U.S. patent application number 16/359602 was filed with the patent office on 2019-07-18 for extended-release drug delivery compositions.
The applicant listed for this patent is ORBIS BIOSCIENCES, INC.. Invention is credited to Cory Berkland, Nathan Dormer.
Application Number | 20190216825 16/359602 |
Document ID | / |
Family ID | 54834368 |
Filed Date | 2019-07-18 |
United States Patent
Application |
20190216825 |
Kind Code |
A1 |
Dormer; Nathan ; et
al. |
July 18, 2019 |
EXTENDED-RELEASE DRUG DELIVERY COMPOSITIONS
Abstract
An extended-release drug delivery composition and method of
administering the same is provided. The composition comprises
microspheres loaded with a biologically-active agent and suspended
in a soluble polymer capable of forming a film upon injection onto
a biological surface.
Inventors: |
Dormer; Nathan; (Mission,
KS) ; Berkland; Cory; (Lawrence, KS) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ORBIS BIOSCIENCES, INC. |
Lenexa |
KS |
US |
|
|
Family ID: |
54834368 |
Appl. No.: |
16/359602 |
Filed: |
March 20, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15643857 |
Jul 7, 2017 |
10238663 |
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16359602 |
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14738174 |
Jun 12, 2015 |
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15643857 |
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62011380 |
Jun 12, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0019 20130101;
A61K 9/1635 20130101; A61P 27/16 20180101; A61K 9/0046 20130101;
A61K 9/10 20130101; A61K 38/38 20130101; A61K 47/32 20130101; A61K
31/573 20130101; A61K 47/38 20130101; A61K 31/713 20130101; A61K
47/26 20130101; A61K 47/10 20130101; A61K 31/43 20130101; A61K
31/711 20130101; A61K 9/1647 20130101 |
International
Class: |
A61K 31/573 20060101
A61K031/573; A61K 38/38 20060101 A61K038/38; A61K 31/711 20060101
A61K031/711; A61K 31/713 20060101 A61K031/713; A61K 31/43 20060101
A61K031/43; A61K 9/16 20060101 A61K009/16; A61K 47/38 20060101
A61K047/38; A61K 47/26 20060101 A61K047/26; A61K 47/10 20060101
A61K047/10; A61K 9/00 20060101 A61K009/00; A61K 9/10 20060101
A61K009/10; A61K 47/32 20060101 A61K047/32 |
Goverment Interests
STATEMENT OF GOVERNMENT INTEREST
[0002] This invention was made with government support under Grant
No. 1R43DC012749-01 awarded by National Institutes of Health. The
government has certain rights in the invention.
Claims
1. A method for treating a subject suffering from a disorder of the
inner ear, comprising: injecting a composition to a biological
tissue of the ear of the subject no more than one time in a 14 day
period, wherein the composition comprises a biologically-active
agent dispersed in a film-forming agent, wherein the film-forming
agent comprises a soluble polymer and a carrier liquid, wherein the
film-forming agent is free of solvent, wherein the carrier liquid
is capable of evaporating at a temperature of about 37.degree. C.,
and wherein the film-forming agent is capable of forming a film on
the biological tissue upon evaporation of at least a portion of the
carrier liquid.
2. The method of claim 1, further comprising, after injecting the
composition to the biological tissue: allowing the at least a
portion of the carrier liquid to evaporate, whereby the
film-forming agent forms a film on the biological tissue.
3. The method of claim 1, wherein the soluble polymer is selected
from the group consisting of polyvinyl alcohol (PVA), polyvinyl
acetate (PVAc), alginate, polyethylene glycol (PEG), hydroxypropyl
methyl cellulose (HPMC), polyvinyl pyrrolidone (PVP), an eudragit,
collagen, gelatin and combinations thereof.
4. The method of claim 1, wherein the carrier liquid is selected
from the group consisting of water, ethanol, benzyl alcohol, and
ethyl acetate.
5. The method of claim 1, wherein the soluble polymer is from about
0.5%-10% w/v of the film-forming agent.
6. The method of claim 1, wherein the biological tissue is selected
from the middle ear or the round window membrane of the inner
ear.
7. A method for treating a subject suffering from a disorder of the
inner ear, comprising: injecting a composition to a biological
tissue of the ear of the subject no more than one time in a 14 day
period, wherein the composition comprises a biologically-active
agent dispersed in a film-forming agent, wherein the film-forming
agent comprises polyvinyl alcohol and a carrier liquid, wherein the
polyvinyl alcohol has a molecular weight of from about 20,000 to
30,000 Daltons, wherein the film-forming agent is free of solvent,
wherein the carrier liquid is capable of evaporating at a
temperature of about 37.degree. C., wherein the film-forming agent
is capable of adhering to the biological tissue for an extended
period of time, and wherein said extended period of time is at
least 14 days.
8. The method of claim 7, further comprising, after injecting the
composition to the biological tissue: allowing the at least a
portion of the carrier liquid to evaporate, whereby the
film-forming agent forms a film on the biological tissue.
9. The method of claim 7, wherein the carrier liquid is selected
from the group consisting of water, ethanol, benzyl alcohol, and
ethyl acetate.
10. The method of claim 7, wherein the PVA is from about 0.5%-10%
w/v of the film-forming agent.
11. The method of claim 7, wherein the biological tissue is
selected from the middle ear or the round window membrane of the
inner ear.
12. A method for treating a subject suffering from sensorineural
hearing loss, comprising: injecting a composition to a biological
tissue of the ear of the subject no more than one time in a 14 day
period, wherein the composition comprises a biologically-active
agent dispersed in a film-forming means.
13. The method of claim 12, wherein the biological tissue is
selected from the middle ear or the round window membrane of the
inner ear.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation of U.S.
application Ser. No. 15/643,857 filed on Jul. 7, 2017, which is a
continuation of U.S. application Ser. No. 14/738,174 filed on Jun.
12, 2015, which claims priority to U.S. Provisional Application No.
62/011,380 filed on Jun. 12, 2014, each of which is incorporated
herein by reference in its entirety.
BACKGROUND
[0003] One of the challenges in drug delivery is the ability to
target the treatment to a particular area of the body or a
particular biological tissue and maintain delivery at the area or
tissue. In most instances, repetitive treatments are needed over
the course of days to weeks in order to maintain the necessary
therapeutic level of an active agent. Simply stated, this approach
is inconvenient and costly.
[0004] For example, sudden sensorineural hearing loss (SSNHL) is a
disease that attacks 4,000 Americans annually and is characterized
by near complete hearing loss in as little as a few hours. The most
efficacious treatment for SSNHL consists of frequent injections of
an anti-inflammatory steroid into the middle ear, which diffuses
into the inner ear via the round-window membrane (RWM). The
invasive nature of these injections, especially if delivery is
desired directly on the surface of the RWM, results in low patient
compliance and a loss of efficacy. Thus, SSNHL patients and
patients having other conditions that require a localized long-term
treatment protocol would benefit from a drug delivery platform that
permits the use of a single injection while providing an
extended-release profile of the therapeutic agent.
SUMMARY
[0005] The present disclosure relates to an extended-release drug
delivery platform. In one embodiment, an extended-release
therapeutic composition is provided. The composition comprises a
film forming agent and a biologically active agent. The film
forming agent can be a soluble polymer, whether in water or some
other solvent, including, but not limited to, ethanol, benzyl
alcohol, or ethyl acetate. Examples of suitable polymers include,
but are not limited to polyvinyl alcohol (PVA), polyvinyl acetate
(PVAc), alginate, polyethylene glycol (PEG), hydroxypropyl methyl
cellulose (HPMC), polyvinyl pyrrolidone (PVP), eudragits, collagen,
and gelatin. The biologically active agent can be, for example, a
therapeutic compound or a diagnostic agent. The biologically active
agent can be loaded in a plurality of microspheres or
microcapsules. The composition may further comprise a surfactant.
The surfactant can be, for example, polysorbate or sorbitan
laurate.
[0006] In another embodiment, a single-injection method for
administration of a composition to a target tissue is provided. The
method comprises the step of injecting a composition onto a
biological tissue of a subject, wherein the composition comprises a
film forming agent and a biologically active agent. In one
instance, the biological tissue is the round window membrane of the
inner ear and the step of injecting includes the use of an
intratympanic injection. The method may further comprise allowing
the composition to form a film on the biological tissue by
maintaining the subject in a position to facilitate retention of
the composition on the biological tissue.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] The patent or application file contains at least one drawing
executed in color. Copies of this patent or patent application
publication with color drawing(s) will be provided by the Office
upon request and payment of the necessary fee. Some specific
example embodiments of the disclosure may be understood by
referring, in part, to the following description and the
accompanying drawings.
[0008] FIG. 1 describes (A) the process of intratympanic injection,
whereas the film forming formulation is deposited directly on the
RWM, (B) illustrates the attachment of the drug delivery system, in
this instance with microspheres, to the RWM, and (C) illustrates
the replacement of multiple therapeutic injections with a single
injection film forming drug delivery system.
[0009] FIG. 2 shows (A) scanning electron micrographs of
microspheres formed from emulsion methods, compared to (B,C,D)
discrete sizes made by precision particle fabrication technology,
and (E) the relative size distribution of precision particle
fabrication technology compared to emulsion methods whereas 90% of
the PPF-produced microspheres (B-D) are within 2% of mean diameter
(Scale bar=100 .mu.m).
[0010] FIG. 3 shows betamethasone-loaded PLGA microspheres created
with precision particle fabrication technology with a size of
approximately 30 .mu.m.
[0011] FIG. 4 shows that microspheres with film forming agent are
adhered to the RWM at (A) 21 and (C) 35 days post-injection,
whereas microspheres injected without a film forming component
(i.e. only normal saline) are not present on the RWM at (B) 21 or
(D) 35 days post-injection. Scalebar=(A, B) 400 .mu.m and (C,
D)=300 .mu.m.
[0012] FIG. 5 shows histological staining of the RWM surrounding
tissue for the inflammatory protein tumor necrosis factor (TNF)
alpha. Staining intensity indicates that no significant
inflammatory response was present in mice (A) with the film forming
formulation compared to (B) without the film forming
formulation.
[0013] FIG. 6 demonstrates release profiles for various active
ingredients in a common film forming agent without encapsulation of
the active ingredient.
[0014] FIG. 7 demonstrates release profiles of dexamethasone from
various film forming agent formulations without encapsulation of
the dexamethasone.
[0015] FIG. 8 demonstrates release profiles of various encapsulated
active ingredients in a common film forming agent formulation.
[0016] FIG. 9 demonstrates release profiles of betamethasone
encapsulated in two different microsphere types in a common film
forming agent formulation.
[0017] FIG. 10 demonstrates release profiles of betamethasone
encapsulated in three different sizes of microspheres in a common
film forming agent formulation.
DESCRIPTION
[0018] The present disclosure provides an extended release drug
delivery platform using a fast film forming agent (FFA). The FFA
can be applied to a surface of a target tissue where it is allowed
to form a film. The film retains a biologically-active agent that
is then released over a desired period of time and in many
instances, over weeks. This provides the advantage of maintaining a
proper localization for the treatment and also permits a fine
tuning of the release profile. In one embodiment, the FFA can be
used to deliver drug-loaded microcapsules or microspheres to the
round membrane window via an intratynpanic injection thereby
eliminating the need for multiple, painful injections while
providing for more predictable drug levels within the inner ear
perilymph for treatment of inner ear disorders such as SSNHL. To
this end, FIG. 1 provides a representation of the intratympanic
injection procedure in relationship to the anatomy of the ear
(panel A). Panel B of FIG. 1 depicts intratympanic injection of
drug-loaded microspheres (orange circles) which localize to the
round window membrane (RWM) using the present FFA composition
(green squares). Using the present FFA composition, a delivery
system for maintaining localization of a therapeutic agent to the
RWM with a single injection is possible, in contrast to multiple
injections. Thus, the present disclosure provides compositions
comprising the FFA and methods of using the same to provide an
extended-release therapy for treatment of various disorders that
require long-term localized treatment, including inner ear
disorders.
[0019] In one embodiment, a composition that provides an
extended-release profile is provided. The composition comprises a
film forming agent and a biologically active agent.
[0020] The film-forming agent (FFA) is a means for forming a film
on a biological tissue of a subject (also referred to herein as
"film forming means" or "FFA means"). The film forming means of the
present disclosure is capable of: (i) serving as the injectable
carrier for a biologically-active agent, such as drug-loaded
microspheres or microcapsules, and (ii) adhering the
biologically-active agent to a target membrane, biological tissue,
or surface, such as the round window membrane (RWM) of the inner
ear, for an extended period of time, for example 20 to 35 days. The
FFA means is comprised of Generally Accepted as Safe (GRAS)
materials and is readily soluble in water or other appropriate
solvents, allowing it to be delivered in a dry powder syringe for
resuspension immediately prior to use. The FFA means, in one
embodiment, comprise a soluble polymer such as polyvinyl alcohol
(PVA), polyvinyl acetate (PVAc), alginate, polyethylene glycol
(PEG), hydroxypropyl methyl cellulose (HPMC), polyvinyl pyrrolidone
(PVP), eudragits, collagen, and gelatin. For example, in one
embodiment, the film forming means is PVA having a molecular weight
range of 20,000 to 30,000 and in some instances may by hydrolyzed
(e.g., 88% hydrolyzed).
[0021] In certain embodiments, the film forming means may comprise
0.5-10% w/v of the composition. However, it should be understood
that the film forming means may be formulated at different
percentages based on the particular polymer employed. For example,
a FFA means comprising PEG could account for 60-90% w/v of the
composition.
[0022] The film forming means further comprises a carrier liquid.
The carrier liquid utilized is dependent on the polymer or other
substance used for the film forming agent and may be a water or a
solvent. Furthermore, the carrier liquid should possess the ability
to evaporate at physiological temperatures, such as 37.degree. C.
Thus, the excess carrier liquid that does not form part of the film
will evaporate quickly. The carrier liquid of the film forming
means includes, for example, water, ethanol, benzyl alcohol, and
ethyl acetate.
[0023] The composition may further comprise a number of different
excipients including a surfactant, a stabilizer, a release
modifier, or a densifier. For example, a surfactant is used in
certain embodiments of the present composition based on the
solubility of the biologically-active agent. In the instance the
biologically active agent is hydrophobic, polysorbate can be used
as the surfactant. However, sorbitan laurate can be used in the
instance the biologically-active agent is hydrophilic. The
surfactant can be polysorbate 20, polysorbate 60, or polysorbate 80
based on the desired release profiles of the biologically-active
agent. The excipient may comprise approximately 0.1%-10% w/v of the
composition, and in some instance, 0.5-5% w/v of the
composition.
[0024] Upon injection at the target surface, the film forming means
generally forms a film upon evaporation of the water or solvent
content of the composition which, in some instances, will occur in
about 20-50 minutes post-injection. It should be understood that
use of the FFA means to deliver biologically-active agents to the
inner ear is just one embodiment of the technology and the FFA
means could be used in a variety of other applications. Referring
now to panel B of FIG. 1, examples of target biological surfaces or
tissues in which the FFA means is preferable are those surfaces,
tissues, or membranes that provide a barrier between a
predominately non-fluid or air-filled cavity and a fluid-rich or
tissue-dense region, such surfaces referred to herein as biological
barrier structures. Examples of biological barrier structures are
the round membrane window of the inner ear or the external surface
of a nasal polyp. In these instances, the FFA means is applied to
the side of the membrane, tissue, or surface exposed to the
non-fluid or air-filled cavity which permits the FFA means to dry
and form a film on the surface. The liquid or tissue on the other
side of the membrane, surface, or tissue facilitates diffusion of
the biologically-active agent from the FFA means into the
fluid-filled area thereby targeting the therapy or diagnostic to
the target region.
[0025] The biologically-active agent may comprise a therapeutic or
diagnostic compound and thus may be, for example, a steroid,
antibody, peptide, nucleic acid, antioxidant, chemical, small
molecule, and other similar compounds. In one embodiment, the
biologically-active agent is betamethasone, dexamethasone, or
penicilin.
[0026] The biologically-active agent can be formulated as
nanoparticle or microsphere. For example, the biologically active
compound may be fabricated using the Precision Particle Formation
(PPF) method as described in U.S. Pat. Nos. 6,669,961, 7,368,130,
and 7,309,500, all of which are incorporated by reference herein in
their entireties. Briefly, in this method, a drug-matrix solution
is sprayed through a nozzle with (i) vibrational excitation to
produce uniform droplets, and (ii) an annular, non-solvent carrier
stream to reduce the diameter of the exiting jet. The microspheres
can be formed of poly (D,L-lactic-co-glycolic acid) (PLGA),
poly(lactic acid) (PLA), poly(glycolic acid) (PGA),
poly(caprolactone) (PCL), poly(ethylene glycol) (PEG), poly(vinyl
acetate) (PVAc), ethyl cellulose, or similar biodegradable polymers
compatible with precision particle fabrication technology as
described in U.S. Pat. Nos. 6,669,961, 7,368,130, and
7,309,500.
[0027] Alternatively, in certain other embodiments, rather than
comprising a homogenous mixture of the biologically-active agent
and polymer materials, the microsphere may comprise a hydrophobic
matrix layer and a core, wherein the biologically-active agent is
dispersed within the core and is surround by the hydrophobic matrix
layer. These microspheres may also be fabricated using the PPF
method referred to above. The hydrophobic matrix may be a
hydrophobic wax material, a lipid material, a glycol polymer, or a
combination thereof. In certain embodiments, suitable hydrophobic
matrix materials have a melting point at or above about 45.degree.
C. and a viscosity when melted sufficient to allow spraying.
[0028] Suitable lipid materials should be solid at room temperature
and have a melting temperature at or above about 45.degree. C.
Examples of suitable lipid materials include, but are not limited
to, glycerol fatty acid esters, such as triacylglycerols (e.g.,
tripalmitin, tristearin, glyceryl trilaurate, coconut oil),
hydrogenated fats, ceramides, and organic esters from and/or
derived from plants, animals, minerals.
[0029] Suitable glycol polymers should be solid at room temperature
and have a melting temperature at or above about 45.degree. C.
Examples of suitable glycol polymers include, but are not limited
to, high molecular weight glycols (e.g., polyethylene glycol with a
minimum of 20 repeating units), cellulose ethers (e.g., ethyl
cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose,
microcrystalline cellulose), cellulose esters (e.g., cellulose
acetate, cellulose acetate phthalate, hydroxypropyl methyl
cellulose phthalate), polyacrylates derivatives, polymethacrylates
derivatives, poloxamers, and starch and its derivatives.
[0030] In certain embodiments, the hydrophobic matrix may be a
hydrophobic wax material. The hydrophobic wax matrix may be any
wax-like material suitable for use with the active ingredient.
Examples of suitable hydrophobic waxes include, but are not limited
to, ceresine wax, beeswax, ozokerite, microcrystalline wax,
candelilla wax, montan wax, carnauba wax, paraffin wax, cauassu
wax, Japan wax, and Shellac wax.
[0031] In certain embodiments of the present composition employing
a hydrophobic wax matrix, the microspheres further comprise a
densifier. A densifier may used to increase the density of a
particle. For example, a densifier may be used to make a particle
heavier so that it will approach or be closer to the density of a
liquid vehicle in which the microspheres may be suspended. Examples
of suitable densifiers include, but are not limited to, titanium
dioxide, calcium phosphate, and calcium carbonate. In one
embodiment, the one or more densifiers may be present in the
microspheres in an amount in the range of from about 0% to about
40% by weight of the microspheres.
[0032] The hydrophobic matrix may be present in the microspheres in
an amount in the range of from about 5% to about 90%, about 5% to
about 30%, about 20% to about 80%, or about 40% to about 60% by
weight of the microcapsule. In another embodiment, the hydrophobic
matrix may be present in the microcapsule in an amount sufficient
to provide sustained release of the active ingredient over a period
ranging between about 1 hour to about 12 hours or more. For
example, the wax may be present in the microspheres in an amount
sufficient to provide sustained release of the hydrophilic active
ingredient over a period of about 1 hour, 2 hours, 4 hours, 6
hours, 8 hours, 10 hours, 12 hours, 18 hours, 24 hours, or longer.
In certain embodiments, the hydrophobic matrix may be increased or
decreased depending on the particular release characteristics
desired. In addition, more than one hydrophobic matrix layer may be
used to achieve the particular sustained release desired. In
general, higher hydrophobic matrix concentrations favor longer,
more sustained release of the active ingredient and lower
concentrations favor faster, more immediate release.
[0033] In certain embodiments, the microspheres of the present
disclosure comprise a stabilizer. The stabilizer may improve the
properties of the hydrophobic wax matrix and provide improved
stability of the microspheres over time, as well as improved
dissolution profiles. Changes in microspheres can occur over time
that affect the particle's performance. Such changes include
physical, chemical, or dissolution instability. These changes are
undesirable as they can affect a formulation's shelf stability,
dissolution profile, and bioavailability of the active ingredient.
For example the hydrophobic wax matrix or active ingredient may
relax into a lower energy state, the particle may become more
porous, and the size and interconnectivity of pores may change.
Changes in either the active ingredient or hydrophobic wax matrix
may affect the performance of the particle. The present disclosure
is based, at least in part, on the observation that a stabilizer
added to the hydrophobic wax matrix improves the stability and
performance of the microspheres of the present disclosure. By way
of explanation, and not of limitation, it is believed that the
stabilizer interacts with the hydrophobic wax material making it
resistant to physical changes. Accordingly, the microspheres of the
present disclosure comprise a stabilizer. Examples of suitable
stabilizers include but are not limited to, cellulose, ethyl
cellulose, hydroxyproylmethyl cellulose, microcrystalline
cellulose, cellulose acetate, cellulose phthalate, methyl
cellylose, chitin, chitosan, pectin, polyacrylates,
polymethacrylates, polyvinyl acetate, Elvax.RTM. EVA resins,
acetate phthalate, polyanhydrides. polyvinylalcohols, silicone
elastomers, and mixtures thereof. Stabilizers may be used alone or
in combination. The stabilizer may be present in the microspheres
in an amount from about 0.1% to about 10% by weight of the
particle. For example, the stabilizer may be present in an amount
from about 0.1% to about 5%, about 0.5% to about 2.5%, and about 5%
to about 10% by weight of the particle.
[0034] In certain embodiments, the microspheres of the present
disclosure also comprise a release modifier. The present disclosure
is also based on the observation that a release modifier improves
the performance of hydrophobic wax matrix microspheres particularly
during the later stages of the active ingredient's release. The
release modifier is believed also to interact with the stabilizer
(e.g., improve the stabilizer's solubility) to facilitate
preparation of the microspheres. It is also believed that the
release modifier may adjust the relative hydrophobicity of the
hydrophobic wax material. Examples of suitable release modifiers
include but are not limited to, stearic acid, sodium stearate,
magnesium stearate, glyceryl monostearate, cremophor (castor oil),
oleic acid, sodium oleate, lauric acid, sodium laurate, myristic
acid, sodium myristate, vegetable oils, coconut oil, mono-, di-,
tri-glycerides, stearyl alcohol, span 20, span 80, and polyethylene
glycol (PEG). Release modifiers may be used alone or in
combination. For example, in certain embodiments, the release
modifier may be a combination of stearic acid and glyceryl mono
stearate. The release modifier may be present in the microspheres
in an amount from about 0.5% to about 90% by weight of the
particle. For example, the release modifier may be present in an
amount from about 0.5% to about 10%, about 1% to about 5%, about
2.5% to about 5%, about 5% to about 10%, about 10% to about 25%,
about 20% to about 90%, about 40% to about 80%, about 50% to about
70%, about 60% to about 80%, and about 80% to about 90% by weight
of the particle. In general, higher release modifier concentrations
favor faster release of the active ingredient and lower
concentrations favor longer, sustained release.
[0035] Moreover, in certain embodiments, the microspheres used in
the present compositions can have a particle size diameter of less
than 150 .mu.m, less than 100 .mu.m, less than 50 .mu.m, and more
preferably for use in intratympanic injections, the microspheres
can have a particle size diameter of about 30 .mu.m to about 60
.mu.m. Thus, the compositions of the present invention, in certain
embodiments, comprise a plurality of microspheres having a mean
particle diameter of less than 150 .mu.m, less than 100 .mu.m, less
than 50 .mu.m, and more preferably for use in intratympanic
injections, the microspheres can have a particle size diameter of
about 30 .mu.m to about 60 .mu.m.
[0036] The size and size uniformity of drug-encapsulated
microspheres directly controls their release profiles. Very small
particles (<5 .mu.m or so), often called "fines", release drug
quickly, leading to an initial "burst" release effect. Very large
particles (>500 .mu.m), on the other hand, tend to slowly
release drug over a prolonged period of time. Polydisperse mixtures
of drug-encapsulated particles, therefore, offer poor control of
drug release. The Precision Particle Fabrication technology
produces uniform microspheres that allow for precise control of
release properties. Thus, the microspheres of the present
composition may possess a particle size distribution that deviates
from the mean particle diameter by 10% or less, by 5% or less, or
by 2% or less as shown in FIG. 2 (panels B, C, D, and E).
Comparatively, other encapsulation methods, including
precipitation, phase separation, and/or emulsion technique (panel
A) demonstrate standard deviations equal to 25-50% or more of the
mean as shown in panel E of FIG. 2.
[0037] One exemplary composition of the present disclosure is
provided for delivering at least 1.0 .mu.g of a biologically-active
compound to the RWM over 30 days. Here, the FFA is 10% w/v
Poly(vinyl alcohol)(Mw: 20,000-30,000, 88% hydrolyzed), the
surfactant is 5.0% w/v Tween 80, and the biolgocially-active agent
is betamethasone. The betamethasone is loaded in microspheres
(approximately 30 .mu.m particle size) using the PPF method at any
one of the following loading and particle concnetrations in a 2
.mu.L total composition volume: (1) 10 mg/ml particle concentration
with a particle loading of 5.0% betamethasone; (2) 50 mg/ml
particle concentration with a particle loading of 1.0%
betamethasone; and (3) 100 mg/ml particle concentration with a
particle loading of 0.5% betamethasone. Other specific formulations
of the present compositions are presented in the examples
below.
[0038] Thus, in one embodiment, an injectable composition is
provided. The injectable composition of the present embodiment
comprises a means for forming a film on a biological tissue. The
means comprises a soluble polymer and a carrier liquid, wherein the
soluble polymer is from 0.5% to about 10% w/v of the composition,
and wherein the carrier liquid is able to evaporate at 37.degree.
C. The composition further comprises a biologically-active agent.
The composition may further comprise an excipient, wherein the
excipient is from about 0.5 to about 5% w/v of the composition.
[0039] In certain embodiments, the soluble polymer is selected from
the group consisting of polyvinyl alcohol (PVA), polyvinyl acetate
(PVAc), alginate, polyethylene glycol (PEG), hydroxypropyl methyl
cellulose (HPMC), polyvinyl pyrrolidone (PVP), eudragits, collagen,
and gelatin.
[0040] In certain embodiments, the carrier liquid is selected from
the group consisting of water, ethanol, benzyl alcohol, and ethyl
acetate.
[0041] In certain embodiments, the excipient is a surfactant
selected from the group consisting of polysorbate 20, polysorbate
60, polysorbate 80 or sorbitan laurate.
[0042] In certain embodiments, the biologically-active agent is
selected from the group consisting of a steroid, an antibody, a
peptide, a nucleic acid, an antioxidant, and a small molecule. In
certain embodiments, the biologically-active agent is betamethasone
or dexamethasone.
[0043] In certain embodiments, the injectable composition further
comprises a microsphere, wherein the biologically-active agent is
present in the microsphere. The microsphere further comprises a
material selected from selected from the group consisting of poly
(D,L-lactic-co-glycolic acid) (PLGA), poly(lactic acid) (PLA),
poly(glycolic acid) (PGA), poly(caprolactone) (PCL), poly(ethylene
glycol) (PEG), poly(vinyl acetate) (PVAc), and ethyl cellulose.
[0044] In certain embodiments, the microspheres of the present
composition possess a mean particle diameter of less than 150
.mu.m, less than 100 .mu.m, less than 50 .mu.m, and in some
instances, from about 30 .mu.m to about 60 .mu.m. In certain
embodiments, 90% of the microspheres of the composition comprise a
particle diameter that does not deviate from the mean particle
diameter by more than 10%, 5%, or 2%.
[0045] A single-injection method for administration of a
composition of the present disclosure to a biological barrier
structure is also provided. The method can be performed using any
of the above-described compositions. The composition can be loaded
in a syringe or catheter. Due to the small particle sizes (30
.mu.m) that can be generated using the PPF technology, syringe
gauges of 28 and 30 can be used. In one embodiment, a method for
administration of an extended-release therapeutic is provided. The
method comprises injecting one of the compositions described herein
onto a biological barrier structure and allowing the composition to
form a film on the biological barrier structure. In a specific
embodiment, a method of treating disorders of the inner ear is
provided. In this embodiment, intratympanic injection is
accomplished with standard out-patient steroid solution
administration techniques, requiring minimal extra effort on the
part of physicians and patients. The composition is injected onto
the surface of the RWM where it forms a film following evaporation
of the water or other solvent used to carry the composition. The
film allows the therapeutic, for example, betamethasone, to be
retained at the RWM for extended periods of time thereby providing
a single injection method for long-term administration of the
therapeutic to the inner ear.
[0046] In certain instance, the method may further comprise the
step of maintaining the subject in a position during the injection
and for a time period following the injection sufficient to permit
the composition to form a film on the round window membrane. In
certain embodiments, the subject is suffering from SSNHL. In
instances where the method is performed on a subject suffering from
SSNHL, examples of biologically-active agents include, but are not
limited to steroids such as betamethasone or dexamethasone,
antioxidants such as vitamin A, vitamin C, and vitamin E, and
nucleic acids such as siRNA directed to reduce expression of genes
that restrict hair cell proliferation and other gene targets that
otherwise would prevent regeneration of hair cells as well as gene
therapies that would promote hair cell regeneration.
EXAMPLES
[0047] The examples herein are illustrations of various embodiments
of the present invention and are not intended to limit it in any
way.
Example 1: In Vivo Analysis of FFA: Localization and Inflammatory
Response
[0048] Uniform betamethasone-loaded biodegradable microspheres were
prepared using the Precision Particle Fabrication technology.
Briefly, betamethasone was dissolved in dichloromethane (DCM), to
which a 50:50 poly (D,L-lactic-co-glycolic acid) (PLGA) was added
such that the betamethasone comprised 1.0% w/w of the total solids
content. The suspension was loaded into a syringe pump and used to
produce microspheres using the Precision Particle Fabrication (PPF)
nozzle. The microspheres were collected in a solution of poly
(vinyl alcohol) in deionized (DI) water. Following a 3-hour solvent
evaporation step, the particles were filtered and lyophilized for
48 hours. The resulting particles are shown in FIG. 3.
[0049] Betamethasone-loaded microspheres suspended in the FFA were
delivered to mice RWM as follows. C57/BL6 mice were anesthetized
with a Ketamine/Xylazine cocktail, laid on their side, and
immobilized. The skin and soft tissue was retracted, and an access
hole to the tympanic cavity was created with a 28 GA needle.
.about.2.0 .mu.L injections of 50 mg/mL fluorescent dye-loaded
microspheres were then delivered directly above the RWM with a 10
.mu.L Hamilton syringe. The mice were kept in this position for 5
minutes before being sutured and imaged on an IVIS in vivo Imaging
System (Perkin-Elmer, Waltham Mass.) to confirm localization of the
formulation to the inner ear space, and brought out of anesthesia.
Negative control mice were injected with fluorescent microspheres
without the FFA component (saline vehicle). At 21 and 35 days
timepoints, mice were sacrificed and necropsy was performed to
evaluate microsphere localization.
[0050] To measure potential inflammatory response, mice were
euthanized at 28 days, and the inner ear anatomy was isolated,
removed, decalcified, and paraffin-embedded. Samples were sectioned
and immunohistochemically stained for two major inflammatory
markers, interleukin (IL)-6 and tumor necrosis factor
(TNF)-.alpha., in addition to hematoxylin and eosin (H&E). In
vitro dissolution testing of betamethasone-loaded microspheres
demonstrated that microsphere size plays a role in controlling the
release of drug from the microspheres.
[0051] Referring now to FIG. 4, mice treated with microspheres
suspended in the FFA had microspheres localized directly on the RWM
at 21 days with a thin film as intended (panel A). There appeared
to be only a slight loss of sphericity, indicating that some
degradation of the particles occurred, but the overall integrity of
the delivery system was maintained. Negative control mice displayed
no visible microspheres, indicating that the particles had migrated
away from the surgical site due to lack of an FFA component (panel
B). Similarly, at 35 days, an analogous set of mice were euthanized
and dissected. Once again, we were able to see a deposition of
microspheres in the space directly adjacent to the RWM in mice
treated with microspheres suspended in the FFA (panel C), and an
absence of microspheres in negative control mice (panel D).
[0052] Staining indicated that the microspheres and FFA caused no
significant inflammatory response. The intensity of TNF-.alpha. and
IL-6 development was similar between the groups (data not shown),
and H&E revealed no discernible changes in hair cell anatomy or
apparent tissue reaction as shown in FIG. 5, panels A and B.
[0053] Suspending betamethasone-loaded microspheres a film forming
agent provided an injectable, extended release intratympanic
delivery system that can localize drug to the RWM of mice for
greater than 35-days with minimal inflammatory response.
Example 2: Various Pharmaceutical Ingredient Release from One
Film-Forming Agent (FFA) Type
[0054] This example illustrates how one film-forming agent type can
accommodate release of many pharmaceutical ingredients, without the
need for a microsphere component. They are displayed in FIG. 6.
Dexamethasone
[0055] An FFA was made, consisting of 10% w/v poly(vinyl alcohol)
and 5% v/v Tween 80 dissolved in deionized water. Dexamethasone was
dispersed within the film forming agent via sonication at a
concentration of 1 mg/mL. On a Franz cell apparatus fitted with a
cellulose acetate membrane and 5% w/v Brij O20 receptor phase, 1.0
mL of the dexamethasone/FFA was deposited. Drug diffusion across
the membrane at 37.degree. C. was measured for 14 days, and
quantified with HPLC. The drug release was normalized to total
detected dexamethasone at 14 days.
Penicillin
[0056] An FFA was made, consisting of 10% w/v poly(vinyl alcohol)
and 5% v/v Tween 80 dissolved in deionized water. Penicillin was
dispersed within the film forming agent via sonication at a
concentration of 1 mg/mL. On a Franz cell apparatus fitted with a
cellulose acetate membrane and 5% w/v Brij O20 receptor phase, 1.0
mL of the penicillin/FFA was deposited. Drug diffusion across the
membrane at 37.degree. C. was measured for 14 days, and quantified
with HPLC. The drug release was normalized to total detected
penicillin at 14 days.
siRNA
[0057] An FFA was made, consisting of 10% w/v poly(vinyl alcohol)
and 5% v/v Tween 80 dissolved in deionized water. SiRNA was
dispersed within the film forming agent via sonication at a
concentration of 1 .mu.g/mL. On a Franz cell apparatus fitted with
a cellulose acetate membrane and 5% w/v Brij O20 receptor phase,
1.0 mL of the SiRNA/FFA was deposited. Drug diffusion across the
membrane at 37.degree. C. was measured for 14 days, and quantified
with a picogreen assay. The drug release was normalized to total
detected SiRNA at 14 days.
DNA
[0058] An FFA was made, consisting of 10% w/v poly(vinyl alcohol)
and 5% v/v Tween 80 dissolved in deionized water. DNA was dispersed
within the film forming agent via sonication at a concentration of
1 .mu.g/mL. On a Franz cell apparatus fitted with a cellulose
acetate membrane and 5% w/v Brij O20 receptor phase, 1.0 mL of the
DNA/FFA was deposited. Drug diffusion across the membrane at
37.degree. C. was measured for 14 days, and quantified with a
picogreen assay. The drug release was normalized to total detected
DNA at 14 days.
Example 3: One Pharmaceutical Ingredient Release from Multiple
Film-Forming Agent (FFA) Types
[0059] This example illustrates how multiple film-forming agent
types can accommodate release of a single pharmaceutical
ingredient, without the need for a microsphere component. They are
displayed in FIG. 7.
10% PVA+5% Tween 80
[0060] A FFA was made, consisting of 10% w/v poly(vinyl alcohol)
and 5% v/v Tween 80 dissolved in deionized water. Dexamethasone was
dispersed within the film forming agent via sonication at a
concentration of 1 mg/mL. On a Franz cell apparatus fitted with a
cellulose acetate membrane and 5% w/v Brij O20 receptor phase, 1.0
mL of the dexamethasone/FFA was deposited. Drug diffusion across
the membrane at 37.degree. C. was measured for 5 days, and
quantified with HPLC. The drug release was normalized to total
detected dexamethasone at 5 days.
60% PEG 2000 in H2O
[0061] A FFA was made, consisting of 60% w/v poly(ethylene glycol)
2000 dissolved in deionized water. Dexamethasone was dispersed
within the film forming agent via sonication at a concentration of
1 mg/mL. On a Franz cell apparatus fitted with a cellulose acetate
membrane and 5% w/v Brij O20 receptor phase, 1.0 mL of the
dexamethasone/FFA was deposited. Drug diffusion across the membrane
at 37.degree. C. was measured for 5 days, and quantified with HPLC.
The drug release was normalized to total detected dexamethasone at
5 days.
2% Ethylcellulose in Ethyl Acetate
[0062] A FFA was made, consisting of 2% ethylcellulose dissolved in
ethyl acetate. Dexamethasone was dispersed within the film forming
agent via sonication at a concentration of 1 mg/mL. On a Franz cell
apparatus fitted with a cellulose acetate membrane and 5% w/v Brij
O20 receptor phase, 1.0 mL of the dexamethasone/FFA was deposited.
Drug diffusion across the membrane at 37.degree. C. was measured
for 5 days, and quantified with HPLC. The drug release was
normalized to total detected dexamethasone at 5 days.
0.67% HPMC in Ethanol
[0063] A FFA was made, consisting of 0.67%
hydroxyproplymethylcellulose (HPMC) dissolved in ethanol.
Dexamethasone was dispersed within the film forming agent via
sonication at a concentration of 1 mg/mL. On a Franz cell apparatus
fitted with a cellulose acetate membrane and 5% w/v Brij O20
receptor phase, 1.0 mL of the dexamethasone/FFA was deposited. Drug
diffusion across the membrane at 37.degree. C. was measured for 5
days, and quantified with HPLC. The drug release was normalized to
total detected dexamethasone at 5 days.
2% PVAc in Benzyl Alcohol
[0064] A FFA was made, consisting of 2% poly(vinyl acetate)
dissolved in benzyl alcohol. Dexamethasone was dispersed within the
film forming agent via sonication at a concentration of 1 mg/mL. On
a Franz cell apparatus fitted with a cellulose acetate membrane and
5% w/v Brij O20 receptor phase, 1.0 mL of the dexamethasone/FFA was
deposited. Drug diffusion across the membrane at 37.degree. C. was
measured for 5 days, and quantified with HPLC. The drug release was
normalized to total detected dexamethasone at 5 days.
Example 4: Various Pharmaceutical Ingredient Release from One
Microsphere Type
[0065] The following examples illustrate how one microsphere type
can accommodate release of a multiple pharmaceutical ingredients,
without the need for a film forming agent component. They are
displayed in FIG. 8.
Dexamethasone
[0066] Dexamethasone was dispersed in a polymer solution consisting
of 5050 PLGA (I.V. 0.45 dL/g with ester end group) dissolved in
dichloromethane. The drug/polymer solution was processed with
precision particle fabrication to make microspheres of .about.40
.mu.m, which were collected, filtered, and lyophilized. On a Franz
cell apparatus fitted with a cellulose acetate membrane and 5% w/v
Brij O20 receptor phase, .about.20 mg of the dexamethasone-loaded
microspheres were deposited. Drug diffusion across the membrane at
37.degree. C. was measured for 35 days, and quantified with HPLC.
Microspheres released approximately 1.7 .mu.g dexamethasone, and
the drug release was normalized to total detected dexamethasone at
35 days.
Penicillin
[0067] Penicillin was dispersed in a polymer solution consisting of
5050 PLGA (I.V. 0.45 dL/g with ester end group) dissolved in
dichloromethane. The drug/polymer solution was processed with
precision particle fabrication to make microspheres of .about.40
.mu.m, which were collected, filtered, and lyophilized. On a Franz
cell apparatus fitted with a cellulose acetate membrane and 5% w/v
Brij O20 receptor phase, .about.20 mg of the penicillin-loaded
microspheres were deposited. Drug diffusion across the membrane at
37.degree. C. was measured for 35 days, and quantified with HPLC.
Microspheres released approximately 77 .mu.g penicillin, and the
drug release was normalized to total detected penicillin at 35
days.
Albumin
[0068] Albumin was dissolved in water, then dispersed by sonication
into a polymer solution consisting of 5050 PLGA (I.V. 0.45 dL/g
with ester end group) dissolved in dichloromethane. The
protein/polymer solution was processed with precision particle
fabrication to make microspheres of .about.40 .mu.m, which were
collected, filtered, and lyophilized. On a Franz cell apparatus
fitted with a cellulose acetate membrane and 5% w/v Brij O20
receptor phase, .about.20 mg of the albumin-loaded microspheres
were deposited. Protein diffusion across the membrane at 37.degree.
C. was measured for 35 days, and quantified with a micro-BCA assay.
Microspheres released approximately 4.9 mg albumin, and the protein
release was normalized to total detected albumin at 35 days.
SiRNA
[0069] SiRNA was dissolved in water, then dispersed by sonication
into a polymer solution consisting of 5050 PLGA (I.V. 0.45 dL/g
with ester end group) dissolved in dichloromethane. The nucleic
acid/polymer solution was processed with precision particle
fabrication to make microspheres of .about.40 .mu.m, which were
collected, filtered, and lyophilized. On a Franz cell apparatus
fitted with a cellulose acetate membrane and 5% w/v Brij O20
receptor phase, .about.20 mg of the SiRNA-loaded microspheres were
deposited. Nucleic acid diffusion across the membrane at 37.degree.
C. was measured for 35 days, and quantified with a picogreen assay.
Microspheres released approximately 1.1 .mu.g, and the nucleic acid
release was normalized to total detected SiRNA at 35 days.
DNA
[0070] DNA was dissolved in water, then dispersed by sonication
into a polymer solution consisting of 5050 PLGA (I.V. 0.45 dL/g
with ester end group) dissolved in dichloromethane. The
nucleic/polymer solution was processed with precision particle
fabrication to make microspheres of .about.40 .mu.m, which were
collected, filtered, and lyophilized. On a Franz cell apparatus
fitted with a cellulose acetate membrane and 5% w/v Brij O20
receptor phase, .about.20 mg of the DNA-loaded microspheres were
deposited. Nucleic acid diffusion across the membrane at 37.degree.
C. was measured for 35 days, and quantified with a picogreen assay.
Microspheres released approximately 1.4 .mu.g, and the nucleic acid
release was normalized to total detected DNA at 35 days.
Example 5: One Pharmaceutical Ingredient Release from Different
Microsphere Types in a Single Film-Forming Agent Type
[0071] This example illustrates how different microsphere types can
change release of a single pharmaceutical ingredient, without the
need for changing the film forming agent component. They are
displayed in FIG. 9.
5050 PLGA 3A
[0072] Betamethasone was dispersed in a polymer solution consisting
of 5050 PLGA (I.V. 0.30 dL/g with acid end group) dissolved in
dichloromethane. The drug/polymer solution was processed with
precision particle fabrication and the microspheres were collected,
filtered, and lyophilized. On a Franz cell apparatus fitted with a
cellulose acetate membrane and 5% w/v Brij O20 receptor phase,
.about.10 mg of the betamethasone-loaded microspheres were
suspended in 100 uL of 10% w/v poly(vinyl alcohol) and 5% v/v Tween
80 film-forming agent and deposited. Drug diffusion across the
membrane at 37.degree. C. was measured for 8 days, and quantified
with HPLC. The drug release was normalized to total entrapped drug,
which was approximately 0.75% w/w of the microspheres.
5050 PLGA 4.5E
[0073] Betamethasone was dispersed in a polymer solution consisting
of 5050 PLGA (I.V. 0.45 dL/g with ester end group) dissolved in
dichloromethane. The drug/polymer solution was processed with
precision particle fabrication and the microspheres were collected,
filtered, and lyophilized. On a Franz cell apparatus fitted with a
cellulose acetate membrane and 5% w/v Brij O20 receptor phase,
.about.10 mg of the betamethasone-loaded microspheres were
suspended in 100 uL of 10% w/v poly(vinyl alcohol) and 5% v/v Tween
80 film-forming agent and deposited. Drug diffusion across the
membrane at 37.degree. C. was measured for 8 days, and quantified
with HPLC. The drug release was normalized to total entrapped drug,
which was approximately 0.38% w/w of the microspheres.
Example 6: One Pharmaceutical Ingredient Release from Different
Microsphere Sizes in a Single Film-Forming Agent Type
[0074] This example illustrates how different microsphere sizes can
change release of a single pharmaceutical ingredient, without the
need for changing the film forming agent component or microsphere
material chemistry. They are displayed in FIG. 10.
40 .mu.m
[0075] Betamethasone was dispersed in a polymer solution consisting
of 5050 PLGA (I.V. 0.30 dL/g with acid end group) dissolved in
dichloromethane. The drug/polymer solution was processed with
precision particle fabrication to make microspheres of .about.40
.mu.m, which were collected, filtered, and lyophilized. On a Franz
cell apparatus fitted with a cellulose acetate membrane and 5% w/v
Brij O20 receptor phase, .about.10 mg of the betamethasone-loaded
microspheres were suspended in 100 uL of 10% w/v poly(vinyl
alcohol) and 5% v/v Tween 80 film-forming agent and deposited. Drug
diffusion across the membrane at 37.degree. C. was measured for 28
days, and quantified with HPLC. Microspheres contained
approximately 0.38% w/w betamethasone, and the drug release was
normalized to total detected betamethasone at 28 days.
50 .mu.m
[0076] Betamethasone was dispersed in a polymer solution consisting
of 5050 PLGA (I.V. 0.30 dL/g with acid end group) dissolved in
dichloromethane. The drug/polymer solution was processed with
precision particle fabrication to make microspheres of .about.50
.mu.m, which were collected, filtered, and lyophilized. On a Franz
cell apparatus fitted with a cellulose acetate membrane and 5% w/v
Brij O20 receptor phase, .about.10 mg of the betamethasone-loaded
microspheres were suspended in 100 uL of 10% w/v poly(vinyl
alcohol) and 5% v/v Tween 80 film-forming agent and deposited. Drug
diffusion across the membrane at 37.degree. C. was measured for 28
days, and quantified with HPLC. Microspheres contained
approximately 0.65% w/w betamethasone, and the drug release was
normalized to total detected betamethasone at 28 days.
60 .mu.m
[0077] Betamethasone was dispersed in a polymer solution consisting
of 5050 PLGA (I.V. 0.30 dL/g with acid end group) dissolved in
dichloromethane. The drug/polymer solution was processed with
precision particle fabrication to make microspheres of .about.60
.mu.m, which were collected, filtered, and lyophilized. On a Franz
cell apparatus fitted with a cellulose acetate membrane and 5% w/v
Brij O20 receptor phase, .about.10 mg of the betamethasone-loaded
microspheres were suspended in 100 uL of 10% w/v poly(vinyl
alcohol) and 5% v/v Tween 80 film-forming agent and deposited. Drug
diffusion across the membrane at 37.degree. C. was measured for 28
days, and quantified with HPLC. Microspheres contained
approximately 0.69% w/w betamethasone, and the drug release was
normalized to total detected betamethasone at 28 days.
[0078] Therefore, the present invention is well adapted to attain
the ends and advantages mentioned as well as those that are
inherent therein. The particular embodiments disclosed above are
illustrative only, as the present invention may be modified and
practiced in different but equivalent manners apparent to those
skilled in the art having the benefit of the teachings herein.
Furthermore, no limitations are intended to the details of
construction or design herein shown, other than as described in the
claims below. It is therefore evident that the particular
illustrative embodiments disclosed above may be altered or modified
and all such variations are considered within the scope and spirit
of the present invention.
[0079] While compositions and methods are described in terms of
"comprising," "containing," or "including" various components or
steps, the compositions and methods can also "consist essentially
of" or "consist of" the various components and steps.
[0080] All numbers and ranges disclosed above may vary by some
amount. Whenever a numerical range with a lower limit and an upper
limit is disclosed, any number and any included range falling
within the range is specifically disclosed. In particular, every
range of values (of the form, "from about a to about b," or,
equivalently, "from approximately a to b," or, equivalently, "from
approximately a-b") disclosed herein is to be understood to set
forth every number and range encompassed within the broader range
of values.
[0081] Also, the terms in the claims have their plain, ordinary
meaning unless otherwise explicitly and clearly defined by the
patentee. Moreover, the indefinite articles "a" or "an", as used in
the claims, are defined herein to mean one or more than one of the
element that it introduces. If there is any conflict in the usages
of a word or term in this specification and one or more patent or
other documents that may be incorporated herein by reference, the
definitions that are consistent with this specification should be
adopted.
* * * * *