U.S. patent application number 12/701339 was filed with the patent office on 2010-08-05 for process for purifying guar.
This patent application is currently assigned to ALCON RESEARCH, LTD.. Invention is credited to John C. BAKER, James W. DAVIS, Howard Allen KETELSON, David L. MEADOWS.
Application Number | 20100196415 12/701339 |
Document ID | / |
Family ID | 42397915 |
Filed Date | 2010-08-05 |
United States Patent
Application |
20100196415 |
Kind Code |
A1 |
DAVIS; James W. ; et
al. |
August 5, 2010 |
PROCESS FOR PURIFYING GUAR
Abstract
The present invention relates to processes for purifying guar
comprising combining borate and guar in an aqueous solution and
treating the aqueous solution with an organic solvent to induce
precipitation of purified guar. Another embodiment of the present
invention is directed to ophthalmic formulations comprising
purified guar produced by the processes described.
Inventors: |
DAVIS; James W.; (Argyle,
TX) ; KETELSON; Howard Allen; (Dallas, TX) ;
MEADOWS; David L.; (Colleyville, TX) ; BAKER; John
C.; (Fort Worth, TX) |
Correspondence
Address: |
ALCON
IP LEGAL, TB4-8, 6201 SOUTH FREEWAY
FORT WORTH
TX
76134
US
|
Assignee: |
ALCON RESEARCH, LTD.
Fort Worth
TX
|
Family ID: |
42397915 |
Appl. No.: |
12/701339 |
Filed: |
February 5, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61150215 |
Feb 5, 2009 |
|
|
|
Current U.S.
Class: |
424/195.18 ;
530/213 |
Current CPC
Class: |
C08B 37/0096 20130101;
A61K 9/0048 20130101; A61P 27/02 20180101; A61K 36/48 20130101;
A61K 47/36 20130101; C08B 37/0003 20130101 |
Class at
Publication: |
424/195.18 ;
530/213 |
International
Class: |
A61K 31/736 20060101
A61K031/736; C09F 1/04 20060101 C09F001/04; A61P 27/02 20060101
A61P027/02 |
Claims
1. A process for manufacturing guar comprising: combining borate
and guar in an aqueous solution; and precipitating guar by adding
an organic solvent to said aqueous solution.
2. A process according to claim 1 wherein said organic solvent is
acetone.
3. A process according to claim 1 further comprising: filtering
precipitated guar.
4. A process according to claim 3, wherein said filtering comprises
filtering precipitated guar using one or more filters having a pore
size of 40 .mu.m or less.
5. A process according to claim 4, wherein said filters have a pore
size selected from the group consisting of: 40 .mu.m, 20 .mu.m, and
10 .mu.m.
6. A process according to claim 1 wherein said combining comprises
adding borate to an aqueous guar solution.
7. A process according to claim 6 wherein said aqueous guar
solution is filtered before said adding of borate.
8. A process according to claim 1 wherein said borate is selected
from the group consisting of: sodium borate, potassium borate,
boric acid, alkyl borates, trimethyl borate, phenyl borates, and
combinations thereof.
9. A process according to claim 1 wherein said borate is added
during said combining to form a concentration of 0.05% to 0.05% w/v
in said aqueous solution.
10. A process according to claim 1 wherein said guar is at a
concentration of less than 1.0% w/v in said aqueous solution.
11. Guar produced by a process of claim 1.
12. The guar of claim 11, wherein said guar is hydroxyethyl guar,
hydroxypropyl guar galactomannan, or carboxymethylhydroxypropyl
guar.
13. An ophthalmic formulation comprising: guar produced by a
process of claim 1 and one or more excipients.
14. An ophthalmic formulation of claim 13 wherein said guar is
selected from the group consisting of: hydroxyethyl guar,
hydroxypropyl guar galactomannan, carboxymethylhydroxypropyl guar,
and combinations thereof.
15. An ophthalmic formulation of claim 13 wherein said guar is
hydroxypropyl guar galactomannan.
16. An ophthalmic formulation of claim 13 wherein said guar is
present at a concentration of 0.1% to 0.25% w/v.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims priority under 35 U.S.C. .sctn.119
to U.S. Provisional Patent Application No. 61/150,215, filed Feb.
5, 2009, the entire contents of which are incorporated herein by
reference.
TECHNICAL FIELD OF THE INVENTION
[0002] The present invention relates to guar and guar derivatives,
and more particularly to processes for producing purified guar and
guar derivatives.
BACKGROUND OF THE INVENTION
[0003] Guar gum is obtained from the endosperm of the guar (also
known as clusterbean) plant Cyamopsis tetragonoloba (L.) Taub. Guar
gum powder is typically produced by mechanically separating the
endosperm (also known as guar "splits") from guar seed and
hydrating the endosperm material in basic solution, followed by
mechanical milling and drying to form the guar powder. U.S. Pat.
No. 5,536,825 to Yeh et al. discloses techniques that may be used
to form guar gum powder from guar splits.
[0004] Guar gum powder itself is comprised mostly of a water
soluble, non-ionic polysaccharide consisting of a linear backbone
chain of mannose linked together by .beta.-(1-4) glycosidic
linkage, and which forms branch points from the 6 position to
galactose units through .alpha.-(1-6) linkage. Processing
techniques have been disclosed to improve or modify guar gum powder
for food grade applications, drilling and hydraulic fracturing
fluids, and other industrial applications. U.S. Pat. No. 4,754,027
to Applegren describes a technique for processing guar gum powder
to produce an ingestible guar end product.
[0005] Many ophthalmic formulations comprise compounds that provide
lubricity and other desirable properties. When these formulations
are instilled in the eye, the properties of such compounds can
prevent undesirable problems such as bioadhesion and the formation
of friction-induced tissue damage, as well as encourage the natural
healing and restoration of previously damaged tissues. Guar and
guar derivatives such as hydroxypropyl guar (HP-guar) are used to
provide characteristics such as lubricity to ophthalmic
formulations.
[0006] Guar gum powder can be processed and purified by dissolving
the powder in aqueous solution and adding organic solvents to
induce precipitation. However, the precipitate thus formed often
flocculates, forming a gum or viscous semi-solid having a fibrous
character. Such precipitates tend to foul filtration and mixing
equipment, making it difficult or impossible to utilize the guar
material in a commercial-scale process for manufacturing aqueous
pharmaceutical products, e.g., sterile ophthalmic solutions.
[0007] Prior approaches for addressing this problem have required
that the resulting precipitate be mechanically milled or cut,
either before or after a drying step, to render a dry solid. For
example, EP 0514890 to Maruyama et al., discloses a method for
purifying polysaccharides, including guar gum. The method of
Maruyama requires the use of a precipitate cutter to generate the
desired polysaccharide particle sizes for further processing and
preferably uses isopropanol solution to induce precipitation.
However, the dry solid thus rendered is of very low density, making
it more expensive and inconvenient to ship and store in bulk
quantities. In addition, this process has long processing and
drying times due to the large amount of organics remaining after
precipitation.
[0008] Previous disclosures have discussed the usefulness of guar
and borate combinations for use in topical ophthalmic formulations,
particularly gelling formulations. U.S. Pat. No. 6,403,609 to
Asgharian describes such guar/borate combinations, but does not
disclose a process for producing guar from guar gum powder.
BRIEF SUMMARY OF THE INVENTION
[0009] The present invention generally relates to processes for
producing guar and guar derivatives. The materials produced via the
processes of the present invention are particularly useful as
components of aqueous ophthalmic pharmaceuticals products.
[0010] The present inventors have unexpectedly discovered that
combining borate and guar in aqueous solution as part of a guar
processing method yields a granular guar precipitate with improved
purity, solubility, clarity, and thermal stability properties
relative to guar produced by known processes. Guar produced by
processes according to the present invention also has improved
hydration characteristics.
[0011] Without being bound by theory, it appears that guar forms an
anionic polyelectrolyte polymer with borate that can phase separate
via salting out. This means that, in solution, if the charge of the
polymer is adjusted with salts, buffers and/or pH then it can go
from a solution to a highly crosslinked particle that can
precipitate over time. Addition of any organic solvent will further
induce the thus-formed precipitate to sediment from the
supernatant. This discovery can be incorporated into scaleable
manufacturing processes with few controlled process and rheological
parameters. The guar thus produced has desirable viscosity and
solution transmission properties, hydrates quickly in solution, and
has an improved purity profile.
[0012] Embodiments of the present invention are directed to
processes for manufacturing pharmaceutical grade guar compositions
which comprise combining borate and guar in aqueous solution and
precipitating guar by adding an organic solvent to the aqueous
solution.
[0013] The present invention is further directed to processes for
producing guar derivatives (e.g., hydroxyethyl guar and
carboxymethylhydroxypropyl guar) that are particularly suitable for
use in ophthalmic pharmaceutical compositions that are formulated
for local administration.
[0014] The present invention is also directed to the provision of
compositions produced by the described processes that are
well-suited for pharmaceutical and medical applications,
particularly as lubricants and viscosity enhancers.
[0015] The foregoing brief summary broadly describes the features
and technical advantages of certain embodiments of the present
invention. Additional features and technical advantages will be
described in the detailed description of the invention that
follows. Novel features which are believed to be characteristic of
the invention will be better understood from the detailed
description of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] A more complete understanding of the present invention and
the advantages thereof may be acquired by referring to the
following description, taken in conjunction with the figures of the
accompanying drawing in which like reference numbers indicate like
features and wherein:
[0017] FIG. 1 is a bar graph comparing the measured stability of
heat-sterilized guars; and
[0018] FIG. 2 is a bar graph comparing the measured viscosity of
guar according to the present invention compared to
hydroxypropylated guars processed using different techniques.
DETAILED DESCRIPTION OF THE INVENTION
[0019] Guar powder and water are combined to form an aqueous
solution or slurry. The guar and water slurry is then mixed to
disperse the guar. The guar concentration in water may vary, but is
typically 0.1% to 1.5% w/v. In preferred embodiments, the guar is
added in an amount sufficient to provide a final concentration of
less than 1.0% w/v and preferably about 0.5% to 0.8% w/v and
allowed to hydrate in the water for 2 hours or more at a pH of
about 6.0 to 7.0. Different times and pH conditions for hydration
may be used in other embodiments. Various temperatures may also be
used for hydration. In one embodiment, hydration at 70.degree. C.
is preferred.
[0020] The aqueous guar solution is then combined with a borate
source, optionally following one or more filtration steps prior to
combination with borate. Following the addition of borate, an
organic solvent is added to the borate and guar solution to induce
precipitation of guar. The precipitated guar is then isolated,
optionally with one or more precipitation and/or washing steps
preceding the isolation. The isolated guar is dried and optionally
milled to produce a desired particle size and homogeneity.
[0021] Guar gum and guar derivatives are generally available in
powder form with various levels of purity. These powders are
preferred for use in embodiments of the present invention. Guar
derivatives that are commercially available include, but are not
limited to, derivatives such as those containing hydroxyethyl,
hydroxypropyl and carboxymethylhydroxypropyl substitutions, and
other hydrophobic derivatives. Other guar derivatives used with
embodiments of the present invention include cationic, anionic guar
gums. Such guar and guar derivatives may be obtained, for example,
from Rhodia, Inc. (Cranbury, N.J.), Hercules, Inc. (Wilmington,
Del.), TIC Gum, Inc. (Belcamp, Md.), AEP Colloids, Inc. (Hadley,
N.Y.), and Lamberti USA, Inc. (Hungerford, Tex.). A preferred guar
gum powder is USP or general grade guar powder obtained from TIC
Gum.
[0022] Borate sources used in embodiments of the present invention
are boric acid and other borate salts such as sodium borate (borax)
and potassium borate. Boric acid is preferred. Borate is typically
added to a concentration of 0.05% to 0.5% w/v when combined with
aqueous guar; 0.01% w/v is preferred. However, other concentrations
may be used in processes of the present invention. Also, the
concentration of borate may vary depending on pH, the concentration
of guar in the aqueous guar solution, mixing time, etc. The use of
alkyl borates (e.g., trimethyl borate) and phenyl borates may allow
for the subsequent precipitation step to occur at higher pH.
[0023] The processes of the present invention comprise a
precipitation step utilizing the addition of an organic solvent. In
preferred embodiments, the organic solvent is added to the guar and
borate solution to induce precipitation. Various organic solvents
may be used, such as ethanol, acetone, and isopropanol; however,
acetone is preferred. One or more organic solvents may be used, and
the solvents may additionally be mixed with water in various
ratios. For the initial guar precipitation, a to 1:1 acetone and
water solution is preferred, and the solution is added gradually to
a final ratio of 1:1 with the guar and borate solution.
[0024] The optional filtration step preceding the combination of
borate and guar may utilize various filters and filtration
techniques known to those of skill in the art. A preferred
filtration technique utilizes depth filters, such as the 40 .mu.m,
20 .mu.m and 10 .mu.m SealKleen.RTM. filters produced by Pall Corp.
(East Hills, N.Y.). Activated carbon filters such as the
MilliStak.TM. series produced by Millipore (Billerica, Mass.) may
also be used. Pressure and temperature control may be utilized
during the filtration step depending on the filters and filter
systems used.
[0025] The guar solid produced following the precipitation step(s)
of the present invention may be isolated using filtration equipment
known to those of skill in the art, such as 10 micron filter plates
or filters readily available from companies such as Whatman, Inc.
(Florham Park, N.J.). Other separation techniques such as
centrifugation may also be used.
[0026] Once the precipitate resulting from the final precipitation
and washing is separated by filtration or centrifugation or other
separation techniques, the precipitate may be dried and optionally
milled using available techniques for these procedures to generate
a final purified guar powder.
[0027] The guar compositions produced by the processes of the
present invention may be used in various types of products, but are
particularly useful in pharmaceutical and medical products that
function as lubricants and/or humectants. Such formulations may
optionally comprise one or more additional excipients and/or one or
more additional active ingredients.
[0028] Excipients commonly used in pharmaceutical formulations
include, but are not limited to, tonicity agents, preservatives,
chelating agents, buffering agents, and surfactants. Other
excipients comprise solubilizing agents, stabilizing agents,
comfort-enhancing agents, polymers, emollients, pH-adjusting agents
and/or lubricants. Any of a variety of excipients may be used in
formulations of the present invention including water, mixtures of
water and water-miscible solvents, such as C1-C7-alkanols,
vegetable oils or mineral oils comprising from 0.5 to 5% non-toxic
water-soluble polymers, natural products, such as alginates,
pectins, tragacanth, karaya gum, xanthan gum, carrageenin, agar and
acacia, starch derivatives, such as starch acetate and
hydroxypropyl starch, and also other synthetic products such as
polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether,
polyethylene oxide, preferably cross-linked polyacrylic acid and
mixtures of those products. The concentration of the excipient is,
typically, from 1 to 100,000 times the concentration of the guar.
In preferred embodiments, the excipients to be included in the
formulations are typically selected on the basis of their inertness
towards the guar component of the formulations.
[0029] Relative to ophthalmic formulations, suitable
tonicity-adjusting agents include, but are not limited to,
mannitol, sodium chloride, glycerin, sorbitol and the like.
Suitable buffering agents include, but are not limited to,
phosphates, borates, acetates and the like. Suitable surfactants
include, but are not limited to, ionic and nonionic surfactants
(though nonionic surfactants are preferred), RLM 100, POE 20
cetylstearyl ethers such as Procol.RTM. CS20 and poloxamers such as
Pluronic.RTM. F68.
[0030] The formulations set forth herein may comprise one or more
preservatives. Examples of such preservatives include
p-hydroxybenzoic acid ester, sodium perborate, sodium chlorite,
alcohols such as chlorobutanol, benzyl alcohol or phenyl ethanol,
guanidine derivatives such as polyhexamethylene biguanide, sodium
perborate, polyquaternium-1, amino alcohols such as AMP-95, or
sorbic acid. In certain embodiments, the formulation may be
self-preserved so that no preservation agent is required.
[0031] For ophthalmic administration, the formulation may be a
solution, a suspension, or a gel. In preferred aspects,
formulations that include the guar or guar derivative will be
formulated for topical application to the eye in aqueous solution
in the form of drops. The term "aqueous" typically denotes an
aqueous formulation wherein the formulation is >50%, more
preferably >75% and in particular >90% by weight water. These
drops may be delivered from a single dose ampoule which may
preferably be sterile and thus render bacteriostatic components of
the formulation unnecessary. Alternatively, the drops may be
delivered from a multi-dose bottle which may preferably comprise a
device which extracts any preservative from the formulation as it
is delivered, such devices being known in the art.
[0032] In other aspects, components of the invention may be
delivered to the eye as a concentrated gel or a similar vehicle, or
as dissolvable inserts that are placed beneath the eyelids.
[0033] The formulations of the present invention that are adapted
for topical administration to the eye are preferably isotonic, or
slightly hypotonic in order to combat any hypertonicity of tears
caused by evaporation and/or disease. This may require a tonicity
agent to bring the osmolality of the formulation to a level at or
near 210-320 milliosmoles per kilogram (mOsm/kg). The formulations
of the present invention generally have an osmolality in the range
of 220-320 mOsm/kg, and preferably have an osmolality in the range
of 235-300 mOsm/kg. The ophthalmic formulations will generally be
formulated as sterile aqueous solutions.
[0034] In certain embodiments, the guar compositions of the present
invention are formulated with one or more tear substitutes. A
variety of tear substitutes are known in the art and include, but
are not limited to: monomeric polyols, such as, glycerol, propylene
glycol, and ethylene glycol; polymeric polyols such as polyethylene
glycol; cellulose esters such hydroxypropylmethyl cellulose,
carboxy methylcellulose sodium and hydroxy propylcellulose;
dextrans such as dextran 70; vinyl polymers, such as polyvinyl
alcohol; and carbomers, such as carbomer 934P, carbomer 941,
carbomer 940 and carbomer 974P. Certain formulations of the present
invention may be used with contact lenses or other ophthalmic
products.
[0035] It is also contemplated that the concentrations of the
ingredients comprising the formulations of the present invention
can vary. In preferred embodiments, the guar component is present
in ophthalmic formulations at a concentration of about 0.1% to
0.25% w/v. However, the concentrations can vary depending on the
addition, substitution, and/or subtraction of ingredients in a
given formulation.
[0036] Preferred formulations are prepared using a buffering system
that maintains the formulation at a pH of about 3 to a pH of about
8.0. Topical formulations (particularly topical ophthalmic
formulations, as noted above) are preferred which have a
physiological pH matching the tissue to which the formulation will
be applied or dispensed.
[0037] In particular embodiments an ophthalmic formulation
comprising a guar composition of the present invention is
administered once a day. However, the formulations may also be
formulated for administration at any frequency of administration,
including once a week, once every 5 days, once every 3 days, once
every 2 days, twice a day, three times a day, four times a day,
five times a day, six times a day, eight times a day, every hour,
or any greater frequency. Such dosing frequency is also maintained
for a varying duration of time depending on the therapeutic
regimen. The duration of a particular therapeutic regimen may vary
from one-time dosing to a regimen that extends for months or years.
The formulations are administered at varying dosages, but typical
dosages are one to two drops at each administration, or a
comparable amount of a gel or other form of guar composition. One
of ordinary skill in the art would be familiar with determining a
therapeutic regimen for a specific indication.
[0038] The following examples are presented to further illustrate
selected embodiments of the present invention.
Example 1
[0039] A preferred process of the present invention utilizes USP
grade guar powder obtained from TIC Gum, Inc. The raw guar powder
is used to form a 0.8% aqueous guar solution. The solution is
prepared by mixing guar (8 g) in water at a pH of 6-7 for 4 hrs.
The aqueous guar solution is then pressure filtered (5 psi) at
25.degree. C. through 40 .mu.m pore size depth filters followed by
20 .mu.m and 10 .mu.m pore size depth filters (Pall
SealKleen.RTM.). Boric acid (2 g) is then added to and dissolved in
the filtered 0.8% guar solution. After dissolution of the boric
acid, the pH is adjusted to 6-6.5 if necessary.
[0040] A guar precipitate is then formed from the guar and boric
acid solution by titrating in acetone (10 mL/min) until precipitate
starts to form while mixing. The mixing is stopped and the
precipitate allowed to settle out for 30 min. Additional acetone is
added and the resulting precipitate allowed to settle out for an
additional 30 min. A total of 1 L of acetone was used for this
quantity of guar and borate. Following the conclusion of the
precipitation steps, the supernatant is decanted and the
precipitate washed. A water:acetone solution (1:1; 1 L) is added to
the precipitate and mixed for 1 hour. Following the wash, the
supernatant is decanted. A second precipitation step is performed
identically to that previously described. Following the second
precipitation, a second wash step using 500 mL of acetone and 1
hour of mixing is performed. Precipitate is allowed to settle for
30 minutes and the supernatant is decanted.
[0041] Washed guar is then isolated by adding acetone (250 mL) and
rinse and transfer with additional acetone to isolate guar in a
Buchner funnel using filter paper (Whatman, Inc; Florham Park,
N.J.). Isolated guar is then transferred to a drying plate and
dried under vacuum (30 mmHg) at 60.degree. C. for 24 hours.
Example 2
[0042] TABLES 1 and 2 below show the result of an experiment
comparing unprocessed guar (USP Grade; TIC Gum, Inc.) in aqueous
solution compared to (i) guar purified using only ethanol/acetone
precipitation and washing steps and (ii) guar purified using borate
addition and ethanol/acetone. The 500 nm wavelength selected for
transmission measurements is present in the visible spectrum region
and corresponds to visual clarity of the solution, while the 280 nm
wavelength is in the absorption region of protein impurities and is
accordingly an indirect measurement of retained impurity.
[0043] As shown in TABLE 1, guar produced according to a process of
the present invention ("Purified Guar") demonstrates better
hydration characteristics compared to unpurified guar powder in
aqueous solution ("Raw Guar") and guar purified using
ethanol/acetone precipitation without the addition of borate.
Purified Guar also shows superior transmission at 500 nm and 280 nm
(TABLE 2), indicating much better visual clarity (500 nm) and a
lower concentration of impurities (280 nm). Also, 0.5% aqueous
solutions of Purified Guar did not produce precipitates after 4
weeks at room temperature, while other guars tested (raw guar,
HP8A, and HPGG) all formed precipitates.
TABLE-US-00001 TABLE 1 0.5% Aqueous Guar Solutions at pH of 7 in DI
water only and before autoclaving: Hydration Rate (% H) Formulation
% Hyd @ 2 hrs % Hyd @ 4 hrs Raw GUAR 80.1 88.0 GUAR Purified Using
Only 65.9 93 Ethanol/Acetone Precipitation Purified Guar 100
100
TABLE-US-00002 TABLE 2 0.5% Aqueous Guar Solutions at pH of 7 in DI
water only and before autoclaving: Transmission (% T) Formulation %
T @ 500 nm % T @ 280 nm Raw GUAR 47.5 6.8 GUAR Purified Using Only
52.1 14.1 Ethanol/Acetone Precipitation Purified Guar 92.5 73.7
TABLE-US-00003 TABLE 3 0.5% Aqueous Guar Solutions at pH of 7 in DI
water only after autoclaving Formulation Precipitate Raw GUAR GUAR
using Ethanol/Acetone Precipitation Purified Guar HP8A HPGG-75
Example 3
[0044] The thermal stability of guar produced according to the
present invention was compared to that of unprocessed guar and
guars processed using other techniques. In this experiment, guar
samples were autoclaved for 35 minutes at 121.degree. C. The
results of the experiment are presented in FIG. 1.
[0045] As shown, raw guar and guar produced using an ethanol and
acetone precipitation technique had poor thermal stability, with
only 3.2% and 29.5% of pre-autoclave viscosity retained. Guar
purified with a technique according to an embodiment of the present
invention had viscosity retention comparable to that of
commercially available HP8A guar and a hydroxypropylated guar
derivative HPGG-75.
Example 4
[0046] The pH sensitivity of a guar formulation according to an
embodiment of the present invention was compared to that of
commercially available HP8A guar and a hydroxypropylated guar
derivative HPGG-75. The formulations comprised guar with boric
acid, sodium chloride, sorbitol and polyquaternium-1. The viscosity
was measured after one week at 40.degree. C. As shown in FIG. 2,
guar purified using the processes of the present invention showed
good viscosity retention at physiological pH (7-8) and was
significantly more sensitive to pH changes than was HP8A or
HPGG-75, and demonstrates viscosity increases at pH 8.0.
[0047] The present invention and its embodiments have been
described in detail. However, the scope of the present invention is
not intended to be limited to the particular embodiments of any
process, manufacture, composition of matter, compounds, means,
methods, and/or steps described in the specification. Various
modifications, substitutions, and variations can be made to the
processes, compositions, and formulations described herein without
departing from the spirit and/or essential characteristics of the
present invention. Accordingly, one of ordinary skill in the art
will readily appreciate from the disclosure that later
modifications, substitutions, and/or variations performing
substantially the same function or achieving substantially the same
result as embodiments described herein may be utilized according to
such related embodiments of the present invention. Thus, the
following claims are intended to encompass within their scope
modifications, substitutions, and variations to processes,
manufactures, compositions of matter, compounds, means, methods,
and/or steps disclosed herein.
* * * * *