U.S. patent application number 16/735130 was filed with the patent office on 2020-05-07 for apparatus and method for promoting fluid uptake into an implant.
This patent application is currently assigned to Nano Precision Medical, Inc.. The applicant listed for this patent is Nano Precision Medical, Inc.. Invention is credited to Kathleen Fischer, William G.M. Fischer, Adam D. Mendelsohn, Adam Monkowski, Wouter E. Roorda.
Application Number | 20200139099 16/735130 |
Document ID | / |
Family ID | 56544203 |
Filed Date | 2020-05-07 |
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United States Patent
Application |
20200139099 |
Kind Code |
A1 |
Roorda; Wouter E. ; et
al. |
May 7, 2020 |
APPARATUS AND METHOD FOR PROMOTING FLUID UPTAKE INTO AN IMPLANT
Abstract
The invention pertains to apparatuses, means and methods to
promote uptake of fluids into a reservoir of an implantable drug
delivery system though a porous membrane. Embodiments of the
invention promote fluid uptake by creating a pressure differential
between the reservoir of the drug delivery device and the
environment of the device after implantation, for instance a
subcutaneous pocket.
Inventors: |
Roorda; Wouter E.;
(Emeryville, CA) ; Fischer; William G.M.;
(Emeryville, CA) ; Fischer; Kathleen; (Emeryville,
CA) ; Mendelsohn; Adam D.; (Emeryville, CA) ;
Monkowski; Adam; (Emeryville, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Nano Precision Medical, Inc. |
Emeryville |
CA |
US |
|
|
Assignee: |
Nano Precision Medical,
Inc.
Emeryville
CA
|
Family ID: |
56544203 |
Appl. No.: |
16/735130 |
Filed: |
January 6, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
15419487 |
Jan 30, 2017 |
10525248 |
|
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16735130 |
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PCT/US2016/014750 |
Jan 25, 2016 |
|
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15419487 |
|
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|
62107912 |
Jan 26, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0024 20130101;
A61M 2039/0205 20130101; A61M 37/0069 20130101; A61M 39/0208
20130101 |
International
Class: |
A61M 39/02 20060101
A61M039/02; A61M 37/00 20060101 A61M037/00 |
Claims
1. An accessory unit for promoting fluid uptake into an implantable
drug delivery device, the drug delivery device being disposed
within a tubular outer member of an apparatus to promote fluid
uptake into the drug delivery device, the accessory unit
comprising: a first chamber having a septum suitable for accessing
the first chamber with the tubular outer member and for maintaining
a sealing mechanism around the tubular outer member after accessing
the first chamber; and a second chamber, the first chamber and the
second chamber being connected through a valved connector, the
second chamber configured for holding liquid for uptake into the
implant.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a Divisional application of U.S.
patent application Ser. No. 15/419,487, filed Jan. 30, 2017,
allowed, which application is a Continuation of PCT/US2016/014750
filed Jan. 25, 2016; which claims priority to U.S. Provisional
Application No. 62/107,912 filed Jan. 26, 2015, the teachings of
which are hereby incorporated by reference in their entirety for
all purposes.
BACKGROUND OF THE INVENTION
[0002] Many beneficial substances, including many therapeutic
agents, require long-term delivery to a target site of action to be
optimally effective. Well-known examples include drugs that need to
be administered for extended periods of time to a patient. Many
extended release formulations have been developed for this purpose.
A common issue with all of these formulations is that the drugs
administered need to be stabilized in the formulation for the
duration of the shelf-life of their dosage form, in addition to the
stabilization required during the extended release period.
[0003] In many cases, drugs are more stable in a dry or solid
formulation than in a dissolved state, hence formulations having a
solid formulation during shelf life are often preferred. In some
instances, the solid drug may be dispersed in a liquid, resulting
in a liquid formulation comprising a solid drug. However, in order
to be released from their dosage form, drugs almost always rely on
some type of diffusional mechanism, which inherently requires the
drugs to be in solution. Therefore, many dosage forms rely on the
uptake of water after administration to a patient to bring the
drugs from a solid form into solution, prior to release from the
dosage form.
[0004] One type of dosage form that has been developed to address
the issue of extended release of therapeutic agents is that of
implantable drug delivery devices, in which a reservoir holding a
drug formulation is combined with a release rate controlling
mechanism, such as a release rate controlling membrane. In many
instances, when a solid or dry formulation, like a powder, is
filled into such a reservoir, a quantity of air is included in the
reservoir. As was mentioned above, many of these dosage forms rely
on the uptake of water to bring their drugs from the solid form
into solution, essentially requiring that air inside the reservoir
be replaced with water. Oftentimes, this will require simultaneous
mass transport of water into a device and air out of the device.
For those dosage forms that do not allow for such simultaneous
transport, proper hydration of the formulation inside the reservoir
may be impeded. One type of dosage form where this can be the case
is implantable drug delivery systems having a capsule encapsulating
a reservoir containing a therapeutic agent in a dry form, and a
release rate controlling membrane based on nanopores. In many
cases, the reservoir and the nanopores will contain an amount of
air in addition to the therapeutic agent, and mass transport of
interstitial fluid into the reservoir after implantation may be
impeded by the presence of the air. Therefore, additional
technologies are desired that allow for proper hydration in such
dosage forms.
BRIEF SUMMARY OF THE INVENTION
[0005] In one embodiment, the present invention provides an
apparatus for promoting fluid uptake into an implantable drug
delivery device, the apparatus comprising: [0006] a housing; [0007]
a tubular outer member extending from the housing in a distal
direction; [0008] an obturator, at least partially slideably
disposed within the tubular outer member; and [0009] a pressure
reducer.
[0010] In certain instances, the pressure reducer is a slideable
pressure reducer.
[0011] In certain instances, the pressure reducer is at least
partially disposed within the tubular outer member.
[0012] In certain instances, the obturator is tubular, and wherein
the slideable pressure reducer is at least partially disposed
within the tubular obturator.
[0013] In certain instances, the pressure reducer is tubular, and
wherein the slideable obturator is at least partially disposed
within the tubular pressure reducer.
[0014] In certain instances, the tubular outer member is attached
to the housing.
[0015] In certain instances, the tubular outer member is a
slideable member, partially disposed within the housing.
[0016] In certain instances, the obturator is attached to the
housing.
[0017] In certain instances, the apparatus further comprises:
[0018] a cylindrical cavity having an inner wall, the cavity being
located within the housing and being connected with the tubular
outer member; [0019] wherein the slideable pressure reducer is at
least partially disposed within the cylindrical cavity and
comprises: [0020] a slideable cylindrical sealing plug in sealing
contact with the inner wall of the cylindrical cavity; [0021] a
handle, attached to the sealing plug and extending through the
cylindrical cavity in a proximal direction; and [0022] an aperture
in the sealing disk, the obturator being disposed through the
aperture, the aperture forming a sealing mechanism around the
obturator.
[0023] In certain instances, the apparatus further comprises an
implantable drug delivery device, the device being disposed within
the tubular outer member in a location distal to the obturator and
the pressure reducer, the device comprising a reservoir and a
porous membrane, the membrane providing a pathway for mass
transport through fluid flow between the reservoir and an
environment of the drug delivery device, the membrane being in
fluid contact with the pressure reducer.
[0024] In certain instances, the porous membrane is a nanoporous
membrane.
[0025] In certain instances, the porous membrane is a titania
nanotube membrane.
[0026] In certain instances, the apparatus further comprises a
plug, disposed within the tubular outer member in a location distal
to the implantable drug delivery device, the plug providing a
sealing mechanism within the tubular outer member.
[0027] In certain instances, the plug is a soluble plug.
[0028] In certain instances, the plug is a biodegradable plug.
[0029] In certain instances, the apparatus further comprises a
quantity of gas disposed within the tubular outer member, wherein
the quantity of gas includes at least 10% by weight of one or more
gases with a solubility in water at a temperature of 37.degree. C.
and a pressure of 1 atmosphere that is higher than the solubility
of air in water at a temperature of 37.degree. C. and a pressure of
1 atmosphere.
[0030] In another embodiment, the present invention provides an
apparatus for promoting fluid uptake into an implantable drug
delivery device, the apparatus comprising: [0031] a housing with a
distal end and a proximal end; [0032] a tubular outer member with a
distal end and a proximal end, the tubular outer member being
attached to the housing towards the distal end of the housing;
[0033] a slideable obturator, at least partially disposed within
the tubular outer member; and [0034] means to reduce pressure
inside the implantable drug delivery device.
[0035] In certain instances, the means comprise a slideable
pressure reducer in fluid contact with the implantable drug
delivery device.
[0036] In certain instances, the slideable pressure reducer is at
least partially disposed within the tubular outer member.
[0037] In certain instances, the obturator is tubular, and wherein
the slideable pressure reducer is at least partially disposed
within the tubular obturator.
[0038] In certain instances, the pressure reducer is tubular, and
wherein the slideable obturator is at least partially disposed
within the tubular pressure reducer.
[0039] In certain instances, the tubular outer member is attached
to the housing.
[0040] In certain instances, wherein the tubular outer member is a
slideable member, partially disposed within the housing.
[0041] In certain instances, the obturator is attached to the
housing.
[0042] In certain instances, the apparatus further comprises:
[0043] a cylindrical cavity having an inner wall, the cavity being
located within the housing and being connected with the tubular
outer member; [0044] wherein the slideable pressure reducer is at
least partially disposed within the cylindrical cavity and
comprises: [0045] a slideable cylindrical sealing plug in sealing
contact with the inner wall of the cylindrical cavity; [0046] a
handle, attached to the sealing plug and extending through the
cylindrical cavity in a proximal direction; and [0047] an aperture
in the sealing disk, the obturator being disposed through the
aperture, the aperture forming a sealing mechanism around the
obturator.
[0048] In certain instances, the apparatus further comprises the
implantable drug delivery device, the device being disposed within
the tubular outer member in a location distal to the obturator and
the pressure reducer, the device comprising a reservoir and a
porous membrane, the membrane providing a pathway for mass
transport through fluid flow between the reservoir and an
environment of the drug delivery device, the membrane being in
fluid contact with the pressure reducer.
[0049] In certain instances, the porous membrane is a nanoporous
membrane.
[0050] In certain instances, the apparatus further comprises a
plug, disposed within the tubular outer member in a location distal
to the implantable drug delivery device, the plug providing a
sealing mechanism within the tubular outer member.
[0051] In certain instances, the plug is a soluble plug.
[0052] In certain instances, the plug is a biodegradable plug.
[0053] In certain instances, the apparatus further comprising a
quantity of gas disposed within the tubular outer member, wherein
the quantity of gas includes at least 10% by weight of one or more
gases with a solubility in water at a temperature of 37.degree. C.
and a pressure of 1 atmosphere that is higher than the solubility
of air in water at a temperature of 37.degree. C. and a pressure of
1 atmosphere.
[0054] In one embodiment, the present invention provides a method
for promoting fluid uptake into an implantable drug delivery
device, the method comprising: [0055] providing an apparatus;
[0056] the apparatus comprising: [0057] a housing; [0058] a tubular
outer member extending from the housing in a distal direction;
[0059] an obturator, at least partially slideably disposed within
the tubular outer member; and [0060] a pressure reducer; [0061]
providing the implantable drug delivery device in a location within
the tubular outer member distal to the obturator; [0062] operating
the pressure reducer to reduce pressure inside the reservoir;
introducing the implantable drug delivery device from the outer
member into an environment containing a fluid; and [0063] exposing
the reservoir through the membrane to the fluid.
[0064] In certain instances, the pressure reducer is a slideable
pressure reducer.
[0065] In certain instances, the pressure reducer is at least
partially disposed within the tubular outer member.
[0066] In certain instances, the obturator is tubular, and wherein
the slideable pressure reducer is at least partially disposed
within the tubular obturator.
[0067] In certain instances, the pressure reducer is tubular, and
wherein the slideable obturator is at least partially disposed
within the tubular pressure reducer.
[0068] In certain instances, the tubular outer member is attached
to the housing.
[0069] In certain instances, tubular outer member is a slideable
member, partially disposed within the housing.
[0070] In certain instances, the obturator is attached to the
housing.
[0071] In certain instances, the apparatus further comprises:
[0072] a cylindrical cavity having an inner wall, the cavity being
located within the housing and being connected with the tubular
outer member; [0073] wherein the slideable pressure reducer is at
least partially disposed within the cylindrical cavity and
comprises: [0074] a slideable cylindrical sealing plug in sealing
contact with the inner wall of the cylindrical cavity; [0075] a
handle, attached to the sealing plug and extending through the
cylindrical cavity in a proximal direction; and [0076] an aperture
in the sealing disk, the obturator being disposed through the
aperture, the aperture forming a sealing mechanism around the
obturator.
[0077] In certain instances, the device comprises a reservoir and a
porous membrane, the membrane providing a pathway for mass
transport through fluid flow between the reservoir and an
environment of the drug delivery device, the membrane being in
fluid contact with the pressure reducer.
[0078] In certain instances, the porous membrane is a nanoporous
membrane.
[0079] In certain instances, the porous membrane is a titania
nanotube membrane.
[0080] In certain instances, the apparatus further comprises a
plug, disposed within the tubular outer member in a location distal
to the implantable drug delivery device, the plug providing a
sealing mechanism within the tubular outer member.
[0081] In certain instances, the plug is a soluble plug.
[0082] In certain instances, the plug is a biodegradable plug.
[0083] In certain instances, the apparatus further comprises a
quantity of gas disposed within the tubular outer member, wherein
the quantity of gas includes at least 10% by weight of one or more
gases with a solubility in water at a temperature of 37.degree. C.
and a pressure of 1 atmosphere that is higher than the solubility
of air in water at a temperature of 37.degree. C. and a pressure of
1 atmosphere.
[0084] In certain instances, the pressure inside the apparatus is
reduced to less than 0.5 atmosphere.
[0085] In certain instances, the pressure inside the apparatus is
reduced to less than 0.1 atmosphere.
[0086] In certain instances, the pressure inside the apparatus is
reduced to less than 0.01 atmosphere.
[0087] In yet another embodiment, the present invention provides an
apparatus for promoting fluid uptake into an implantable drug
delivery device, the apparatus comprising: [0088] a housing with a
distal end and a proximal end; [0089] a tubular outer member with a
distal end and a proximal end, the tubular outer member being
attached to the housing towards the distal end of the housing;
[0090] a slideable obturator, at least partially disposed within
the tubular outer member; and [0091] a connector for connecting to
a pressure reducer.
[0092] In certain instances, the connector is attached to one of
the tubular outer member and the slideable obturator.
[0093] In certain instances, the apparatus further comprises the
implantable drug delivery device, the device being disposed within
the tubular outer member in a location distal to the obturator and
the pressure reducer, the device comprising a reservoir and a
porous membrane, the membrane providing a pathway for mass
transport through fluid flow between the reservoir and an
environment of the drug delivery device, the membrane being in
fluid contact with the pressure reducer.
[0094] In certain instances, the porous membrane is a nanoporous
membrane.
[0095] In certain instances, the porous membrane is a titania
nanotube membrane.
[0096] In certain instances, the apparatus further comprises a
plug, disposed within the tubular outer member in a location distal
to the implantable drug delivery device, the plug providing a
sealing mechanism within the tubular outer member.
[0097] In certain instances, the plug is a soluble plug.
[0098] In certain instances, the plug is a biodegradable plug.
[0099] In certain instances, the apparatus further comprises a
quantity of gas disposed within the tubular outer member, wherein
the quantity of gas includes at least 10% by weight of one or more
gases with a solubility in water at a temperature of 37.degree. C.
and a pressure of 1 atmosphere that is higher than the solubility
of air in water at a temperature of 37.degree. C. and a pressure of
1 atmosphere.
[0100] In still yet another embodiment, the present invention
provides an accessory unit for promoting fluid uptake into an
implantable drug delivery device, the drug delivery device being
disposed within a tubular outer member of an apparatus to promote
fluid uptake into the drug delivery device, the accessory unit
comprising: [0101] a first chamber having a septum suitable for
accessing the first chamber with the tubular outer member and for
maintaining a sealing mechanism around the tubular outer member
after accessing the first chamber; and [0102] a second chamber, the
first chamber and the second chamber being connected through a
valved connector, the second chamber configured for holding liquid
for uptake into the implant.
[0103] In certain instances, the implantable drug delivery device
contains a formulation of a peptide or protein.
[0104] In certain instances, the protein or peptide is selected
from the group consisting of beta-glucocerobrosidase, interferon
alpha, interferon beta, agasidase alpha, agasidase beta, exenatide,
octreotide, LHRH, LHRH analog, calcitonin, nutropin/somatropin,
factor VIII, aldesleukin, forigerimod, NP fusion proteins, IL-12, a
melanocyte stimulating hormone, and bapineuzumab.
[0105] In certain instances, the protein or peptide is a member
selected from the group consisting of exenatide and octreotide.
[0106] In certain instances, the protein or peptide is
exenatide.
[0107] In certain instances, the amount of exenatide is from about
60 .mu.g to about 50 mg.
[0108] In certain instances, the implantable drug delivery device
contains a formulation of a peptide or protein.
[0109] In certain instances, the protein or peptide is selected
from the group consisting of beta-glucocerobrosidase, interferon
alpha, interferon beta, agasidase alpha, agasidase beta, exenatide,
octreotide, LHRH, LHRH analog, calcitonin, nutropin/somatropin,
factor VIII, aldesleukin, forigerimod, NP fusion proteins, IL-12, a
melanocyte stimulating hormone, and bapineuzumab.
[0110] In certain instances, the protein or peptide is a member
selected from the group consisting of exenatide and octreotide.
[0111] In certain instances, the protein or peptide is
exenatide.
[0112] In certain instances, the amount of exenatide is from about
60 .mu.g to about 50 mg.
[0113] In certain instances, the implantable drug delivery device
contains a formulation of a peptide or protein.
[0114] In certain instances, the protein or peptide is selected
from the group consisting of beta-glucocerobrosidase, interferon
alpha, interferon beta, agasidase alpha, agasidase beta, exenatide,
octreotide, LHRH, LHRH analog, calcitonin, nutropin/somatropin,
factor VIII, aldesleukin, forigerimod, NP fusion proteins, IL-12, a
melanocyte stimulating hormone, and bapineuzumab.
[0115] In certain instances, the protein or peptide is a member
selected from the group consisting of exenatide and octreotide.
[0116] In certain instances, the protein or peptide is
exenatide.
[0117] In certain instances, the amount of exenatide is from about
60 .mu.g to about 50 mg.
[0118] In certain instances, the implantable drug delivery device
contains a formulation of a peptide or protein.
[0119] In certain instances, the protein or peptide is selected
from the group consisting of beta-glucocerobrosidase, interferon
alpha, interferon beta, agasidase alpha, agasidase beta, exenatide,
octreotide, LHRH, LHRH analog, calcitonin, nutropin/somatropin,
factor VIII, aldesleukin, forigerimod, NP fusion proteins, IL-12, a
melanocyte stimulating hormone, and bapineuzumab.
[0120] In certain instances, the protein or peptide is a member
selected from the group consisting of exenatide and octreotide.
[0121] In certain instances, the protein or peptide is
exenatide.
[0122] In certain instances, the amount of exenatide is from about
60 .mu.g to about 50 mg.
[0123] In another embodiment, the present invention provides a
method to improve fluid uptake into an implantable drug delivery
device, the method comprising: [0124] providing an implantable drug
delivery device, the device comprising a reservoir and a porous
membrane, the membrane providing a pathway for mass transport
through fluid flow between the reservoir and an environment of the
drug delivery device; [0125] reducing pressure inside the drug
delivery device prior to implantation; and [0126] implanting the
device into a subject.
[0127] These and other aspects, objects and embodiments will become
more apparent when read with the detailed description of the
invention and the figures which follow.
BRIEF DESCRIPTION OF THE DRAWINGS
[0128] FIG. 1 illustrates a cross-sectional side view of an
embodiment of the invention.
[0129] FIG. 2 illustrates a cross-sectional side view of an
embodiment of the invention.
[0130] FIG. 3 illustrates a cross sectional side view of an
embodiment of the invention using sealing mechanisms like
O-rings.
[0131] FIG. 4A-4C illustrate cross sectional side views of an
embodiment of the invention in different stages of use.
[0132] FIG. 5 illustrates a cross sectional side view of an
embodiment of the invention.
[0133] FIG. 6 illustrates a cross sectional side view of an
embodiment of the invention.
[0134] FIG. 7 illustrates a cross sectional side view of the use of
an embodiment of the invention to hydrate a drug formulation in a
reservoir of a drug delivery device.
[0135] FIG. 8 illustrates a cross sectional side view of an
embodiment of an accessory unit according to the invention.
[0136] FIG. 9 illustrates a cross sectional side view of an
embodiment of the invention inserted under the skin of a
patient.
[0137] FIG. 10 is a graph showing weight gain as a function of time
after hydration.
[0138] FIG. 11 is a graph showing fluid uptake over time.
[0139] FIG. 12 is a graph showing drug release over time as a
function of atmospheric pressure.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0140] "Obturator" refers to an elongated member, suitable for
moving an object within a tubular member with respect to the
tubular member.
[0141] "Membrane" refers to a porous structure allowing mass
transport of molecules from one side of the structure to the other
through the structure.
[0142] "Porous membrane" refers to a porous structure wherein at
least some of its pores are open on both ends and form fluid-filled
pathways allowing for mass transport through the structure by fluid
flow.
[0143] "Nanoporous membrane" refers to a porous structure wherein
at least some of its pores are open on both ends and form
fluid-filled pathways having a smallest dimension less than one
micrometer and allowing for mass transport through the structure by
fluid flow.
[0144] "Titania nanotube membrane" refers to a nanoporous membrane
having an array of titania nanotubes on a titanium substrate where
at least a portion of the titania nanotubes are open at both ends
and capable of allowing mass transport from one side of the
membrane to the other through the titania nanotubes by fluid
flow.
[0145] "Polypeptide," "peptide," and "protein" are used
interchangeably herein to refer to a polymer of amino acid
residues. All three terms apply to amino acid polymers in which one
or more amino acid residue is an artificial chemical mimetic of a
corresponding naturally occurring amino acid, as well as to
naturally occurring amino acid polymers and non-naturally occurring
amino acid polymers. As used herein, the terms encompass amino acid
chains of any length, including full length proteins, wherein the
amino acid residues are linked by covalent peptide bonds.
[0146] "Fluid contact" refers to a location of two or more entities
relative to each other in a manner that allows for fluid-phase mass
transport between the entities.
[0147] "Water-soluble gas" refers to a gas that has a solubility in
water at a temperature of 37.degree. C. and a pressure of 1
atmosphere that is greater than the solubility of air in water at a
temperature of 37.degree. C. and a pressure of 1 atmosphere. The
equilibrium solubility of air (oxygen and nitrogen combined) in
water under these conditions is about 22 mg/liter (22 .mu.g/mL). A
water soluble gas (or mixture of gases) has a solubility of more
than 22 mg/liter such as 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,
33, 34, 35, 36, 37, 38, 39, 40 or more than 40 mg/liter.
[0148] The term "distal" in reference to a medical device or part
thereof generally refers to an orientation away from a medical user
of the device and towards a subject or patient. The term "proximal"
in reference to a medical device or part thereof generally refers
to an orientation towards a medical user of the device and away
from a subject or patient.
[0149] The term "biodegradable" refers to the ability of a
polymeric substance to degrade into lower molecular weight species
when introduced into a biological environment. Examples include
biodegradable polymers such as poly(lactic-co-glycolic acid)
(PLGA).
[0150] The term "soluble" refers to the ability of a substance to
dissolve into a solvent such as a biological fluid, without
degrading into lower molecular weight species. Examples include
biocompatible polymers like polyethylene glycol and polyvinyl
prrrolidone.
Embodiments
[0151] The invention pertains to the field of implantable drug
delivery devices having a reservoir containing a therapeutic agent,
and having one or more membranes providing pathways for mass
transport through fluid flow between the reservoir and an
environment of the drug delivery device. In preferred embodiments
the membranes are porous membranes. The membranes may be configured
to provide sustained release of the therapeutic agent after
implantation of the device in the body of a subject. In some
embodiments the membrane is a microporous membrane. In some
embodiments the membrane is a nanoporous membrane such as those
described in U.S. Patent Application Pub. No. 2014/0371687,
incorporated herein by reference.
[0152] For shelf-stability purposes (i.e., shelf-life), it is often
preferred that the therapeutic agent in such devices is in a solid
state during storage of the device. In order for release of the
therapeutic agent to occur, fluids may need to be introduced into
the reservoir to dissolve the therapeutic agent and enable its
release through the porous membrane.
[0153] Embodiments of the invention include apparatuses, methods
and means to promote uptake of fluids into the reservoir of an
implantable drug delivery device. In some embodiments a drug
delivery device is part of the embodiment. In certain instances,
the apparatuses, methods and means enable implantation of a drug
delivery device having a reservoir into a subject, wherein the
reservoir has a pressure which is less than atmospheric pressure
(sub-atmospheric i.e., reduced pressure), such as less than 1.0,
0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07,
0.06, 0.05, 0.04, 0.03, 0.02, 0.01, less than 0.01 atmosphere
(<0.01) or even less. In certain aspects, the reservoir has a
pressure of 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002,
0.001 atm or even less. The reduced pressure promotes the uptake of
interstitial fluid into the reservoir.
[0154] Embodiments of the invention promote uptake of fluids into a
reservoir of an implantable drug delivery device through a porous
membrane by creating a pressure differential between the reservoir
in the device and a fluid-filled environment of the device. For
instance, creation of a reduced pressure inside a reservoir of an
implantable drug delivery device having a porous membrane combined
with insertion of the device in a subcutaneous pocket may promote
the uptake of biological fluids, such as interstitial fluid,
through the membrane and into the reservoir.
[0155] It should be understood that in the absence of the pressure
differential created by embodiments of the invention interstitial
fluid will ultimately be absorbed into the drug delivery device,
mostly by slow dissolution of air inside the device into the
incoming interstitial fluid. However, the time required for such
hydration may not be medically acceptable. Embodiments of the
invention allow for the time required for hydration or rehydration
to be brought within medically acceptable limits. Since those
limits may differ from one application to another, the extent to
fluid uptake needs to be accelerated may be application dependent.
In particular, the delay of drug release from a second implant,
inserted after explantation of a first, depleted or substantially
depleted implant, a so-called "drug holiday," may determine the
acceptability of the rate of hydration of a dosage form. For
instance, for a drug with a wide therapeutic window, and an
elimination half-life of 18 hours or more, a delay in release after
implantation of a second dosage form of 2 days or more may be
acceptable. For a drug with a narrow therapeutic window, and
half-life of a few hours, a 12-24 hour delay may be the maximum
acceptable range.
[0156] In general, embodiments of the invention provide substantial
hydration and initiation of significant drug release within 48
hours of implantation of a device in a subject. Preferred
embodiments provide substantial hydration and initiation of
significant drug release within 36 hours of implantation of a
device in a subject. More preferred embodiments provide substantial
hydration and initiation of significant drug release within 24
hours of implantation of a device in a subject.
[0157] Most preferred embodiments provide substantial hydration and
initiation of significant drug release within 12 hours of
implantation of a device in a subject.
[0158] Some embodiments of the invention are suitable for
introducing the drug delivery device into the body of a subject, as
well as for creating a reduced pressure inside a reservoir of a
drug delivery device.
[0159] Some embodiments of the invention comprise a housing.
Functions of the housing may include holding other components of
the invention together into an apparatus suitable for use,
providing a handle for an user to hold and operate the apparatus,
and the like. The housing may be constructed out of any suitable
material, including polymers, ceramics, composites and combinations
thereof. Oftentimes, for purposes of ease of manufacturing and cost
reduction, the housing will comprise molded polymeric parts.
[0160] Some embodiments of the invention comprise a tubular outer
member, such as a tubular insertion member or tubular implantation
member, extending from the housing in a distal direction. In some
embodiments the outer member is attached to the housing. In some
embodiments , the outer member is a slideable member, at least
partially slideably disposed within the housing. The outer member
may be configured to hold an implantable drug delivery device. In
some embodiments the insertion member or implantation member is a
sharpened member, such as a hollow needle, suitable to penetrate
the skin, to access areas within the body of a subject, such as the
subcutaneous space, and deliver an implantable drug delivery device
into the subcutaneous space. In some embodiments the tubular
insertion member is a blunt member, suitable to access areas within
the body of a subject after penetrating the skin with a separate
implement, such as a scalpel. In some embodiments the separate
implement is included in the embodiment. The tubular outer member
may be constructed out of any suitable material. Preferred
materials of construction include metals, polymers, ceramics,
composites and combinations thereof. Examples of metals include
stainless steel and titanium. Examples of polymers include
polyethylene, polypropylene, polyurethanes, acrylonitrile butadiene
styrene, polyether ether ketone, etc. In some embodiments, the
tubular outer member is not used for insertion of an implant into
the body of a patient, but to prepare an implant for implantation
just before the actual insertion procedure.
[0161] Some embodiments comprise an obturator. Obturators of the
invention may comprise elongated members, slideably disposed within
a tubular outer member. In some embodiments the obtorators are
slideable obturators. In some embodiments, the obdurators are
attached to the housing, and the tubular outer member is slideable
disposed around the obturator. Functions of the obturator include
providing a means to an operator to move an implantable drug
delivery device, disposed within the tubular outer member, with
respect to the tubular outer member or to hold a drug delivery
device, disposed within a tubular outer member stationary, while
moving the tubular outer member. The obturator may be constructed
out of any suitable material. Preferred materials of construction
include metals, polymers, ceramics, composites and combinations
thereof. Examples of metals include stainless steel and titanium.
Examples of polymers include polyethylene, polypropylene,
polyurethanes, acrylonitrile butadiene styrene, polyether ether
ketone, etc.
[0162] Some embodiments of the invention comprise a pressure
reducer. In embodiments comprising a drug delivery device, the
pressure reducer may be in fluid contact with the membrane of the
drug delivery device. Some embodiments comprise a pressure reducer
configured as a slideable elongated member. In some embodiments the
pressure reducer is at least partially slideably disposed within
the outer member. In some embodiments the obturator is a tubular
obturator, and the pressure reducer is at least partially slideably
disposed within the obturator. In some embodiments, the pressure
reducer is a tubular pressure reducer, and the obturator is at
least partially slideably disposed within the pressure reducer. In
some embodiments, the obturator and the pressure reducer are at
least partially slideably disposed within the outer member in a
side-by-side configuration.
[0163] Some embodiments comprise a slideable pressure reducer
outside the tubular outer member, for instance in a cavity in a
housing, wherein the housing holds the outer member, the obturator
and the pressure reducer.
[0164] Functions of the pressure reducer include providing a means
to an operator to reduce the pressure inside a reservoir of an
implantable drug delivery system to promote uptake of fluids into
the reservoir. The pressure reducer may be constructed out of any
suitable material. Preferred materials of construction include
metals, polymers, ceramics, composites and combinations thereof.
Examples of metals include stainless steel and titanium. Examples
of polymers include polyethylene, polypropylene, polyurethanes,
acrylonitrile butadiene styrene, polyether ether ketone, etc.
[0165] Some embodiments include connectors for connecting to a
separately supplied pressure reducer, such as a syringe or a vacuum
pump.
[0166] As will be explained further below, in some embodiments,
moving a slideable pressure reducer, disposed within a tubular
outer member or within a cavity in a housing, from a distal to a
proximal position inside the tubular outer member or the cavity in
the housing creates a reduced pressure in the tubular outer member
or the cavity in the housing, in a location distal to the pressure
reducer and in fluid contact with a membrane of a drug delivery
device contained within a tubular outer member.
[0167] In some embodiments, operating the pressure reducer reduces
the pressure inside the tubular outer member or inside the cavity
in the housing to less than 0.5 atmosphere. In preferred
embodiments the pressure is reduced to less than 0.1 atmosphere. In
most preferred embodiments, the pressure is reduced to less than
0.01 atmosphere.
[0168] Some embodiments of the invention include an implantable
drug delivery device, slideably disposed within the tubular outer
member. Drug delivery devices useable in the current invention
comprise at least one reservoir containing a formulation of a
therapeutic agent to be delivered from the device. Drug delivery
devices of the invention further comprise at least one membrane to
provide a pathway for delivery of the therapeutic agent out of the
reservoir of the device and into an environment of use. In
preferred embodiments the membrane is configured to control the
release of the therapeutic agent for extended periods of time. In
some preferred embodiments, release of the beneficial substance(s)
is extended over at least one month. In more preferred embodiments,
the release is extended over at least three months, 4, 5, 6, 7, 8,
9, 10, 11, or at least 12 months.
[0169] In some embodiments, a membrane controlling the rate of
release of the therapeutic agent is a nanoporous membrane. In
certain embodiments, there are two or more membranes in the
device.
[0170] In some embodiments, the pores in the membranes are
nanochannels, such as those disclosed in U.S. Pat. No. 8,480,637
incorporated herein by reference. In some embodiments, the pores in
the membranes are nanotubes, such as those disclosed in U.S. Patent
Application Pub. No. 2014/0371687 incorporated herein by
reference.
[0171] In some embodiments, compositions of the invention are
disposed within a reservoir of an extended-release dosage form
controlled by a nanoporous membrane, wherein the nanoporous
membrane is configured to achieve extended-release of the
therapeutic agent from the reservoir of a device. In some
embodiments, the release rate of the therapeutic agent is
controlled by matching the dimensions of the pores in the
nanoporous membrane to the molecular dimensions or the hydrodynamic
dimensions of the therapeutic agent. In some embodiments, the
smallest dimension of the pores is not more than 5 times a
molecular dimension or hydrodynamic dimension of the therapeutic
agent. In some embodiments, the smallest diameter of the pores is
not more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times a
molecular dimension or hydrodynamic dimension of the therapeutic
agent.
[0172] The drug delivery device may be held in place by any desired
means, including means such as a precision fit inside the outer
member with tolerances to provide adequate immobilization of the
device or an adequate sealing function as described below, while
still allowing for sufficient slideability of the device. In some
embodiments the device or the outer member may have a slightly
ovalized section to provide a friction fit to hold the device in
place. Some embodiments of the invention include a separate drug
delivery device, configured to be loaded into a tubular outer
member prior to use. Some embodiments of the invention do not
include a drug delivery device, and are configured to be loaded
with a separately provided drug delivery device.
[0173] In some embodiments the drug delivery device contains a
formulation of protein or peptide. Suitable peptides include, but
are not limited to, beta-glucocerobrosidase, interferon alpha,
interferon beta, interferon gamma, agasidase alpha, agasidase beta,
exenatide, octreotide, LHRH, LHRH analogs, calcitonin,
nutropin/somatropin, factor VIII, aldesleukin, forigerimod, NP
fusion proteins, IL-12, a melanocyte stimulating hormone, and
bapineuzumab. In some embodiments, the protein or peptide
therapeutic agents are Glucagon-Like Peptide-1 receptor agonists
also known as GLP-1 receptor agonists. In some embodiments, the
GLP-1 receptor agonist is exenatide. In certain instances,
exenatide has CAS No. 141732-76-5 and an empirical formula of
C.sub.184H.sub.282N.sub.50O.sub.60S. In preferred embodiments, the
amount of exenatide can be from about 60 .mu.g to about 50 mg, such
as 100 .mu.g, 200 .mu.g, 300 .mu.g, 400 .mu.g, 500 .mu.g, 600
.mu.g, 700 .mu.g, 800 .mu.g, 900 .mu.g, 1 mg, 10 mg, 20 mg, 30 mg,
40 mg, or 50 mg.
[0174] Turning now to FIGS. 1-9, the structure and mode of
operation of the invention will be illustrated by way of a number
of exemplary embodiments. In the embodiment illustrated in FIG. 1,
slideably disposed within tubular outer member 1001 are implantable
drug delivery device 1002 having an internal reservoir as described
above, and slideable tubular obturator 1003. Disposed within
tubular obturator 1003 is slideable pressure reducer 1004. Porous
membrane 1005 is located towards the proximal end of drug delivery
device 1002. Located between the distal end of tubular obturator
1003 and the proximal end of drug delivery device 1002 is connector
1006. Connector(s) 1006 is configured to provide a sealing
mechanism between the distal end of tubular obturator 1003 and the
proximal end of drug delivery device 1002 to maintain a reduced
pressure during operation of the embodiment. Connector(s) 1006 is
attached to tubular obturator 1003, for instance by use of an
adhesive, or, in the case of an O-ring or a washer by having a
pressure fit inside a rim or groove provided along the outer
perimeter of the distal end of obturator 1003, or by any other
suitable means or combination of means. In some embodiments, the
distal end of obturator 1003 itself forms a sealing mechanism with
the proximal end of drug delivery device 1002. Pressure reducer
1004 and tubular obturator 1003 are manufactured with adequate
precision that the interface between the inner surface of obturator
1003 and the outer surface of pressure reducer 1004 provides a
sealing mechanism to maintain a reduced pressure during operation
of the embodiment.
[0175] In an alternative embodiment, a sealing mechanism is
provided by a plug disposed within an outer member, distal to an
implantable drug delivery device. As illustrated in FIG. 2.
slideably disposed within tubular outer member 2001 are implantable
drug delivery device 2002 having an internal reservoir as described
above, and slideable tubular pressure reducer 2003. Disposed within
tubular pressure reducer 2003 is slideable obturator 2004. Porous
membrane 2005 is located towards the proximal end of drug delivery
device 2002. Located towards distal tip 2006 of tubular outer
member 2001 is plug 2007. Plug 2007 is preferably a soluble or a
biocompatible material. Similar plugs have been described in
International Patent Application PCT/US15/63940, incorporated
herein by reference. In some embodiments, plug 2007 may extend into
the space between the wall of tubular outer member 2001 and
implantable drug delivery device 2002. This may be the case, for
instance, when plug 2007 is introduced into outer member 2001 in
liquid form after placement of drug delivery device 2002, and
allowed to penetrate the space between the wall of outer member
2001 and drug delivery device 2002, and to harden in place. In some
embodiments, plug 2007 may act as a sealing mechanism. In some
embodiments, the implantable drug delivery device and the tubular
outer member may be manufactured with a precision that allows the
drug delivery device itself to act as a plug and form a sealing
mechanism.
[0176] As illustrated in FIG. 3, sealing mechanisms like gaskets,
washers and O-rings may be incorporated between sliding members of
the apparatus to provide improved sealing mechanisms. In FIG. 3,
O-ring 3010 is located in a groove 3011 on tubular obturator 3003
inside outer member 3001, and O-ring 3012 is located in groove 3013
on sliding pressure reducer 3004. The invention does not put any a
priori limitations on the locations or number of the seals, other
than that a low pressure lumen can be created to reduce the
pressure inside a reservoir of a drug delivery device. For
instance, O-ring seals may be positioned between any two sliding
surfaces of embodiments of the invention. Various sealing
mechanisms and means, such as washer, gaskets, O-rings, precision
fits and the like can be used interchangeably on embodiments of the
invention, and those with ordinary skills in the art of mechanical
engineering and medical device design will be able to determine the
most suitable mechanisms based on such considerations as cost,
quality, reliability, durability, sterilizability and the like.
[0177] The general function of some embodiments of the invention,
and their method of use are illustrated in an exemplary embodiment
in FIG. 4A-4C. In FIG. 4A, tubular outer member 4001 extends from
housing 4007 in a distal direction, and is partially disposed
within housing 4007 in a slideable manner. Tubular outer member
4001 is configured as a hollow needle with a sharpened distal tip
4014. Tubular obturator 4004 is disposed within outer member 4001
and within housing 4007, and is attached to housing 4007 though
posts 4009. Slideable pressure reducer 4003 is partially disposed
within obturator 4004. O-ring 4012 forms a sealing mechanism
between obturator 4004 and outer member 4001, and O-ring 4013 forms
a sealing mechanism between pressure reducer 4003 and obturator
4004. Implantable drug delivery device 4002 is located within outer
member 4001 towards sharpened distal tip 4014. Plug 4006 seals the
lumen of outer member 4001 distal to implantable drug delivery
device 4002. Housing 4007 holds the various components of the
apparatus, including outer member slider 4015 attached to outer
member 4001.
[0178] During operation of the device an operator may insert outer
member 4001 underneath the skin of a subject. As illustrated in
FIG. 4B, the operator moves slideable pressure reducer in a
proximal direction, creating a reduced pressure in lumen 4016 of
tubular obturator 4004. Because of the sealing action of O-rings
4012 and 4013, and of plug 4006, the reduced pressure is propagated
into the reservoir of drug delivery device 4002 through membrane
4005. In a next step, as illustrated in FIG. 4C, the operator may
move outer member slider 4015, and, consequently, outer member 4001
in a proximal direction within housing 4007. By holding housing
4007, attached to obturator 4004 through posts 4009, stationary,
obturator 4009 is held stationary under the skin. Consequently,
drug delivery device 4002 and plug 4006 are held stationary under
the skin, while outer member 4001 is withdrawn in a distal
direction. Once drug delivery device 4002 is essentially expelled
from the outer member, device 4002 is exposed to interstitial
fluid, and the reduced pressure inside the reservoir may promote
fluid uptake.
[0179] Yet an alternative embodiment is illustrated in FIG. 5.
Slideably disposed within tubular outer member 5001 are implantable
drug delivery device 5002 having an internal reservoir as described
above, and slideable obturator 5003. Outer member 5001 is attached
to housing 5004. Implantable drug delivery device 5002 and outer
member 5001 are machined with adequate precision that device 5002
forms a sealing mechanism within outer member 5001. In some
embodiments, a sealing aid, such as a sealing fluid like a wax or a
biocompatible oil may be used to improve the sealing mechanism.
Housing 5004 holds outer member 5001 and obturator 5003. Housing
5004 has an internal cylindrical cavity 5005. Slideably disposed
within cavity 5005 is plunger-shaped pressure reducer 5006,
comprising handle 5007 and sealing disk 5008. Sealing disk 5008
forms a sealing mechanism with the wall of cavity 5005. Sealing
disk 5008 has an aperture 5010, which forms a slideable seal around
obturator 5003.
[0180] During use of the device a user may move pressure reducer
5006 from a distal to a proximal position until sealing disk 5008
abuts disk stops 5011, thereby creating reduced pressure inside the
cavity section distal to sealing disk 5008, inside outer member
5001 and inside the reservoir of drug delivery device 5002 through
membrane 5009. After insertion into the body of a subject, for
instance in a subcutaneous space, the user may hold obturator 5003
stationary, and continue to move pressure reducer 5006 in a
proximal direction. Since sealing disk 5008 abuts disk stops 5011,
housing 5004 with attached outer member 5001 will move in a distal
direction. Since obturator 5003 is held stationary, drug delivery
device 5002 will essentially be expelled from outer member 5001
under the skin of the subject. Alternatively, pressure reducer 5006
may be immobilized against disk stops 5011, for instance by a
including a ratchet mechanism on handle 5007 and disk stop 5011,
allowing the user to use housing 5004 as a handle to move the
housing, outer member 5001 and pressure reducer 5006 in a proximal
direction.
[0181] In some embodiments an external pressure reducer may be
employed in connection with embodiments of the invention. For
instance, as shown in FIG. 6, slideable tubular obturator 6003 may
be fitted with a connector 6013. Connector 6013 may be connected to
an external pressure reducer, which may, for example be a vacuum
pump, a vacuum line, or a syringe that can be used to create a
reduced pressure in lumen 6008. Alternatively, outer member 6001
may be fitted with a connector to an external vacuum source, for
instance in combination with a sealing plug inside hollow outer
member 6001, distal to implantable drug delivery device 6002.
[0182] In addition to the exemplary embodiments described above,
other features may be included to improve control and facilitate
operation of the inventions, such as levers and gears to operate
moving parts, spring-loaded mechanisms, battery-operated
embodiments, ergonomic shaping of the housing or of a handle to be
included, etc. Those with ordinary skills in the art of mechanical
engineering or medical device design will be able to design such
features within the scope of the present invention.
[0183] The potential effect of the pressure reduction to promote
fluid uptake can be calculated and the actual effectiveness
experimentally determined in straightforward procedures.
Determination of the theoretical reduction in pressure can be
performed from construction drawings of the apparatus. For
instance, as illustrated in FIG. 4A-4C, lumen 4016 is significantly
enlarged by moving pressure reducer 4003 from a distal position, as
illustrated in FIG. 4A, to a proximal position as illustrated in
FIG. 4B. As was stated above, various components of the invention
may be fabricated with adequate precision to form sealing
mechanisms, and various sealing mechanisms, such as O-rings, may be
incorporated into the embodiments. In the case that these sealing
mechanisms provide substantially hermetic seals, at least for the
duration of the procedure to be performed by a medical
professional, the resulting pressure reduction inside the
embodiments can be calculated from the ratio of the sum of the
volumes in the reservoir inside the drug delivery device and inside
the void space in the tubular outer member before moving the
pressure reducer, and the sum of the volumes in the reservoir
inside the drug delivery device and inside the void space in the
tubular outer member after moving the pressure reducer. Analogous
calculations can be performed for other embodiments. Also, during
the design phase of the embodiments, a pressure sensor can be
introduced into volume 4016, or into the reservoir of drug delivery
device 4002 to measure the actually achieved pressure reduction,
and any decay in the reduction over time, due to potentially less
than hermetic sealing by the various components. Experimentally,
the adequacy of the pressure reduction can be determined by
gravimetric measurement of fluid uptake into the reservoir of
device 4002 after pressure reduction and exposure to fluids.
[0184] As described in International Patent Application
PCT/US15/63940, incorporated herein by reference, it may be
advantageous to include a water-soluble gas in implantable drug
delivery devices, such as the ones in this disclosure, instead of
air. As defined in International Patent Application PCT/US15/63940,
the term "water-soluble gas" refers to a gas that has a higher
solubility in water at 37.degree. C. and 1 atmosphere than the
solubility of air in water under those conditions. In such
embodiments the water-soluble gas can act as a humectant, and
attract water into the reservoir of the device to promote
dissolution and release of the therapeutic agent. The concepts
disclosed in PCT/US15/63940 can be advantageously combined with
embodiments of the present invention. During manufacture of the
apparatus air inside the reservoir of drug delivery device and in
the interior lumens of the apparatus can be replaced with a
water-soluble gas. Such embodiments have multiple advantages,
including a combined action of reduced pressure and humectant
activity of the water-soluble gas, as well as potentially improved
shelf-stability of the product, since water-soluble gases like
CO.sub.2 are less reactive with drug substance than the oxygen in
air.
[0185] As illustrated in FIG. 7, in an alternative embodiment of
use of the invention, a user can perform essentially the same
procedure to promote hydration, but rather than inserting the outer
member into a subject, the user submerges the distal end of outer
member 7001 in a container 7010 with a liquid 7011 such as a buffer
used for uptake into the reservoir. After creating the reduced
pressure, drug delivery device 7002 is expelled into liquid 7011.
After sufficient time has passed for liquid uptake to occur, the
device is retrieved from container 7010, and is ready to be
implanted into a subject by any means deemed desirable by the
user.
[0186] Some embodiments of the invention comprise an accessory unit
suitable for improving fluid uptake into a reservoir outside the
body of a subject. FIG. 8 illustrates an embodiment of the
invention having such an accessory unit. Chamber 8015 is fitted
with septum 8016. Chamber 8015 may contain any suitable gas, such
as air, N.sub.2O or CO.sub.2, and may be at any desirable pressure.
Chamber 8015 is connected with chamber 8017 by means of valved
connector 8018. Drug delivery device 8002 and obturator 8003 are
slideably disposed within tubular outer member 8001. Drug delivery
device 8002 has a porous membrane 8005. Obturator 8003 and tubular
outer member 8001 are machined such that a sealing mechanism is
formed between the outer surface of obturator 8003 and the inner
surface of tubular outer member 8001. In these embodiments,
obturator 8003 may perform functions of a pressure reducer
described in embodiments of FIGS. 1-7.
[0187] During use, a user inserts the sharpened tip of tubular
outer member 8001 into chamber 8015 through septum 8016, and
subsequently pulls obturator 8003 in a proximal direction to create
a reduced pressure in spaces 8015, 8019 and 8020. The reduced
pressure is propagated into the reservoir of drug delivery device
8002 through porous membrane 8005. Once a sufficiently reduced
pressure has been achieved, the user opens valved connector 8018,
to let fluid 8021 from chamber 8017 into chamber 8015.
[0188] In other embodiments the valved connector may be an
automatic connector, responsive to reduced pressure in chamber
8015. In order to facilitate the fluid transfer, chamber 8017 may
have a variable volume, for instance by manufacturing the wall of
chamber 8017 from a flexible material. The reduced pressure in the
reservoir of drug delivery device 8002 facilitates uptake of the
fluid 8021 through membrane 8005.
[0189] Some embodiments of the invention create a reduced pressure
in the reservoir of a drug delivery device upon insertion of a
tubular outer member into the body of a subject such as a human. As
illustrated in FIG. 9, drug delivery device 9002 and tubular
obturator 9004 are slideably disposed within tubular outer member
9001. Slideable pressure reducer 9003 is disposed within tubular
obturator 9004. Drug delivery device 9002 has porous membrane 9005.
During use, a user inserts the distal tip of tubular outer member
9001 into the body of a subject on a location outside of any major
blood vessels, for instance in a subdermal space or pocket 9009
between skin 9010 and underlying tissue 9011. In such locations the
tissue pocket may provide a sealing mechanisms over the tip of
outer member 9001. By pulling pressure reducer 9003 in a proximal
direction, a reduced pressure is created in lumen 9007 of tubular
outer member 9001, and propagated into the reservoir of drug
delivery device 9002. After sufficient time has elapsed to allow
reduced pressure to develop in the reservoir through porous
membrane 9005, drug delivery device 9002 is expelled into
subcutaneous tissue pocket by withdrawing outer member 9001 in a
proximal direction, while holding obturator 9004 stationary.
EXAMPLES
Example 1
[0190] 9 devices with 39 microliter titanium reservoirs were sealed
with titanium screw caps holding nanoporous membranes as described
in U.S. Patent Application Pub. No. 2014/0371687.
[0191] The devices were inserted in a stainless steel outer member
with a volume of about 0.8 ml. The outer member was sealed with a
plug at the distal end and attached to a 60 cc syringe at the
proximal end. Reduced pressure was applied by moving the syringe
plunger proximally, resulting in a pressure reduction to about
0.013 atm.
[0192] The devices were distributed in 3 groups, and reduced
pressure was held for 15 seconds, 1 minute or 5 minutes for the
individual groups. After the allotted time was elapsed, the tips of
the outer members were submerged in water, and the devices expelled
from the outer members. Water uptake was measured gravimetrically
at 3 hours for 1 device in each group, and for all devices at 20
hours. The results are depicted in FIG. 10.
Example 2
[0193] 7 devices with 39 microliter titanium reservoirs were filled
with 13-18 mg of a dry powder formulation of exenatide. The
reservoirs were sealed with titanium screw caps holding nanoporous
membranes as described in U.S. Patent Application Pub. No.
2014/0371687. Initial weights of the powder-filled devices were
recorded.
[0194] 3 devices were submerged in phosphate buffered saline pH 7.4
(PBS) at 37.degree. C. at atmospheric pressure in HPLC vials,
without further pretreatment. 4 devices were subjected to a
pressure reduction by introducing them into a vacuum chamber and
reducing the pressure in the chamber to 0.03 atm. The devices were
submerged in PBS at 37.degree. C. by introducing the PBS into the
vacuum chamber, after which they were transferred to individual
HPLC vials and incubated at 37.degree. C. The weight increases and
exenatide release of the devices were followed over time. Weights
were corrected for 11 mg of "outside" PBS caught in the threads and
other features of the devices, as determined in a separate
experiment.
[0195] FIG. 11 shows the difference in the average rate of PBS
uptake between the two groups. Release rates were measured by
performing HPLC on the incubation solutions. The incubation
solutions were refreshed at regular intervals to avoid
complications due to excessive degradation of exenatide in the
buffer.
[0196] The results are shown in FIG. 12. No release of exenatide
was detected in any of the vials without a vacuum pretreatment. The
vacuum treated devices showed drug release as of the first day.
[0197] It is understood that the examples and embodiments described
herein are for illustrative purposes only and that various
modifications or changes in light thereof will be suggested to
persons skilled in the art and are to be included within the spirit
and purview of this application and scope of the appended claims.
All publications, patents, and patent applications cited herein are
hereby incorporated by reference in their entirety for all
purposes.
* * * * *