U.S. patent application number 13/988298 was filed with the patent office on 2014-01-30 for therapeutic agent formulations for implanted devices.
This patent application is currently assigned to ForSight Vision4, Inc.. The applicant listed for this patent is Yair Alster, Blaine Bueche, Randolph E. Campbell, Steven M. Chamow, Eugene de Juan, JR., Signe Erickson, Kathleen Cogan Farinas, K. Angela MacFarlane, Cary J. Reich. Invention is credited to Yair Alster, Blaine Bueche, Randolph E. Campbell, Steven M. Chamow, Eugene de Juan, JR., Signe Erickson, Kathleen Cogan Farinas, K. Angela MacFarlane, Cary J. Reich.
Application Number | 20140031769 13/988298 |
Document ID | / |
Family ID | 45217703 |
Filed Date | 2014-01-30 |
United States Patent
Application |
20140031769 |
Kind Code |
A1 |
de Juan, JR.; Eugene ; et
al. |
January 30, 2014 |
THERAPEUTIC AGENT FORMULATIONS FOR IMPLANTED DEVICES
Abstract
An injectable formulation of therapeutic agent may comprise the
therapeutic agent and a stabilizer such that a substantial portion
of the stabilizer remains in the therapeutic device to stabilize
the therapeutic agent when the therapeutic agent is released from
the therapeutic device. The injectable formulation may comprise one
or more of binding agent particles or erodible material particles,
such that the formulation can be injected into the therapeutic
device. The binding agent particles can bind reversibly to the
therapeutic agent so as to modulate release of the therapeutic
agent, and the erodible material particles can generate protons of
an acid so as to increase stability of the therapeutic agent and
may modulate release of the therapeutic agent. The therapeutic
agent can be combined with one or more of the stabilizer, the
binding agent particles or the erodible particles to increase
stability of the therapeutic agent and may modulate release.
Inventors: |
de Juan, JR.; Eugene; (Menlo
Park, CA) ; Alster; Yair; (Menlo Park, CA) ;
Chamow; Steven M.; (Menlo Park, CA) ; Farinas;
Kathleen Cogan; (Menlo Park, CA) ; MacFarlane; K.
Angela; (Menlo Park, CA) ; Reich; Cary J.;
(Menlo Park, CA) ; Campbell; Randolph E.; (Menlo
Park, CA) ; Erickson; Signe; (Menlo Park, CA)
; Bueche; Blaine; (Menlo Park, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
de Juan, JR.; Eugene
Alster; Yair
Chamow; Steven M.
Farinas; Kathleen Cogan
MacFarlane; K. Angela
Reich; Cary J.
Campbell; Randolph E.
Erickson; Signe
Bueche; Blaine |
Menlo Park
Menlo Park
Menlo Park
Menlo Park
Menlo Park
Menlo Park
Menlo Park
Menlo Park
Menlo Park |
CA
CA
CA
CA
CA
CA
CA
CA
CA |
US
US
US
US
US
US
US
US
US |
|
|
Assignee: |
ForSight Vision4, Inc.
Menlo Park
CA
|
Family ID: |
45217703 |
Appl. No.: |
13/988298 |
Filed: |
November 18, 2011 |
PCT Filed: |
November 18, 2011 |
PCT NO: |
PCT/US11/61535 |
371 Date: |
October 14, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61415674 |
Nov 19, 2010 |
|
|
|
Current U.S.
Class: |
604/294 |
Current CPC
Class: |
A61F 9/0017 20130101;
A61K 9/1652 20130101; A61K 9/1647 20130101; A61K 31/573 20130101;
A61K 9/0051 20130101; A61P 27/02 20180101 |
Class at
Publication: |
604/294 |
International
Class: |
A61F 9/00 20060101
A61F009/00 |
Claims
1-76. (canceled)
77. A device to treat an eye, the device comprising: a reservoir
chamber having a volume sized to receive an injection of an amount
of a formulation of a therapeutic agent; a porous structure to
release therapeutic amounts of the therapeutic agent for an
extended time; and a stabilizer to maintain stability of the
therapeutic agent in the reservoir chamber, the stabilizer
comprising a molecular weight of at least about 5 k Daltons such
that a portion of the stabilizer remains in the reservoir chamber
for the extended time.
78. The device of claim 77, wherein the stabilizer comprises a
molecular weight of at least about 10 k.
79. The device of claim 77, wherein the stabilizer comprises a
molecular weight of at least about 25% of a molecular weight of the
therapeutic agent.
80. The device of claim 79, wherein the therapeutic agent comprises
a molecular weight of at least about 40 k.
81. The device of claim 80, wherein the therapeutic agent comprises
a Fab antibody fragment or a derivative thereof.
82. The device of claim 81, wherein the therapeutic agent comprises
ranibizumab.
83. The device of claim 77, further comprising an amount of an
erodible material to maintain the pH of the chamber at no more than
about 6.5 for an extended time of at least about one month.
84. The device of claim 77, further comprising an amount of an
erodible material to maintain the pH of the chamber at no more than
about 6.0 for an extended time of at least about one month.
85. The device of claim 77, further comprising a plurality of
particles to bind reversibly to the therapeutic agent, a majority
of the plurality of particles having a size greater than channels
of the porous structure such that the particles remain in the
reservoir chamber for the extended time.
86.-107. (canceled)
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] The present PCT application claims priority to U.S. Prov.
Pat. App. Ser. No. 61/415,674, filed Nov. 19, 2010, entitled
"THERAPEUTIC AGENT FORMULATIONS FOR IMPLANTED DEVICES", the full
disclosure of which is incorporated herein by reference.
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED
RESEARCH AND DEVELOPMENT
[0002] NOT APPLICABLE
BACKGROUND
[0003] Described herein are devices and methods of delivery of
therapeutic agents to the posterior segment of the eye. Although
specific reference is made to the delivery of macromolecules
comprising antibodies or antibody fragments to the posterior
segment of the eye, various related variations can be used to
deliver many therapeutic agents to many tissues of the body. For
example, some variations can be used to deliver therapeutic agent
to one or more of the following tissues: intravascular,
intra-articular, intrathecal, pericardial, intraluminal, and
gut.
[0004] The eye is critical for vision. The eye has a cornea and a
lens that form an image on the retina. The image formed on the
retina is detected by rods and cones on the retina. The light
detected by the rods and cones of the retina is transmitted to the
occipital cortex brain via the optic nerve, such that the
individual can see the image formed on the retina. Visual acuity is
related to the density of rods and cones on the retina. The retina
comprises a macula that has a high density of cones, such that the
user can perceive color images with high visual acuity.
[0005] Unfortunately, diseases can affect vision. In some instances
the disease affecting vision can cause damage to the retina, even
blindness in at least some instances. One example of a disease that
can affect vision is age-related macular degeneration (hereinafter
"AMD"). Although therapeutic drugs are known that can be provided
to minimize degradation of the retina, in at least some instances
the delivery of these drugs can be less than ideal.
[0006] In some instances a drug is injected into the eye through
the sclera. One promising class of drugs for the treatment of AMD
is known as vascular endothelial growth factor (hereinafter "VEGF")
inhibitors. Unfortunately, in at least some instances injection of
drugs can be painful for the patient, involve at least some risk of
infection and hemorrhage and retinal detachment, and can be time
consuming for the physician and patient. Consequently, in at least
some instances the drug may be delivered less often than would be
ideal, such that at least some patients may receive less drug than
would be ideal in at least some instances.
[0007] Although at least some of the prior proposed implanted
devices may permit an injection of a formulation of therapeutic
agent into the device, the performance of commercially available
formulations of therapeutic agents can be less than ideal in at
least some instances when injected into an implantable device. For
example, the commercially available formulation may have one or
more stabilizers having a molecular weight substantially less than
the therapeutic agent, such that stabilizer may be released from
the device at a rate faster than the therapeutic agent.
Consequently, the therapeutic agent injected into the device may
not receive the benefit of the stabilizer as long as would be ideal
and may degrade more quickly than would be ideal in at least some
instances. Also, the initial rate of release of the therapeutic
agent can be somewhat greater than would be ideal and the rate at
an extended time can be somewhat lower than would be ideal, such
that profile of the rate of release can be less than ideal in at
least some instances.
[0008] Work in relation to the various related variations suggests
that the pH provided in situ after injection into a therapeutic
device may be less than ideal for maintaining stability of the
therapeutic agent for an extended time in at least some instances.
The stability of the therapeutic agent can be related to a pH of
the formulation within the device in at least some instances. For
example, deamidation of a protein based therapeutic agent may be
related to stability of the therapeutic agent, and the deamidation
can be related to pH in at least some instances. Work in relation
to variations suggests that prior formulations may provide less
than ideal stability in one or more ways when injected into a
therapeutic device in at least some instances. For example, a
buffer of the injected formulation may be released from the device
into the vitreous in at least some instances. Also, diffusion of
hydrogen ions and hydroxide ions between the reservoir and the
vitreous may affect the pH of the formulation within the
device.
[0009] In at least some instances, one or more molecular components
such as a buffer may enter the device when placed in the body, and
at least some of the prior formulations may be less stable than
would be ideal in at least some instances when exposed to
physiological buffer. For example, a buffer of a fluid of the eye
such as the vitreous humor having a physiological pH may enter the
device and affect the pH of the formulation within the device, such
that the stability of the therapeutic agent may be less than ideal
in at least some instances.
[0010] Work in relation to the various related variations suggests
that injection of prior formulations of therapeutic agents into a
therapeutic device may result in at least some aggregation of the
therapeutic agent in at least some instances, and the aggregation
of therapeutic agent may decrease stability of the therapeutic
agent, such that the stability of the therapeutic agent when
injected into the therapeutic device with prior formulations can be
less than ideal in at least some instances.
[0011] In light of the above, it would be desirable to provide
improved formulations of therapeutic agents for therapeutic devices
that overcome at least some of the above deficiencies of the known
formulations, for example with improved drug release that can be
maintained over an extended time when implanted.
SUMMARY
[0012] Described herein are improved formulations of therapeutic
agents and improved methods and apparatus for placement into
therapeutic devices for an extended time. A flowable, for example
injectable, formulation of therapeutic agent may comprise the
therapeutic agent and a stabilizer such that a substantial portion
of the stabilizer remains in the therapeutic device so as to
stabilize the therapeutic agent when the therapeutic agent is
released from the therapeutic device. The formulation comprising
the therapeutic agent can be placed in the therapeutic device in
many ways, and can be injected into the therapeutic device, drawn
into the therapeutic device with aspiration, or combinations
thereof. The injectable formulation may comprise one or more of
binding agent particles or erodible material particles, such that
the formulation can be injected into the therapeutic device. The
binding agent particles can bind reversibly to the therapeutic
agent so as to modulate release of the therapeutic agent, and the
erodible material particles can generate protons of an acid so as
to increase stability of the therapeutic agent and may modulate
release of the therapeutic agent. The therapeutic agent can be
combined with one or more of the stabilizer, the binding agent
particles or the erodible particles, so as to increase stability of
the therapeutic agent and may modulate release of the therapeutic
agent from the device.
[0013] The stabilizer can interact in many ways with the
therapeutic agent so as to increase a stability of the therapeutic
agent. The stabilizer may comprise one or more functional groups so
as to form a complex with the therapeutic agent. The stabilizer may
comprise a co-solute with excluded volume that favors the native
state of the protein over the denatured state, so as to increase
the stability of the protein. The co-solute with the excluded
volume may comprise a stabilizer having a plurality of hydrophilic
functional groups so as to provide the excluded volume to favor the
native state of the protein. The stabilizer may comprise one or
more of a substantially water soluble high molecular weight
stabilizer having a molecular weight of at least about 2 k Daltons
or micelles sized so as to correspond to a molecular weight of at
least about 2 k Daltons. In many variations, the molecular weight
of the stabilizer comprises at least about 25% of the molecular
weight of the therapeutic agent, such that a substantial portion of
the stabilizer injected into the chamber of the therapeutic device
with the therapeutic agent remains in the chamber of the
therapeutic device for an extended time when the therapeutic agent
is released in therapeutic amounts through a porous structure.
[0014] The particles of the binding agent may comprise functional
groups to bind reversibly to the therapeutic agent such that a
substantial portion of the therapeutic agent injected into the
chamber of the device may be reversibly bound to the binding agent.
The binding agent may comprise porous particles having porous
internal channels extending outer surfaces of the particles so as
to bind reversibly to the therapeutic agent. The particles may
comprise porous resin particles having derivatized functional
groups on surfaces of the inner channels. The functional groups can
be located on the outer surface and the surfaces of the inner
channels so as to bind reversibly to the therapeutic agent, and the
surfaces of the inner channels can be fluidically coupled to the
outer surface of the particles such that the therapeutic agent can
be released from the surfaces of the inner channels. The
therapeutic agent released from the binding agent can form a
complex with the stabilizer, or dissociate from the binding agent
into solution, or combinations thereof. The therapeutic agent bound
reversibly to the binding agent, the therapeutic agent complexed
with the stabilizer and therapeutic agent in solution can be in
substantial equilibrium within the chamber of the device so as to
modulate release of the therapeutic agent when the therapeutic
agent is stabilized.
[0015] The particles of erodible material to generate protons of an
acid can maintain a pH of the formulation less than about 7, for
example less than about 6.5, when injected into the therapeutic
device. The pH less than about 7 can result in decreased amounts of
degradation of the therapeutic agent that may occur with one or
more degradation pathways. The degradation pathway affected with
the pH less than 7 can be one or more of deamidation of the
therapeutic agent, such as oxidation of the therapeutic agent,
isomerization of the therapeutic agent, clipping of the therapeutic
agent, hydrolysis of the therapeutic agent, fragmentation of the
therapeutic agent, or aggregation of the therapeutic agent, or
combinations thereof. The particles of erodible material may
comprise a polymer, such as polylactic acid (hereinafter "PLA",
polyglutamic acid (hereinafter "PGA"), or combinations thereof, and
the particles may generate protons of an acid in response to
degradation such as hydrolysis. In many variations, the particles
of binding agent are pH sensitive so as to bind less with increased
pH, such that therapeutic agent can be released from the particles
in response to an increase in pH.
[0016] In a first aspect, variations provide a flowable
formulation. The flowable formulation comprises a therapeutic
agent, and a stabilizer having a molecular weight of at least about
2 k Daltons.
[0017] In many variations, the stabilizer increases an amount of
time the therapeutic agent has a therapeutic effect when placed in
a therapeutic device placed in a patient. The stabilizer may
comprise one or more of, a buffer to maintain a pH of the
formulation, hydrophilic functional groups, hydrophilic functional
group to provide a co-solvent stabilization, a charged functional
group to provide charge interaction, or a functional group to form
a complex with the therapeutic agent, so as to increase one or more
of physical stability or chemical stability of the therapeutic
agent and maintain biological activity of the therapeutic agent.
The stabilizer can be soluble and may comprise one or more of a
sugar, an alcohol, a polyol, or a carbohydrate and wherein the
functional group comprises a hydroxyl group.
[0018] In many variations, the therapeutic agent provides a
therapeutic effect when placed in the body.
[0019] In many variations, the stabilizer comprises a molecular
weight of at least about 3 k Daltons. The stabilizer may comprise a
molecular weight of at least about 5 k Daltons, and may comprise a
molecular weight of at least about 10 k Daltons, for example at
least about 25 k Daltons.
[0020] In many variations, the stabilizer comprises a molecular
weight of at least about 25% of a molecular weight of the
therapeutic agent. The stabilizer and the therapeutic agent may
each comprise a half-life when placed, for example injected, into a
therapeutic device, and the half-life of the stabilizer may
comprise at least about 25% of the half-life of the therapeutic
agent. The half-life of the stabilizer may comprise of at least
about 50% of the half-life of the therapeutic agent.
[0021] In many variations, the stabilizer is water-soluble and
comprises a molecular weight of no more than about 500% of the
molecular weight of the therapeutic agent.
[0022] In many variations, the stabilizer is substantially
insoluble in water and comprises a molecular weight of no more than
about 5000% of the molecular weight of the therapeutic agent.
[0023] In many variations, the stabilizer comprises a plurality of
substantially water insoluble particles. The stabilizer may
comprise a plurality of substantially water insoluble particles
having hydrophilic functional groups and a molecular weight of no
more than about 5000% of the molecular weight of the therapeutic
agent.
[0024] In many variations, the therapeutic agent comprises a
molecular weight of at least about 40 k. The therapeutic agent may
comprise a Fab antibody fragment or a derivative thereof. The
therapeutic agent comprises the Fab antibody fragment and
deamidized derivatives of the Fab antibody fragment.
[0025] In many variations, the therapeutic agent may comprise
ranibizumab. The therapeutic agent may comprise ranibizumab and
degradation products of ranibizumab, and the degradation products
may comprise one or more of deamidized ranibizumab or oxidized
ranibizumab.
[0026] In many variations, the stabilizer comprising the molecular
weight comprises one or more of: HA (hyaluronic acid) having the
molecular weight of at least 2 k, histidine polymer buffer having
the molecular weight of at least 2 k, sugar having the molecular
weight of at least 2 k, polysaccharides having the molecular weight
of at least 2 k, carbohydrate having the molecular weight of at
least 2 k, starch having the molecular weight of at least 2 k,
alcohol having the molecular weight of at least 2 k, polyol having
the molecular weight of at least 2 k, or polyethylene oxide having
the molecular weight of at least 2 k, so as to stabilize the
therapeutic agent and decrease release of the therapeutic agent
when placed in a therapeutic device.
[0027] In many variations, the stabilizer comprising the molecular
weight comprises one or more of: a phenol, a protein, or a charged
stabilizers such as a metal comprising one or more of zinc ion,
calcium ion, or iron ion, so as to form a reversible complex with
the therapeutic agent.
[0028] In many variations, the stabilizer comprises a plurality of
micelles and wherein the molecular weight of the stabilizer
corresponds to a weight of each micelle of the plurality such that
diffusion of the plurality of micelles corresponds to the weight of
said each micelle. The plurality of micelles may comprise a
reservoir of the stabilizer. The stabilizer may comprise a
surfactant, and a concentration of surfactant comprises at least
about two times a critical micelle concentration of the surfactant.
The concentration of surfactant may comprise at least about two
times the critical micelle concentration, and may comprise at least
about four times the critical micelle concentration.
[0029] In many variations, stabilizer comprises a polysorbate.
[0030] In many variations, an amount of the stabilizer corresponds
to at least about 0.05% by weight of the formulation when injected
into the eye.
[0031] In many variations, said each of the plurality of micelles
forms a complex with the therapeutic agent so as to stabilize the
therapeutic agent and decrease diffusion of the therapeutic
agent.
[0032] In many variations, the container comprises a plurality of
particles having a dimension across within a range from about 0.1
um across to about 200 um across, such that the plurality of
particles is sized to pass through a lumen of a needle. The
dimension across can be within a range from about 0.1 um across to
about 50 um across, such that the plurality of particles is sized
to pass through a lumen of a 33 Gauge needle.
[0033] In many variations, the container comprises a plurality of
pellets having a dimension across within a range from about 0.1 um
to about 500 um, such that the plurality of particles is sized to
pass through a lumen of a 19 Gauge needle.
[0034] In many variations, the plurality of particles comprises one
or more of a plurality of stabilizer particles, a plurality of
erodible particles to generate protons of an acid, or a plurality
of binding agent particles.
[0035] In many variations, the container comprises a plurality of
binding agent particles having a dimension across within a range
from about 0.1 um across to about 200 um across, the binding agent
particles providing a plurality of reversible binding sites having
the therapeutic agent reversibly bound thereon.
[0036] In many variations, the therapeutic agent comprises a first
portion in solution comprising a first concentration and a second
portion reversibly bound to the plurality of binding agent
particles comprising a second concentration. An amount of the
second portion of the therapeutic agent reversibly bound to the
plurality of binding agent particles and a dimension across the
plurality of binding agent particles corresponds to the second
concentration of the therapeutic agent. The second concentration
can be greater than the first concentration.
[0037] In many variations, each of the plurality of binding agent
particles comprises internal channels extending therein and wherein
the internal channels comprise the plurality of reversible binding
sites. The plurality of binding agent particles may comprise resin
particles having the internal channels and an external surface and
wherein the internal surface and the external surface have been
treated so as to bind reversibly with the therapeutic agent. The
binding agent may comprise a surface derivatized with at least one
functional group so as to bind reversibly with the therapeutic
agent. The derivatized surface may comprise an anion exchange
surface and wherein the at least one functional group comprises one
or more of quaternary amines, diethylaminoehtly (hereinafter
"DEAE"), quaternary aminoethly (hereinafter "QAE"), or quaternatry
ammonidum (hereinafter "Q"). The derivatized surface comprises a
cation exchange surface and wherein the at least one functional
group comprises one or more of carboxy methyl (hereinafter "CM"),
Sulphoproply (hereinafter "SP"), or methyl sulphonate (hereinafter
"SP").
[0038] In many variations, the binding agent comprises a negatively
charged surface within a range of about pH 5.5 to about pH 7.5 so
as to bind reversibly to positive charges of the therapeutic agent.
The binding agent comprises a net negative surface charge within a
range about pH 6 to about pH 7 and wherein the therapeutic agent
comprises a net positive charge so as to bind reversibly to the
therapeutic agent. The therapeutic agent comprises an isoelectric
pH (pI) of at least about 8 and wherein binding of the therapeutic
agent to the binding agent decreases substantially when the pH
increases from about 6 to about 7. The therapeutic agent comprises
at least about ten positive charges and at least about ten negative
charges and wherein derivatized surface comprises positive and
negative charges to bind reversibly to the therapeutic agent.
[0039] In many variations, the at least one functional group
increases a stability of the therapeutic agent when reversibly
bound to the therapeutic agent.
[0040] In many variations, the plurality of binding agent particles
have the dimension within the range from about 0.1 um to about 200
um such that the plurality of binding agent particles comprises a
suspension suitable for injection into a chamber of a therapeutic
device. The range from about 0.1 um to about 50 um such that the
plurality of binding agent particles comprises a suspension
suitable for injection through a lumen of a 33 Gauge needle. The
plurality of binding agent particles may have the dimension within
the range from about 0.5 um to about 100 um such that diffusion of
the suspension of binding agent particles through a porous
structure is substantially inhibited.
[0041] In many variations, the plurality of binding agent particles
have the dimension across each particle sized greater than a
dimension across channels of a porous structure such that passage
of the particles through the porous structure is inhibited
substantially.
[0042] In many variations, the formulation further comprises a
plurality of particles of an erodible material to release protons
of an acid. The plurality of erodible particles may comprise one or
more of a suspension or a slurry of the erodible particles for
injection into or exchange from a therapeutic device.
[0043] In many variations, the formulation comprises a pH of at
least about 5.5. The plurality of particles of formulation may be
capable of releasing about 1E-10 (1.times.10-10) moles of protons
per uL of device reservoir volume so as to maintain a pH of the
formulation below about 7 for an extended time of at least about 1
month.
[0044] In many variations, the plurality of particles of the
erodible material comprises an amount corresponding to about 0.01%
to about 5% by weight of the formulation. The erodible material a
polymer, the polymer comprising one or more of polylactic acid
(PLA), polyglutamic acid (PGA) or PLA/PGA copolymer.
[0045] In many variations, the formulation further comprises an
amount of the erodible material to maintain the pH of the chamber
at no more than about 6.5 for an extended time of at least about 1
month when injected into a chamber of a therapeutic device coupled
to the eye with a porous structure. In many variations, an amount
of an erodible material to maintain the pH of the chamber at no
more than about 6.0 for an extended time of at least about 1 month
when exposed to physiological phosphate buffer diffused through the
porous structure. The amount of an erodible material may be
sufficient to maintain the pH of the chamber at no more than about
6.0 for an extended time of at least about 3 months when exposed to
physiological phosphate buffer diffused through the porous
structure.
[0046] In many variations, the plurality of erodible particles
comprises a ratio of PLA to PGA to erode and release protons at a
rate to maintain the pH.
[0047] In many variations, the plurality of erodible particles
comprises a portion of the particles covered with a coating to
delay erosion of the portion.
[0048] In many variations, the plurality of erodible particles
comprises distribution of sizes so as to erode and release protons
at a rate to maintain the pH.
[0049] In many variations, the plurality of particles comprises the
stabilizer mixed with the erodible material to provide the
stabilizer when the particle erodes.
[0050] In an interrelated aspect, variations provide an injectable
formulation. The injectable formulation comprises therapeutic
agent, and a stabilizer comprising a plurality of micelles.
[0051] In many variations, each of the plurality of micelles
comprises a weight corresponding to molecular weight of at least
about 2 k Daltons, and the plurality of micelles comprises a
reservoir of the stabilizer. A first portion of the stabilizer
comprises a solution of the stabilizer and a second portion of the
stabilizer comprises the micelles and wherein the stabilizer is
released from the micelles to the solution maintain a concentration
of the first portion of the stabilizer in solution. The stabilizer
may comprise a polymeric surfactant and wherein a concentration of
polymeric surfactant is higher than a threshold concentration to
form one or more of the plurality of micelles and wherein the
concentration of the polymeric surfactant comprises the first
portion and the second portion.
[0052] In another interrelated aspect, variations provide
injectable formulation, the formulation comprises a therapeutic
agent, and an erodible material to generate protons of an acid. The
erodible material comprises an amount to erode and maintain a pH of
no more than about 6.5 when the formulation is combined with
physiological amounts of phosphate buffer.
[0053] In many variations, the injectable formulation further
comprises a plurality of particles, wherein each of the plurality
of particles comprises the erodible material and a hydrophilic
stabilizer such that the hydrophilic stabilizer is released when
said each particle of the plurality erodes.
[0054] In another interrelated aspect, variations provide method of
preparing an injectable formulation, the method comprising:
combining a therapeutic agent and a stabilizer.
[0055] In many variations, the stabilizer has a molecular weight of
at least about 2 k Daltons.
[0056] In another interrelated aspect, variations provide device to
treat an eye. The device comprises a reservoir chamber having a
volume sized to receive an injection of an amount of a formulation
of a therapeutic agent, and a porous structure to release
therapeutic amounts of the therapeutic agent for an extended time.
A stabilizer is configured to maintain stability of the therapeutic
agent in the reservoir chamber, and the stabilizer comprises a
molecular weight of at least about 5 k Daltons such that a portion
of the stabilizer remains in the reservoir chamber for the extended
time.
[0057] In many variations, the stabilizer comprises a molecular
weight of at least about 10 k. The stabilizer may comprise a
molecular weight of at least about 25% of a molecular weight of the
therapeutic agent, and the molecular weight can be at least about
40 k. The therapeutic agent comprises a Fab antibody fragment or a
derivative thereof. The therapeutic agent may comprise
ranibizumab.
[0058] In many variations, the stabilizer further comprising an
amount of an erodible material to maintain the pH of the chamber at
no more than about 6.5 for an extended time of at least about 1
month.
[0059] In many variations, the stabilizer further comprising an
amount of an erodible material to maintain the pH of the chamber at
no more than about 6.0 for an extended time of at least about 1
month.
[0060] In many variations, the stabilizer comprises a plurality of
particles to bind reversibly to the therapeutic agent, a majority
of the plurality of particles having a size greater than channels
of the porous structure such that the particles remain in the
reservoir chamber for the extended time.
[0061] In another interrelated aspect, variations provide method of
treating an eye. A therapeutic device comprising a reservoir
chamber and a porous structure is provided, in which the reservoir
chamber has a volume sized to receive an injection of an amount of
a formulation of a therapeutic agent, and the porous structure is
configured to release therapeutic amounts of the therapeutic agent
for an extended time. A stabilizer and the therapeutic agent are
injected into the reservoir chamber, and the stabilizer maintains
stability of the therapeutic agent in the reservoir chamber, the
stabilizer comprising a molecular weight of at least about 5 k
Daltons, and a substantial portion of the stabilizer remains in the
reservoir chamber for the extended time.
[0062] In another interrelated aspect, variations provide an
apparatus to treat an eye. A first container comprises a
formulation of a therapeutic agent, the formulation comprising a
stabilizer and the therapeutic agent, and a second container
comprises an erodible material to release protons of an acid.
[0063] In many variations, the second container comprises particles
of the erodible material such that the particles form a suspension
of the erodible material when mixed with the formulation.
[0064] In many variations, the erodible material releases an acid
when wet so as to maintain substantially a pH of the formulation
when mixed with the formulation and injected into a therapeutic
device.
[0065] In many variations, the second container comprises a syringe
having the erodible material stored therein, and the syringe
comprises an exchange syringe.
[0066] In many variations, the second container comprises a
cartridge having the erodible material stored therein, the
cartridge configured to couple to a syringe having the formulation
of the therapeutic agent contained therein, so as to mix the
erodible material with the formulation upon injection into or
exchange with a therapeutic device.
[0067] In many variations, the container stores the erodible
material substantially without water.
[0068] In many variations, the stabilizer comprises a molecular
weight of at least about 5 k Daltons and the therapeutic agent
comprises a molecular weight of at least about 25 k Daltons.
[0069] In many variations, the container comprises a plurality of
binding agent particles having a dimension across within a range
from about 0.1 um across to about 200 um across, the binding agent
particles providing a plurality of reversible binding sites to
receive the therapeutic agent.
[0070] In many variations, the dimension across is within a range
from about 0.5 um across to about 100 um across.
[0071] In many variations, each of the plurality of binding agent
particles comprises internal channels extending therein and wherein
the internal channels comprise the plurality of reversible binding
sites. The plurality of binding agent particles may comprise resin
particles having the internal channels and an external surface
treated so as to bind reversibly with the therapeutic agent.
[0072] In many variations, the plurality of particles comprises a
second stabilizer so as to release the second stabilizer when the
erodible material erodes and generates the protons of the acid.
[0073] In many variations, the second stabilizer comprises one or
more of a sugar, an alcohol, a polyol, a polysaccharide, or a
carbohydrate.
[0074] In many variations, the second stabilizer comprises one or
more of a buffer or pH modifier.
[0075] In many variations, the second stabilizer comprises hydroxyl
groups.
[0076] In another interrelated aspect, variations provide a method
of preparing a formulation. A formulation of a therapeutic agent
can be provided, in which the formulation comprises a stabilizer
and the therapeutic agent. An erodible material is provided to
release protons of an acid, and the formulation is mixed with the
erodible material.
[0077] In another interrelated aspect, variations provide an
injectable and exchangeable formulation to treat an eye. The
formulation comprises a therapeutic agent having a molecular weight
of at least about 40 k Daltons, and a stabilizer having a molecular
weight of at least about 10 k Daltons. The stabilizer is capable of
forming a complex with the therapeutic agent to stabilize the
therapeutic agent. A first plurality of binding agent particles has
a plurality of sites to bind reversibly the therapeutic agent. A
second plurality of erodible particles to generate an acid, wherein
the first plurality of binding agent particles and the second
plurality of erodible particles comprise a suspension such that the
formulation is capable of injection into a therapeutic device and
exchange from the therapeutic device.
[0078] In another interrelated aspect, variations provide method of
treating an eye. A formulation is provided, and the formulation
comprises a therapeutic agent, a stabilizer, a first plurality of
binding agent particles and a second plurality of erodible
particles, the therapeutic agent having a molecular weight of at
least about 40 k Daltons. The formulation is placed in a chamber of
a therapeutic device.
[0079] In many variations, the stabilizer has a molecular weight of
at least about 10 k Daltons, and the stabilizer is capable of
forming a complex with the therapeutic agent to stabilize the
therapeutic agent. The first plurality of binding agent particles
has a plurality of sites to bind reversibly the therapeutic agent.
The second plurality of erodible particles generates an acid, and
the first plurality of binding agent particles and the second
plurality of erodible particles comprise a suspension such that the
formulation is capable of injection into a therapeutic device and
exchange from the therapeutic device.
[0080] In many variations, placing comprises exchanging the
formulation with a portion of a previously placed formulation, in
which the portion of the previously placed formulation comprises,
water, deamidated therapeutic agent, and binding agent
particles.
[0081] The details of one or more variations of the subject matter
described herein are set forth in the accompanying drawings and the
description below. Other features and advantages of the subject
matter described herein will be apparent from the description and
drawings, and from the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0082] FIG. 1 shows an eye suitable for incorporation of variations
of the therapeutic device;
[0083] FIG. 1A-1 shows a therapeutic device implanted at least
partially within the sclera of the eye as in FIG. 1;
[0084] FIG. 1A-1-1 and 1A-1-2 show a therapeutic device implanted
under the conjunctiva and extending through the sclera to release a
therapeutic agent into vitreous humor of the eye so as to treat the
retina, in accordance with variations described herein;
[0085] FIG. 1A-2 shows structures of a therapeutic device
configured for placement in an eye as in FIGS. 1A-1 and 1A-1-1, in
accordance with variations described herein;
[0086] FIG. 1A-2-1 shows a therapeutic device loaded into an
insertion cannula, in which the device comprises an elongate narrow
shape for insertion into the sclera, and in which the device is
configured to expand to a second elongate wide shape for retention
at least partially in the sclera, in accordance with variations
described herein;
[0087] FIG. 1A-2-2 shows a therapeutic device comprising a
reservoir suitable for loading in a cannula, in accordance with
variations described herein;
[0088] FIG. 1B shows a therapeutic device configured for placement
in an eye as in FIG. 1A-1 and 1A-1-1, in accordance with variations
described herein;
[0089] FIG. 1C shows a therapeutic device configured for placement
in an eye as in FIG. 1A-1 and 1A-1-1, in accordance with variations
described herein;
[0090] FIG. 1C-A shows at least one exit port, according to
variations described herein;
[0091] FIG. 1C-B shows a syringe being filled with a formulation
190 comprising therapeutic agent 110 and one or more of stabilizer
192, binding agent 194 or particles 196, for injection into the
therapeutic device, in accordance with variations described
herein;
[0092] FIG. 2 shows an access port suitable for incorporation with
the therapeutic device, in accordance with variations described
herein;
[0093] FIG. 3A shows components of a formulation comprising
therapeutic agent, stabilizer corresponding to the therapeutic
agent, binding agent and erodible particles, in accordance with
variations described herein;
[0094] FIG. 3B1 shows a stabilizer as in FIG. 3A, in accordance
with variations described herein;
[0095] FIG. 3B2 shows a micelle of a stabilizer as in FIG. 3A, in
accordance with variations described herein;
[0096] FIG. 3C shows a binding agent having porous channels as in
FIG. 3A, in accordance with variations described herein;
[0097] FIG. 3D shows an erodible material comprising an erodible
polymer to generate a proton of an acid as in FIG. 3A, in
accordance with variations described herein;
[0098] FIG. 3E shows reactions and equilibrium corresponding to
components to determine release rates of the formulation as in FIG.
3A when injected into a therapeutic device, in accordance with
variations described herein;
[0099] FIG. 4A shows released fragments of antibodies, and FIG. 4B
shows antibody fragments reversibly bound to a substrate, in
accordance with variations described herein;
[0100] FIG. 4C shows net charge of ranibizumab from pH 3 to about
pH 13, in accordance with variations described herein;
[0101] FIG. 5A shows a therapeutic device coupled to an injector to
insert therapeutic agent into the device, in accordance with
variations described herein;
[0102] FIG. 5A-1 shows a therapeutic device coupled to an injector
to simultaneously inject and remove material from the device, in
accordance with variations described herein;
[0103] FIG. 5B shows a therapeutic device comprising a micro loop
channel, in accordance with variations described herein;
[0104] FIG. 5C-1 shows a therapeutic device comprising a tortuous
channel, in accordance with variations described herein;
[0105] FIG. 5C-2 shows a therapeutic device comprising a coiled
channel, in accordance with variations described herein;
[0106] FIG. 5D shows an expandable and contractible structure to
retain the therapeutic agent and an outer rigid casing to couple to
the sclera, in accordance with variations described herein;
[0107] FIG. 5E shows a membrane disposed over an exit port of a
therapeutic device, in accordance with variations described
herein;
[0108] FIG. 5F shows a therapeutic device comprising a tubular
membrane clamped onto the therapeutic device, in accordance with
variations described herein;
[0109] FIG. 6A-1 shows a therapeutic device comprising a container
having a penetrable barrier disposed on a first end, a porous
structure disposed on a second end to release therapeutic agent for
an extended period, and a retention structure comprising an
extension protruding outward from the container to couple to the
sclera and the conjunctiva, in accordance with variations described
herein;
[0110] FIG. 6A-2 shows a therapeutic device as in FIG. 6A-1
comprising a rounded distal end, in accordance with variations
described herein;
[0111] FIG. 6B shows a rigid porous structure configured for
sustained release with a device as in FIG. 6A-1, in accordance with
variations described herein;
[0112] FIG. 6B-1 shows interconnecting channels extending from a
first side to a second side of the porous structure as in FIG. 6B,
in accordance with variations described herein;
[0113] FIG. 7 shows a therapeutic device coupled to an injector
that removes material from the device and injects therapeutic agent
into the device, according to variations described herein;
[0114] FIG. 8A shows an apparatus comprising a first container
having the formulation of therapeutic agent and the second
container comprising a syringe having particles of an erodible
material loaded thereon to generate a proton of an acid when mixed
with the formulation, in accordance with variations described
herein;
[0115] FIG. 8B shows the first and second containers as in FIG. 8A
used to prepare the formulation of therapeutic agent prior to
injection, in accordance with variations described herein;
[0116] FIG. 8C shows an apparatus comprising a first container
having a commercially available formulation of therapeutic agent
and the second container comprising a syringe having one or more
of, a stabilizer, a binding agent comprising porous particles, an
erodible material to generate a proton of an acid, in accordance
with variations described herein;
[0117] FIG. 8D shows the first and second containers as in FIG. 8C
used to prepare the formulation of therapeutic agent prior to
injection, in accordance with variations described herein; and
[0118] FIG. 9 shows calibration curves of fluorescein serially
diluted in PBS or PBS containing 100 or 1000 ug/mL BSA, in
accordance with variations described herein.
DETAILED DESCRIPTION
[0119] Although specific reference is made to the delivery of
macromolecules comprising antibodies or antibody fragments to the
posterior segment of the eye, a variety of implementations
described herein can be used to deliver many therapeutic agents to
many tissues of the body. For example, variations described herein
can be used to deliver therapeutic agent for an extended period to
one or more of the following tissues: intravascular, intra
articular, intrathecal, pericardial, intraluminal, and gut.
[0120] Various implementations as described herein are suitable for
combination in accordance with U.S. patent application Ser. No.
12/696,678 filed on Jan. 29, 2010, entitled "POSTERIOR SEGMENT DRUG
DELIVERY," published on Oct. 7, 2010 as U.S. Pub. No. 2010/0255061,
the full disclosure of which is incorporated herein by
reference.
[0121] Variations described herein provide sustained release of a
therapeutic agent to the posterior segment of the eye or the
anterior segment of the eye, or combinations thereof. Therapeutic
amounts of a therapeutic agent can be released into the vitreous
humor of the eye, such that the therapeutic agent can be
transported by at least one of diffusion or convection to the
retina or other ocular tissue, such as the choroid or ciliary body,
for therapeutic effect.
[0122] The formulations as described herein can be combined with
many therapeutic agents, and may comprise one or more components of
commercially available formulations. The stabilizers and erodible
particles as described herein can be combined with commercially
available formulations, for example, so as to decrease degradation
of the therapeutic agent injected into the device.
[0123] The formulations as described herein can be combined in many
ways and can be used with one or more of many therapeutic devices
so as to provide therapeutic amounts for an extended time. The
formulation can be provided within a therapeutic device prior to
implantation, and can be placed in the therapeutic device when the
device has been implanted, for example.
[0124] The formulation can be placed in a therapeutic device placed
in the eye in many ways. Many variations as described herein are
particularly well suited for injection into a therapeutic device
implanted in the body. Alternatively or in combination, the
formulation can be placed in a container and the container placed
in the therapeutic device implanted in the eye, for example.
[0125] As used herein, the release rate index encompasses (PA/FL)
where P comprises the porosity, A comprises an effective area, F
comprises a curve fit parameter corresponding to an effective
length and L comprises a length or thickness of the porous
structure. The units of the release rate index (RRI) comprise units
of mm unless indicated otherwise and can be determined in
accordance with the teachings described hereon.
[0126] As used herein, sustained release encompasses release of
therapeutic amounts of an active ingredient of a therapeutic agent
for an extended period of time. The sustained release may encompass
first order release of the active ingredient, zero order release of
the active ingredient, or other kinetics of release such as
intermediate to zero order and first order, or combinations
thereof.
[0127] As used herein, a therapeutic agent referred to with a
trademark encompasses the active ingredient available under the
trademark and derivatives thereof.
[0128] As used herein, similar numerals indicate similar structures
and/or similar steps.
[0129] As used herein, Trehalose encompasses an alpha-linked
disaccharide formed by an .alpha.,.alpha.-1,1-glucoside bond
between two .alpha.-glucose units. Trehalose can be referred to as
mycose or tremalose.
[0130] As used herein, the critical micelle concentration (CMC)
encompasses the concentration of surfactants above which micelles
are spontaneously formed.
[0131] As used herein, a surfactant encompasses a wetting agent
capable of lowering the surface tension of water.
[0132] As used herein, scientific notation of the form
a.times.10.sup.-b can be expressed as aE-b (or ae-b) with E
notation known to persons of ordinary skill in the art familiar
with the use of computer programs, calculators and
spreadsheets.
[0133] The therapeutic agent may be contained within a chamber of a
container, for example within a reservoir comprising the container
and chamber. The therapeutic agent may comprise a formulation such
as solution of therapeutic agent, a suspension of a therapeutic
agent or a dispersion of a therapeutic agent, for example. Examples
of therapeutic agents suitable for use in accordance with
variations of the therapeutic device are described herein, for
example with reference to Table 1A below and elsewhere.
[0134] Examples of known surfactants suitable for combination with
therapeutic agents in accordance with variations as described
herein can be found in Table 1B and at one or more locations on the
world wide web, such as at the known website Wikipedia
(en.wikipedia.org/wiki/Surfactant). The surfactant may comprise an
amount sufficient so as to form micelles comprising a reservoir of
stabilizer.
[0135] The surfactant may comprise a head and a tail. The
surfactant may be categorized according to a head of the surfactant
and a tail of the surfactant. The tail may comprise one or more of
a hydrocarbon chain, an alkyl ether chain, a fluorocarbon chain or
a siloxane chain. The hydrocarbon chain may comprise one or more of
aromatic hydrocarbons (arenes), alkanes (alkyl), alkenes,
cycloalkanes, or alkyne-based chains. The alkyl ether chain may
comprise one or more of: ethoxylated surfactants, such as
polyethylene oxides inserted so to increase the hydrophilic
character of a surfactant; or propoxylated surfactants:
polypropylene oxides inserted to increase the lipophilic character
of a surfactant. The fluorocarbon chain may comprise
fluorosurfactants. The siloxane chain may comprise siloxane
surfactants. Surfactant can have one or two tails (double chained
surfactants).
[0136] A surfactant may be categorized by the presence of formally
charged groups in its head. A non-ionic surfactant may have no
charge groups in the head. The head of an ionic surfactant can
carry a net charge. When the charge is negative, the surfactant can
be more specifically called anionic. When the charge is positive,
the surfactant can be called cationic. When a surfactant contains a
head with two oppositely charged groups, the surfactant can be
referred to as zwitterionic.
[0137] Examples of known polyscahharides that may be combined with
the therapeutic agent in accordance with variations described
herein are as listed in Table 1C, and can be found on the World
Wide Web (en.wikipedia.org/wiki/Polysaccharide).
[0138] The therapeutic agent may comprise a macromolecule, for
example an antibody or antibody fragment. The therapeutic
macromolecule may comprise a VEGF inhibitor, for example the active
ingredient ranibizumab of Lucentis.TM. and derivatives thereof. The
VEGF (Vascular Endothelial Growth Factor) inhibitor can cause
regression of the abnormal blood vessels and improvement of vision
when released into the vitreous humor of the eye. Examples of VEGF
inhibitors include Lucentis.TM., Avastin.TM., Macugen.TM., and VEGF
Trap that can be provided with formulations in accordance with
variations described herein.
[0139] The therapeutic agent may comprise small molecules such as
of a corticosteroid and analogues thereof. For example, the
therapeutic corticosteroid may comprise one or more of
trimacinalone, trimacinalone acetonide, dexamethasone,
dexamethasone acetate, fluocinolone, fluocinolone acetate, or
analogues thereof. Alternatively or in combination, the small
molecules of therapeutic agent may comprise a tyrosine kinase
inhibitor comprising one or more of axitinib, bosutinib, cediranib,
dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib,
nilotinib, semaxanib, sunitinib, toceranib, vandetanib, or
vatalanib, for example.
[0140] The therapeutic agent may comprise an anti-VEGF therapeutic
agent. Anti-VEGF therapies and agents can be used in the treatment
of certain cancers and in age-related macular degeneration.
Examples of anti-VEGF therapeutic agents suitable for use in
accordance with the variations described herein include one or more
of monoclonal antibodies such as bevacizumab (Avastin.TM.) or
antibody derivatives such as ranibizumab (Lucentis.TM.), or small
molecules that inhibit the tyrosine kinases stimulated by VEGF such
as lapatinib (Tykerb.TM.), sunitinib (Sutent.TM.), sorafenib
(Nexavar.TM.), axitinib, or pazopanib.
[0141] The therapeutic agent may comprise a therapeutic agent
suitable for treatment of dry AMD such as one or more of
Sirolimus.TM. (Rapamycin), Copaxone.TM. (Glatiramer Acetate),
Othera.TM., Complement C5aR blocker, Ciliary Neurotrophic Factor,
Fenretinide or Rheopheresis.
[0142] The therapeutic agent may comprise a therapeutic agent
suitable for treatment of wet AMD such as one or more of REDD14NP
(Quark), Sirolimus.TM. (Rapamycin), ATG003; Regeneron.TM. (VEGF
Trap) or complement inhibitor (POT-4).
[0143] The therapeutic agent may comprise a kinase inhibitor such
as one or more of bevacizumab (monoclonal antibody), BIBW 2992
(small molecule targeting EGFR/Erb2), cetuximab (monoclonal
antibody), imatinib (small molecule), trastuzumab (monoclonal
antibody), gefitinib (small molecule), ranibizumab (monoclonal
antibody), pegaptanib (small molecule), sorafenib (small molecule),
dasatinib (small molecule), sunitinib (small molecule), erlotinib
(small molecule), nilotinib (small molecule), lapatinib (small
molecule), panitumumab (monoclonal antibody), vandetanib (small
molecule) or E7080 (targeting VEGFR2/VEGFR2, small molecule
commercially available from Esai, Co.)
[0144] The amount of therapeutic agent within the therapeutic
device may comprise from about 0.01 mg to about 100 mg, for example
Lucentis.TM., so as to provide therapeutic amounts of the
therapeutic agent for the extended time, for example at least 30
days. The extended time may comprise at least 90 days or more, for
example at least 180 days or for example at least 1 year, at least
2 years or at least 3 years or more. The target threshold
therapeutic concentration of a therapeutic agent such as
Lucentis.TM. in the vitreous may comprise at least a therapeutic
concentration of 0.1 ug/mL. For example the target threshold
concentration may comprise from about 0.1 ug/mL to about 5 ug/mL
for the extended time, where the upper value is based upon
calculations shown in Example 9 of U.S. patent application Ser. No.
12/696,678 filed on Jan. 29, 2010, entitled "POSTERIOR SEGMENT DRUG
DELIVERY," published on Oct. 7, 2010 as U.S. Pub. No. 2010/0255061,
the full disclosure of which has been previously incorporated by
reference. The target threshold concentration is drug dependent and
thus may vary for other therapeutic agents.
[0145] The delivery profile may be configured in many ways to
obtain a therapeutic benefit from the sustained release device. For
example, an amount of the therapeutic agent may be inserted into
the container at monthly intervals so as to ensure that the
concentration of therapeutic device is above a safety protocol or
an efficacy protocol for the therapeutic agent, for example with
monthly or less frequent injections into the container. The
sustained release can result in an improved delivery profile and
may result in improved results. For example, the concentration of
therapeutic agent may remain consistently above a threshold amount,
for example 0.1 ug/mL, for the extended time.
[0146] The insertion method may comprise inserting a dose into the
container of the therapeutic device. For example, a single
injection of Lucentis.TM. may be injected into the therapeutic
device.
[0147] The duration of sustained delivery of the therapeutic agent
may extend for twelve weeks or more, for example four to six months
from a single insertion of therapeutic agent into the device when
the device is inserted into the eye of the patient.
[0148] The therapeutic agent may be delivered in many ways so as to
provide a sustained release for the extended time. For example, the
therapeutic device may comprise a therapeutic agent and a binding
agent. The binding agent may comprise small particles configured to
couple releasably or reversibly to the therapeutic agent, such that
the therapeutic agent is released for the extended time after
injection into the vitreous humor. The particles can be sized such
that the particles remain in the vitreous humor of the eye for the
extended time.
[0149] The therapeutic agent may be delivered with a device
implanted in the eye. For example, the drug delivery device can be
implanted at least partially within the sclera of the eye, so as to
couple the drug delivery device to the sclera of the eye for the
extended period of time. The therapeutic device may comprise a drug
and a binding agent. The drug and binding agent can be configured
to provide the sustained release for the extended time. A membrane
or other diffusion barrier or mechanism may be a component of the
therapeutic device to release the drug for the extended time.
[0150] The lifetime of the therapeutic device and number of
injections can be optimized for patient treatment. For example, the
device may remain in place for a lifetime of 30 years, for example
with AMD patients from about 10 to 15 years. For example, the
device may be configured for an implantation duration of at least
two years, with 8 injections (once every three months) for
sustained release of the therapeutic agent over the two year
duration. The device may be configured for implantation of at least
10 years with 40 injections (once every three months) for sustained
release of the therapeutic agent.
[0151] The therapeutic device can be refilled in many ways. For
example, the therapeutic agent can be refilled into the device in
the physician's office.
[0152] The therapeutic device may comprise many configurations and
physical attributes, for example the physical characteristics of
the therapeutic device may comprise at least one of a drug delivery
device with a suture, positioning and sizing such that vision is
not impaired, and biocompatible material. The device may comprise a
reservoir capacity from about 0.005 cc to about 0.2 cc, for example
from about 0.01 cc to about 0.1 cc, and a device volume of no more
than about 2 cc. A vitrectomy may be performed for device volumes
larger than 0.1 cc. The length of the device may not interfere with
the patient's vision and can be dependent on the shape of the
device, as well as the location of the implanted device with
respect to the eye. The length of the device may also depend on the
angle in which the device is inserted. For example, a length of the
device may comprise from about 4 to 6 mm. Since the diameter of the
eye is about 24 mm, a device extending no more than about 6 mm from
the sclera into the vitreous may have a minimal effect on patient
vision.
[0153] Variations may comprise many combinations of implanted drug
delivery devices. The therapeutic device may comprise a drug and
binding agent. The device may also comprise at least one of a
membrane, an opening, a diffusion barrier, a diffusion mechanism so
as to release therapeutic amounts of therapeutic agent for the
extended time.
[0154] FIG. 1 shows an eye 10 suitable for incorporation of the
therapeutic device. The eye has a cornea 12 and a lens 22
configured to form an image on the retina 26. The cornea can extend
to a limbus 14 of the eye, and the limbus can connect to a sclera
24 of the eye. A conjunctiva 16 of the eye can be disposed over the
sclera. The lens can accommodate to focus on an object seen by the
patient. The eye has an iris 18 that may expand and contract in
response to light. The eye also comprises a choroid 28 disposed
between the sclera 24 and the retina 26. The retina comprises the
macula 32. The eye comprises a pars plana 25, which comprises an
example of a region of the eye suitable for placement and
retention, for example anchoring, of the therapeutic device 100 as
described herein. The pars plana region may comprise sclera and
conjunctiva disposed between the retina and cornea. The therapeutic
device can be positioned so as to extend from the pars plana region
into the vitreous humor 30 to release the therapeutic agent. The
therapeutic agent can be released into the vitreous humor 30, such
that the therapeutic agent arrives at the retina and choroids for
therapeutic effect on the macula. The vitreous humor of the eye
comprises a liquid disposed between the lens and the retina. The
vitreous humor may comprise convection currents to deliver the
therapeutic agent to the macula.
[0155] FIG. 1A-1 shows a therapeutic device 100 implanted at least
partially within the sclera 24 of the eye 10 as in FIG. 1. The
therapeutic device may comprise a retention structure, for example
a protrusion, to couple the device to the sclera. The therapeutic
device may extend through the sclera into vitreous humor 30, such
that the therapeutic device can release the therapeutic agent into
the vitreous humor.
[0156] FIGS. 1A-1-1 and 1A-1-2 shows a therapeutic device 100
implanted under the conjunctiva 16 and extending through the sclera
24 to release a therapeutic agent 110 into vitreous humor 30 of the
eye 10 so as to treat the retina of the eye. The therapeutic device
100 may comprise a retention structure 120 such as a smooth
protrusion configured for placement along the sclera and under the
conjunctiva, such that the conjunctiva can cover the therapeutic
device and protect the therapeutic device 100. When the therapeutic
agent 110 is inserted into the device 100, the conjunctiva may be
lifted away, incised, or punctured with a needle to access the
therapeutic device. The eye may comprise an insertion of the tendon
27 of the superior rectus muscle to couple the sclera of the eye to
the superior rectus muscle. The device 100 may be positioned in
many locations of the pars plana region, for example away from
tendon 27 and one or more of posterior to the tendon, under the
tendon, or with nasal or temporal placement of the therapeutic
device.
[0157] While the implant can be positioned in the eye in many ways,
work in relation to variations suggests that placement in the pars
plana region can release therapeutic agent into the vitreous to
treat the retina, for example therapeutic agent comprising an
active ingredient composed of large molecules.
[0158] Therapeutic agents 110 suitable for use with device 100
includes many therapeutic agents, for example as listed in Table
1A, herein below. The therapeutic agent 110 of device 100 may
comprise one or more of an active ingredient of the therapeutic
agent, a formulation of the therapeutic agent, components of a
formulation of the therapeutic agent, a physician prepared
formulation of therapeutic agent, or a pharmacist prepared
formulation of the therapeutic agent. The therapeutic agent may be
referred to with generic name or a trademark, for example as shown
in Table 1A.
[0159] The therapeutic device 100 can be implanted in the eye to
treat the eye for as long as is helpful and beneficial to the
patient. For example, the device can be implanted for at least
about 5 years, such as permanently for the life of the patient.
Alternatively or in combination, the device can be removed when no
longer helpful or beneficial for treatment of the patient.
[0160] FIG. 1A-2 shows structures of therapeutic device 100
configured for placement in an eye as in FIGS. 1A-1, 1A-1-1 and
1A-1-2. The device may comprise retention structure 120 to couple
the device 100 to the sclera, for example a protrusion disposed on
a proximal end of the device. The device 100 may comprise a
container 130 affixed to the retention structure 120. An active
ingredient, for example therapeutic agent 110, can be contained
within a reservoir 140, for example a chamber 132 defined by a
container 130 of the device. The container 130 may comprise a
porous structure 150 comprising a porous material 152, for example
a porous glass frit 154, and a barrier 160 to inhibit release of
the therapeutic agent, for example non-permeable membrane 162. The
non-permeable membrane 162 may comprise a substantially
non-permeable material 164. The non-permeable membrane 162 may
comprise an opening 166 sized to release therapeutic amounts of the
therapeutic agent 110 for the extended time. The porous structure
150 may comprise a thickness 150T and pore sizes configured in
conjunction with the opening 166 so as to release therapeutic
amounts of the therapeutic agent for the extended time. The
container 130 may comprise reservoir 140 having a chamber with a
volume 142 sized to contain a therapeutic quantity of the
therapeutic agent 110 for release over the extended time. The
device may comprise a needle stop 170. Proteins in the vitreous
humor may enter the device and compete for adsorption sites on the
porous structure and thereby may contribute to the release of
therapeutic agent. The therapeutic agent 110 contained in the
reservoir 140 can equilibrate with proteins in the vitreous humor,
such that the system is driven towards equilibrium and the
therapeutic agent 110 is released in therapeutic amounts.
[0161] The non-permeable material such as the non-permeable
membrane 162, the porous material 152, the reservoir 140, and the
retention structure 120, may comprise many configurations to
deliver the therapeutic agent 110. The non-permeable membrane 162
may comprise an annular tube joined by a disc having at least one
opening formed thereon to release the therapeutic agent. The porous
material 152 may comprise an annular porous glass frit 154 and a
circular end disposed thereon. The reservoir 140 may be
shape-changing for ease of insertion; i.e., it may assume a thin
elongated shape during insertion through the sclera and then assume
an extended, ballooned shape, once it is filled with therapeutic
agent.
[0162] The porous structure 150 can be configured in many ways to
release the therapeutic agent in accordance with an intended
release profile. The porous structure may comprise a single hole or
a plurality of holes extending through a barrier material such as a
rigid plastic or a metal. Alternatively or in combination, the
porous structure may comprise a porous structure having a plurality
of openings on a first side facing the reservoir and a plurality of
openings on a second side facing the vitreous humor, with a
plurality of interconnecting channels disposed therebetween so as
to couple the openings of the first side with the openings of the
second side, for example a sintered rigid material. The porous
structure 150 may comprise one or more of a permeable membrane, a
semi-permeable membrane, a material having at least one hole
disposed therein, nano-channels, nano-channels etched in a rigid
material, laser etched nano-channels, a capillary channel, a
plurality of capillary channels, one or more tortuous channels,
tortuous microchannels, sintered nano-particles, an open cell foam
or a hydrogel such as an open cell hydrogel.
[0163] FIG. 1A-2-1 shows therapeutic device 100 loaded into an
insertion cannula 210 of an insertion apparatus 200, in which the
device 100 comprises an elongate narrow shape for insertion into
the sclera, and in which the device is configured to expand to a
second elongate wide shape for retention at least partially in the
sclera.
[0164] FIG. 1A-2-2 shows a therapeutic device 100 comprising
reservoir 140 suitable for loading in a cannula, in which the
reservoir 140 comprises an expanded configuration when placed in
the eye.
[0165] FIG. 1B shows therapeutic device 100 placed in an eye as in
FIG. 1A-1 and 1A-1-1. The device comprises retention structure 120
to couple to the sclera, for example flush with the sclera, and the
barrier 160 comprises a tube 168. An active ingredient 112
comprising the therapeutic agent 110 is contained within tube 168
comprising non-permeable material 164. A porous structure 150
comprising a porous material 152 is disposed at the distal end of
the tube 168 to provide a sustained release of the therapeutic
agent at therapeutic concentrations for the extended period. The
non-permeable material 164 may extend distally around the porous
material 152 so as to define an opening to couple the porous
material 152 to the vitreous humor when the device is inserted into
the eye.
[0166] FIG. 1C shows a therapeutic device configured for placement
in an eye as in FIG. 1A-1 and 1A-1-1. An injectable formulation 190
of therapeutic agent 110 can be placed in therapeutic device 100
prior to placement in the eye. The formulation 190 can be
injectable and may comprise therapeutic agent 110, a stabilizer
192, a binding agent 194 and erodible particles 196. The
formulation 190 comprising stabilizer 192 and therapeutic agent 110
may be loaded into device 100 by injection into the device through
an access port 180. The device 100 may comprise binding, leak, and
barrier functions to deliver the therapeutic agent for the extended
time. The stabilizer 192 and therapeutic agent 110 can be aspirated
to replace the stabilizer and therapeutic agent. The stabilizer can
be at least one of flushed or replaced when at least majority of
the therapeutic agent has been released, such that additional
therapeutic agent can be delivered from a second, injected
formulation comprising the stabilizer and the therapeutic agent. A
membrane 195 can be disposed over the periphery of the therapeutic
device 100. The membrane 195 may comprise methylcellulose,
regenerated cellulose, cellulose acetate, nylon, polycarbonate,
poly(tetrafluoroethylene) (PTFE), polyethersulfone, and
polyvinylidene difluoride (PVDF). The therapeutic device may
comprise barrier 160 shaped such that opening 166 comprises an exit
port. The therapeutic agent may be released through at least one of
a diffusion mechanism or convection mechanism. The number, size,
and configuration of exit ports may determine the release rate of
the therapeutic agent. The exit port may comprise a convection
port, for example at least one of an osmotically driven convection
port or a spring driven convection port. The exit port may also
comprise a tubular path to which the therapeutic agent may
temporarily attach, and then be released under certain physical or
chemical conditions.
[0167] FIG. 1C-A shows at least one exit port 167, the exit port
can be disposed on the device 100 to allow liquid to flow from
inside the device outward, for example when fluid is injected into
an injection port 182 of the device or when an insert such as a
glass frit is inserted into the device. The therapeutic device may
comprise an access port 180 for injection and/or removal, for
example a septum. Additionally or in the alternative, when the
therapeutic device is refilled, the contents of the device may be
flushed into the vitreous of the eye.
[0168] The access port 180 may be sized to receive an insert
comprising a container having the therapeutic agent therein. For
example, the porous structure 150 may comprise a container to
contain a formulation 190 of the therapeutic agent as described
herein, in which the container comprising porous structure 150 can
be removed from the device 100 and replaced.
[0169] FIG. 1C-B shows a syringe being filled with a formulation
190 comprising therapeutic agent 110 and one or more of stabilizer
192, binding agent 194 or particles 196, for injection into the
therapeutic device. The needle 189 coupled to syringe 188 of
injector 187 can be used to draw formulation 190 comprising
therapeutic agent 110, stabilizer 192, binding agent 194 and
particles 196 from a container HOC. The container 110C may comprise
a commercially available container, such as a bottle with a septum,
a single dose container, or a container suitable for mixing
formulations. A quantity 110V of therapeutic agent 110 can be drawn
into injector 187 for injection into the therapeutic device 100
positioned within the eye. The quantity 110V may comprise a
predetermined quantity, for example based on the volume of the
container of the therapeutic device 110 and an intended injection
into the vitreous humor. For example, the quantity 110V may exceed
the volume of the reservoir container so as to inject a first
portion of quantity 110V into the vitreous humor through the
therapeutic device and to contain a second portion of quantity 110V
within the reservoir container of the therapeutic device 110.
Container 110C may comprise a formulation 190 of the therapeutic
agent 110.
[0170] The formulation 190 may comprise formulations of therapeutic
agent as described herein comprising therapeutic agent 110 and one
or more of stabilizer 192, binding agent 194 or particles 196, for
example therapeutic agents as described herein and with reference
to Table 1A. The formulation 190 may comprise components of a
concentrated or diluted formulation of a commercially available
therapeutic agent, for example Avastin.TM.. The osmolarity and
tonicity of the vitreous humor can be within a range from about 290
to about 320 mOsm, for example, and the formulation can be
substantially isotonic with one or more fluids of the body and
within a range from about 250 to about 250 mOsm. For example, a
formulation of Avastin.TM. may be diluted so as to comprise a
formulation having an osmolarity and tonicity substantially similar
to the osmolarity and tonicity of the vitreous humor, for example
within a range from about 280 to about 340, for example about 300
mOsm. While the injectable formulation 190 comprising therapeutic
agent 110, stabilizer 192, binding agent 194 and particles 196 may
comprise an osmolarity and tonicity substantially similar to the
vitreous humor, the formulation 190 may comprise a hyper osmotic
solution relative to the vitreous humor or a hypo osmotic solution
relative to the vitreous humor. The formulation and osmolarity of
the therapeutic agent can be determined empirically to provide
release of therapeutic agent for an extended time.
[0171] The formulation 190 may comprise components of a
commercially available formulation such as Avastin.TM. or
Lucentis.TM. combined with one or more of the stabilizer, the
erodible particles, the surfactant, or the micelles as described
herein, for example.
[0172] For example, in the United States, Avastin.TM. (bevacizumab)
is approved as an anticancer drug and in clinical trials are
ongoing for AMD. For cancer, the commercial solution is a pH 6.2
solution for intravenous infusion. Avastin.TM. is supplied in 100
mg and 400 mg preservative-free, single-use vials to deliver 4 mL
or 16 mL of Avastin.TM. (25 mg/mL). The 100 mg product is
formulated in 240 mg .alpha.,.alpha.-trehalose dihydrate, 23.2 mg
sodium phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate
(dibasic, anhydrous), 1.6 mg polysorbate 20, and Water for
Injection, USP. The 400 mg product is formulated in 960 mg
.alpha.,.alpha.-trehalose dihydrate, 92.8 mg sodium phosphate
(monobasic, monohydrate), 19.2 mg sodium phosphate (dibasic,
anhydrous), 6.4 mg polysorbate 20, and Water for Injection, USP.
The commercial formulations are diluted in 100 mL of 0.9% sodium
chloride before administration and the amount of the commercial
formulation used varies by patient and indication. Based on the
teachings described herein, formulations of Avastin.TM. can be
determined to inject into therapeutic device 100. In Europe, the
Avastin.TM. formulation can be substantially similar to the
formulation of the United States.
[0173] For example, in the United States, there are two forms of
Triamcinolone used in injectable solutions, the acetonide and the
hexacetonide. The acetamide is approved for intravitreal injections
in the U.S. The acetamide is the active ingredient in TRIVARIS
(Allergan), 8 mg triamcinolone acetonide in 0.1 mL (8% suspension)
in a vehicle containing w/w percents of 2.3% sodium hyaluronate;
0.63% sodium chloride; 0.3% sodium phosphate, dibasic; 0.04% sodium
phosphate, monobasic; and water, pH 7.0 to 7.4 for injection. The
acetamide is also the active ingredient in Triesence.TM. (Alcon), a
40 mg/ml suspension.
[0174] Osmolarity for these formulations can be determined. The
degree of dissociation of the active ingredient in solution can be
determined and used to determine differences of osmolarity from the
molarity in these formulations. For example, considering at least
some of the formulations may be concentrated (or suspensions), the
molarity can differ from the osmolarity.
[0175] The formulation of therapeutic agent injected into
therapeutic device 100 may comprise many known formulations of
therapeutic agents modified in accordance with variations described
herein, and the formulation therapeutic agent may comprise an
osmolarity suitable for release for an extended time from device
100. Table 2 shows examples of osmolarity (Osm) of saline and some
of the commercially formulations of Table 1A can be modified in
accordance with the variations described herein.
TABLE-US-00001 TABLE 2 Summary of Calculations Description Osm (M)
Saline (0.9%) 0.308 Phosphate Buffered Saline (PBS) 0.313 Lucentis
.TM. 0.289 Avastin .TM. 0.182 Triamcinolone Acetonide
(Trivaris-Allergan) 0.342 Triamcinolone Acetonide
(Triessence-Alcon) Isotonic* Triamcinolone Acetonide
(Kenalog-Apothecon) Isotonic* *As described in package insert
[0176] The vitreous humor of the eye comprises an osmolarity of
about 290 mOsm to about 320 mOsm. Formulations of therapeutic agent
having an osmolarity from about 280 mOsm to about 340 mOsm are
substantially isotonic and substantially iso-osmotic with respect
to the vitreous humor of the eye. Although the formulations listed
in Table 2 are substantially iso-osmotic and isotonic with respect
to the vitreous of the eye and suitable for injection into the
therapeutic device, the formulation of the therapeutic agent
injected into the therapeutic device can be hypertonic
(hyper-osmotic) or hypotonic (hypo-osmotic) with respect to the
tonicity and osmolarity of the vitreous. Work in relation to
variations suggests that a hyper-osmotic formulation may release
the active ingredient of the therapeutic agent into the vitreous
somewhat faster initially when the solutes of the injected
formulation equilibrate with the osmolatiry of the vitreous, and
that a hypo-osmotic formulation such as Avastin.TM. may release the
active ingredient of the therapeutic agent into the vitreous
somewhat slower initially when the solutes of the injected
formulation equilibrate with the eye. The appropriate reservoir
chamber volume and porous structure for a formulation of
therapeutic agent disposed in the reservoir chamber can be
determined so as to release therapeutic amounts of the therapeutic
agent for an extended time and to provide therapeutic
concentrations of therapeutic agent in the vitreous within a range
of therapeutic concentrations that is above the minimum inhibitory
concentration for the extended time.
[0177] FIG. 2 shows an access port 180 suitable for incorporation
with the therapeutic device 100. The access port 180 may be
combined with the therapeutic devices described herein. The access
port may be disposed on a proximal end of the device. The access
port 180 may comprise an opening formed in the retention structure
120 with a penetrable barrier 184 comprising a septum 186 disposed
thereon. The penetrable barrier can receive the needle 189 sized to
pass the formulation 190 as described herein. The access port may
180 be configured for placement under the conjunctiva 16 of the
patient and above the sclera 24.
[0178] FIG. 3A shows components of formulation 190 comprising
therapeutic agent, stabilizer 192 corresponding to the therapeutic
agent, reversible binding agent 194 and erodible material 196. The
stabilizer 192 may comprise at least about 20% of the weight of the
therapeutic agent, such that diffusion of the stabilizer
corresponds at least partially to diffusion of the therapeutic
agent. The reversible binding agent 194 may comprise a plurality of
particles of binding agent. The erodible material 196 may comprise
a plurality of particles.
[0179] The stabilizer 192 can interact with the therapeutic agent
110 in one or more of many ways so as to decrease degradation of
the therapeutic agent. For example, the therapeutic agent 110 may
comprise protein such as a Fab antibody fragment or a derivative
thereof, and the stabilizer 192 may comprise one or more
hydrophilic functional groups 192F that promote protein
stabilization by a co-solvent effect. Alternatively or in
combination, the stabilizer 192 may form a complex 192C with the
therapeutic agent 110.
[0180] The stabilizers having the molecular weights as described
herein can be particularly well suited to provide stabilization of
the therapeutic agent comprising protein with the co-solvent
effect, for example co-solvent stabilization of ranibizumab
protein. A protein solvent effect as described by Arakawa et al.,
Adv Drug Delivery Reviews, 10 (1993) 1-28, can be modified and/or
combined in accordance with variations as described herein. In many
variations, there can be a decreased amount of the stabilizing
co-solute in the immediate vicinity of the therapeutic agent
comprising protein relative to bulk solution such that the
therapeutic agent comprising protein is preferentially hydrated.
For example, the co-solutes can be preferentially excluded from
contact with the surface of the therapeutic agent comprising
protein so as to preferentially hydrate the therapeutic agent
comprising protein. Although the exclusion can be entropically
unfavorable, the thermodynamic penalty for exclusion can be even
higher for protein in the denatured state due to the larger exposed
surface area of the denatured protein. The lower penalty for the
native versus denatured therapeutic agent comprising protein can
result in stabilization of the therapeutic agent comprising
protein, for example with the high molecular weight stabilizers of
at least 2 k Daltons as described herein. Similar stabilization may
be provided with micelles comprising stabilizer having hydrophilic
functional groups as described herein, for example.
[0181] The stabilizer 192 may comprise one or more functional
groups 192F, for example one or more hydroxyl groups, so as to form
a complex 192C with the therapeutic agent 110. The dynamics of
complex formation and dissociation may be slowed down when the
stabilizer has more than one functional group interacting with the
therapeutic agent at the same time. Hence, larger molecular weight
stabilizers may have multiple interactions, which may slow the
diffusion and depletion of stabilizer present in the device
reservoir, so as to provide a formulation having improved
stability.
[0182] The binding agent 194 may comprise a plurality of binding
sites to bind reversibly the therapeutic agent 110. The reversible
binding 194B can be pH sensitive. The binding agent 194 may
comprise a plurality of channels 194C and an outer surface 194S.
The plurality of channels 194C can extend from an opening 1940 of
the surface 194S substantially through the particle of the binding
agent 194. The therapeutic agent 110 can be bound reversibly to an
inner surface of channel 194C or outer surface 194S. The particle
of binding agent 194 may comprise a resin having derivatized inner
and outer surfaces so as to bind reversibly to therapeutic agent
110. The formulation 190 may comprise a plurality of the particles
of binding agent and may comprise one or more of a suspension or a
slurry.
[0183] The erodible material 196 may comprise a plurality of
particles of the erodible material. The erodible material 196 may
comprise an erodible polymer such as one or more of PLA, PGA or
PLA/PGA copolymer (hereinafter "PLGA"). The polymer can erode with
hydrolysis so as to provide a proton 196H of an acid 196A. The
hydrolysis may comprise hydrolysis of ester linkages so as to
provide one proton per linkage hydrolyzed.
[0184] FIG. 3B1 shows a stabilizer as in FIG. 3A. The stabilizer
may comprise one or more of an alcohol, a polyol, a phenol, a
carbohydrate, a sugar (sucrose, lactose, and glucose), amino acids
(glycine, alanine, and proline), or amines (betaine and
trimethylamine N-oxide), for example. The stabilizer may comprise a
molecular weight corresponding to the therapeutic agent, for
example at least about 20% of the molecular weight of the
therapeutic agent. The molecular weight can be sufficient such that
a portion of the stabilizer remains in the device 100 when a
portion of the therapeutic agent is released so as to stabilize a
remaining portion of the therapeutic agent. The stabilizer 192 may
comprise a high molecular weight polymer 192P, for example at least
about 2 k Daltons. The stabilizer may comprise one or more forms of
cellulose (e.g., carboxymethylcellulose, hydroxyethyl cellulose,
hydroxypropyl cellulose, hydroxypropyl methylcellulose,
methylcellulose), chitin (e.g., chitosan), other oligosaccharides
and polysaccharides, or polymeric forms of amino acids.
[0185] The diffusion constant of the stabilizer can be determined,
for example based on an estimate of hydrodynamic radius
corresponding to the cube root of the molecular weight as described
herein.
[0186] Table ZZZ shows diffusion co-efficients and estimates of
device half-life relative to Ranibizumab.
TABLE-US-00002 Diffusion relative to Ranibizumab Equiv diameter
assumes unit density and is Diff Coeff the diameter Compound MW
Temp C. (cm{circumflex over ( )}2/s) per molecule Ranibizumab
48,000 37 1.0E-06 % In mW/ Device Half- Equiv Equiv device Example
(Ran Diff Coeff life relative to volume diameter at TA Compound MW
MW) D/(Ran D) (cm{circumflex over ( )}2/s) Ranibiz. (nm{circumflex
over ( )}3) (nm) Half-life Histidine 156 0.003 6.75 6.8E-06 0.15
0.3 0.8 0.9 Trehalose 378 0.008 5.03 5.0E-06 0.20 0.6 1.1 3.1 500
0.010 4.58 4.6E-06 0.22 0.8 1.2 4.2 1000 0.021 3.63 3.6E-06 0.28
1.7 1.5 8.1 Polysorbate 1227 0.026 3.39 3.4E-06 0.29 2.0 1.6 9.5 20
2000 0.042 2.88 2.9E-06 0.35 3.3 1.9 13.5 5000 0.104 2.13 2.1E-06
0.47 8.3 2.5 22.9 10000 0.208 1.69 1.7E-06 0.59 16.6 3.2 31.1 20000
0.417 1.34 1.3E-06 0.75 33.2 4.0 39.5 30,000 0.625 1.17 1.2E-06
0.85 49.8 4.6 44.5 Ranibizumab 48,000 1.000 1.00 1.0E-06 1.00 79.7
5.3 50.0 50,000 1.042 0.99 9.9E-07 1.01 83.0 5.4 50.5 BSA 66,000
1.375 0.90 9.0E-07 1.11 109.6 5.9 53.6 100,000 2.083 0.78 7.8E-07
1.28 166.1 6.8 58.1 Bevacizumab 149,000 3.104 0.69 6.9E-07 1.46
247.4 7.8 62.2 200,000 4.167 0.62 6.2E-07 1.61 332.1 8.6 65.0
500,000 10.417 0.46 4.6E-07 2.18 830.3 11.7 72.8 1,000,000 20.833
0.36 3.6E-07 2.75 1660.6 14.7 77.7 2,500,000 52.083 0.27 2.7E-07
3.73 4151.4 19.9 83.1 3.94E+07 8.E+02 1.1E-01 1.1E-07 9.4 6.5E+04
50.0 92.9 3.15E+08 7.E+03 5.3E-02 5.3E-08 18.7 5.2E+05 100 96.4
2.52E+09 5.E+04 2.7E-02 2.7E-08 37.5 4.2E+06 200 98.2 3.94E+10
8.E+05 1.1E-02 1.1E-08 93.6 6.5E+07 500.0 99.3 3.15E+11 7.E+06
5.3E-03 5.3E-09 187.3 5.2E+08 1000.0 99.6 2.52E+12 5.E+07 2.7E-03
2.7E-09 374.6 4.2E+09 2000.0 99.8 3.94E+13 8.E+08 1.1E-03 1.1E-09
936.4 6.5E+10 5000.0 99.9
[0187] Table ZZZ shows that the molecular weight, diffusion
co-efficient, equivalent diameter of ranibizumab is about 48 k
Daltons, 1.0E-6, and 5.3 nm, respectively.
[0188] The molecular weight of the stabilizer can be provided in 1
k Dalton increments from about 1 k Dalton to about 200 k Daltons
and provide in a Table having about 200 rows similar to Table ZZZ.
The parameters of Table ZZZ determined such as the half-life in the
device, the equivalent volume, the equivalent diameter, and % in
the device at the half-life of the therapeutic agent 110. The table
may comprise a row for each molecular weight in 1 k Dalton
increments, and the % of stabilizer in the device compared with the
therapeutic agent 110. The table may include columns for two
half-lives of the therapeutic agent, three half-lives of the
therapeutic agent, four half-lives of the therapeutic agent, and
the corresponding percentage of stabilizer remaining in the
device.
[0189] The percentage at 1, 2, 3, 4 5, and 6 half-lives can be
determined.
[0190] The molecular weight, diffusion coefficient and equivalent
diameter of trehalose is about 0.4 k Daltons, 5.0E-6, and 1.1 nm,
respectively. The relative molecular weight of trehalose to
ranibizumab is about 0.8%, and the relative half-life of trehalose
in device 100 is about 20% of ranibizumab. The relative amount of
trehalose remaining in therapeutic device 100 at the half-life of
ranibizumab is about 3.1%. This decreased half-life of trehalose
and amount in the device 100 relative to ranibizumab is related to
the decreased molecular weight of trehalose relative to
ranibizumab.
[0191] A disaccharide such as trehalose can be combined with one or
more of micelles or polymeric proteins as described herein, so as
to associate with the one or more of the micelles or the polymeric
proteins so as to decrease a rate of release of the disaccharide
from the reservoir chamber.
[0192] The molecular weight, diffusion coefficient and equivalent
diameter of polysorbate 20 is about 1.2 k Daltons, 3.4E-6, and 1.6
nm, respectively. The relative molecular weight of polysorbate to
ranibizumab is about 2.6%, and the relative half-life of
polysorbate 20 in device 100 is about 29% of ranibizumab. The
relative amount of polysorbate 20 remaining in therapeutic device
100 at the half-life of ranibizumab is about 9.5%. This decreased
half-life of polysorbate and amount in the device 100 relative to
ranibizumab is related to the decreased molecular weight of
polysorbate relative to ranibizumab.
[0193] The diffusion coefficients of Table ZZZ can be determined
based on weight for molecular weights up to about 2.5 M Daltons,
and based on size above about 2.5 M Daltons.
[0194] The stabilizer may comprise a molecular weight that is at
least about 10% of the molecular weight of the therapeutic agent;
such that the half-life of the stabilizer corresponds to at least
about 50% of the half-life of the therapeutic agent. For example, a
stabilizer 192 with a molecular weight of about 5 k Daltons
corresponding to about 10% of the molecular weight of ranibizumab,
the relative half life of the stabilizer is about half (0.47) of
the half life of ranibizumab. When the half-life of the stabilizer
is about half that of the therapeutic agent, about 1/4 of the
stabilizer may remain in the therapeutic device for an extended
time corresponding to the half-life of the therapeutic agent. For
example, when the half-life of the therapeutic agent ranibizumab in
the device is about 100 days, about 1/4 of a 5 k Dalton molecular
weight stabilizer will remain in the therapeutic device.
[0195] The stabilizer may comprise a molecular weight that is at
least about 20% of the molecular weight of the therapeutic agent,
such that the half life of the stabilizer corresponds to at least
about 50% of the half life of the therapeutic agent. At a time of
two half lives post-placement in the therapeutic device, the
relative proportion of stabilizer to therapeutic agent is about 1
to 4. This amount of stabilizer is sufficient to stabilize the
therapeutic agent in many variations.
[0196] FIG. 3B2 shows a micelle 192M of a stabilizer as in FIG. 3A.
The stabilizer 192 may comprise a micelle 192M of the stabilizer
192. The micelle 192M may comprise a weight corresponding to a
molecular weight of the therapeutic agent, such that a substantial
portion of the micelles of the injected formulation remain in the
reservoir chamber of the therapeutic device when the therapeutic
agent is released. The weight of each micelle may correspond to a
molecular weight of at least about 10% of the therapeutic agent,
for example at least about 20%, such that the micelle comprises a
size so as to inhibit diffusion of the micelle from the reservoir
chamber through the porous structure 150.
[0197] The micelle 192M may comprise a reservoir of the stabilizer.
For example, the stabilizer may comprise a first micelle portion
and a second solution portion. The second solution portion may
comprise a portion of the surfactant molecule dissolved as a solute
in solution. The second solution portion may correspond to a
critical micelle concentration (hereinafter "CMC"). Above this
critical threshold concentration, additional surfactant added to
the solution may be present in the form of micelles. The micelle
portion can remain substantially within the reservoir chamber based
on the size and weight of the micelle as described herein. In many
variations, each of the micelles may comprise 50 or more surfactant
molecules, in which each surfactant molecule comprises a molecular
chain. The diffusion coefficient of a micelle of this size may have
a weight and corresponding diffusion coefficient equal or larger
than the therapeutic agent, for example. As individual molecules of
the stabilizer in solution diffuse through the porous structure
150, the micelle can release stabilizer into solution such that the
concentration of stabilizer in solution remains substantially
constant. The micelles may comprise polymeric surfactants that may
comprise a first micelle portion and a second solution portion in
equilibrium, such that as the second portion comprising molecules
dissolved in solution diffuses through the porous structure the
polymeric surfactant on the micelles is released into solution so
as to maintain the concentration of polymeric surfactant in
solution.
[0198] The surfactant may comprise one or more of polysorbates (for
example, polysorbate 20 and polysorbate 80, also known as Tween 20
and Tween 80), block copolymers of ethylene oxide or propylene
oxide of various sizes marketed by BASF as Pluronic.RTM., or
ethoxylated emulsifiers marketed by BASF as Cremophor.RTM., and
combinations thereof.
[0199] The surfactant may increase the stability of the therapeutic
agent by occupying interfaces so as to displace therapeutic agent
comprising protein from the interfaces. The interface may comprise
an inner surface of the reservoir chamber exposed to the
formulation such that the inner surface may interact with the
protein, for example an inner surface housing or a surface of the
porous structure 150. Proteins may undergo conformational changes
at interfaces that may then lead to degradation via any of a number
of pathways such as aggregation, deamidation, oxidation, etc. The
surfactant may compete with and displace protein at air-liquid
interfaces such as at the surface of a bubble or liquid-solid
interfaces such as with displacement of the protein at the exposed
surface inside a porous structure within the device. High
concentrations of surfactant, near or beyond the CMC may be helpful
so as to substantially displace protein from interfaces and inhibit
interaction of the protein with the inner surfaces of device 100.
In many variations, the surfactant concentration within the
reservoir chamber of the device can be maintained near or above the
CMC for an extended time as described herein.
[0200] The CMC can be determined from a variety of techniques such
as measurements of surface tension using a Wilhelmy plate. The CMC
for a particular surfactant may be dependent on a variety of
parameters such as the concentrations of other components in the
formulation and the temperature. Values ranging from 1E-5 to 8E-5
are reported in the literature for polysorbate 20.
[0201] Table K1 shows amounts of polysorbate 20 sufficient to
maintain the presence of micelles in representative devices for an
extended time of at least about 6 months, such that the
concentration of surfactant stabilizer in device 100 is at least
about the CMC of the surfactant stabilizer comprising Polysorbate
20. The diffusion coefficients of 3.4E-6 and 8.8E-7 cm2/s for the
single molecule (corresponding to the second portion) and the
micelle (corresponding to the micelle portion), respectively, are
obtained based upon molecular weight of 1227 for polysorbate 20 and
assuming a plurality of approximately 50 molecules of polysorbate
20 per micelle, in which each of the 50 molecules comprises a
molecular chain such as a polymeric chain. The corresponding
particle weight of the micelle comprising the plurality of 50
polysorbate 20 molecules can be about 61,350, so as to correspond
to a diffusion coefficient about 3.86 lower than Polysorbate 20,
based on the cube root of the weight of the micelle particle
relative to the weight of the individual Polysorbate 20 molecule
(cube root of 50 is about 3.86). The examples show polysorbate 20
concentrations 6 or more times larger than the CMC can be
sufficient so as to maintain micelles in the device at least about
6 months after placement of the therapeutic agent and micelles in
device 100. In many variations, concentrations of at least about
0.04% may be sufficient so as to maintain concentration of micelles
above the CMC.
TABLE-US-00003 TABLE K1 Minimum concentration of polysorbate 20
sufficient to maintain micelles in device 100, as a function of CMC
and device parameters. CMC (M) 1e-5 8e-5 1e-5 8e-5 CMC (wt %)
0.001% 0.01% 0.001% 0.01% Device RRI (mm) 0.02 0.02 0.06 0.02
Device Volume (uL) 25 25 25 100 Minimal Conc. to replenish single
0.005% 0.042% 0.016% 0.042% chain diffusion (wt %) Half-life of
Therapeutic Agent 100 100 30 400 Ranibizumab (days) Minimal Conc.
corresponding to 0.004% 0.029% 0.033% 0.013% micelle diffusion (wt
%) Total Minimal Conc. (wt %) 0.009% 0.071% 0.048% 0.054% Ratio of
Total Minimal Conc. to 7 7 40 6 CMC
[0202] Table K1 shows that substantial amounts of surfactant can be
provided for an extended time of at least about 6 months so as to
stabilize the therapeutic agent within device 100. In many
variations, ranibizumab can be delivered in therapeutic amounts for
an extended time of at least about 6 months when therapeutic device
100 comprises a half-life of at least about 90 days or more, for
example.
[0203] The amount of surfactant in device 100 can be combined with
an amount of one or more of many therapeutic agents 110 as
described herein. The half life of the therapeutic agent may
correspond to the amount of surfactant sufficient to maintain the
concentration of surfactant above the CMC.
[0204] The amount of surfactant to provide for an intended extended
time can be determined empirically. For example, the above table
shows amounts of surfactant sufficient to provide surfactant above
the CMC for 6 months. Similar tables for a target intended time of
12 months, for example, can be determined.
[0205] Alternatively or in combination, amounts of surfactant can
be determined to provide concentrations above the CMC for an
intended extended time. For example, to achieve a surfactant
concentration above the CMC for an extended time of about one year,
the minimal concentration corresponding to micelle diffusion can be
increased by about 4.times. when the intended time is increased by
about 2.times., so as to provide micelles within device 100 for at
least about 1 year, for example. With device 100 having a reservoir
chamber volume of 100 uL and an RRI of about 0.02, to achieve
micelles for at least about one year with a CMC of 0.01%, the
concentration of Polysorbate 20 corresponding to micelle diffusion
can be increased from about 0.013% to about 0.017%, and the
concentration of Polysorbate 20 corresponding to individual
surfactant molecule diffusion can be increased from about 0.04% to
about 0.08%, such that the total concentration of Polysorbate 20
comprises about 0.1%.
[0206] The micelle 192M may form a complex 192C with the
therapeutic agent 110. Alternatively or in combination, the chains
of individual molecules may associate with the therapeutic agent,
for example form a complex with the therapeutic agent.
[0207] FIG. 3C shows a particle of a binding agent having porous
channels as in FIG. 3A. The particle may comprise a plurality of
channels and a plurality of openings sized to allow the therapeutic
agent 110 to diffuse along the channel 194C and out opening 1940.
The porous channels may comprise the derivatized surface as
described herein.
[0208] FIG. 3D shows an erodible material comprising an erodible
polymer to generate a proton of an acid as in FIG. 3A. The polymer
may comprise one or more of polylactic acid 196LA or polyglyoclic
acid 196GA, or combinations thereof, for example. The polymer may
comprise many biodegradable erodible materials, such as
polycaprolactone, for example. The particle may comprise a
substantial polymer chain 196P, such that the particle is sized so
as to inhibit diffusion of the particle through the porous
structure to release the proton of the acid within the reservoir
chamber of the therapeutic device 100.
[0209] The proton generation based on erodible material such as
biodegradable polymers comprising PLGA can be provided in many
ways. In many variations, therapeutic agent is located in the fluid
surrounding the erodible particles, and may not be encapsulated
inside of the particles such that the protons released from the
particle can be diluted with the fluid surrounding the erodible
particle.
[0210] The rate of proton generation can be determined by the
composition of the particles. Variables capable of modulating the
degradation of PLGA can include one or more of a ratio of PLA to
PGA, molecular weight, crystallinity, particle size, porosity, and
pore size distributions, shape, and processing conditions. For
example, increasing the ratio of PLA to PGA can decrease the rate
of degradation, and decreasing the ratio of PLA to PGA can increase
the rate of degradation. Providing particles with lower porosity
may reduce the fraction of water filled pores and can result in a
lower erosion rate. Increasing molecular weight, crystallinity, and
particle size may decrease degradation rates and the rate of proton
production.
[0211] PLGA particles prepared for encapsulation and delivery of
drugs may achieve drug release for extended periods on the order of
weeks or months. However, water-soluble drug can be substantially
depleted from PLGA particles before the polymer is completely
degraded. Hence, protons may be supplied from erosion of PLGA for
several months beyond the time sustained drug delivery is achieved.
Furthermore, PLGA intended as proton generators can have lower
porosity during the erosion process if they do not have additional
pores forming from depletion of encapsulated drug. Hence,
biodegradable particles for proton generation may be prepared where
protons are generated for periods of a year or longer.
[0212] The erodible particles may be coated with an excipient that
dissolves slowly in water, so as to delay the time when the
biodegradable material is hydrated and so as to delay the
corresponding erosion process. The erodible particles may comprise
enteric coatings. The enteric coatings can remain intact at
slightly acidic conditions and dissolve when pH is increased toward
physiological pH, such that proton generation can be started at a
time post injection when pH has risen above a targeted threshold.
The time profile of the release of the protons of the acid can be
determined based on a mixture of the particles. For example, the
time profile of proton generation may be modulated by using a
mixture of particles with varying properties, for example, varying
particle size or thickness of the enteric coating.
[0213] Coatings with slow dissolution may comprise polymers with
limited solubility in water, such as ethylcellulose, and may be
mixed with polymers (e.g., hydroxyethylcellulose, sodium
carboxymethylcellulose, methyl hydroxyethylcellulose) that are
soluble in water to achieve the desired dissolution profile. The
coatings may also comprise polymers with lower critical solution
temperatures, such as methylcellulose, hydroxypropyl cellulose, and
hydroxypropyl methylcellulose, that are insoluble at high
temperature and have dramatically increased solubility in cold
water. The desired dissolution profile may be achieved by selection
of molecular weights (e.g., increase in molecular weight decreases
solubility and dissolution rate) and by mixing with other soluble
and insoluble polymers and excipients.
[0214] Commonly used enteric coating polymers are shown in Table
XX. These may be combined with the coatings above.
TABLE-US-00004 TABLE XX Enteric Coating Polymers Polymer Solubility
Profile Shellac Above pH 7 Cellulose acetate phthalate (CAP) Above
pH 6 Polyvinylacetate phthalate (PVAP) Above pH 5 Hydroxypropyl
methylcellulose phthalate (HPMCP) Above pH 4.5 Polymers of
methacrylic acid and its esters Above pH 6
[0215] The above polymers used as coatings may also serve as a
protein stabilizer once dissolved into the solution inside the
device. These coatings may stabilize the therapeutic agent by
forming a complex with the therapeutic agent or may stabilize by
acting as a co-solute.
[0216] Stabilizers larger than 2 kDa may have sufficiently limited
solubility to be present as a suspension in the formulation (e.g.,
ethylcellulose, methylcellulose, hydroxypropyl cellulose, and
hydroxypropyl methyl cellulose). For example, small particles of
these polymers could be prepared by micronization and milling, or
by emulsion or spray drying techniques.
[0217] Coatings that delay dissolution, whether pH triggered or
not, may also be used with other solid reservoirs of stabilizers
that replenish stabilizer as it is depleted and delivered to the
vitreous. For example, micronized trehalose could be coated for
delayed dissolution.
[0218] The erodible material to generate the proton of the acid and
stabilizers to decrease degradation of the therapeutic agent can be
combined in many ways. For example, formulation stabilizers, such
as buffers and sugars, may be encapsulated in biodegradable
particles so as to release a second portion of stabilizer that
replenishes a first portion stabilizer that has been released into
the vitreous. For example, as trehalose is stable at acidic
conditions, the erodible particles may comprise trehalose
stabilizer and the erodible material. Alternatively or in
combination, the erodible particles may comprise buffer so as to
release the buffer with erosion of the particles. The buffer may
comprise one or more buffers including, for example, acetate,
succinate, gluconate, histidine, citrate, and organic acid buffers.
The stabilizer may also comprise pH modulators such as chloride
salts.
[0219] Table Z1 to Table Z5 shows amounts of PLGA polymer to
provide a pH of about 5.5 for an extended time of at least about 1
year. These tables include calculations for the flux of protons out
of the device 100, and also calculations of physiological phosphate
into the device, so as to determine amounts of erodible polymer
based on diffusion of vitreous buffer into device 100.
TABLE-US-00005 TABLE Z1 Molecular weights of PGA, PLA and PLGA MW
of repeat unit PGA 58 PLA 76 Ave. 67
[0220] As shown in Table Z1, PGA and PLA have molecular weights of
58 and 76 respectively, with an average of about 67 k Daltons.
These molecular weights correspond to about 67 mg per mmole of
PLGA.
TABLE-US-00006 TABLE Z2 Phosphate pKa's and concentrations in the
vitreous humor. Phosphate pKa2 7.21 Ka2 6.17E-08 Phosphate (M)
0.01
[0221] Table Z2 shows the pKa2 of phosphate to be about 7.21, and
the Ka2 to be about 6.17E08. The molarity of the phosphate buffer
is about 0.1, which corresponds to the vitreous humor and many
bodily fluids, for example blood. After an amount of time within a
range from about two weeks to about three months, a formulation
with a small molecular weight buffer (e.g., histidine) may be
depleted in the reservoir of the device. At that time, the
reservoir may be in substantial equilibrium with the buffers in the
vitreous (e.g., phosphate) and comprise physiological
concentrations of the vitreous buffers.
TABLE-US-00007 TABLE Z3 The change of H2PO4 concentration and
corresponding pH's HPO4 pH [H+] pOH [OH-] HPO4/H2PO4 H2PO4 (M) (M)
Extra H+ (M) 5.5 3.16E-06 8.5 3.16E-09 0.02 0.00981 0.00019 0.0059
7.4 3.98E-08 6.6 2.51E-07 1.55 0.00392 0.00608
[0222] The pH within the device can be about 5.5, and the pH of the
vitreous humor can be about 7.4. Addition of phosphate into a
device at pH 5.5 may change the pH of the device unless additional
protons are provided. Table Z3 shows information on the
concentrations of phosphate species at the vitreous and device pH
values, to enable calculation of the amount of protons required to
maintain pH in the device in the presence of 0.1 M phosphate. The
corresponding [H+], pOH, and [OH-] values are shown. The ratio of
[HPO.sub.4.sup.2-] to [H.sub.2PO.sub.4.sup.-] is shown to be 0.02
and 1.55 for pH 5.5 and 7.5, respectively. The corresponding
molarities (M) of H.sub.2PO.sub.4.sup.-, HPO.sub.4.sup.2-, and
extra proton to decrease the pH are shown.
TABLE-US-00008 TABLE Z3 RRI, reservoir volume and density RRI (mm)
0.02 Reservoir vol (uL) 25 Density of PLGA (mg/uL) 1
[0223] Table Z3 shows an example of a device having an RRI of 0.02
and reservoir volume of 25 uL. The density of PLGA is about 1
mg/ul.
[0224] The half-life of Lucentis.TM. in device 100 having the RRI
of 0.02 and reservoir volume of 25 uL is about 100 days, as
described in U.S. Pub. No. 2010/0255061, the full disclosure of
which has been previously incorporated by reference and suitable
for combination in accordance with variations described herein.
TABLE-US-00009 TABLE Z4 PLGA to preplace H+ that diffuses across
the porous structure 150, also referred to as rate control element
(hereinafter "RCE"). PLGA to replace H+ that diffuses out across
RCE H+ OH- Diffusion Coeff 9.31E-05 5.28E-05 Source: Cussler,
(cm{circumflex over ( )}2/s) E. L., "Diffusion", Cambridge
University Press, first edition, 1984, pg 147 Conc in Reservoir (M)
3.16E-06 3.16E-09 Conc in Receiver (M) 3.98E-08 2.51E-07 Conc
Change across 3.12E-06 -2.48E-07 RCE (M) Rate (mmole/day) 5.02E-08
-2.26E-09 Assume amount of OH- transported is negligible compared
to H+ Rate (mmole/month) 1.51E-06 Rate (mmole/year) 1.83E-05
-8.26E-07 Rate (ug PLGA/year) 1.23 Rate (uL PLGA/year) 1.23E-03
Volume fraction 0.005%
[0225] Table Z4 shows that erosion of about 1.23E-03 ug of PLGA per
year corresponds to the diffusion of H+ ions across porous
structure 150. The corresponding volume fraction is about 0.005% of
the 25 uL volume. The diffusion coefficient of H+ proton ions in
solution is about 9.31E-05.
[0226] Table Z5 shows PLGA to protonate phosphate that diffuses
into device 100 across porous structure 150 from a bodily fluid
such as the vitreous humor.
TABLE-US-00010 PLGA required to protonate phosphate (change of pH
from 7.4 to 5.5 or value set above). Assumes all histidine buffer
has diffused out of the device and device now contains phosphate at
concentrations in equilibrium with the vitreous (0.01M) H+ Extra H+
(M) 0.0059 Extra H+ 1.47E-04 Concentration converted to amount
based (mmole) upon reservoir volume PLGA (ug) 9.86 PLGA (uL)
9.86E-03 Volume fraction 0.039%
[0227] Table Z5 shows that the extra H+ to be protonated
corresponds to about 0.0059 M based on Table Z3 above. The amount
of PLGA per year corresponds to about 9.86 ug having a volume of
about 9.86 uL. For the 25 uL device, this corresponds to about
0.039% of the device.
[0228] Tables Z1 to Z5 show amounts of erodible material in
accordance with many variations. One or more of the following may
be adjusted in accordance with the variations described herein:
target pH within device 100, volume of device 100, release rate of
porous structure 150, half-life of therapeutic agent in device 100,
rate of erosion of the erodible material comprising PLGA.
[0229] FIG. 3E shows reactions and equilibrium corresponding to
components to determine release rates of the formulation as in FIG.
3A when injected into a therapeutic device. The stabilizer 192 and
therapeutic agent 110 can be in equilibrium with complex 192C
having a corresponding equilibrium constant Ks. The binding agent
194 and therapeutic agent 110 can be in pH dependent equilibrium
with reversible binding 194B of therapeutic agent and binding agent
corresponding to pH dependent equilibrium constant Kb. The erodible
polymer can generate protons of an acid 196A with hydrolysis
corresponding to equilibrium constant. The corresponding
concentrations of therapeutic agent 110, complex 192C of stabilizer
192 and therapeutic agent 110 and protons H+ can be used to
determine the diffusive flux of each of these components through
porous structure 150 so as to determine the profile of the rate of
release of therapeutic agent 110.
[0230] The release of therapeutic agent 110 may be modulated by one
or more of the pH or the concentration of stabilizer 192 within the
reservoir chamber. The increase in pH from about 6.5 to about 7 can
shift the equilibrium of the binding agent and therapeutic agent
toward dissociated therapeutic agent so as to increase the rate of
release of the therapeutic agent. The decreased amount of
stabilizer can shift the equilibrium of stabilizer and therapeutic
agent away from complexed therapeutic agent and toward dissociated
therapeutic agent in solution, so as to increase the rate of
release of the therapeutic agent.
[0231] FIG. 4A shows released antibodies comprising antibody
fragments 410 and a substrate 420 comprising binding agent 194, and
FIG. 4B shows antibody fragments 410 reversibly bound to a
substrate 420 with binding agent 194, in accordance with variations
described herein. The anti-body fragments can be reversibly bound
to the substrate comprising the binding agent, such that the bound
antibody fragments are in equilibrium with the unbound antibody
fragments. Many substrates comprising binding agent can reversibly
bind at least a portion of an antibody. Examples of binding media
may include particulates used in chromatography, such as:
Macro-Prep t-Butyl HIC Support, Macro-Prep DEAE Support, CHT
Ceramic, Hydroxyapatite Type I, Macro-Prep CM Support, Macro-Prep
Methyl HIC Support, Macro-Prep Ceramic Hydroxyapatite Type II,
UNOsphere S Cation Exchange Support, UNOsphere Q Strong Anion
Exchange Support, Macro-Prep High-S Support, and Macro-Prep High-Q
Support. Additional media to test for binding include ion exchange
and bioaffinity chromatography media based on a hydrophilic
polymeric support (GE Healthcare) that bind proteins with high
capacity, and a hydrophilic packing material from Harvard Apparatus
made from poly(vinyl alcohol) that binds more protein than silica.
It should be appreciated that other candidates are considered
herein.
[0232] The resin of the plurality of binding particles may comprise
one or more of polystyrene or divinyl benzene. The particles may
comprise spherical particles and may comprise a plurality of
channels. When the reservoir chamber of the therapeutic device
corresponds to a net negative charge of the therapeutic agent, the
derivatized surface may comprise an anion exchange surface such as
one or more of diethylaminoehtly (DEAE), Quaternary aminoethly
(QAE), or quaternatry ammonidum (Q), for example. When the
reservoir chamber of the therapeutic device corresponds to a net
positive charge of the therapeutic agent, the derivitized surface
may comprise a cation exchange surface such as one or more of
carboxy methyl (CM), Sulphoproply (SP), or methyl sulphonate (SP),
for example.
[0233] FIG. 4C shows net charge of ranibizumab from pH 3 to about
pH 13. Similar plots can be determined for many proteins based
therapeutic agents such as Fab antibody fragments and derivatives
thereof, such as ranibizumab and derivatives thereof. The charge of
the therapeutic agent can be used to determine reversible binding
of the therapeutic agent to the binding agent. In many variations,
the therapeutic agent comprising a protein such as ranibizumab may
comprise an improved stability when the pH in the reservoir chamber
of device is at least about 2 pH units from the isoelectric
point.
TABLE-US-00011 TABLE YYY Charge of ranibizumab as a function of pH.
Charge 45 10 2 1 -50 -60 pH 3 5 7 9 11.5 13
[0234] Table YYY shows the charge of the ranibizumab molecule as a
function of pH. The isoelectric point is around pH 9. The charge at
pH 5 can be about +10, and the charge at pH 7 can be about +2, such
that the amount of ranibizumab reversibly bound to the binding
agent may change substantially from about pH 5 to about pH 7. Based
on interpolation, the charge at about pH 6 is about 6. The change
in charge from pH 6 to pH 7 is about 4, which can provide
substantial change in binding so as to modulate the release of the
therapeutic with pH.
[0235] Near the isoelectric the total number of negative and
positive charges can be substantial, for example about 36 positive
and 35 negative charges, such that there can be many charges to
couple to the binding agent reversibly. The reversible binding
agent may comprise a plurality of functional groups having both
positive and negative charges to bind reversibly with the
therapeutic agent. The composition of the buffer may be modulated,
for example with salt so as to shield at least some of the charge
interactions, so as to modulate the ratio of the portion of
therapeutic agent bound to the binding agent to the unbound portion
of the therapeutic agent, for example.
[0236] FIG. 5A shows therapeutic device 100 coupled to injector 187
to insert therapeutic agent 110 into container 130 of the device.
The injector 187 may comprise needle 189 coupled to a syringe
188.
[0237] FIG. 5A-1 shows a therapeutic device 100 coupled to an
injector 187 to inject and remove material from the device. The
injector may comprise needle 189 having a first lumen 189A and a
second lumen 189B configured to insert into a container of the
device. The injector may simultaneously inject 510 therapeutic
agent into and withdraw 520 liquid from the device.
[0238] The injector may comprise a first one way valve and a second
one way valve coupled to the first lumen and the second lumen,
respectively.
[0239] FIG. 5B shows a therapeutic device comprising a microloop
channel 530. The microloop channel may extend to a first port 530A
and a second port 530B, such that the therapeutic agent can be
injected into the first port, for example with a binding agent, and
flowable material, for example liquid comprising binding agent, can
be drawn from the microloop channel 530.
[0240] FIG. 5C-1 shows therapeutic device 100 comprising a tortuous
channel 540. The tortuous channel may comprise extend from a first
port 540A to a second port 540B, such that the therapeutic agent
can be injected into the first port and flowable material, for
example liquid comprising the binding agent, can be drawn from the
second channel.
[0241] FIG. 5C-2 shows a therapeutic device comprising a tortuous
coiled channel 550. The coiled channel 550 can extend to an exit
port 552. A needle 189 can be inserted into the access port 180 to
inject therapeutic agent into device 100.
[0242] FIG. 5D shows an expandable and contactable structure 562 to
retain the therapeutic agent and an outer rigid casing 560 to
couple to the sclera. The expandable structure 562 may comprise a
membrane, such as at least one of a bag, a balloon, a flexible
reservoir, a diaphragm, or a bag. The outer rigid casing may extend
substantially around the structure 562 and may comprise an opening
to release liquid into the vitreous humor when the structure is
expanded.
[0243] FIG. 5E shows a membrane 565 disposed over an exit port 552
of therapeutic device 100.
[0244] FIG. 5F shows therapeutic device 100 comprising a tubular
membrane 572 clamped onto the therapeutic device over side ports
570 of device 100.
[0245] When the protective membranes have pores of 0.2 um diameter,
they are 20 or more times larger than the proteins of interest,
which may comprise a model for delivery of the therapeutic agent.
For example, molecular weights and diameters of models of proteins
of therapeutic interest are:
TABLE-US-00012 (a) IgG 150 kDa 10.5 nm (b) BSA 69 kDa 7.2 nm (c)
Fab fragment of IgG 49 kDa hydrodynamic diameter not reported
[0246] Therefore, solutions of therapeutic compounds in the size
range of IgG and BSA should flow relatively easily through 0.2 um
pore size protective membranes used to stop passage of bacterial
and other cells.
[0247] Binding Materials/Agents may comprise at least one of a
chemical binding agent/material, a structural binding agent or
material, or an electrostatic binding agent or material. The types
of binding agent may comprise a classification composed of
non-biodegradable material, for example glass beads, glass wool or
a glass rod. A surface can be derivatized with at least one
functional group so as to impart the binding agent or material with
the potential for at least one of ionic, hydrophobic, or
bioaffinity binding to at least one therapeutic compound.
[0248] The binding agent may comprise a biodegradable material. For
example, the biodegradation, binding, or a combination of the
previous processes may control the diffusion rate.
[0249] The binding agent may comprise ion exchange, and the ion
exchange may comprise at least one of a functional group, a pH
sensitive binding or a positive or negative charge. For example,
ion exchange can be performed with at least one of
diethylaminoethyl or carboxymethyl functional groups.
[0250] The binding agent may comprise a pH sensitive binding agent.
For example, the binding agent can be configured to elute
therapeutic agent at a pH of 7, and to bind the therapeutic agent
at a pH from about 4 to about 6.5. A cation exchange binding agent
can be configured, for example, such that at a pH of 7, the net
negative charge of the binding agent decreases causing a decrease
in binding of the positively charged drug and release of the
therapeutic agent. A target buffer can be provided with the binding
agent to reversibly couple the binding agent to the therapeutic
agent. The rate of release can be controlled, for example slowed
down, by using insolubility of the buffer in the vitreous.
Alternatively or in combination, the elution can be limited by
using a porous membrane or a physical property such as a size of an
opening.
[0251] The ion exchange may comprise positive or negative ion
exchange.
[0252] The binding agent may comprise hydrophobic interaction. For
example, the binding agent may comprise at least one binding to
hydrophobic pockets, for example at least one of methyl, ethyl,
propyl, butyl, t-butyl or phenyl functional groups.
[0253] The binding agent may comprise affinity, for example at
least one of a macromolecular affinity or a metal chelation
affinity. Examples can include a hydroxyapatite, or chelated metal,
for example zinc. Iminodiacetic acid can be chelated with zinc.
[0254] The binding agent may comprise at least one of the following
functions: charging, recharging or elution. The charging may
comprise a porous material injected therein so as to release the
active ingredient. The porous matter may have an extremely large
inert surface area, which surface area is available for binding.
The recharging may comprise removing carrier+therapeutic agent; and
adding freshly "charged" carrier+therapeutic agent.
[0255] The elution may comprise a byproduct, for example unbound
binding agent that can be removed. For example, a mechanism such as
diffusion or plug flow of vitreous maychange a condition such as pH
so as to reduce interaction of therapeutic agent and carriers.
[0256] Additionally or in the alternative, a sustained drug
delivery system of the therapeutic agent may comprise drug delivery
packets; e.g., microspheres that are activated. The packets can be
activated with at least one of photochemical activation, thermal
activation or biodegradation.
[0257] The therapeutic device may comprise at least one structure
configured to provide safety precautions. The device may comprise
at least one structure to prevent at least one of macrophage or
other immune cell within the reservoir body; bacterial penetration;
or retinal detachment.
[0258] The therapeutic device may be configured for other
applications in the body. Other routes of administration of drugs
may include at least one of intraocular, oral, subcutaneous,
intramuscular, intraperitoneal, intranasal, dermal, intrathecal,
intravascular, intra articular, pericardial, intraluminal in organs
and gut or the like.
[0259] Conditions that may be treated and/or prevented using the
drug delivery device and method described herein may include at
least one of the following: hemophilia and other blood disorders,
growth disorders, diabetes, leukemia, hepatitis, renal failure, HIV
infection, hereditary diseases such as cerebrosidase deficiency and
adenosine deaminase deficiency, hypertension, septic shock,
autoimmune diseases such as multiple sclerosis, Graves disease,
systemic lupus erythematosus and rheumatoid arthritis, shock and
wasting disorders, cystic fibrosis, lactose intolerance, Crohn's
disease, inflammatory bowel disease, gastrointestinal or other
cancers, degenerative diseases, trauma, multiple systemic
conditions such as anemia, and ocular diseases such as, for
example, retinal detachment, proliferative retinopathy,
proliferative diabetic retinopathy, degenerative disease, vascular
diseases, occlusions, infection caused by penetrating traumatic
injury, endophthalmitis such as endogenous/systemic infection,
post-operative infections, inflammations such as posterior uveitis,
retinitis or choroiditis and tumors, such as neoplasms and
retinoblastoma.
[0260] Examples of therapeutic agents 110 that may be delivered by
the therapeutic device 100 are described in Table 1A and may
include Triamcinolone acetonide, Bimatoprost (Lumigan), Ranibizumab
(Lucentis.TM.), Travoprost (Travatan, Alcon), Timolol (Timoptic,
Merck), Levobunalol (Betagan, Allergan), Brimonidine (Alphagan,
Allergan), Dorzolamide (Trusopt, Merck), Brinzolamide (Azopt,
Alcon). Additional examples of therapeutic agents that may be
delivered by the therapeutic device include antibiotics such as
tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin,
gramicidin, cephalexin, oxytetracycline, chloramphenicol kanamycin,
rifampicin, ciprofloxacin, tobramycin, gentamycin, erythromycin and
penicillin; antifungals such as amphotericin B and miconazole;
anti-bacterials such as sulfonamides, sulfadiazine, sulfacetamide,
sulfamethizole and sulfisoxazole, nitrofurazone and sodium
propionate; antivirals such as idoxuridine, trifluorotymidine,
acyclovir, ganciclovir and interferon; anti allergenics such as
sodium cromoglycate, antazoline, methapyriline, chlorpheniramine,
pyrilamine, cetirizine and prophenpyridamine; anti-inflammatories
such as hydrocortisone, hydrocortisone acetate, dexamethasone,
dexamethasone 21-phosphate, fluocinolone, medrysone, prednisolone,
prednisolone 21-phosphate, prednisolone acetate, fluoromethalone,
betamethasone, and triamcinolone; non-steroidal anti-inflammatories
such as salicylate, indomethacin, ibuprofen, diclofenac,
flurbiprofen and piroxicam; decongestants such as phenylephrine,
naphazoline and tetrahydrozoline; miotics and anticholinesterases
such as pilocarpine, salicylate, acetylcholine chloride,
physostigmine, eserine, carbachol, diisopropyl fluorophosphate,
phospholine iodide and demecarium bromide; mydriatics such as
atropine sulfate, cyclopentolate, homatropine, scopolamine,
tropicamide, eucatropine and hydroxyamphetamine; sypathomimetics
such as epinephrine; antineoplastics such as carmustine, cisplatin
and fluorouracil; immunological drugs such as vaccines and immune
stimulants; hormonal agents such as estrogens, estradiol,
progestational, progesterone, insulin, calcitonin, parathyroid
hormone and peptide and vasopressin hypothalamus releasing factor;
beta adrenergic blockers such as timolol maleate, levobunolol Hcl
and betaxolol Hcl; growth factors such as epidermal growth factor,
fibroblast growth factor, platelet derived growth factor,
transforming growth factor beta, somatotropin and fibronectin;
carbonic anhydrase inhibitors such as dichlorophenamide,
acetazolamide and methazolamide and other drugs such as
prostaglandins, antiprostaglandins and prostaglandin precursors.
Other therapeutic agents known to those skilled in the art which
are capable of controlled, sustained release into the eye in the
manner described herein are also suitable for use in accordance
with variations described herein.
[0261] The therapeutic agent 110 may comprise one or more of the
following: Abarelix, Abatacept, Abciximab, Adalimumab, Aldesleukin,
Alefacept, Alemtuzumab, Alpha-1-proteinase inhibitor, Alteplase,
Anakinra, Anistreplase, Antihemophilic Factor, Antithymocyte
globulin, Aprotinin, Arcitumomab, Asparaginase, Basiliximab,
Becaplermin, Bevacizumab, Bivalirudin, Botulinum Toxin Type A,
Botulinum Toxin Type B, Capromab, Cetrorelix, Cetuximab,
Choriogonadotropin alfa, Coagulation Factor IX, Coagulation factor
VIIa, Collagenase, Corticotropin, Cosyntropin, Cyclosporine,
Daclizumab, Darbepoetin alfa, Defibrotide, Denileukin diftitox,
Desmopressin, Dornase Alfa,Drotrecogin alfa, Eculizumab,
Efalizumab, Enfuvirtide, Epoetin alfa, Eptifibatide, Etanercept,
Exenatide, Felypressin, Filgrastim, Follitropin beta, Galsulfase,
Gemtuzumab ozogamicin, Glatiramer Acetate, Glucagon recombinant,
Goserelin, Human Serum Albumin, Hyaluronidase, Ibritumomab,
Idursulfase, Immune globulin, Infliximab, Insulin Glargine
recombinant, Insulin Lyspro recombinant, Insulin recombinant,
Insulin, porcine, Interferon Alfa-2a, Recombinant, Interferon
Alfa-2b, Recombinant, Interferon alfacon-1, Interferonalfa-n1,
Interferon alfa-n3, Interferon beta-1b, Interferon gamma-1b,
Lepirudin, Leuprolide, Lutropin alfa, Mecasermin, Menotropins,
Muromonab, Natalizumab, Nesiritide, Octreotide, Omalizumab,
Oprelvekin, OspA lipoprotein, Oxytocin, Palifermin, Palivizumab,
Panitumumab, Pegademase bovine, Pegaptanib, Pegaspargase,
Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b,
Pegvisomant, Pramlintide, Ranibizumab, Rasburicase, Reteplase,
Rituximab, Salmon Calcitonin, Sargramostim, Secretin, Sermorelin,
Serum albumin iodonated, Somatropin recombinant, Streptokinase,
Tenecteplase, Teriparatide, Thyrotropin Alfa, Tositumomab,
Trastuzumab, Urofollitropin, Urokinase, or Vasopressin. The
molecular weights of the molecules and indications of these
therapeutic agents are set for below in Table 1A, below.
[0262] The therapeutic agent 110 may comprise one or more of
compounds that act by binding members of the immunophilin family of
cellular proteins. Such compounds are known as "immunophilin
binding compounds." Immunophilin binding compounds include but are
not limited to the "limus" family of compounds. Examples of limus
compounds that may be used include but are not limited to
cyclophilins and FK506-binding proteins (FKBPs), including
sirolimus (rapamycin) and its water soluble analog SDZ-RAD,
tacrolimus, everolimus, pimecrolimus, CCl-779 (Wyeth), AP23841
(Ariad), and ABT-578 (Abbott Laboratories).
[0263] The limus family of compounds may be used in the
compositions, devices and methods for the treatment, prevention,
inhibition, delaying the onset of, or causing the regression of
angiogenesis-mediated diseases and conditions of the eye, including
choroidal neovascularization. The limus family of compounds may be
used to prevent, treat, inhibit, delay the onset of, or cause
regression of AMD, including wet AMD. Rapamycin may be used to
prevent, treat, inhibit, delay the onset of or cause regression of
angiogenesis-mediated diseases and conditions of the eye, including
choroidal neovascularization. Rapamycin may be used to prevent,
treat, inhibit, delay the onset of, or cause regression of AMD,
including wet AMD.
[0264] The therapeutic agent 110 may comprise one or more of:
pyrrolidine, dithiocarbamate (NF.kappa.B inhibitor); squalamine;
TPN 470 analogue and fumagillin; PKC (protein kinase C) inhibitors;
Tie-1 and Tie-2 kinase inhibitors; inhibitors of VEGF receptor
kinase; proteosome inhibitors such as Velcade.TM. (bortezomib, for
injection; ranibuzumab (Lucentis.TM.) and other antibodies directed
to the same target; pegaptanib (Macugen.TM.); vitronectin receptor
antagonists, such as cyclic peptide antagonists of vitronectin
receptor-type integrins; .alpha.-v/.beta.-3 integrin antagonists;
.alpha.-v/.beta.-1 integrin antagonists; thiazolidinediones such as
rosiglitazone or troglitazone; interferon, including
.gamma.-interferon or interferon targeted to CNV by use of dextran
and metal coordination; pigment epithelium derived factor (PEDF);
endostatin; angiostatin; tumistatin; canstatin; anecortave acetate;
acetonide; triamcinolone; tetrathiomolybdate; RNA silencing or RNA
interference (RNAi) of angiogenic factors, including ribozymes that
target VEGF expression; Accutane.TM. (13-cis retinoic acid); ACE
inhibitors, including but not limited to quinopril, captopril, and
perindozril; inhibitors of mTOR (mammalian target of rapamycin);
3-aminothalidomide; pentoxifylline; 2-methoxyestradiol;
colchicines; AMG-1470; cyclooxygenase inhibitors such as nepafenac,
rofecoxib, diclofenac, rofecoxib, NS398, celecoxib, vioxx, and
(E)-2-alkyl-2(4-methanesulfonylphenyl)-1-phenylethene; t-RNA
synthase modulator; metalloprotease 13 inhibitor;
acetylcholinesterase inhibitor; potassium channel blockers;
endorepellin; purine analog of 6-thioguanine; cyclic peroxide
ANO-2; (recombinant) arginine deiminase;
epigallocatechin-3-gallate; cerivastatin; analogues of suramin;
VEGF trap molecules; apoptosis inhibiting agents; Visudyne.TM.,
snET2 and other photo sensitizers, which may be used with
photodynamic therapy (PDT); inhibitors of hepatocyte growth factor
(antibodies to the growth factor or its receptors, small molecular
inhibitors of the c-met tyrosine kinase, truncated versions of HGF
e.g. NK4).
[0265] The therapeutic agent 110 may comprise a combination with
other therapeutic agents and therapies, including but not limited
to agents and therapies useful for the treatment of angiogenesis or
neovascularization, particularly CNV. Non-limiting examples of such
additional agents and therapies include pyrrolidine,
dithiocarbamate (NF.kappa.B inhibitor); squalamine; TPN 470
analogue and fumagillin; PKC (protein kinase C) inhibitors; Tie-1
and Tie-2 kinase inhibitors; inhibitors of VEGF receptor kinase;
proteosome inhibitors such as Velcade.TM.; bortezomib, for
injection; ranibuzumab (Lucentis.TM.) and other antibodies directed
to the same target; pegaptanib (Macugen.TM.); vitronectin receptor
antagonists, such as cyclic peptide antagonists of vitronectin
receptor-type integrins; alpha-v/beta-3 integrin antagonists;
alpha-v/beta-1 integrin antagonists; thiazolidinediones such as
rosiglitazone or troglitazone; interferon, including
.gamma.-interferon or interferon targeted to CNV by use of dextran
and metal coordination; pigment epithelium derived factor (PEDF);
endostatin; angiostatin; tumistatin; canstatin; anecortave acetate;
acetonide; triamcinolone; tetrathiomolybdate; RNA silencing or RNA
interference (RNAi) of angiogenic factors, including ribozymes that
target VEGF expression; Accutane.TM. (13-cis retinoic acid); ACE
inhibitors, including but not limited to quinopril, captopril, and
perindozril; inhibitors of mTOR (mammalian target of rapamycin);
3-aminothalidomide; pentoxifylline; 2-methoxyestradiol;
colchicines; AMG-1470; cyclooxygenase inhibitors such as nepafenac,
rofecoxib, diclofenac, rofecoxib, NS398, celecoxib, vioxx, and
(E)-2-alkyl-2(4-methanesulfonylphenyl)-1-phenylethene; t-RNA
synthase modulator; metalloprotease 13 inhibitor;
acetylcholinesterase inhibitor; potassium channel blockers;
endorepellin; purine analog of 6-thioguanine; cyclic peroxide
ANO-2; (recombinant) arginine deiminase;
epigallocatechin-3-gallate; cerivastatin; analogues of suramin;
VEGF trap molecules; inhibitors of hepatocyte growth factor
(antibodies to the growth factor or its receptors, small molecular
inhibitors of the c-met tyrosine kinase, truncated versions of HGF
e.g. NK4); apoptosis inhibiting agents; Visudyne.TM., snET2 and
other photo sensitizers with photodynamic therapy (PDT); and laser
photocoagulation.
[0266] The therapeutic agents may be used in conjunction with a
pharmaceutically acceptable carrier such as, for example, solids
such as starch, gelatin, sugars, natural gums such as acacia,
sodium alginate and carboxymethyl cellulose; polymers such as
silicone rubber; liquids such as sterile water, saline, dextrose,
dextrose in water or saline; condensation products of castor oil
and ethylene oxide, liquid glyceryl triester of a lower molecular
weight fatty acid; lower alkanols; oils such as corn oil, peanut
oil, sesame oil, castor oil, and the like, with emulsifiers such as
mono- or di-glyceride of a fatty acid, or a phosphatide such as
lecithin, polysorbate 80, and the like; glycols and polyalkylene
glycols; aqueous media in the presence of a suspending agent, for
example, sodium carboxymethylcellulose, sodium hyaluronate, sodium
alginate, poly(vinyl pyrrolidone) and similar compounds, either
alone, or with suitable dispensing agents such as lecithin,
polyoxyethylene stearate and the like. The carrier may also contain
adjuvants such as preserving, stabilizing, wetting, emulsifying
agents or other related materials.
[0267] The therapeutic device may comprise a container configured
to hold at least one therapeutic agent, the container comprising a
chamber to hold the at least one therapeutic agent with at least
one opening to release the at least one therapeutic agent to the
vitreous humor and porous structure 150 placed within the at least
one opening. The porous structure 150 may comprise a fixed
tortuous, porous material such as a sintered metal, a sintered
glass or a sintered polymer with a defined porosity and tortuosity
that controls the rate of delivery of the at least one therapeutic
agent to the vitreous humor. The rigid porous structures provide
certain advantages over capillary tubes, erodible polymers and
membranes as a mechanism for controlling the release of a
therapeutic agent or agents from the therapeutic device. These
advantages include the ability of the rigid porous structure to
comprise a needle stop, simpler and more cost effective
manufacture, flushability for cleaning or declogging either prior
to or after implantation, high efficiency depth filtration of
microorganisms provided by the labyrinths of irregular paths within
the structure and greater robustness due to greater hardness and
thickness of the structure compared to a membrane or erodible
polymer matrix. Additionally, when the rigid porous structure is
manufactured from a sintered metal, ceramic, glass or certain
plastics, it can be subjected to sterilization and cleaning
procedures, such as heat or radiation based sterilization and
depyrogenation that might damage polymer and other membranes. In
certain variations, as illustrated in example 9, the rigid porous
structure may be configured to provide a therapeutically effective,
concentration of the therapeutic agent in the vitreous for at least
6 months. This release profile provided by certain configurations
of the rigid porous structures enables a smaller device, which is
preferred in a small organ such as the eye where larger devices may
alter or impair vision.
[0268] FIG. 6A-1 shows a therapeutic device 100 comprising a
container 130 having a penetrable barrier 184 disposed on a first
end, a porous structure 150 disposed on a second end to release
therapeutic agent for an extended period, and a retention structure
120 comprising an extension protruding outward from the container
to couple to the sclera and the conjunctiva. The extending
protrusion of the retention structure may comprise a diameter 120D.
The retention structure may comprise an indentation 1201 sized to
receive the sclera. The container may comprise a tubular barrier
160 that defines at least a portion of the reservoir, and the
container may comprise a width, for example a diameter 134. The
diameter 134 can be sized within a range, for example within a
range from about 0.5 to about 4 mm, for example within a range from
about 1 to 3 mm and can be about 2 mm, for example. The container
may comprise a length 136, sized so as to extend from the
conjunctiva to the vitreous to release the therapeutic agent into
the vitreous. The length 136 can be sized within a range, for
example within a range from about 2 to about 14 mm, for example
within a range from about 4 to 10 mm and can be about 7 mm, for
example. The volume of the reservoir may be substantially
determined by an inner cross-sectional area of the tubular
structure and distance from the porous structure to the penetrable
barrier. The retention structure may comprise an annular extension
having a retention structure diameter greater than a diameter of
the container. The retention structure may comprise an indentation
configured to receive the sclera when the extension extends between
the sclera and the conjunctive. The penetrable barrier may comprise
a septum disposed on a proximal end of the container, in which the
septum comprises a barrier that can be penetrated with a sharp
object such as a needle for injection of the therapeutic agent. The
porous structure may comprise a cross sectional area 150A sized to
release the therapeutic agent for the extended period.
[0269] The porous structure 150 may comprise a first side coupled
to the reservoir 15051 and a second side to couple to the vitreous
150S2. The first side may comprise a first area 150A1 and the
second side may comprise a second area 150A2. The porous structure
may comprise a thickness 105T. The porous structure many comprise a
diameter 150D.
[0270] The volume of the reservoir 140 may comprise from about 5 uL
to about 2000 uL of therapeutic agent, or for example from about 10
uL to about 200 uL of therapeutic agent.
[0271] The therapeutic agent stored in the reservoir of the
container comprises at least one of a solid comprising the
therapeutic agent, a solution comprising the therapeutic agent, a
suspension comprising the therapeutic agent, particles comprising
the therapeutic agent adsorbed thereon, or particles reversibly
bound to the therapeutic agent. For example, reservoir may comprise
a suspension of a cortico-steroid such as triamcinolone acetonide
to treat inflammation of the retina. The reservoir may comprise a
buffer and a suspension of a therapeutic agent comprising
solubility within a range from about 1 ug/mL to about 100 ug/mL,
such as from about 1 ug/mL to about 40 ug/mL. For example, the
therapeutic agent may comprise a suspension of triamcinolone
acetonide having a solubility of approximately 19 ug/mL in the
buffer at 37C when implanted.
[0272] The release rate index may comprise many values, and the
release rate index with the suspension may be somewhat higher than
for a solution in many variations, for example. The release rate
index may be no more than about 5, and can be no more than about
2.0, for example no more than about 1.5, and in many variations may
be no more than about 1.2, so as to release the therapeutic agent
with therapeutic amounts for the extended time.
[0273] The therapeutic device, including for example, the retention
structure and the porous structure, may be sized to pass through a
lumen of a catheter.
[0274] The porous structure may comprise a needle stop that limits
penetration of the needle. The porous structure may comprise a
plurality of channels configured for the extended release of the
therapeutic agent. The porous structure may comprise a rigid
sintered material having characteristics suitable for the sustained
release of the material.
[0275] FIG. 6A-2 shows a therapeutic device as in FIG. 6A-1
comprising a rounded distal end.
[0276] FIG. 6B shows a rigid porous structure as in FIG. 6A-1. The
rigid porous structure 158 comprises a plurality of interconnecting
channels 156. The porous structure comprises a sintered material
composed of interconnected grains 155 of material. The
interconnected grains of material define channels that extend
through the porous material to release the therapeutic agent. The
channels may extend around the sintered grains of material, such
that the channels comprise interconnecting channels extending
through the porous material.
[0277] The rigid porous structure can be configured for injection
of the therapeutic agent into the container in many ways. The
channels of the rigid porous structure may comprise substantially
fixed channels when the therapeutic agent is injected into the
reservoir with pressure. The rigid porous structure comprises a
hardness parameter within a range from about 160 Vickers to about
500 Vickers. In some variations the rigid porous structure is
formed from sintered stainless steel and comprises a hardness
parameter within a range from about 200 Vickers to about 240
Vickers. In some variations it is preferred to inhibit ejection of
the therapeutic agent through the porous structure during filling
or refilling the reservoir of the therapeutic device with a fluid.
In these variations the channels of the rigid porous structure
comprise a resistance to flow of an injected solution or suspension
through a thirty gauge needle such that ejection of said solution
or suspension through the rigid porous structure is substantially
inhibited when said solution or suspension is injected into the
reservoir of the therapeutic device. Additionally, these variations
may optionally comprise an evacuation vent or an evacuation
reservoir under vacuum or both to facilitate filling or refilling
of the reservoir.
[0278] The reservoir and the porous structure can be configured to
release therapeutic amounts of the therapeutic agent in many ways.
The reservoir and the porous structure can be configured to release
therapeutic amounts of the therapeutic agent corresponding to a
concentration of at least about 0.1 ug per ml of vitreous humor for
an extended period of at least about three months. The reservoir
and the porous structure can be configured to release therapeutic
amounts of the therapeutic agent corresponding to a concentration
of at least about 0.1 ug per ml of vitreous humor and no more than
about 10 ug per ml for an extended period of at least about three
months. The therapeutic agent may comprise at least a fragment of
an antibody and a molecular weight of at least about 10 k Daltons.
For example, the therapeutic agent may comprise one or more of
ranibizumab or bevacizumab. Alternatively or in combination, the
therapeutic agent may comprise a small molecule drug suitable for
sustained release. The reservoir and the porous structure may be
configured to release therapeutic amounts of the therapeutic agent
corresponding to a concentration of at least about 0.1 ug per ml of
vitreous humor and no more than about 10 ug per ml for an extended
period of at least about three months or at least about six months.
The reservoir and the porous structure can be configured to release
therapeutic amounts of the therapeutic agent corresponding to a
concentration of at least about 0.1 ug per ml of vitreous humor and
no more than about 10 ug per ml for an extended period of at least
about twelve months or at least about two years or at least about
three years. The reservoir and the porous structure may also be
configured to release therapeutic amounts of the therapeutic agent
corresponding to a concentration of at least about 0.01 ug per ml
of vitreous humor and no more than about 300 ug per ml for an
extended period of at least about 3 months or 6 months or 12 months
or 24 months.
[0279] The channels of the rigid porous structure comprise a
hydrogel configured to limit a size of molecules passed through the
channels of the rigid porous structure. For example, the hydrogel
can be formed within the channels and may comprise an acrylamide
gel. The hydrogel comprises a water content of at least about 70%.
For example, the hydrogel may comprise a water content of no more
than about 90% to limit molecular weight of the therapeutic agent
to about 30 k Daltons. The hydrogel comprises a water content of no
more than about 95% to limit molecular weight of the therapeutic
agent to about 100 k Daltons. The hydrogel may comprise a water
content within a range from about 90% to about 95% such that the
channels of the porous material are configured to pass Lucentis.TM.
and substantially not pass Avastin.TM..
[0280] The rigid porous structure may comprise a composite porous
material that can readily be formed in or into a wide range of
different shapes and configurations. For example, the porous
material can be a composite of a metal, aerogel or ceramic foam
(i.e., a reticulated inter-cellular structure in which the interior
cells are interconnected to provide a multiplicity of pores passing
through the volume of the structure, the walls of the cells
themselves being substantially continuous and non-porous, and the
volume of the cells relative to that of the material forming the
cell walls being such that the overall density of the intercellular
structure is less than about 30 percent theoretical density)
through pores of which are impregnated with a sintered powder or
aerogel. The thickness, density, porosity and porous
characteristics of the final composite porous material can be
varied to conform with the desired release of the therapeutic
agent.
[0281] Variations comprise a method of making an integral (i.e.,
single-component) porous structure. The method may comprise
introducing particles into a mold having a desired shape for the
porous structure. The shape includes a proximal end defining a
plurality of proximal porous channel openings to couple to the
reservoir, a distal end defining a plurality of outlet channel
openings to couple to the vitreous humor of the eye, a plurality of
blind inlet cavities extending into the filter from the proximal
openings, and a plurality of blind outlet cavities extending into
the porous structure from the outlet channel openings. The method
further includes applying pressure to the mold, thereby causing the
particles to cohere and form a single component, and sintering the
component to form the porous structure. The particles can be
pressed and cohere to form the component without the use of a
polymeric binder, and the porous structure can be formed
substantially without machining.
[0282] The mold can be oriented vertically with the open other end
disposed upwardly, and metal powder having a particle size of less
than 20 micrometers can be introduced into the cavity through the
open end of the mold while vibrating the mold to achieve
substantially uniform packing of the metal powder in the cavity. A
cap can be placed on the open other end of the mold, and pressure
is applied to the mold and thereby to the metal powder in the
cavity to cause the metal powder to cohere and form a cup-shaped
powdered metal structure having a shape corresponding to the mold.
The shaped powdered metal structure can be removed from the mold,
and sintered to obtain a porous sintered metal porous
structure.
[0283] The metal porous structure can be incorporated into the
device by a press fit into an impermeable structure with an opening
configured to provide a tight fit with the porous structure. Other
means, such as welding, can be used to incorporate the porous
structure into the device. Alternatively, or in combination, the
powdered metal structure can be formed in a mold where a portion of
the mold remains with the shaped powdered metal structure and
becomes part of the device. This may be advantageous in achieving a
good seal between the porous structure and the device.
[0284] The release rate of therapeutic agent through a porous body,
such as a sintered porous metal structure or a porous glass
structure, may be described by diffusion of the therapeutic agent
within the porous structure with the channel parameter, and with an
effective diffusion coefficient equal to the diffusion coefficient
of the therapeutic agent in the liquid that fills the reservoir
multiplied by the Porosity and a Channel Parameter of the porous
body:
Release Rate=(DP/F)A(c.sub.R-c.sub.v)/L, where:
c.sub.R=Concentration in reservoir c.sub.v=Concentration outside of
the reservoir or in the vitreous D=Diffusion coefficient of the
therapeutic agent in the reservoir solution P=Porosity of porous
structure F=Channel parameter that may correspond to a tortuosity
parameter of channels of porous structure A=Area of porous
structure L=Thickness (length) of porous structure
Cumulative Release=1-cR/cR0=1-exp((-DPA/FLV.sub.R)t), where
t=time, Vr=reservoir volume
[0285] The release rate index can (hereinafter "RRI") be used to
determine release of the therapeutic agent. The RRI may be defined
as (PA/FL), and the RRI values herein will have units of mm unless
otherwise indicated. Many of the porous structures used in the
therapeutic delivery devices described herein have an RRI of no
more than about 5.0, often no more than about 2.0, and can be no
more than about 1.2 mm.
[0286] The channel parameter can correspond to an elongation of the
path of the therapeutic agent released through the porous
structure. The porous structure may comprise many interconnecting
channels, and the channel parameter can correspond to an effective
length that the therapeutic agent travels along the interconnecting
channels of the porous structure from the reservoir side to the
vitreous side when released. The channel parameter multiplied by
the thickness (length) of the porous structure can determine the
effective length that the therapeutic agent travels along the
interconnecting channels from the reservoir side to the vitreous
side. For example, the channel parameter (F) of about 1.5
corresponds to interconnecting channels that provide an effective
increase in length traveled by the therapeutic agent of about 50%,
and for a 1 mm thick porous structure the effective length that the
therapeutic agent travels along the interconnecting channels from
the reservoir side to the vitreous side corresponds to about 1.5
mm. The channel parameter (F) of at least about 2 corresponds to
interconnecting channels that provide an effective increase in
length traveled by the therapeutic agent of about 100%, and for a 1
mm thick porous structure the effective length that the therapeutic
agent travels along the interconnecting channels from the reservoir
side to the vitreous side corresponds to at least about 2.0 mm. As
the porous structure comprises many interconnecting channels that
provide many alternative paths for release of the therapeutic
agent, blockage of some of the channels provides no substantial
change in the effective path length through the porous structure as
the alternative interconnecting channels are available, such that
the rate of diffusion through the porous structure and the release
of the therapeutic agent are substantially maintained when some of
the channels are blocked.
[0287] If the reservoir solution is aqueous or has a viscosity
similar to water, the value for the diffusion coefficient of the
therapeutic agent (TA) in water at the temperature of interest may
be used. The following equation can be used to estimate the
diffusion coefficient at 37.degree. C. from the measured value of
D.sub.BSA,20C=6.1 e-7 cm2/s for bovine serum albumin in water at
20.degree. C. (Molokhia et al, Exp Eye Res 2008):
D.sub.TA,37C=D.sub.BSA,20C(.eta..sub.20C/.eta..sub.37C)(MW.sub.BSA/MW.su-
b.TA).sup.1/3 where
MW refers to the molecular weight of either BSA or the test
compound and .eta. is the viscosity of water. The following lists
diffusion coefficients of proteins of interest.
TABLE-US-00013 Diff Coeff Compound MW Temp C. (cm{circumflex over (
)}2/s) BSA 69,000 20 6.1E-07 BSA 69,000 37 9.1E-07 Ranibizumab
48,000 20 6.9E-07 Ranibizumab 48,000 37 1.0E-06 Bevacizumab 149,000
20 4.7E-07 Bevacizumab 149,000 37 7.1E-07
Small molecules have a diffusion coefficient similar to fluorescein
(MW=330, D=4.8 to 6 e-6 cm.sup.2/s from Stay, M S et al. Pharm Res
2003, 20(1), pp. 96-102). For example, the small molecule may
comprise a glucocorticoid such as triamcinolone acetonide having a
molecular weight of about 435.
[0288] The porous structure comprises a porosity, a thickness, a
channel parameter and a surface area configured to release
therapeutic amounts for the extended period. The porous material
may comprise a porosity corresponding to the fraction of void space
of the channels extending within the material. The porosity
comprises a value within a range from about 3% to about 70%. In
other variations, the porosity comprises a value with a range from
about 5% to about 10% or from about 10% to about 25%, or for
example from about 15% to about 20%. Porosity can be determined
from the weight and macroscopic volume or can be measured via
nitrogen gas adsorption
[0289] The porous structure may comprise a plurality of porous
structures, and the area used in the above equation may comprise
the combined area of the plurality of porous structures.
[0290] The channel parameter may comprise a fit parameter
corresponding to the tortuosity of the channels. For a known
porosity, surface area and thickness of the surface parameter, the
curve fit parameter F, which may correspond to tortuosity of the
channels can be determined based on experimental measurements. The
parameter PA/FL can be used to determine the desired sustained
release profile, and the values of P, A, F and L determined. The
rate of release of the therapeutic agent corresponds to a ratio of
the porosity to the channel parameter, and the ratio of the
porosity to the channel parameter can be less than about 0.5 such
that the porous structure releases the therapeutic agent for the
extended period. For example, the ratio of the porosity to the
channel parameter is less than about 0.1 or, for example, less than
about 0.2 such that the porous structure releases the therapeutic
agent for the extended period. The channel parameter may comprise a
value of at least about 1, such as at least about 1.2. For example,
the value of the channel parameter may comprise at least about 1.5,
for example at least about 2, and may comprise at least about 5.
The channel parameter can be within a range from about 1.1 to about
10, for example within a range from about 1.2 to about 5. The
channel parameter to release the therapeutic agent for an intended
release rate profile can be determined empirically.
[0291] The area in the model originates from the description of
mass transported in units of flux; i.e., rate of mass transfer per
unit area. For simple geometries, such as a porous disc mounted in
an impermeable sleeve of equal thickness, the area corresponds to
one face of the disc and the thickness, L, is the thickness of the
disc. For more complex geometries, such as a porous body in the
shape of a truncated cone, the effective area is a value in between
the area where therapeutic agent enters the porous body and the
area where therapeutic agent exits the porous body.
[0292] A model can be derived to describe the release rate as a
function of time by relating the change of concentration in the
reservoir to the release rate described above. This model assumes a
solution of therapeutic agent where the concentration in the
reservoir is uniform. In addition, the concentration in the
receiving fluid or vitreous is considered negligible (c.sub.V=0).
Solving the differential equation and rearrangement yields the
following equations describing the concentration in the reservoir
as a function of time, t, and volume of the reservoir, V.sub.R, for
release of a therapeutic agent from a solution in a reservoir
through a porous structure.
c.sub.R=C.sub.R0 exp((-DPA/FLV.sub.R)t)
and Cumulative Release=1-c.sub.R/c.sub.R0
[0293] When the reservoir contains a suspension, the concentration
in reservoir, c.sub.R, is the dissolved concentration in
equilibrium with the solid (i.e., the solubility of the therapeutic
agent). In this case, the concentration in the reservoir is
constant with time, the release rate is zero order, and the
cumulative release increases linearly with time until the time when
the solid is exhausted.
[0294] Therapeutic concentrations for many ophthalmic therapeutic
agents may be determined experimentally by measuring concentrations
in the vitreous humor that elicit a therapeutic effect. Therefore,
there is value in extending predictions of release rates to
predictions of concentrations in the vitreous. A one-compartment
model may be used to describe elimination of therapeutic agent from
eye tissue.
[0295] Current intravitreal administration of therapeutic agents
such as Lucentis.TM. involves a bolus injection. A bolus injection
into the vitreous may be modeled as a single exponential with rate
constant, k=0.693/half-life and a cmax=dose/V.sub.v where V.sub.v
is the vitreous volume. As an example, the half-life for
ranibizumab is approximately 3 days in the rabbit and the monkey
(Gaudreault et al.) and 9 days in humans (Lucentis.TM. package
insert). The vitreous volume is approximately 1.5 mL for the rabbit
and monkey and 4.5 mL for the human eye. The model predicts an
initial concentration of 333 ug/mL for a bolus injection of 0.5 mg
Lucentis.TM. into the eye of a monkey. This concentration decays to
a vitreous concentration of 0.1 ug/mL after about a month.
[0296] For devices with extended release, the concentration in the
vitreous changes slowly with time. In this situation, a model can
be derived from a mass balance equating the release rate from the
device (described by equations above) with the elimination rate
from the eye, k c.sub.v V.sub.v. Rearrangement yields the following
equation for the concentration in the vitreous:
c.sub.v=Release rate from device/kV.sub.v.
[0297] Since the release rate from a device with a solution of
therapeutic agent decreases exponentially with time, the
concentration in the vitreous decreases exponentially with the same
rate constant. In other words, vitreous concentration decreases
with a rate constant equal to D PA/FL V.sub.R and, hence, is
dependent on the properties of the porous structure and the volume
of the reservoir.
[0298] Since the release rate is zero order from a device with a
suspension of therapeutic agent, the vitreous concentration will
also be time-independent. The release rate will depend on the
properties of the porous structure via the ratio, PA/FL, but will
be independent of the volume of the reservoir until the time at
which the drug is exhausted.
[0299] The channels of the rigid porous structure can be sized in
many ways to release the intended therapeutic agent. For example,
the channels of the rigid porous structure can be sized to pass
therapeutic agent comprising molecules having a molecular weight of
at least about 100 Daltons or for example, at least about 50 k
Daltons. The channels of the rigid porous structure can be sized to
pass therapeutic agent comprising molecules comprising a
cross-sectional size of no more than about 10 nm. The channels of
the rigid porous structure comprise interconnecting channels
configured to pass the therapeutic agent among the interconnecting
channels. The rigid porous structure comprises grains of rigid
material and wherein the interconnecting channels extend at least
partially around the grains of rigid material to pass the
therapeutic agent through the porous material. The grains of rigid
material can be coupled together at loci of attachment and wherein
the interconnecting channels extend at least partially around the
loci of attachment.
[0300] The porous structure and reservoir may be configured to
release the glucocorticoid for an extended time of at least about
six months with a therapeutic amount of glucocorticoid of
corresponding to an in situ concentration within a range from about
0.05 ug/mL to about 4 ug/mL, for example from 0.1 ug/mL to about 4
ug/mL, so as to suppress inflammation in the retina-choroid.
[0301] The porous structure comprises a sintered material. The
sintered material may comprise grains of material in which the
grains comprise an average size of no more than about 20 um. For
example, the sintered material may comprise grains of material in
which the grains comprise an average size of no more than about 10
um, an average size of no more than about 5 um, or an average size
of no more than about 1 um. The channels are sized to pass
therapeutic quantities of the therapeutic agent through the
sintered material for the extended time based on the grain size of
the sintered material and processing parameters such as compaction
force and time and temperature in the furnace. The channels can be
sized to inhibit penetration of microbes including bacteria and
fungal spores through the sintered material.
[0302] The sintered material comprises a wettable material to
inhibit bubbles within the channels of the material.
[0303] The sintered material comprises at least one of a metal, a
ceramic, a glass or a plastic. The sintered material may comprise a
sintered composite material, and the composite material comprises
two or more of the metal, the ceramic, the glass or the plastic.
The metal comprises at least one of Ni, Ti, nitinol, stainless
steel including alloys such as 304, 304L, 316 or 316L, cobalt
chrome, elgiloy, hastealloy, c-276 alloy or Nickel 200 alloy. The
sintered material may comprise a ceramic. The sintered material may
comprise a glass. The plastic may comprise a wettable coating to
inhibit bubble formation in the channels, and the plastic may
comprise at least one of polyether ether ketone (PEEK),
polyethylene, polypropylene, polyimide, polystyrene, polycarbonate,
polyacrylate, polymethacrylate, or polyamide.
[0304] The rigid porous structure may comprise a plurality of rigid
porous structures coupled to the reservoir and configured to
release the therapeutic agent for the extended period. For example,
additional rigid porous structure can be disposed along the
container, for example the end of the container may comprise the
porous structure, and an additional porous structure can be
disposed along a distal portion of the container, for example along
a tubular sidewall of the container.
[0305] The therapeutic device can be tuned to release therapeutic
amounts of the therapeutic agent above the minimum inhibitory
concentration for an extended time based on bolus injections of the
therapeutic agent. For example, the volume of the chamber of the
reservoir can be sized with the release rate of the porous
structure based on the volume of the bolus injection. A formulation
of a therapeutic agent can be provided, for example a known
intravitreal injection formulation. The therapeutic agent can be
capable of treating the eye with bolus injections, such that the
formulation has a corresponding period between each of the bolus
injections to treat the eye. For example the bolus injections may
comprise monthly injections. Each of the bolus injections comprises
a volume of the formulation, for example 50 uL. Each of the bolus
injections of the therapeutic agent may correspond to a range of
therapeutic concentrations of the therapeutic agent within the
vitreous humor over the time course between injections, and the
device can be tuned so as to release therapeutic amounts of the
therapeutic agent such that the vitreous concentrations of the
released therapeutic agent from the device are within the range of
therapeutic concentrations of the corresponding bolus injections.
For example, the therapeutic agent may comprise a minimum
inhibitory concentration to treat the eye, for example at least
about 3 ug/mL, and the values of the range of therapeutic
concentrations can be at least about 3 ug/mL. The therapeutic
device can be configured to treat the eye with an injection of the
monthly volume of the formulation into the device, for example
through the penetrable barrier. The reservoir of the container has
a chamber to contain a volume of the therapeutic agent, for example
35 uL, and a mechanism to release the therapeutic agent from the
chamber to the vitreous humor.
[0306] The volume of the container and the release mechanism can be
tuned to treat the eye with the therapeutic agent with vitreous
concentrations within the therapeutic range for an extended time
with each injection of the quantity corresponding to the bolus
injection, such that the concentration of the therapeutic agent
within the vitreous humor remains within the range of therapeutic
concentrations and comprises at least the minimum inhibitory
concentration. The extended time may comprise at least about twice
the corresponding period of the bolus injections. The release
mechanism comprises one or more of a porous frit, a sintered porous
frit, a permeable membrane, a semi-permeable membrane, a capillary
tube or a tortuous channel, nano-structures, nano-channels or
sintered nano-particles. For example, the porous frit may comprise
a porosity, cross-sectional area, and a thickness to release the
therapeutic agent for the extended time. The volume of the
container reservoir can be sized in many ways in relation to the
volume of the injected formulation and can be larger than the
volume of injected formulation, smaller than the volume of injected
formulation, or substantially the same as the volume of injected
formulation. For example, the volume of the container may comprise
no more than the volume of the formulation, such that at least a
portion of the formulation injected into the reservoir passes
through the reservoir and comprises a bolus injection to treat the
patient immediately. As the volume of the reservoir is increased,
the amount of formulation released to the eye through the porous
structure upon injection can decrease along with the concentration
of active ingredient of the therapeutic agent within the reservoir,
and the release rate index can be increased appropriately so as to
provide therapeutic amounts of therapeutic agent for the extended
time. For example, the volume of the reservoir of the container can
be greater than the volume corresponding to the bolus injection, so
as to provide therapeutic amounts for at least about five months,
for example six months, with an injection volume corresponding to a
monthly injection of Lucentis.TM.. For example, the formulation may
comprise Lucentis.TM. modified in accordance with variations, 50
uL, and the reservoir may comprise a volume of about 100 uL and
provide therapeutic vitreous concentrations of at least about 3
ug/mL for six months with 50 uL of Lucentis.TM. injected into the
reservoir.
[0307] The chamber may comprise a substantially fixed volume and
the release rate mechanism comprises a substantially rigid
structure to maintain release of the therapeutic agent above the
minimum inhibitory concentration for the extended time with each
injection of a plurality of injections.
[0308] A first portion of the injection may pass through the
release mechanism and treat the patient when the formulation is
injected, and a second portion of the formulation can be contained
in the chamber when the formulation is injected.
[0309] FIG. 6B-1 shows interconnecting channels 156 extending from
first side 15051 to second side 15052 of the porous structure as in
FIG. 6B. The interconnecting channels 156 extend to a first opening
158A1, a second opening 158A2 and an Nth opening 158AN on the first
side 15051. The interconnecting channels 156 extend to a first
opening 158B1, a second opening 158B2 and an Nth opening 158BN on
the second side 150S2. Each of the openings of the plurality of
channels on the first side is connected to each of the openings of
plurality of channels on the second side, such that effective
length traveled along the channels is greater than thickness 150T.
The channel parameter can be within a range from about 1.1 to about
10, such that the effective length is within a range from about 1.1
to 10 times the thickness 150T. For example, the channel parameter
can be about 1 and the porosity about 0.2, such that the effective
length corresponds to at least about 5 times the thickness
150T.
[0310] The rigid porous structure can be shaped and molded in many
ways for example with tubular shapes, conical shapes, discs and
hemispherical shapes. The rigid porous structure may comprise a
molded rigid porous structure. The molded rigid porous structure
may comprise at least one of a disk, a helix or a tube coupled to
the reservoir and configured to release the therapeutic agent for
the extended period.
[0311] The formulation can be injected into many therapeutic
devices, for example as described in U.S. Pat. Nos. 5,466,233;
5,972,369; 6,719,750; and U.S. Patent Publication No. 2003/0014036
A1.
[0312] The porous structure 150 may comprise a plurality of
elongate nano-channels extending from a first side of the porous
structure to a second side of the porous structure. The porous
structure 150 may comprise a rigid material having the holes formed
thereon, and the holes may comprise a maximum dimension across such
as a diameter. The diameter of the nano-channels may comprise a
dimension across, for example from about 10 nm across, to about
1000 nm across, or larger. The channels may be formed with etching
of the material, for example lithographic etching of the material.
The channels may comprise substantially straight channels such that
the channel parameter F comprises about 1, and the parameters area
A, and thickness or length L correspond to the combined
cross-sectional area of the channels and the thickness or length of
the porous structure.
[0313] The porous structure 150 may comprise interconnecting
nano-channels, for example formed with a sintered
nano-material.
[0314] The injection of therapeutic agent into the device 100 as
described herein can be performed before implantation into the eye
or alternatively when the therapeutic device is implanted into the
eye.
[0315] FIG. 7 shows a therapeutic device 100 coupled to an injector
701 that removes material from the device and injects therapeutic
agent 702 into the device. The injector picks up spent media 703
and refills the therapeutic device with fresh therapeutic agent.
The therapeutic agent is injected into the therapeutic device. The
spent media is pulled up into the injector. The injector may
comprise a stopper mechanism 704.
[0316] The injector 701 may comprise a first container 702C to
contain a formulation of therapeutic agent 702 and a second
container 703C to receive the spent media 703. Work in relation to
variations suggests that the removal of spent media 703 comprising
material from the container reservoir of the therapeutic device can
remove particulate from the therapeutic device, for example
particles comprised of aggregated therapeutic agent such as
protein. The needle 189 may comprise a double lumen needle with a
first lumen coupled to the first container and a second lumen
coupled to the second container, such that spent media 703 passes
from the container reservoir of device 100 to the injector. A valve
703V, for example a vent, can be disposed between the second lumen
and the second container. When the valve is open and therapeutic
agent is injected, spent media 703 from the container reservoir of
the therapeutic device 100 passes to the second container of the
injector, such that at least a portion of the spent media within
the therapeutic device is exchanged with the formulation. When the
valve is closed and the therapeutic agent is injected, a portion of
the therapeutic agent passes from the reservoir of the therapeutic
device into the eye. For example, a first portion of formulation of
therapeutic agent can be injected into therapeutic device 100 when
the valve is open such that the first portion of the formulation is
exchanged with material disposed within the reservoir; the valve is
then closed and a second portion of the formulation is injected
into therapeutic device 100 such that at least a portion of the
first portion passes through the porous structure into the eye.
Alternatively or in combination, a portion of the second portion of
injected formulation may pass through the porous structure when the
second portion is injected into the eye. The second portion of
formulation injected when the valve is closed may correspond to a
volume of formulation that passes through the porous structure into
the vitreous humor to treat the patient immediately.
[0317] The needle 189 may comprise a dual lumen needle, for example
as described in U.S. patent application Ser. No. 12/696,678, filed
Jan. 29, 2010, entitled "POSTERIOR SEGMENT DRUG DELIVERY,"
published Oct. 7, 2010 as U.S. Patent Publication No. 2010/0255061,
the full disclosure of which has been previously incorporated
herein by reference.
[0318] The penetrable barrier 184, for example the septum, can be
inserted into the access port 180. The penetrable barrier may
comprise an elastic material sized such that the penetrable barrier
can be inserted into the access port 180. The penetrable barrier
may comprise one or more elastic materials such as siloxane or
rubber. The penetrable barrier may comprise tabs 184T to retain the
penetrable barrier in the access port. The penetrable barrier 184
may comprise a beveled upper rim 184R sized to seal the access port
180. The access port 180 of the reservoir container 130 may
comprise a beveled upper surface to engage the beveled rim and seal
the penetrable barrier against the access port 180 when the tabs
184T engage an inner annular or elongate channel of the access
port. The penetrable barrier 184 may comprise an opaque material,
for example a grey material, for example silicone, such that the
penetrable barrier can be visualized by the patient and treating
physician.
[0319] The reservoir container 130 of the device may comprise a
rigid biocompatible material that extends at least from the
retention structure to the rigid porous structure, such that the
reservoir comprises a substantially constant volume when the
therapeutic agent is released with the rigid porous structure so as
to maintain a stable release rate profile, for example when the
patient moves. Alternatively or in combination, the reservoir
container 130 may comprise an optically transmissive material such
that the reservoir container 130 can be translucent, for example
transparent, such that the chamber of reservoir 140 can be
visualized when the device is loaded with therapeutic agent outside
the patient prior to implantation, for example when injected with a
formulation of therapeutic agent prior to implantation in the
physician's office. This visualization of the reservoir 140 can be
helpful to ensure that the reservoir 140 is properly filled with
therapeutic agent by the treating physician or assistant prior to
implantation. The reservoir container may comprise one or more of
many biocompatible materials such as acrylates,
polymethylmethacrylate, siloxanes, metals, titanium stainless
steel, polycarbonate, polyetheretherketone (PEEK), polyethylene,
polyethylene terephthalate (PET), polyimide, polyamide-imide,
polypropylene, polysulfone, polyurethane, polyvinylidene fluoride
or PTFE. The biocompatible material of the reservoir container may
comprise an optically transmissive material such as one or more of
acrylate, polyacrylate, methlymethacraylate, polymethlymethacrylate
(PMMA), polyacarbonate or siloxane. The reservoir container 130 can
be machined from a piece of material, or injection molded, so as to
form the retention structure 120 comprising flange 122 and the
elongate narrow portion 120NE. The flange 122 may comprise a
translucent material such that the physician can visualize tissue
under the flange to assess the patient and to decrease appearance
of the device 100 when implanted. The reservoir container 130 may
comprise a channel extending along axis 100A from the access port
180 to porous structure 150, such that formulation injected into
device 100 can be released in accordance with the volume of the
reservoir and release rate of the porous structure 150, as
described herein. The porous structure 150 can be affixed to the
distal end of therapeutic device 100, for example with glue.
Alternatively or in combination, the distal end of the reservoir
container 130 may comprise an inner diameter sized to receive the
porous structure 150, and the reservoir container 130 may comprise
a stop to position the porous structure 150 at a predetermined
location on the distal end so as to define a predetermined size of
reservoir 140.
[0320] Tuning of Therapeutic Device for Sustained Release Based on
an Injection of a Formulation of Therapeutic Agent Having One or
More of a Large Molecular Weight Stabilizer, Erodible Particles, Or
Binding Agent Particles, or Combinations Thereof
[0321] The tuned release can be used to determine the release of
the therapeutic agent and stabilizer combined with one or more of
the binding agent or erodible material as described herein. One or
more of calculations, computer modeling, numerical simulations or
finite element analysis can be used to determine the release rate
profile of the therapeutic agent, as described herein. The affect
of one or more of the stabilizer, reversible binding agent
particles, or erodible particles on the modulation of the rate of
release can be determined, for example.
[0322] In many variations, the stabilizer may comprise a molecular
weight that corresponds to at least about 20% of the molecular
weight of the therapeutic agent.
[0323] The amount of stabilizer and release rate profile of the
stabilizer through the porous structure can be determined based on
the concentration of the stabilizer, the volume of the reservoir,
and the release rate index of the porous structure 150. The release
rate profile may also include the fraction of stabilizer complexed
with the therapeutic agent and the corresponding diffusion
coefficient of the complexed therapeutic agent.
[0324] The reversible binding characteristics of the therapeutic
agent and binding agent can be used to determine the release rate
profile. The amount of therapeutic agent in solution, the amount of
therapeutic agent complexed with the stabilizer, and the amount of
therapeutic agent reversibly bound to the binding agent can be
determined, for example as a function of pH. The amount of
therapeutic agent in solution and the amount of therapeutic agent
complexed with the stabilizer and corresponding diffusion
coefficients can be used to determine the rate of release of the
therapeutic agent through the porous structure. The rate of release
of therapeutic agent through the porous structure may comprise the
rate of release of the therapeutic agent in solution and the
therapeutic agent complexed with the stabilizer.
[0325] In many variations, the binding agent is sized such that
diffusion through the porous structure is substantially inhibited,
and the particles of binding agent may have dimensions greater than
the channels of the porous structure 150, or smaller than the
channels of the porous structure. For example, particles greater
than 5 um may not pass through the porous structure, even when
there is convection of fluid through the porous structure such as
when the device is refilled with formulation (i.e., the particles
may be trapped in the porous structure as in a depth filter or may
be trapped on the surface of the porous structure as in a surface
filter). Although particles having a size as large as the size of
the channels of porous structure 150 may pass through the channels
of the porous structure under convection, these particles may have
no substantial diffusive flux because the diffusion coefficient may
be substantially larger than the diffusion coefficient of the
therapeutic agent. For example, particles having a size of about
0.050 um (50 nm) may have a diffusion coefficient that is about one
tenth of the diffusion coefficient of ranibizumab, for example. The
particles may comprise a size within a range from about 50 um to
about 0.5 um, for example, based substantially on the molecular
weight of the therapeutic agent and the size of the channels of the
porous structure 150.
[0326] The rate of erosion of the erodible particles can be used to
determine the rate of generation of protons to maintain the pH in
the reservoir chamber below about 7. The rate of generation of
protons may correspond to one or more of the pH, ionic strength or
osmolarity of the components of the formulation 190 in the
reservoir chamber of the device.
[0327] The therapeutic device 100 can be tuned to deliver a target
therapeutic concentration profile based on the volume of
formulation injected into the device. The injected volume may
comprise a substantially fixed volume, for example within about
+/-30% of an intended pre-determined target volume. The volume of
the reservoir can be sized with the release rate index so as to
release the therapeutic agent for an extended time substantially
greater than the treatment time of a corresponding bolus injection.
The device can also be tuned to release the therapeutic agent based
on the half-life of the therapeutic agent in the eye. The device
volume and release rate index comprise parameters that can be tuned
together based on the volume of formulation injected and the
half-life of the therapeutic agent in the eye. The following
equations can be used to determine therapeutic device parameters
suitable for tuning the device.
Rate=Vr(dCr/dt)=-D(PA/TL)Cr
where Rate=Rate of release of therapeutic agent from device
Cr=concentration of therapeutic agent in reservoir Vr=volume of
reservoir D=Diffusion constant
PA/TL=RRI
P=porosity A=area T=tortuosity=F=channel parameter. For a
substantially fixed volume injection,
Cr0=(Injection Volume)(Concentration of Formulation)/Vr
[0328] Where Cr0=initial concentration in reservoir following
injection of formulation
For Injection Volume=50 uL
[0329] Cr0=(0.05 mL)(10 mg/mL)/Vr(1000 ug/1 mg)=500 ug/Vr
Rate=x(500 ug)exp(-xt)
where t=time
x=(D/Vr)(PA/TL)
With a mass balance on the vitreous
Vv(dCv/dt)=Rate from device=kVvCv
where Vv=volume of vitreous (about 4.5 ml) Cv=concentration of
therapeutic agent in vitreous k=rate of drug from vitreous
(proportional to 1/half-life of drug in vitreous) For the situation
appropriate for the variations as described herein where Cv remains
substantially constant and changes slowly with time (i.e. dCv/dt is
approximately 0),
Cv=(Rate from device)/(kVv)
Since kVv is substantially constant, the max value of Cv will
correspond to conditions that maximize the Rate from the device. At
a given time since injection into the device (e.g., 180 days), the
maximum Cv is found at the value of x that provides the maximum
rate. The optimal value of x satisfies
d(Rate)/dx=0 at a given time.
Rate=500(x)exp(-xt)=f(x)g(x) where f(x)=500.times. and
g(x)=exp(-xt)
d(Rate)/dx=f(x)g(x)+f(x)g'(x)=500(1-xt)exp(-xt)
For a given time, t, d(Rate)/dx=0 when 1-xt=0 and xt=1 The rate is
maximum when (D/Vr)(PA/TL)t=1. For a given volume, optimal
PA/TL=optimal RRI=Vr/(Dt) Therefore the highest Cv at a given time,
t, occurs for the optimal RRI=(PA/FL) for a given Vr. Also, the
ratio (Vr)/(RRI)=(Vr)/(PA/TL)=Dt will determine the optimal rate at
the time.
[0330] The above equations provide approximate optimized values
that, when combined with numerical simulations, can provide optimal
values of Vr and PA/TL. The final optimum value can depend on
additional parameters, such as the filling efficiency.
[0331] The above parameters can be used to determine the optimal
RRI, and the therapeutic device can be tuned to the volume of
formulation injected into the device with a device reservoir volume
and release rate index within about +/-50% of the optimal values,
for example +/-30% of the optimal values. For example, for an
optimal release rate index of the porous structure and an optimal
reservoir volume sized to receive a predetermined quantity of
therapeutic agent, e.g., 50 uL, so as to achieve therapeutic
concentrations above a minimum inhibitory concentration for a
predetermined extended time such as 90 days, the maximum volume of
the reservoir can be limited to no more than about twice the
optimal volume. This tuning of the reservoir volume and the porous
structure to the injected volume of the formulation can increase
the time of release of therapeutic amounts from the device as
compared to a much larger reservoir volume that receives the same
volume of injectable formulation. Although many examples as
described herein show a porous fit structure and reservoir volume
tuned together to receive a quantity of formulation and provide
release for an extended time, the porous structure tuned with the
reservoir may comprise one or more of a porous frit, a permeable
membrane, a semi-permeable membrane, a capillary tube or a tortuous
channel, nano-structures, nano-channels or sintered nano-particles,
and the release rate characteristics can be determined, for example
a release rate index, so as to tune the one or more porous
structures and the volume to receive the quantity of the
formulation and release therapeutic amounts for an extended
time.
[0332] As an example, the optimal RRI at 180 days can be determined
for a reservoir volume of about 125 uL. Based on the above
equations (Vr/Dt)=optimal RRI, such that the optimal RRI at 180
days is about 0.085 for the 50 uL formulation volume injected into
the device. The corresponding Cv is about 3.19 ug/mL at 180 days
based on the Rate of drug released from the device at 180 days and
the rate of the drug from the vitreous (k corresponding to a half
life of about 9 days). A device with a container reservoir volume
of 63 uL and RRI of 0.044 will also provide the optimal Cv at 180
days since the ratio of Vr to PA/TL is also optimal. Although an
optimal value can be determined, the therapeutic device can be
tuned to provide therapeutic amounts of drug at a targeted time,
for example 180 days, with many values of the reservoir volume and
many values of the release rate index near the optimal values, for
example within about +/-50% of the optimal values. Although the
volume of the reservoir can be substantially fixed, the volume of
the reservoir can vary, for example within about +/-50% as with an
expandable reservoir such as a balloon reservoir.
[0333] The half-life of the drug in the vitreous humor of the eye
can be determined based on the therapeutic agent and the type of
eye, for example human, rabbit or monkey, such that the half-life
may be determined based on the species of the eye, for example.
With at least some animal models the half life of the therapeutic
agent in the vitreous humor can be shorter than for human eyes, for
example by a factor of about two in at least some instances. For
example, the half-life of the therapeutic agent Lucentis.TM.
(ranibizumab) can be about nine days in the human eye and about two
to four days in the rabbit and monkey animal models. For small
molecules, the half life in the vitreous humor of the human eye can
be about two to three hours and can be about one hour in the monkey
and rabbit animal models. The therapeutic device can be tuned to
receive the volume of formulation based on the half-life of the
therapeutic agent in the human vitreous humor, or an animal
vitreous humor, or combinations thereof. The half life of the
therapeutic agent in the eye can be determined empirically based on
the type of eye and the therapeutic agent, such that the reservoir
and porous structure can be tuned together so as to receive the
volume of formulation and provide therapeutic amounts for the
extended time.
[0334] The formulation 190 may comprise components that result in
slowing the diffusion of the therapeutic agent until those
components are depleted via release to the vitreous (i.e.,
effective diffusion coefficient for the therapeutic agent that is
lower than that in a dilute solution of the therapeutic agent in
water). This may occur due to an increase in the viscosity of the
formulation or due to interactions. The component that slows down
diffusion may be a high concentration of the therapeutic agent
itself. As time proceeds, depletion of the component may correspond
to an increase in diffusion coefficient of the therapeutic agent,
thereby generating a release profile that is more constant.
[0335] Soluble, high molecular weight species that interact with
the therapeutic agent 110 of interest can be added to the
formation. The interaction of the therapeutic agent 110 and the
high molecular weight species will modulate the diffusion of the
therapeutic agent 110 through the solution, and thus affect the
release rate of the therapeutic agent 110 from the device 100.
[0336] Insoluble resins such as ion exchange resins or resins
containing hydrophobic groups that reversibly bind the therapeutic
agent 110 of interest can be added to the formulation. The
interaction of the resins and the therapeutic agent 110 will affect
the concentration of the therapeutic agent 110 in solution, and
thus modulate the release rate of the therapeutic agent 110 from
the device 100.
[0337] High molecular weight stabilizers can be added to the
formulation of the therapeutic agent 110 of interest. If the
molecular weight of the stabilizer is approximately the same as
that of the therapeutic agent 110, the two will diffuse from the
therapeutic device 100 at approximately the same rate, thus keeping
the ratio of stabilizer to therapeutic agent 110 approximately
constant over time. If the molecular weight of the stabilizer is
higher than that of the therapeutic agent 110, the ratio of
stabilizer to therapeutic agent 110 in the device will actually
increase over time. Both of these scenarios may increase the
stability of the therapeutic agent 110 in the device during the
delivery period.
[0338] FIG. 8A shows an apparatus comprising a first container 110C
having the formulation 190 of therapeutic agent and the second
container comprising a syringe 188 having erodible material 196 to
generate a proton of an acid. The particles of erodible material
can be mixed with the formulation of therapeutic agent within about
one day or less prior to injection such that erosion of the
material is decreased and also to maintain the pH of the
formulation above about 4.5, for example. The first container 110C
may contain formulation 190 comprising the therapeutic agent 110,
the stabilizer 192 and the reversible binding agent 194, and may
contain a buffer such as a phosphate buffer, for example. The
second container may comprise particles of erodible material in a
substantially dry configuration so as to decrease erosion of the
erodible material.
[0339] FIG. 8B shows the syringe 188 as in FIG. 8A used to prepare
the formulation of therapeutic agent prior to injection. A needle
189 can be inserted into container 110C and the formulation 190
drawn into the second container comprising syringe 188 so as to mix
the formulation prior to injection into therapeutic device 100. The
mixed formulation can be exchanged and the syringe may comprise an
exchange syringe, for example.
[0340] FIG. 8C shows an apparatus comprising a first container
having a commercially available formulation 110F of therapeutic
agent, and the second container comprising a syringe 188 having one
or more of, a stabilizer 192, a binding agent 194 comprising porous
particles, or an erodible material 196 to generate a proton of an
acid, in accordance with variations;
[0341] FIG. 8D shows the first and second containers as in FIG. 8C
used to prepare the formulation 190 of therapeutic agent prior to
injection. A needle 189 can be inserted into container 110C and the
formulation 110F drawn into the second container comprising syringe
188 so as to mix and provide the formulation 190 prior to injection
into therapeutic device 100. The mixed formulation can be exchanged
and the syringe may comprise an exchange syringe, for example. The
mixed formulation 190 prior to injection may comprise the
therapeutic agent 110, and one or more of a stabilizer 192, a
binding agent 194 comprising porous particles, or an erodible
material 196 to generate a proton of an acid. For example, prior to
drawing formulation 110F, the syringe 188 may comprise a stabilizer
192 and an erodible material 196 as a substantially dry
combination, and the formulation 110F of container 110C may
comprise Lucentis.TM.. Upon drawing an amount of the commercially
available formulation of Lucentis.TM. into the syringe, the
formulation 190 can be provided for injection into therapeutic
device 100. Syringe 188 may comprise a substantially single use
disposable syringe, for example.
[0342] The first and second containers can be configured in many
ways. For example, the second container may comprise a cartridge
having the erodible material stored therein, in which the cartridge
is configured to couple to a syringe having the formulation of the
therapeutic agent contained therein, so as to mix the erodible
material with the formulation upon injection into or exchange with
a therapeutic device. The cartridge may be configured to couple to
the needle and the syringe. For example, the cartridge may comprise
a first end to couple to the syringe and a second end to couple to
a needle. The container may comprise an amount of the particles
corresponding to a volume of the reservoir chamber of the device so
as to combine with an amount of the formulation corresponding to
the volume of the reservoir chamber, so as to provide a
concentration of particles and formulation loaded into device 100
corresponding to an intended target concentration of particles and
formulation.
Determination of Isoelectric Point of Ranibizumab
[0343] Determining the isoelectric point of a protein can be used
to determine the stability of a protein formulation, or to develop
a related assay. The isoelectric point of Lucentis.TM. can be
estimated from the primary amino acid sequence obtained from the
Novartis package insert of Lucentis.TM. marketed in Australia, CAS
number 347396-82-1.
[0344] The total number of ionizable acidic and basic amino acids
were tabulated. The pKa values of the ionizable side groups were
estimated using the Sigma-Aldrich table available on the World Wide
Web
(sigmaaldrich.com/life-science/metabolomics/bioultra-reagents/amino-acids-
.html).
[0345] The local environments in a protein can shift pKa values of
single amino acids, but average values should be useful to estimate
the overall effect. Table Y1 is a list of the sequence number
position and total number of the acidic and basic amino acids
present in Lucentis.TM.. The acidic groups of Asp and Glu total 32
amino acids (pKa .about.4), and the basic groups of Tyr, Lys, and
Arg, (pKa .about.10) total 61 amino acids. Therefore with twice as
many basic groups as acidic groups, Lucentis.TM. would be
classified as a basic protein with an isoelectric point of about
8.0 to 9.0. After estimating the number of charges versus pH of a
solution including the N-terminus and C-terminus, the plot in FIG.
4C shows the zero net charge state (isoelectric point) to be
achieved at about pH 8.0 to 9.0.
TABLE-US-00014 TABLE Y1 LucentisTM Amino Acid Positions and Total
Number Asp Glu His Tyr Lys Arg A-chain 28 1 31 27 43 19 63 6 107 32
65 38 73 46 174 54 76 66 90 57 210 60 98 67 111 89 230 80 127 87
154 158 94 139 218 222 95 153 227 99 211 101 216 102 219 103 220
109 224 155 228 186 204 B-chain 1 81 55 32 39 18 17 105 189 36 42
61 28 123 198 49 45 108 70 143 86 103 142 82 161 87 107 211 122 165
91 126 151 187 140 145 167 195 173 149 170 213 186 169 175 192 183
188 190 207 Total A & B 18 16 8 25 26 10
[0346] The charge as a function of pH can be determined for many
therapeutic agents as described herein, for example protein based
therapeutic agents comprising a Fab antibody fragment and
derivatives thereof.
EXPERIMENTAL
[0347] Experiments to determine empirically the release rate of the
therapeutic agent and the stabilizer from the formulation 190 are
described herein.
Example 1
[0348] A drug release study was performed using bovine serum
albumin (BSA) as a model therapeutic agent and fluorescein as a
model stabilizer, so as to show formation of ionic complexes
between a model stabilizer and model therapeutic agent, in which
the model stabilizer comprises on or more of an ionic group, a
hydroxyl group, or an aromatic ring and the therapeutic agent
comprises Fab antibody fragment. Similar complexes can be formed
with higher molecular weight stabilizers as described herein, so as
to decrease the rate of release of the therapeutic agent.
[0349] The release rate of BSA and fluorescein were measured from
devices initially loaded with formulations listed in Table E1.
Buffer containing trehalose, polysorbate 20, and histidine was
prepared first and pH was adjusted to 5.5 using HCl. Then BSA and
fluorescein was added and pH was determined by pH paper to be in
the 6.1-6.5 and 6.6-7.0 range for Formulations I and II
respectively.
[0350] Devices were fabricated containing sintered porous titanium
cylinders (Mott Corporation) with a diameter of 0.038 inches and a
thickness of 0.030 inches. The porous cylinders were mounted into
devices machined from poly (methyl methacrylate) with a reservoir
volume of 0.025 mL and a silicone septum. The devices expose one
planar face of the porous titanium to the solution in the reservoir
and the other planar face to the receiver solution in the
vials.
[0351] The devices (n=6 or 7 for each formulation) were filled with
0.05 mL formulation using a tuberculin syringe and a 33 gauge
needle inserted through the septum. Excess formulation was
expressed through the porous titanium and rinsed off the device
prior to the start of the drug release study by submerging in
phosphate buffered saline (PBS). The devices were mounted on
hangers to suspend the devices in the center of PBS in 1.5 mL
microcentrifuge tubes. At periodic intervals, the reservoirs were
moved to new tubes containing degassed PBS as the receiver fluid.
The amount of BSA transported from the reservoir through the porous
cylinder into the receiver fluid was determined by measuring the
amount of BSA in the vials using a Micro BCA.TM. Protein Assay kit
(Pierce, 23235) on a Molecular Devices Plate Reader. Fluorescein
concentrations in the receiver fluid were determined from
absorbance at 492 nm on the plate reader.
TABLE-US-00015 TABLE E1 Compositions of formulations injected into
devices Formulation I II BSA (mg/mL) 20 200 Fluorescein (mg/mL) 1 1
Trehalose (wt %) 10 10 Polysorbate 20 (wt %) 0.01 0.01 Histidine
HCl (M) 0.01 0.01 Sodium azide (wt %) 0.02 0.02
[0352] FIG. 9 shows calibration curves for absorbance of
fluorescein in PBS versus PBS containing 100 and 1000 ug/mL BSA as
the calibration curve diluent. For a given concentration of
fluorescein, the fluorescein absorbance was lower in the standards
containing BSA. When the standards containing BSA were assayed
using the standards without BSA, the fluorescein concentrations
were 74 and 69% of nominal values BSA concentrations of 100 and
1000 ug/mL, respectively, over a fluorescein concentration range of
2 to 30 ug/mL. It is known that fluorescein absorbance is stronger
for the dianion form than the other ionic forms of fluorescein
(Smith et al., Water S A, 28(4), 2002, 395-402). The lower
absorbance from addition of BSA is consistent with formation of an
ionic complex between fluorescein and BSA that may lower the
concentration of fluorescein dianion in solution. Hence, the
release of fluorescein in the presence of BSA is an example of a
model stabilizer that forms an ionic complex with the model
therapeutic agent.
[0353] Table E2 shows the concentrations of BSA and fluorescein
measured in the receiver fluid at the start of the release study.
The initial release rate of BSA is proportional to the BSA
concentration, suggesting the effective diffusion coefficient was
not dependent on concentration of BSA. Concentrations of
fluorescein are corrected for the impact of the presence of BSA
concentration measured in each sample, as described above. The
release rate of fluorescein from the formulation containing 200
mg/mL BSA is slower by a factor of two compared to the formulation
containing 20 mg/mL. The slower release rate can be described by an
effective diffusion coefficient that is lower by a factor of two.
These results demonstrate the ability to slow down diffusion and
drug release of a model stabilizer by formation of ionic complexes
between a model stabilizer and model therapeutic agent.
TABLE-US-00016 TABLE E2 Measured concentrations and initial release
rates of BSA and fluorescein from Formulations I and II.
Formulation I Formulation II (20 mg/mL (200 mg/mL BSA) BSA) Mean SD
Mean SD Measured BSA in Receiver 105 4 1154 135 (ug/mL) Measured
fluorescein in Receiver 10.9 0.5 4.6 0.5 (ug/mL) BSA rate (ug/mL)
13.3 0.5 147.8 18.4 BSA rate, normalized by initial 0.665 0.026
0.739 0.092 BSA conc Fluorescein rate (ug/mL), 1.4 0.1 0.6 0.1
uncorrected Correction factor 0.74 0.74 0.69 0.69 Fluorescein rate
(ug/mL), corrected 1.9 0.1 0.8 0.1
Example 2
Erodible Particles
[0354] PLGA may be purchased from a number of supplies, for
example, PURASORB.RTM. of Purac Biomaterials, RESOMER.RTM. of
Boehringer Ingelheim, Lakeshore Biomaterials.TM. of Surmodics
Pharmaceuticals and Lactel.RTM. of Durect. PLGA is available with a
range of properties as stock or custom polymers. For example,
Durect produces PLGA with time for resorption ranging from a few
months to greater than 24 months. Any commercially available PLGA
can be processed into monodisperse microspheres by using processes
known in the art, such as single and double emulsion processing
schemes. PLGA may be purchased as microparticles. For example,
monodisperse PURASORB.RTM. PLGA 5004 microspheres are available
from Nanomi with particle sizes ranging from 1 to 30 um, prepared
by an emulsification technology, and supplied freeze-dried.
[0355] Microparticles 1 um in size from Naomi can be added to
Lucentis.TM. at concentrations ranging from 0.01% to 1%. The
microparticles can be added just prior to injection into devices.
Control devices can also be injected with Lucentis.TM. only. Drug
release testing could be performed as described in Example 1. The
stability of ranibizumab could be tested by assays such as ELISA
and Ion-Exchange Chromatography HPLC on samples of drug in the
receiver fluid. In addition, the contents in the reservoir of the
devices could be harvested to assay for drug stability and
measurement of pH by, for example, pH paper.
Example 3
Stabilizers
[0356] Various forms (e.g., cellulose acetate, ethylcellulose,
carboxymethylcellulose, methylcellulose) and molecular weights of
cellulose can be purchased from suppliers such as Spectrum
Chemicals and Sigma-Aldrich. Excipients can be removed from
Lucentis.TM. by dialysis to obtain ranibizumab. Then, excipients of
choice can be added to prepare the desired formulations. An example
would be 10 mg/mL ranibizumab, 10% carboxymethyl cellulose with a
molecular weight of about 10 kDa, 0.01% polysorbate 20, 10 mM
histidine HCl pH 5.5.
[0357] Devices can be injected with the various formulations and
Lucentis.TM. as a control and subjected to drug release testing and
stability assays as described in Example 2.
Example 4
Stabilizers and Erodible Particles
[0358] Stabilizers can be encapsulated into erodible particles
using single and double emulsion techniques. PLGA and stabilizers
listed in Examples 2 and 4 and buffers such as histidine
hydrochloride can be dissolved in solvents such as dichloromethane,
tetrahydrofuran, ethyl acetate, chloroform, hexafluoroisopropanol,
and acetone. Surfactant such as polysorbate 20 at concentrations on
the order of 0.01% can be added to water and the PLGA and
stabilizers dissolved in solvent, and sonication applied to form an
emulsion. Solvent can be removed to yield the particles. The
particles can be added to Lucentis.TM. at concentrations on the
order of 1%. Devices can be injected with the various formulations
and Lucentis.TM. as a control and subjected to drug release testing
and stability assays as described in Example 2.
Example 5
Micelle Stabilizer
[0359] Excipients can be removed from Lucentis.TM. by dialysis to
obtain ranibizumab. A series of samples can be generated with
composition identical to Lucentis.TM. but with a range of
polysorbate 20 concentrations, from 0.0005% to 0.1%. Surface
tension measurements may be performed with a Wilhemy plate to
determine the CMC; i.e., polysorbate 20 concentration threshold for
constant surface tension. Devices can then be filled with
formulations containing polysorbate 20 concentrations that are 0,
1, 5 and 20 times the CMC. These devices can be subjected to drug
release testing and stability assays as described in Example 2.
TABLE-US-00017 TABLE 1A Therapeutic Agent List Brands Molecular
Generic Name (Companies) Category Indication Weight
2-Methoxyestradiol (Paloma Angiogenesis AMD analogs
Pharmaceuticals) inhibitors 3-aminothalidomide 13-cis retinoic acid
Accutane TM (Roche Pharmaceuticals) A0003 (Aqumen A0003 AMD
BioPharmaceuticals) A5b1 integrin (Jerini Ophthalmic); Inhibitors
of a5b1 AMD inhibitor (Ophthotech) integrin Abarelix Plenaxis .TM.
(Praecis Anti-Testosterone For palliative treatment 37731
Pharmaceuticals) Agents; of advanced prostate Antineoplastic
cancer. Agents Abatacept Orencia .TM. (Bristol- Antirheumatic For
the second line 37697 Myers Squibb) Agents reduction of the signs
and symptoms of moderate-to-severe active rheumatoid arthritis,
inducing inducing major clinical response, slowing the progression
of structural damage, and improving physical function in adult
patients who have Abciximab ReoPro .TM.; Anticoagulants; For
treatment of 42632 ReoPro .TM. Antiplatelet Agents myocardial
infarction, (Centocor) adjunct to percutaneous 89oronary
intervention, unstable angina ABT-578 (Abbott Limus Immunophilin
Laboratories) Binding Compounds Acetonide Adalimumab Humira .TM.
(Abbott Antirheumatic Uveitis, AMD 25645 Laboratories) Agents;
Immunomodulatory Agents Aldesleukin Proleukin .TM.; Antineoplastic
For treatment of adults 61118 Proleukin .TM. (Chiron Agents with
metastatic renal Corp) cell carcinoma Alefacept Amevive .TM.
Immunomodulatory For treatment of 42632 Agents; moderate to severe
Immunosuppressive chronic plaque Agents psoriasis Alemtuzumab
Campath .TM.; Antineoplastic For treatment of B-cell 6614 Campath
.TM. (ILEX Agents chronic lymphocytic Pharmaceuticals leukemia LP);
MabCampath .TM. Alpha-1-proteinase Aralast .TM. (Baxter); Enzyme
For treatment of 28518 inhibitor Prolastin .TM. (Talecris
Replacement panacinar emphysema Biotherapeutics C Agents formerly
Bayer) Alteplase Activase .TM. Thrombolytic For management of 54732
(Genentech Inc) Agents acute myocardial infarction, acute ischemic
strok and for lysis of acute pulmonary emboli AMG-1470 Anakinra
Kineret .TM. (Amgen Anti-Inflammatory For the treatment of 65403
Inc) Agents, Non- adult rheumatoid Steroidal; arthritis.
Antirheumatic Agents; Immunomodulatory Agents Anecortave acetate
Angiostatin Anistreplase Eminase .TM. (Wulfing Thrombolytic For
lysis of acute 54732 Pharma GmbH) Agents pulmonary emboli,
intracoronary emboli and management of myocardial infarction
Anti-angiogenesis (Eyecopharm) Anti-angiogenesis AMD peptides
peptides Anti-angiogenesis (TRACON Pharma) Anti-angiogenesis AMD
antibodies, antibodies TRC093, TRC105 Anti-angiogeric Icon-1 .TM.
(Iconic Anti-angiogeric AMD bifunctional protein Therapeutics)
bifunctional protein, Icon-1 Anti-endothelial growth factor
Antihemophilic Advate .TM.; Coagulants; For the treatment of 70037
Factor Alphanate .TM.; Thrombotic Agents hemophilia A, von Bioclate
.TM.; Willebrand diseae and Helixate .TM.; Helixate Factor XIII
deficiency FS .TM.; Hemofil M .TM.; Humate-P .TM.; Hyate:C .TM.;
Koate- HP .TM.; Kogenate .TM.; Kogenate FS .TM.; Monarc-M .TM.;
Monoclate-P .TM.; ReFacto .TM.; Xyntha .TM. Antithymocyte Genzyme);
Immunomodulatory For prevention of renal 37173 globulin
Thymoglobulin .TM. Agents transplant rejection (SangStat Medical
Anti-hypertensive (MacuCLEAR) Anti-hypertensive AMD MC1101 MC1101
Anti-platelet devired growth factor Anti-VEGF (Neurotech);
Anti-VEGF AMD Avastin .TM. (NeoVista) AP23841 (Ariad) Limus
Immunophilin Binding Compounds ARC1905 Ophthotech Complement
Cascade Inhibitor (Factor C5) Aprotinin Trasylol .TM.
Antifibrinolytic For prophylactic use to 90569 Agents reduce
perioperative blood loss and the need for blood transfusion in
patients undergoing cardiopulmonary bypass in the course of
coronary artery bypass graft surgery who are at an increased risk
for blood loss and blood transfusio Arcitumomab CEA-Scan .TM.
Diagnostic Agents; For imaging colorectal 57561 Imaging Agents
tumors Asparaginase Elspar .TM. (Merck & Antineoplastic For
treatment of acute 132.118 Co. Inc) Agents lympocytic leukemia and
non-Hodgkins lymphoma Axitinib Tyrosine Kinase 386 Inhibitors
Basiliximab Simulect .TM. (Novartis Immunomodulatory For
prophylactic 61118 Pharmaceuticals) Agents; treatment of kidney
Immunosuppressive transplant rejection Agents Becaplermin Regranex
.TM.; Anti-Ulcer Agents; For topical treatment of 123969 Regranex
.TM. (OMJ Topical skin ulcers (from Pharmaceuticals) diabetes)
Bevacizumab Avastin .TM.; Avastin .TM. Antiangiogenesis For
treatment of 27043 (Genentech Inc) Agents; metastatic colorectal
Antineoplastic cancer Agents Bivalirudin Angiomax .TM.;
Anticoagulants; For treatment of 70037 Angiomax .TM. Antithrombotic
heparin-induced (Medicines Co or Agents thrombocytopenia MDCO);
Angiox .TM. Bortezomib Proteosome Inhibitors Bosutinib Tyrosine
Kinase 530 Inhibitors Botulinum Toxin BOTOX .TM. (Allegran
Anti-Wrinkle For the treatment of 23315 Type A Inc); BOTOX Agents;
cervical dystonia in Cosmetic .TM. Antidystonic adults to decrease
the (Allegran Inc); Agents; severity of abnormal Botox .TM.;
Dysport .TM. Neuromuscular head position and neck Blocking Agents
pain associated with cervical dystonia. Also for the treatment of
severe primary axillary hyperhidrosis that is inadequately managed
with topical Botulinum Toxin Myobloc .TM. (Solstice Antidystonic
Agents For the treatment of 12902 Type B Neurosciences); patients
with cervical Neurobloc .TM. dystonia to reduce the (Solstice
severity of abnormal Neurosciences) head position and neck pain
associated with cervical dystonia. C5 inhibitor (Jerini
Ophthalmic); Inhibitors of C5 AMD (Ophthotech) Cal101 Calistoga
PI3Kdelta Inhibitor AMD, DME Canstatin Capromab ProstaScint .TM.
Imaging Agents For diagnosis of 84331 (Cytogen Corp) prostate
cancer and detection of intra-pelvic metastases Captopril ACE
Inhibitors CCI-779 (Wyeth) Limus Immunophilin Binding Compounds
Cediranib Tyrosine Kinase 450 Inhibitors Celecoxib Cyclooxygenase
Inhibitors Cetrorelix Cetrotide .TM. Hormone For the inhibition of
78617 Antagonists; premature LH surges Infertility Agents in women
undergoing controlled ovarian stimulation Cetuximab Erbitux .TM.;
Erbitux .TM. Antineoplastic For treatment of 42632 (ImClone Systems
Agents metastatic colorectal Inc) cancer. Choriogonadotropin
Novarel .TM.; Fertility Agents; For the treatment of 78617 alfa
Ovidrel .TM.. Gonadotropins female infertility Pregnyl .TM.;
Profasi .TM. Cilary neurotrophic (Neurotech) Cilary neurotrophic
AMD factor factor Coagulation Factor Benefix .TM. (Genetics
Coagulants; For treatment of 267012 IX Institute) Thrombotic Agents
hemophilia (Christmas disease). Coagulation factor NovoSeven .TM.
(Novo Coagulants; For treatment of 54732 VIIa Nordisk) Thrombotic
Agents hemorrhagic complications in hemophilia A and B Colchicines
Collagenase Cordase .TM.; Santyl .TM. Anti-Ulcer Agents; For
treatment of 138885 (Advance Topical chronic dermal ulcers
Biofactures Corp); and severe skin burns Xiaflextm .TM. Complement
factor (Optherion); Complement factor AMD, Geographic H recombinant
(Taligen H recombinant Atrophy Therapeutics) Compstatin (Potentia
Complement Factor AMD derivative peptide, Pharmaceuticals) C3
Inhibitors; POT-4 Compstatin Derivative Peptides Corticotropin ACTH
.TM.; Diagnostic Agents For use as a diagnostic 33927 Acethropan
.TM.; agent in the screening Acortan .TM.; Acthar .TM.; of patients
presumed Exacthin .TM.; H.P. to have adrenocortical Acthar Gel
.TM.; insufficiency. Isactid .TM.; Purified cortrophin gel .TM.;
Reacthin .TM.,
Solacthyl .TM.; Tubex Cosyntropin Cortrosyn .TM.; Diagnostic Agents
For use as a diagnostic 33927 Synacthen depot .TM. agent in the
screening of patients presumed to have adrenocortical
insufficiency. Cyclophilins Limus Immunophilin Binding Compounds
Cyclosporine Gengraf .TM. (Abbott Antifungal Agents; For treatment
of 32953 labs); Neoral .TM. Antirheumatic transplant rejection,
(Novartis); Agents; rheumatoid arthritis, Restasis .TM.;
Dermatologic severe psoriasis Restasis .TM. (Allergan Agents;
Enzyme Inc); Sandimmune .TM. Inhibitors; (Novartis);
Immunomodulatory Sangcya .TM. Agents; Immunosuppressive Agents
Daclizumab Zenapax .TM. Immunomodulatory For prevention of renal
61118 (Hoffmann-La Agents; transplant rejection; Roche Inc)
Immunosuppressive Uveitis Agents Darbepoetin alfa Aranesp .TM.
(Amgen Antianemic Agents For the treatment of 55066 Inc.) anemia
(from renal transplants or certain HIV treatment) Dasatinib
Tyrosine Kinase 488 Inhibitors Defibrotide Dasovas .TM.;
Antithrombotic Defibrotide is used to 36512 Noravid .TM.; Agents
treat or prevent a Prociclide .TM. failure of normal blood flow
(occlusive venous disease, OVD) in the liver of patients who have
had bone marrow transplants or received certain drugs such as oral
estrogens, mercaptopurine, and many others. Denileukin diftitox
Ontak .TM. Antineoplastic For treatment of 61118 Agents cutaneous
T-cell lymphoma Desmopressin Adiuretin .TM.; Antidiuretic Agents;
For the management 46800 Concentraid .TM.; Hemostatics; Renal of
primary nocturnal Stimate .TM. Agents enuresis and indicated as
antidiuretic replacement therapy in the management of central
diabetes insipidus and for the management of the temporary polyuria
and polydipsia following head trauma or surgery in the pitu
Dexamethasone Ozurdex .TM. Glucocorticoid DME, inflammation, 392
(Allergan) macular edema following branch retinal vein occlusion
(BRVO) or central retinal vein occlusion (CRVO) Diclofenac
Cyclooxygenase Inhibitors Dithiocarbamate NF.kappa.B Inhibitor
Dornase Alfa Dilor .TM.; Dilor-400 .TM.; Enzyme For the treatment
of 7656 Lufyllin .TM.; Lufyllin- Replacement cystic fibrosis.
(double 400 .TM.; Agents strand) Neothylline .TM.. Pulmozyme .TM.
(Genentech Inc) Drotrecogin alfa Xigris .TM.; Xigris .TM. (Eli
Antisepsis Agents For treatment of 267012 Lilly & Co) severe
sepsis Eculizumab Soliris .TM.; Soliris .TM. Complement AMD 188333
(Alexion Cascade Inhibitor Pharmaceuticals) (Factor C5) Efalizumab
Raptiva .TM. Immunomodulatory For the treatment of 128771 Raptiva
.TM. Agents; adult patients with (Genentech Inc) Immunosuppressive
moderate to severe Agents chronic plaque psoriasis, who are
candidates for phototherapy or systemic therapy. Endostatin
Enfuvirtide Fuzeon .TM.; Fuzeon .TM. Anti-HIV Agents; For treatment
of HIV 16768 (Roche HIV Fusion AIDS Pharmaceuticals) Inhibitors
Epoetin alfa Epogen .TM. (Amgen Antianemic Agents For treatment of
55066 Inc.); Epogin .TM. anemia (from renal (Chugai); Epomax .TM.
transplants or certain (Elanex); Eprex .TM. HIV treatment)
(Janssen-Cilag. Ortho Biologics LLC); NeoRecormon .TM. (Roche);
Procrit .TM. (Ortho Biotech); Recormon .TM. (Roche) Eptifibatide
Integrilin .TM.; Anticoagulants; For treatment of 7128 Integrilin
.TM. Antiplatelet Agents; myocardial infarction (Millennium Pharm)
Platelet and acute coronary Aggregation syndrome. Inhibitors
Erlotinib Tyrosine Kinase 393 Inhibitors Etanercept Enbrel .TM.;
Enbrel .TM. Antirheumatic Uveitis, AMD 25645 (Immunex Corp) Agents;
Immunomodulatory Agents Everolimus Novartis Limus Immunophilin AMD
Binding Compounds, mTOR Exenatide Byetta .TM.; Byetta .TM.
Indicated as adjunctive 53060 (Amylin/Eli Lilly) therapy to improve
glycemic control in patients with Type 2 diabetes mellitus who are
taking metformin, a sulfonylurea, or a combination of both, but
have not achieved adequate glycemic control. FCFD4514S
Genentech/Roche Complement AMD, Geographic Cascade Inhibitor
Atrophy (Factor D) Felypressin Felipresina .TM. [INN- Renal Agents;
For use as an 46800 Spanish]; Vasoconstrictor alternative to
Felipressina .TM. Agents adrenaline as a [DCIT]; 97ocalizing agent,
Felypressin .TM. provided that local [USAN:BAN:INN]; ischaemia is
not Felypressine .TM. essential. [INN-French]; Felypressinum .TM.
[INN-Latin]; Octapressin .TM. Fenretinide Sirion/reVision Binding
Protein AMD, Geographic Therapeutics Antagonist for Oral Atrophy
Vitamin A Filgrastim Neupogen .TM. Anti-Infective Increases
leukocyte 28518 (Amgen Inc.) Agents; production, for
Antineutropenic treatment in non- Agents; myeloid Immunomodulatory
cancer, neutropenia Agents and bone marrow transplant FK605-binding
Limus Immunophilin proteins, FKBPs Binding Compounds Fluocinolone
Retisert .TM. (Bausch Glucocorticoid Retinal inflammation, 453
Acetonide & Lomb); Iluvien .TM. diabetic macular (Alimera
Sciences, edema Inc.) Follitropin beta Follistim .TM. Fertility
Agents For treatment of 78296 (Organon); Gonal female infertility F
.TM.; Gonal-F .TM. Fumagillin Galsulfase Naglazyme .TM.; Enzyme For
the treatment of 47047 Naglazyme .TM. Replacement adults and
children (BioMarin Agents with Pharmaceuticals)
Mucopolysaccharidosis VI. Gefitinib Tyrosine Kinase 447 Inhibitors
Gemtuzumab Mylotarg .TM.; Antineoplastic For treatment of acute
39826 ozogamicin Mylotarg .TM. (Wyeth) Agents myeloid leukemia
Glatiramer Acetate Copaxone .TM. Adjuvants, For reduction of the
29914 Immunologic; frequency of relapses Immunosuppressive in
patients with Agents Relapsing-Remitting Multiple Sclerosis.
Glucagon GlucaGen .TM. (Novo Antihypoglycemic For treatment of
54009 recombinant Nordisk); Agents severe hypoglycemia, Glucagon
.TM. (Eli also used in Lilly) gastrointestinal imaging Goserelin
Zoladex .TM. Antineoplastic Breast cancer; 78617 Agents; Prostate
carcinoma; Antineoplastic Endometriosis Agents, Hormonal Human
Serum Albutein .TM. (Alpha Serum substitutes For treatment of 39000
Albumin Therapeutic Corp) severe blood loss, hypervolemia,
hypoproteinemia Hyaluronidase Vitragan .TM.; Anesthetic For
increase of 69367 Vitrase .TM.; Vitrase .TM. Adjuvants; absorption
and (Ista Pharma) Permeabilizing distribution of other Agents
injected drugs and for rehydration Ibritumomab Zevalin .TM. (IDEC
Antineoplastic For treatment of non- 33078 Pharmaceuticals) Agents
Hodgkin's lymphoma Idursulfase Elaprase .TM. (Shire Enzyme For the
treatment of 47047 Pharmaceuticals) Replacement Hunter syndrome in
Agents adults and children ages 5 and older. Imatinib Tyrosine
Kinase AMD, DME 494 Inhibitors Immune globulin Civacir .TM.;
Anti-Infectives; For treatment of 42632 Flebogamma .TM.
Immunomodulatory immunodeficiencies, (Instituto Grifols Agents
thrombocytopenic SA); Gamunex .TM. purpura, Kawasaki (Talecris
disease, Biotherapeutics) gammablobulinemia, leukemia, bone
transplant Infliximab Remicade .TM. Immunomodulatory Uveitis, AMD
25645 (Centocor Inc) Agents; Immunosuppressive Agents Insulin
Glargine Lantus .TM. Hypoglycemic For treatment of 156308
recombinant Agents diabetes (type I and II) Insulin Lyspro Humalog
.TM. (Eli Lily); Hypoglycemic For treatment of 154795 recombinant
Insulin Lispro (Eli Agents diabetes (type I and II) Lily) Insulin
recombinant Novolin R .TM. (Novo Hypoglycemic For treatment of
156308 Nordisk) Agents diabetes (type I and II) Insulin, porcine
Iletin II .TM. Hypoglycemic For the treatment of 156308 Agents
diabetes (type I and II) Interferon Interferon Alfa-2a, Roferon A
.TM. Antineoplastic For treatment of 57759 Recombinant (Hoffmann-La
Agents; Antiviral chronic hepatitis C, Roche Inc); Agents hairy
cell leukemia, Veldona .TM. (Amarillo AIDS-related Kaposi's
Biosciences) sarcoma, and chronic myelogenous leukemia. Also for
the treatment of oral warts arising from HIV infection. Interferon
Alfa-2b, Intron A .TM. (Schering Antineoplastic For the treatment
of 57759 Recombinant Corp) Agents; Antiviral hairy cell leukemia,
Agents; malignant melanoma, Immunomodulatory and AIDS-related
Agents Kaposi's sarcoma. Interferon alfacon-1 Advaferon .TM.;
Antineoplastic For treatment of hairy 57759 Infergen .TM. Agents;
Antiviral cell leukemia,
(InterMune Inc) Agents; malignant melanoma, Immunomodulatory and
AIDS-related Agents Kaposi's sarcoma Interferon alfa-n1 Wellferon
.TM. Antiviral Agents; For treatment of 57759 (GlaxoSmithKline)
Immunomodulatory venereal or genital Agents warts caused by the
Human Papiloma Virus Interferon alfa-n3 Alferon .TM. (Interferon
Antineoplastic For the intralesional 57759 Sciences Inc.); Agents;
Antiviral treatment of refractory Alferon LDO .TM.; Agents; or
recurring external Alferon N Injection .TM. Immunomodulatory
condylomata Agents 100cuminate. Interferon beta-1b Betaseron .TM.
(Chiron Antiviral Agents; For treatment of 57759 Corp)
Immunomodulatory relapsing/remitting Agents multiple sclerosis
Interferon gamma- Actimmune .TM.; Antiviral Agents; For treatment
of 37835 1b Actimmune .TM. Immunomodulatory Chronic granulomatous
(InterMune Inc) Agents disease, Osteopetrosis Lapatinib Tyrosine
Kinase 581 Inhibitors Lepirudin Refludan .TM. Anticoagulants; For
the treatment of 70037 Antithrombotic heparin-induced Agents;
Fibrinolytic thrombocytopenia Agents Lestaurtinib Tyrosine Kinase
439 Inhibitors Leuprolide Eligard .TM. (Atrix Anti-Estrogen For
treatment of 37731 Labs/QLT Inc) Agents; prostate cancer,
Antineoplastic endometriosis, uterine Agents fibroids and premature
puberty Lutropin alfa Luveris .TM. (Serono) Fertility Agents For
treatment of 78617 female infertility Mecasermin Increlex .TM.; For
the long-term 154795 Increlex .TM. (Tercica); treatment of growth
Iplex failure in pediatric patients with Primary IGFD or with GH
gene deletion who have developed neutralizing antibodies to GH. It
is not indicated to treat Secondary IGFD resulting from GH
deficiency, malnutrition, hypoth Menotropins Repronex .TM.
Fertility Agents For treatment of 78617 female infertility
Methotrexate Immunomodulatory Uveitis, DME mTOR inhibitors
Muromonab Orthoclone OKT3 .TM. Immunomodulatory For treatment of
organ 23148 (Ortho Biotech) Agents; transplant recipients,
Immunosuppressive prevention of organ Agents rejection Natalizumab
Tysabri .TM. Immunomodulatory For treatment of 115334 Agents
multiple sclerosis. Nepafenac Cyclooxygenase Inhibitors Nesiritide
Natrecor .TM. Cardiac drugs For the intravenous 118921 treatment of
patients with acutely decompensated congestive heart failure who
have dyspnea at rest or with minimal activity. Nilotinib Tyrosine
Kinase 530 Inhibitors NS398 Cyclooxygenase Inhibitors Octreotide
Atrigel .TM.; Anabolic Agents; For treatment of 42687 Longastatin
.TM.; Antineoplastic acromegaly and Sandostatin .TM.; Agents,
Hormonal; reduction of side Sandostatin LAR .TM.; Gastrointestinal
effects from cancer Sandostatin LAR .TM. Agents; Hormone
chemotherapy (Novartis) Replacement Agents Omalizumab Xolair .TM.
(Genentech Anti-Asthmatic For treatment of 29596 Inc) Agents;
asthma caused by Immunomodulatory allergies Agents Oprelvekin
Neumega .TM.; Coagulants; Increases reduced 45223 Neumega .TM.
Thrombotics platelet levels due to (Genetics Institute chemotherapy
Inc) OspA lipoprotein LYMErix .TM. Vaccines For prophylactic 95348
(SmithKline treatment of Lyme Beecham) Disease OT-551 (Othera)
Anti-oxidant AMD eyedrop Oxytocin Oxytocin .TM. (BAM Anti-tocolytic
To assist in labor, 12722 Biotech); Pitocin .TM. Agents; Labor
elective labor (Parke-Davis); Induction Agents; induction, uterine
Syntocinon .TM. Oxytocics contraction induction (Sandoz) Palifermin
Kepivance .TM. Antimucositis For treatment of 138885 (Amgen Inc)
Agents mucositis (mouth sores) Palivizumab Synagis .TM. Antiviral
Agents For treatment of 63689 respiratory diseases casued by
respiratory syncytial virus Panitumumab Vectibix .TM.;
Antineoplastic For the treatment of 134279 Vectibix .TM. (Amgen)
Agents EGFR-expressing, metastatic colorectal carcinoma with
disease progression on or following fluoropyrimidine-,
oxaliplatin-, and irinotecan-containing chemotherapy regimens. PDGF
inhibitor (Jerini Ophthalmic); Inhibitors of PDGF AMD (Ophthotech)
PEDF (pigment epithelium derived factor) Pegademase Adagen .TM.
(Enzon Enzyme For treatment of 36512 bovine Inc.) Replacement
adenosine deaminase Agents deficiency Pegaptanib Macugen .TM.
Oligonucleotide For the treatment of 103121 neovascular (wet) age-
related macular degeneration. Pegaspargase Oncaspar .TM. (Enzon
Antineoplastic For treatment of acute 132.118 Inc) Agents
lymphoblastic leukemia Pegfilgrastim Neulasta .TM. (Amgen
Anti-Infective Increases leukocyte 28518 Inc.) Agents; production,
for Antineutropenic treatment in non- Agents; myeloid cancer,
Immunomodulatory neutropenia and bone Agents marrow transplant
Peginterferon alfa- Pegasys .TM. Antineoplastic For treatment of
hairy 57759 2a (Hoffman-La Roche Agents; Antiviral cell leukemia,
Inc) Agents; malignant melanoma, Immunomodulatory and AIDS-related
Agents Kaposi's sarcoma. Peginterferon alfa- PEG-Intron
Antineoplastic For the treatment of 57759 2b (Schering Corp);
Agents; Antiviral chronic hepatitis C in Unitron PEG .TM. Agents;
patients not previously Immunomodulatory treated with interferon
Agents alpha who have compensated liver disease and are at least 18
years of age. Pegvisomant Somavert .TM. (Pfizer Anabolic Agents;
For treatment of 71500 Inc) Hormone acromegaly Replacement Agents
Pentoxifylline Perindozril ACE Inhibitors Pimecrolimus Limus
Immunophilin Binding Compounds PKC (protein kinase C) inhibitors
POT-4 Potentia/Alcon Complement AMD Cascade Inhibitor (Factor C3)
Pramlintide Symlin .TM.; Symlin .TM. For the mealtime 16988 (Amylin
treatment of Type I and Pharmaceuticals) Type II diabetes in
combination with standard insulin therapy, in patients who have
failed to achieve adequate glucose control on insulin monotherapy.
Proteosome Velcade .TM. Proteosome inhibitors inhibitors
Pyrrolidine Quinopril ACE Inhibitors Ranibizumab Lucentis .TM. For
the treatment of 27043 patients with neovascular (wet) age- related
macular degeneration. Rapamycin (MacuSight) Limus Immunophilin AMD
(siroliums) Binding Compounds Rasburicase Elitek .TM.; Elitek .TM.
Antihyperuricemic For treatment of 168.11 (Sanofi-Synthelabo Agents
hyperuricemia, Inc); Fasturtec .TM. reduces elevated plasma uric
acid levels (from chemotherapy) Reteplase Retavase .TM.
Thrombolytic For lysis of acute 54732 (Centocor); Agents pulmonary
emboli, Retavase .TM. (Roche) intracoronary emboli and management
of myocardial infarction Retinal stimulant Neurosolve .TM. Retinal
stimulants AMD (Vitreoretinal Technologies) Retinoid(s) Rituximab
MabThera .TM.; Antineoplastic For treatment of B-cell 33078 Rituxan
.TM. Agents non-Hodgkins lymphoma (CD20 positive) RNAI (RNA
interference of angiogenic factors) Rofecoxib Vioxx .TM.; Ceoxx
.TM.; Cyclooxygenase Ceeoxx .TM. (Merck & Inhibitors Co.)
Rosiglitazone Thiazolidinediones Ruboxistaurin Eli Lilly Protein
Kinase C DME, diabetic 469 (PKC)-b Inhibitor peripheral retinopathy
Salmon Calcitonin Calcimar .TM.; Antihypocalcemic For the treatment
of 57304 Miacalcin .TM. Agents; post-menopausal (Novartis)
Antiosteporotic osteoporosis Agents; Bone Density Conservation
Agents Sargramostim Immunex .TM.; Anti-Infective For the treatment
of 46207 Leucomax .TM. Agents; cancer and bone (Novartis);
Antineoplastic marrow transplant Leukine .TM.; Agents; Leukine .TM.
(Berlex Immunomodulatory Laboratories Inc) Agents SAR 1118 SARCode
Immunomodulatory Dry eye, DME, Agent conjunctivitis SDZ-RAD Limus
Immunophilin Binding Compounds Secretin SecreFlo .TM.; Diagnostic
Agents For diagnosis of 50207 Secremax .TM., pancreatic exocrine
SecreFlo .TM. dysfunction and (Repligen Corp) gastrinoma Selective
inhibitor of the factor 3 complement cascade Selective inhibitor of
the factor 5 complement cascade Semaxanib Tyrosine Kinase 238
Inhibitors Sermorelin Geref .TM. (Serono Anabolic Agents; For the
treatment of 47402 Pharma) Hormone dwarfism, prevention of
Replacement HIV-induced weight Agents loss Serum albumin Megatope
.TM. (IsoTex Imaging Agents For determination of 39000 iodinated
Diagnostics) total blood and plasma volumes SF1126 Semafore
Pl3k/mTOR AMD, DME Inhibition Sirolimus (MacuSight) Limus
Immunophilin AMD reformulation Binding (rapamycin) Compounds siRNA
molecule (Quark siRNA molecule AMD synthetic, FTP- Pharmaceuticals)
synthetic 801i-14 Somatropin BioTropin .TM. (Biotech Anabolic
Agents; For treatment of 71500 recombinant General); Hormone
dwarfism, acromegaly Genotropin .TM. Replacement and prevention of
HIV- (Pfizer); Agents induced weight loss Humatrope .TM. (Eli
Lilly); Norditropin .TM. (Novo Nordisk); Nutropin .TM. (Genentech
Inc.); NutropinAQ .TM. (Genentech Inc.); Protropin .TM. (Genentech
Inc.); Saizen .TM. (Serono SA); Serostim .TM.; Serostim .TM.
(Serono SA); Tev-Tropin .TM. (GATE) Squalamine Streptokinase
Streptase .TM. (Aventis Thrombolytic For the treatment of 90569
Behringer GmbH) Agents acute evolving transmural myocardial
infarction, pulmonary embolism, deep vein thrombosis, arterial
thrombosis or embolism and occlusion of arteriovenous cannulae
Sunitinib Tyrosine Kinase 398 Inhibitors TA106 Taligen Complement
AMD Cascade Inhibitor (Factor B) Tacrolimus Limus Immunophilin
Binding Compounds Tenecteplase TNKase .TM. Thrombolytic For
treatment of 54732 (Genentech Inc) Agents myocardial infarction and
lysis of intracoronary emboli Teriparatide Apthela .TM.; Bone
Density For the treatment of 66361 Forsteo .TM.; Forteo .TM.;
Conservation osteoporosis in men Fortessa .TM.; Agents and
postmenopausal Opthia .TM.; Optia .TM.; women who are at high
Optiah .TM.; risk for having a Zalectra .TM.; fracture. Also used
to Zelletra .TM. increase bone mass in men with primary or
hypogonadal osteoporosis who are at high risk for fracture.
Tetrathiomolybdate Thalidomide Celgene Anti-inflammatory, Uveitis
Anti-proliferative Thyrotropin Alfa Thyrogen .TM. Diagnostic Agents
For detection of 86831 (Genzyme Inc) residueal or recurrent thyroid
cancer Tie-1 and Tie-2 kinase inhibitors Toceranib Tyrosine Kinase
396 Inhibitors Tositumomab Bexxar .TM. (Corixa Antineoplastic For
treatment of non- 33078 Corp) Agents Hodgkin's lymphoma (CD20
positive, follicular) TPN 470 analogue Trastuzumab Herceptin .TM.
Antineoplastic For treatment of 137912 (Genentech) Agents
HER2-positive pulmonary breast cancer Triamcinolone Triesence .TM.
Glucocorticoid DME, For treatment of 435 acetonide inflammation of
the retina Troglitazone Thiazolidinediones Tumistatin
Urofollitropin Fertinex .TM. (Serono S.A.) Fertility Agents For
treatment of 78296 female infertility Urokinase Abbokinase .TM.;
Thrombolytic For the treatment of 90569 Abbokinase .TM. Agents
107ulmonary (Abbott embolism, coronary Laboratories) artery
thrombosis and IV catheter clearance Vandetanib Tyrosine Kinase 475
Inhibitors Vasopressin Pitressin .TM.; Antidiuretics; For the
treatment of 46800 Pressyn .TM. Oxytocics; enuresis, polyuria,
Vasoconstrictor diabetes insipidus, Agents polydipsia and
oesophageal varices with bleeding Vatalanib Tyrosine Kinase 347
Inhibitors VEGF receptor kinase inhibitor VEGF Trap Aflibercept
.TM. Genetically DME, cancer, retinal 96600 (Regneron Engineered
vein occlusion, Pharmaceuticals, Antibodies choroidal Bayer
HealthCare neovascularization, AG) delay wound healing, cancer
treatment Visual Cycle (Acucela) Visual Cycle AMD Modulator ACU-
Modulator 4229 Vitamin(s) Vitronectin receptor antagonists
Volociximab Ophthotech alpha5beta1 AMD Integrin Inhibitor XL765
Exelixis/Sanofi- Pl3k/mTOR AMD, DME Aventis Inhibition
TABLE-US-00018 TABLE 1B Surfactants Surfactants include: Iconic
Anionic: based on permanent anions (sulfate, sulfonate, phosphate)
or pH-dependent anions (carboxylate): Sulfates: Alkyl sulfates:
ammonium lauryl sulfate, sodium lauryl sulfate (SDS); Alkyl ether
sulfates: sodium laureth sulfate, also known as sodium lauryl ether
sulfate (SLES), sodium myreth sulfate; Sulfonates: Docusates:
dioctyl sodium sulfosucciate; Sulfonate fluorosurfactants:
perfluorooctanesulfonate (PFOS), perfluorobutanesulfonate; Alkyl
benzne sulfonates; Phosphates: Alkyl aryl ether phosphate Alkyl
ether phosphate Carboxylates: Alkyl carboxylates: Fatty acid salts
(soaps): sodium stearate; Sodium lauroyl sarcosinate; Carboxylate
fluorsurfactants: perfluoronoanoate, perfluoroocanoate (PFOA OR
PFO) Cationic: based on: pH-dependent primary, secondary or
tertiary amines become positively charged at pH <10, secondary
amines become charged at pH <4: Octenidine dihydrochloride;
Permanently charged quaternary ammonium cation:
Alkyltrimethylammonium sals: cetyl trimthylammonium bromide (CTAB)
a.k.a. hexadecyl trimethyl ammonium bromide, cetyl
trimethylammonium chloride (CTAC); Cetylpyridinium chloride (CPC);
Polyethoxylated tallow amine (POEA); Benzalkonium chloride (BAC);
Benzethonium chloride (BZT); 5-Bromo-5-nitro-1,2-dioxane;
Dimethyldioctadecylammonium chloride Dioctadecyldimethylammonium
bromide (DODAB) . . . Zitterionic (amphoteric): based on primary,
secondary or tertiary amines or uaternary ammonium cation with:
Sulfonates: CHAPS
(3-[(3-Cholamidopropyl)dimethylammonio]-1-propanesulfonate);
Sultaines: cocamidopropyl hyroxysultaine; Carboxylates: Amino acids
Imino acids Betaines: cocamidopropyl betaine; Phosphates: lecithin
. . . Nonionic Fatty alcohol, Stearyl alcohol, Cetostearyl alcohol
(consistently predominantly of cetyl and stearyl alcohols), Oleyl
alcohol; Polyoxyethylene glycol alkyl ethers (Brij):
CH.sub.3--(CH.sub.2).sub.10-16--(O--C.sub.2H.sub.4).sub.1-25--OH:
Octaethylene glycol monododecyl ether, Pentaethylene glycol
monododecyl ether; Polyoxypropylene glycol alkyl ethers:
CH.sub.3--(CH.sub.2).sub.10-16--(O--C.sub.2H.sub.6).sub.1-25--OH:
Glcoside alkyl ethers:
CH.sub.3--(CH.sub.2).sub.10-16--(O-Glucoside).sub.1-3--OH: Decyl
glucoside, Lauryl glucoside, Octyl glucoside; Polyoxyethylene
glycol octylphenol ethers:
C.sub.8H.sub.17--(C.sub.6H.sub.4)--(O--C.sub.2H.sub.4).sub.1-25--OH:
Triton X-100; Polyoxyethylene glycol alkyphenol ethers:
C.sub.9H.sub.19--(C.sub.6H.sub.4)--(O--C.sub.2H.sub.4).sub.1-25--OH:
Nonxynol-9; Glycerol alkyl esters: Glyceryl laurate Polyoxyethylene
glycol sorbitn alkyl esters: Polysorbates; Sorbitan alkyl esters:
Spans; Cocamide MEA, cocamide DEA; Dodecyl dimethylamine oxide;
Block copolymers of polyethylene glycol and polypropylene glycol:
Poloxamers . . .
TABLE-US-00019 TABLE 1C Types of Carbohydrates General: Aldose
.cndot. Ketose .cndot. Pyranose .cndot. Furanose Geometry
Cyclohexane conformation .cndot. Anomer .cndot. Mutarotation
Trioses Ketotriose (Dihydroyacetone) Aldotriose (Glyceraldehyde)
Tetroses Ketotetrose (Erythrulose) Ketopentose (Ribulose, Xylulose)
Pentoses Aldopentose (Ribose, Arabinose, Xylose, Lyxose)
Monosaccharides Deoxy sugar (Deoxyribose) Ketohexose (Psicose,
Fructose, Sorbose, Tagatose) Hexoses Aldohexose (Alose, Altrose,
Glucose, Mannose, Gulose, Idose, Galactose, Talose) Deoxy sugar
(Fucoe, Fuculose, Rhamnose) >6 Heptose (Sedoheptulose) .cndot.
Octose .cndot. Nonose (Neuraminic acid) Disaccharides Sucrose
.cndot. Lactose .cndot. Maltose .cndot. Trehalose .cndot. Turanose
.cndot. Cellobiose Trisaccharides Raffinose .cndot. Melezitose
.cndot. Maltotriose Tetrasaccharides Acarbose .cndot. Stachyose
Other oligosaccharides Fructooligosaccharide (FOS) .cndot.
Galactooligosaccharides (GOS) .cndot. Mannan- oligosaccharides
(MOS) Multiple Glucose/Glucan: Glycogen .cndot. Starch (Amylose,
Amylopectin) .cndot. Cellulose .cndot. Dextrin/Dextran .cndot.
Beta-glucan (Zymosan, Lentinan, Sizofiran) .cndot. Maltodextrin
Polysaccharides Fructose/Fructan: Inulin .cndot. Levan beta 2-6
Mannose/Mannan Galactose/alactan N-Acetylglucosemine: Chitin
[0360] The variations set forth in the foregoing description do not
represent all variations consistent with the subject matter
described herein. Instead, they are merely some examples consistent
with aspects related to the described subject matter. Wherever
possible, the same reference numbers will be used throughout the
drawings to refer to the same or like parts.
[0361] Although a few variations have been described in detail
above, other modifications or additions are possible. In
particular, further features and/or variations can be provided in
addition to those set forth herein. For example, the variations
described above can be directed to various combinations and
sub-combinations of the disclosed features and/or combinations and
sub-combinations of several further features disclosed above. In
addition, the logic flows and steps for use described herein do not
require the particular order shown, or sequential order, to achieve
desirable results. Other variations can be within the scope of the
claims.
* * * * *