and non
viscous upon dissolving in water.
Example 3
[0100] The tendency of gelation of different acyline batches in
standardized microemulsion (SM) is investigated. The result is
summarized in FIG. 4(a). The formulation of the standard micro
emulsion is shown in FIG. 4(b). The 5 mg and 10 mg formulations of
acyline in a microemulsion are prepared by using the acyline lots
synthesized in FIG. 1. 5 mg and 10 mg dose of acyline batches of XF
173/315-151A which are prepared by using co-solvent during the
lyophilization step appeared clear and transparent after 2
hours.
2. Application of Anti-Gelling Agents in the Formulation of Acyline
Compositions General Procedures of Comparison Experiments
[0101] Different concentrations of acyline composition are prepared
by adding acyline to pH 6.8 buffer solution either at room
temperature or 37.degree. C. All acyline solutions contain 0.6
mg/mL sodium caprate (sodium caprate is referred as C.sub.10 in the
figures). All samples are centrifuged and filtered prior to
analysis. Samples are analyzed by reverse phase HPLC with UV
detection.
Example 4
[0102] 10 mg acyline is transferred into 200 mL volumetric flask. A
pH 6.8 buffer solution is preheated to 37.degree. C. Then, 100 mL
pre-heated buffer solution and 0.6 mg/mL sodium caprate is added to
the flask to prepare a 0.1 mg/mL acyline sample. In a similar
manner, Tween 80 is added to prepare a 0.1 mg/mL acyline solution
with 1% Tween 80. Samples are shaken in a temperature controlled
water bath at 37.degree. C. 5 mL samples are taken at 1, 5, 10, 15,
20, 30 and 120 minutes after mixing acyline with the buffer
solution. Samples are filtered immediately through 0.45 .mu.m
filters and the first 3 mL is discarded. Filtered samples are
analyzed, undiluted, by reverse phase HPLC with UV detection. All
samples are prepared in duplicate and the concentration was
obtained for the analysis from the mean of the duplicates. The
result of comparison of 1% and 0% Tween 80 at 0.1 mg/mL acyline
sample is graphically recorded in FIG. 5. The results show that
sodium caprate alone at a concentration below the CMC is
insufficient to reduce the gelation of acyline. The addition of 1%
Tween 80 successfully reduces the gelation.
Example 5
[0103] A similar experimental procedure as Example 4 is used to
prepare acyline sample for example 5. The result of comparison of 5
mg/mL, 1.0 mg/mL, 0.1 mg/mL, and 0.1% Tween in phosphate buffer
containing 0.6 mg/mL of sodium caprate and 0.1 mg/mL acyline is
graphically recorded in FIG. 6. The results show that only 1% Tween
80 solution may completely inhibit the gelation of acyline.
Example 6
[0104] A similar experimental procedure as Example 4 is used to
prepare acyline sample for example 6. The result of comparison of
1% and 1 mg/mL Tween 80 in 0.1 and 0.01 mg/mL acyline sample is
graphically recorded in FIG. 7. The results show that 1% Tween 80
reduces gelation for both 0.1 mg/mL and 0.01 mg/mL acyline
sample.
Example 7
[0105] A similar experimental procedure as Example 4 is used to
prepare acyline sample for example 7. The result of comparison of
0.01 mg/mL acyline samples having 0.1%, 0.5% and 1% Tween 80 is
graphically recorded in FIG. 8. The results show that the acyline
sample with 1% Tween 80 significantly reduces the gelation.
3. Impact of Sodium Caprate (C10) on the Tendency of Gelation of
Acyline in Water
Example 8
[0106] FIG. 9 graphically demonstrates the impact of different
concentrations of sodium caprate (C10) on the gelation of acyline
in water. When the concentration of sodium caprate is below 10
mg/mL, the recovery of acyline significantly decreases, which
implies an increase of gelation of acyline. The investigators of
the present invention believe that the increase of the gelation is
due to an increased concentration of ions caused by the addition of
sodium caprate. However, when the concentration of sodium caprate
reaches and is above the CMC of sodium caprate (.about.20 mg/mL),
it is observed that there is a sudden and significant increase of
the recovery of acyline, which indicates an effective reduction of
gelation. The CMC of sodium caprate is known as 100 mM (.about.20
mg/mL). (See "kinetic studies of the interaction of fatty acids
with phosphatidylcholine vesicles (liposomes), Rogerson et al.,
Colloids and Surfaces B: Biointerfaces, 48, 24-34 (2006).) When the
concentration of sodium caprate reaches about 50 mg/mL, the
recovery of acyline is almost 100%, which indicates that the
gelation is completely inhibited.
4. Application of Anti-Gelling Agents in Different Micoremulsion
formulations of Acyline Samples
Example 9
[0107] FIG. 11 graphically demonstrates the relative
bioavailability of various formulations of acyline in dogs. The
relative bioavailability is measured by comparing the absolute
bioavailability of various formulations of acyline with the
absolute bioavailability of a standard formulation of acyline,
which is a formulation without any anti-gelling agent. The
formulation of microemulsion 1 (M1/55% Capmul MCM), microemulsion 2
(M2/45% Capmul PG-8), and microemulsion 3 (M3/55% Capmul MCM C10)
are illustrated in FIG. 10(a) through (c). The formulation of the
standard solution is 5 mg acyline, 550 mg sodium caprate and 5 mL
purified water. "C.sub.10" in FIGS. 10 and 11 represents sodium
caprate. "SLS" in FIGS. 10 and 11 represents sodium lauryl
sulphate. The comparison results in FIG. 11 show that all
formulations with anti-gelling agents such as sodium caprate and
sodium lauryl sulphate, increase the bioavailability of acyline
from 7.8 fold to 32.5 fold.
Example 10
[0108] FIG. 12 graphically demonstrates the relative
bioavailability of (1) enteric tablets of 10 mg acyline versus
unenhanced 5 mg acyline solution sample and (2) enteric tablets of
10 mg acyline versus 5 mg acyline standard sample. The formulation
of acyline standard sample is 5 mg acyline, 550 mg sodium caprate
and 5 mL purified water. The acyline in the tablets and the 5 mg
acyline sample is prepared by using a lyophilization step with
water as the solvent. The tablets contained the same amount of
sodium caprate as the 5 mg acyline sample. It is observed that, the
concentration of sodium caprate, 110 mg/mL, is sufficient to reduce
or even inhibit gelation in the solution and enhance the
bioavailability of acyline solution. FIG. 12 demonstrates that the
bioavailability of enhanced tablets is significantly improved
compared to unenhanced tablet.
5. Application of Sodium Caprate and Capric Acid in Insulin
Samples
Example 11
[0109] A study evaluating the effect of sodium caprate (C10) and
capric acid on the stability of bovine insulin is carried out. In
this study, bovine Insulin with a potency of 29 U/mg is used to
prepare a 10 U/mL solution (344.83 mg/L of solution) in a phosphate
buffer pH 8. Using 200 mL vessels, appropriate amounts of C10 is
added to 100 mL aliquots of the insulin solution. Two bottles are
used a controls, containing only the insulin solution. An addition
of 3 g of C10 is added to bottles 3 and 4, 6 g of C10 to bottles 5
and 6, 3 g of Capric Acid to bottles 7 and 8, and 6 g of Capric
Acid to bottles 9 and 10. The bottles are gently swirled and 6 mL
aliquots are removed from each bottle for the T=ZERO sample. The
samples are filtered (Millex-HV 0.45 .mu.m), and the first 5 ml of
filtrate discarded. The appropriate test solutions are stirred and
additional samples are collected from all test solutions at 6, 24
hours etc. The amount of bovine insulin in solution after
filtration is determined against standards (70 mg in 200 ml of 0.01
N HCl).
[0110] The % recovery of intact insulin after the insulin solution
stands for a period of time is recorded in Tables 2 and 3 and
graphically illustrated in FIGS. 13(a) and (b). It is observed that
insulin solutions with sodium caprate are significantly more stable
than the insulin samples without sodium caprate or the solutions
with capric acid. For insulin samples that contain sodium caprate,
at least 90% of insulin is recovered after the solutions stands at
37.degree. C. for at least about 24 hours.
TABLE-US-00001 TABLE 1 Formulation of insulin solutions for Example
11 10 U/mL Bovine Insulin in `blank` simulated 10 U/mL Bovine
Insulin in `blank` 10 U/mL Bovine Insulin in `blank` intestinal
simulated intestinal buffer pH 8 simulated intestinal buffer pH 8
buffer pH 8 Plus Sodium Caprate Plus Capric Acid 1 3 5 7 9 Sample
Control 2 Control 4 Control 6 Control 8 Control 10 Sodium -- -- 30
mg/ml 30 mg/ml 60 mg/ml 60 mg/ml -- -- -- Caprate Capric -- -- --
-- -- -- 30 mg/ml 30 mg/ml 60 mg/ml 60 mg/ml Acid Stirring No Yes
No Yes No Yes No Yes No Yes
TABLE-US-00002 TABLE 2 Bovine insulin fibrillation results with or
without C10 % Recovery % Recovery % Recovery % Recovery % Recovery
% Recovery T = T = T = T = T = T = Sample 0 6 24 29 48 72 1.
Insulin Standing 100.24 100.00 100.25 100.28 100.29 100.29 2.
Insulin Stirring 100.11 100.08 99.42 1.50 0.29 0.22 3. 30 mg/ml C10
98.15 97.85 97.88 97.39 97.15 96.54 Standing 4. 30 mg/ml C10 98.06
97.66 97.74 97.44 97.58 97.05 Stirring 5. 60 mg/ml C10 94.52 94.24
93.99 93.61 93.24 92.12 Standing 6. 60 mg/ml C10 94.79 94.52 94.41
93.98 93.29 92.79 Stirring
TABLE-US-00003 TABLE 3 Bovine insulin fibrillation results with or
without Capric acid Bovine Insulin Fibrillation Expt. Results
Summary % Recovery % Recovery % Recovery % Recovery % Recovery %
Recovery T = T = T = T = T = T = Sample 0 6 24 29 48 72 1. Insulin
Standing 100.24 100.00 100.25 100.28 100.29 100.29 2. Insulin
Stirring 100.11 100.08 99.42 1.50 0.29 0.22 7. 30 mg/ml CA 93.73
68.88 15.32 3.26 1.10 0.44 Standing 8. 30 mg/ml CA 95.06 0.27 0.20
0.24 0.23 0.16 Stirring 9. 60 mg/ml CA 91.96 67.73 19.75 2.59 1.43
2.24 Standing 10. 60 mg/ml CA 91.38 0.27 0.19 0.09 0.13 0.10
Stirring Note: Recovery values based on the theoretical amount
spiked = 0.344591 mg/ml
[0111] The foregoing is illustrative of the present invention and
is not to be construed as limiting thereof. Although a few
exemplary embodiments of this invention have been described, those
skilled in the art will readily appreciate that many modifications
are possible in the exemplary embodiments without materially
departing from the novel teachings and advantages of this
invention. Accordingly, all such modifications are intended to be
included within the scope of this invention as defined in the
claims. Therefore, it is to be understood that the foregoing is
illustrative of the present invention and is not to be construed as
limited to the specific embodiments disclosed, and that
modifications to the disclosed embodiments, as well as other
embodiments, are intended to be included within the scope of the
appended claims. The invention is defined by the following claims,
with equivalents of the claims to be included therein.
* * * * *