U.S. patent application number 16/085083 was filed with the patent office on 2021-06-10 for ophthalmic delivery device and ophthalmic active agent containing compositions.
The applicant listed for this patent is Oxular Limited. Invention is credited to Ricky Barnett, Robert Steven Bley, Stanley R. Conston, Brad Michael Howarth, Tien T. Nguyen, Adam Jonathan Frederick Stops, Ronald Yamamoto.
Application Number | 20210169689 16/085083 |
Document ID | / |
Family ID | 1000005414050 |
Filed Date | 2021-06-10 |
United States Patent
Application |
20210169689 |
Kind Code |
A1 |
Bley; Robert Steven ; et
al. |
June 10, 2021 |
Ophthalmic Delivery Device And Ophthalmic Active Agent Containing
Compositions
Abstract
The present invention provides a delivery device for
administration of active agent (12) containing compositions into
the suprachoroidal space or supraciliary space. The invention
provides methods of treatment of an ocular disease or condition
accordingly. The invention also provides active agent containing
compositions for delivery into the suprachoroidal space or
supraciliary space.
Inventors: |
Bley; Robert Steven; (Menlo
Park, CA) ; Conston; Stanley R.; (San Carlos, CA)
; Nguyen; Tien T.; (Daly City, CA) ; Yamamoto;
Ronald; (San Francisco, CA) ; Howarth; Brad
Michael; (London, GB) ; Stops; Adam Jonathan
Frederick; (Cambridge, GB) ; Barnett; Ricky;
(St Albans, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Oxular Limited |
Oxford |
|
GB |
|
|
Family ID: |
1000005414050 |
Appl. No.: |
16/085083 |
Filed: |
March 16, 2017 |
PCT Filed: |
March 16, 2017 |
PCT NO: |
PCT/GB17/50730 |
371 Date: |
September 14, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62309350 |
Mar 16, 2016 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0051 20130101;
A61K 31/192 20130101; C07K 16/241 20130101; A61F 9/0017 20130101;
A61K 9/1641 20130101; A61K 9/5026 20130101; A61K 9/5015 20130101;
A61K 31/165 20130101; A61K 9/1647 20130101; A61K 9/1652 20130101;
C12N 2310/14 20130101; A61K 9/70 20130101; A61K 31/436 20130101;
A61K 9/5031 20130101; A61K 9/1635 20130101; A61K 31/407 20130101;
C12N 15/113 20130101; A61K 35/28 20130101; A61K 9/5052 20130101;
A61K 9/5057 20130101; A61K 31/196 20130101; A61K 31/573 20130101;
A61K 9/5036 20130101; A61K 9/5042 20130101 |
International
Class: |
A61F 9/00 20060101
A61F009/00; A61K 9/16 20060101 A61K009/16; A61K 9/50 20060101
A61K009/50; A61K 31/573 20060101 A61K031/573; C07K 16/24 20060101
C07K016/24; A61K 31/436 20060101 A61K031/436; A61K 31/196 20060101
A61K031/196; A61K 31/192 20060101 A61K031/192; A61K 31/407 20060101
A61K031/407; A61K 31/165 20060101 A61K031/165; C12N 15/113 20060101
C12N015/113; A61K 35/28 20060101 A61K035/28; A61K 9/00 20060101
A61K009/00; A61K 9/70 20060101 A61K009/70 |
Claims
1. A delivery device comprising an elongated body with a needle
with a lumen at a distal end; a reservoir for an active agent
containing composition to be delivered through the needle; a
plunger with a force element configured to provide a delivery force
to said active agent containing composition prior to or
simultaneous with contact of the distal end of the device to a
tissue surface; and a distal element attached to the distal end of
the device thereby sealing the needle lumen from delivery of said
active agent containing composition under the delivery force;
wherein: the distal element comprises a tissue interface and a
distal seal, and wherein the distal seal is penetrable by a distal
tip of the needle by the application of pressure on a tissue
surface with the distal end of the device; the penetrated distal
element becomes slidable on the needle to allow advancement of the
needle into tissue; and the penetrated distal seal opens a path for
flow or delivery of said active agent containing composition from
the distal end of the needle.
2. A delivery device comprising an elongated body with a needle
with a lumen at a distal end; a first reservoir for a volume of gas
to be delivered through the needle; a second reservoir for an
active agent containing composition to be delivered through the
needle; a gas flow path from the first reservoir to the needle
lumen; a first plunger with a force element configured to provide a
delivery force to said gas prior to or simultaneous with contact of
the distal end of the device to a tissue surface; a second plunger
or push rod configured to provide a delivery force from said force
element to said active agent containing composition; and a distal
element attached to the distal end of the device thereby sealing
the needle lumen from delivery of the gas under the delivery force;
wherein: the distal element comprises a tissue interface and a
distal seal, and wherein the distal seal is penetrable by a distal
tip of the needle by the application of pressure on a tissue
surface with the distal end of the device; the penetrated distal
element becomes slidable on the needle to allow advancement of the
needle into tissue; the penetrated distal seal opens a path for
flow or delivery of the gas from the first reservoir through the
gas flow path to the distal end of the needle; and the active agent
containing composition from the second reservoir is delivered
through the needle lumen by the plunger or push rod and force
element after all or a portion of the volume of gas has been
delivered.
3. The device of claim 2 comprising a first force element to apply
a delivery force to compress the volume of gas and a second force
element to apply a delivery force to the active agent containing
composition.
4. The device of claim 2 or 3 where the gas flow path comprises the
needle lumen, a portion of the needle lumen or a separate
lumen.
5. The device of claim 4 where the gas flow path comprises a sleeve
coaxial to the needle and a hole in a shaft of the needle within
the sleeve.
6. The device of claims 2 through 5 wherein the delivery of the
active agent containing composition is manually triggered by the
user after delivery of at least a portion of the volume of gas.
7. The device of claims 2 through 5 wherein the delivery of the
active agent containing composition is automatically triggered by a
mechanism after delivery of at least a portion of the volume of
gas.
8. The device of claim 7 wherein the mechanism is configured to
sequentially provide a delivery force to the volume of gas and the
active agent containing composition.
9. The device of claim 7 wherein the mechanism is configured to
block the delivery of the active agent containing composition until
delivery of at least a portion of the volume of gas.
10. The device of claim 7 wherein the mechanism comprises a linkage
between the first force element acting on the volume of gas and the
second force element acting on the active agent containing
composition.
11. The device of claim 7 wherein the mechanism comprises a linkage
between the plunger acting on the volume of gas and the plunger or
push rod acting on the active agent containing composition.
12. The device of any preceding claim wherein the needle comprises
a curved distal tip to direct the material for administration at an
angle from the long axis of the needle.
13. The device of any preceding claim wherein the needle comprises
an inner deflecting element in the lumen of the needle at the
needle bevel to direct the material for administration at an angle
from the long axis of the needle.
14. The device of any preceding claim wherein the needle comprises
a deflecting element in the lumen of the needle at the needle bevel
to fragment the material for administration prior to delivery of
the material for administration from the needle distal tip.
15. The device of claim 14 where the deflecting element has a width
of 0.20% to 50% of the needle inner diameter.
16. The device of claim 14 where the deflecting element has a
height of 0.25% to 50% of the needle inner diameter.
17. The device of any preceding claim additionally comprising a
second force element between the body of the device and the distal
element configured to provide a forward directed force on the
distal element during penetration of the distal seal by the distal
tip of the needle.
18. The device of claim 17 wherein the tissue interface comprises
an elastomer with a hardness of 10 to 30 Shore A.
19. The device of claim 17 where the forward directed force is in
the range of 40 to 82 gram force.
20. The device of any preceding claim further comprising an active
agent containing composition wherein the active agent containing
composition is a solid or semisolid.
21. The delivery device of any preceding claim wherein the
reservoir is within the lumen of the needle.
22. The delivery device of any preceding claim wherein the
reservoir is within both the lumen of the needle and an extension
of the needle into the body of the device.
23. The device of any preceding claim additionally comprising a
collapsible element between the body of the device and the distal
element configured to prevent distal movement of the distal element
due to the delivery force.
24. The device of claim 23 wherein the collapsible element
comprises elongated struts.
25. The device of claim 23 or 24 wherein the collapsible element
comprises nitinol or polyimide.
26. The device of any preceding claim additionally comprising a
collapsible element between the body of the device and the distal
element configured to provide a forward directed force on the
distal element during penetration of the distal seal by the distal
tip of the needle.
27. The delivery device of claim 26 wherein the collapsible element
is configured to provide a constant force after an initial force
wherein the initial force is applied during the first 0.5 mm of
travel of the distal element proximally along the needle.
28. The device of any preceding claim wherein the tissue interface
and distal seal are mounted on a tubular distal housing.
29. The device of claim 28 additionally comprising an elastomeric
element which is compressed between the housing and the needle to
seal the housing.
30. The delivery device of any preceding claim wherein the first
and/or second force element is a spring.
31. The delivery device of claim 30 wherein the first force element
is a spring which is mechanically coupled to the plunger.
32. The delivery device of any preceding claim wherein the first
and/or second force element is a pressurized gas.
33. The delivery device of any preceding claim wherein insertion of
the active agent containing composition into the device activates
the force element to apply the delivery force to the active agent
containing composition.
34. The delivery device of any preceding claim wherein the delivery
force is activated by a mechanism to compress the first and/or
second force element from the exterior of the device.
35. The delivery device of any preceding claim wherein the first
and/or second force element is constrained prior to use and the
delivery force is activated by mechanically releasing the
constrained force element.
36. The delivery device of any preceding claim for administration
of an active agent containing composition to the suprachoroidal
space or supraciliary space with an effective full needle length of
1 to 4 mm.
37. The delivery device of any preceding claim for administration
of an active agent containing composition to the vitreous cavity
with an effective full needle length of 10 to 15 mm.
38. The delivery device of any preceding claim for administration
of an active agent containing composition to the subconjunctival
space with an effective full needle length of 0.35 to 2 mm.
39. A method for treatment of an ocular disease or condition by
administration of an active agent containing composition to the
suprachoroidal space or supraciliary space comprising filling the
reservoir of the delivery device of any one of claim 1 to claim 38
with the active agent containing composition, whereby the filling
compresses the force element of the delivery device to provide a
delivery force on the active agent containing composition, placing
the tissue interface of said delivery device on the surface of the
eye and advancing the needle of said device through the distal seal
to open a path for delivery of the active agent containing
composition from the distal tip of the needle, and advancing the
needle into tissue until the active agent containing composition is
delivered.
40. A method for treatment of an ocular disease or condition by
administration of a liquid or flowable semisolid active agent
containing composition to the suprachoroidal space or supraciliary
space comprising filling the delivery device of any one of claim 1
to claim 38 with the active agent containing composition,
activating the force element of said delivery device to provide a
delivery force on the active agent containing composition, placing
the tissue interface of the delivery device on the surface of the
eye and advancing the needle of the device through the distal seal
to open a flow path from the distal tip of the needle, and
advancing the needle into tissue until the active agent containing
composition is delivered.
41. A method for treatment of an ocular disease or condition by
administration of a solid or semisolid active agent containing
composition to the suprachoroidal space or supraciliary space
comprising filling the delivery device of any one of claim 1 to
claim 38 with the active agent containing composition, activating
the force element of said delivery device to provide a delivery
force on the active agent containing composition, placing the
tissue interface of the delivery device on the surface of the eye
and advancing the needle of the device through the distal seal to
open a path for delivery of the active agent containing composition
from the distal tip of the needle, and advancing the needle into
tissue until the active agent containing composition is
delivered.
42. A method for administration of an active agent containing
composition into the suprachoroidal space or supraciliary space
using the device of any one of claim 1 to claim 38 wherein the
active agent containing composition is subjected to a delivery
force by the force element prior to or simultaneous with
introduction of the distal tip of the device into tissues wherein
advancement of the needle through the distal seal opens a path for
delivery of the active agent containing composition from the distal
tip, thereby enabling single-handed use of the device without
actuation of delivery by a valve or trigger on the body of the
delivery device.
43. The method of claims 39 through 42 where the active agent
containing composition comprises a steroid, non-steroidal
anti-inflammatory agent, antibiotic, VEGF inhibitor, anti-TNF alpha
agent, mTOR inhibitor, cell therapy, anti-hypertensive agent,
antihistamine, aminosterol, neuroprotective agent or nucleic acid
based therapeutic.
44. The method of any of claim 39 to claim 43 wherein the ocular
disease or condition comprises inflammation, infection, macular
degeneration, retinal degeneration, neovascularization,
proliferative vitreoretinopathy, glaucoma or edema.
45. An active agent containing composition for delivery to the
suprachoroidal space or supraciliary space comprising a semisolid
material for administration into the suprachoroidal space or
supraciliary space, wherein the semisolid material comprises an
active agent; the semisolid material flows under delivery pressure;
the semisolid material remains localized at the site of
administration during and immediately after administration; and the
semisolid material undergoes dissolution after administration to
migrate in the suprachoroidal space.
46. The active agent containing composition of claim 45 wherein
said semisolid material comprises an excipient that undergoes
dissolution, biodegradation or bioerosion in the suprachoroidal
space or supraciliary space after administration.
47. The composition of claim 46 wherein the excipient comprises a
water soluble polymer, a biodegradable or bioerodible material, an
amphiphilic compound, a lipid, a fatty acid, or a lipid
conjugate.
48. The composition of claim 47 wherein the excipient comprises a
water soluble polymer and the water soluble polymer is
polyvinylpyrollidone, polyvinylpyrollidone co-vinyl acetate,
polyvinyl alcohol, chemically modified cellulose, alginate,
polyethylene glycol, polyethylene oxide, hyaluronic acid,
chondroitin sulfate, dermatin sulfate or sodium alginate.
49. The active agent containing composition of claim 45 wherein the
active agent is in the form of crystals or particles.
50. The composition of claim 49 wherein the particles are
microspheres further comprising at least one polymer.
51. The composition of claim 50 wherein the polymer comprises a
non-toxic water soluble polymer, a biodegradable polymer and/or a
biological polymer.
52. The composition of claim 50 wherein the polymer comprises a
non-toxic water soluble polymer and the water soluble polymer is
polyvinylpyrollidone, polyvinylpyrollidone co-vinyl acetate,
polyvinyl alcohol, polyethylene glycol and/or polyethylene
oxide.
53. The composition of claim 50 wherein the polymer comprises a
biodegradable polymer and the biodegradable polymer is
polyhydroxybutyrate, polydioxanone, polyorthoester,
polycaprolactone, polycaprolactone copolymers,
polycaprolactone-polyethylene glycol copolymers, polylactic acid,
polyglycolic acid, polylactic-glycolic acid copolymer and/or
polylactic-glycolic acid-ethylene oxide copolymer.
54. The composition of claim 50 wherein the polymer comprises a
biological polymer and the biological polymer is gelatin, collagen,
glycosoaminoglycan, cellulose, chemically modified cellulose,
dextran, alginate, chitin and/or chemically modified chitin.
55. The composition of claim 49 or claim 50 wherein the particles
comprise 10% to 90% by weight of the active agent.
56. The composition of claim 49 wherein the particles comprise a
core of active agent with an external surface barrier coating.
57. The composition of claim 56 wherein the barrier coating has a
lower partition coefficient than the active agent or greater water
solubility than the active agent.
58. The composition of claim 56 or claim 57 wherein the surface
barrier coating comprises a non-toxic water soluble polymer, a
biodegradable polymer and/or a biological material.
59. The composition of claim 56 wherein the surface barrier coating
comprises a non-toxic water soluble polymer and the non-toxic water
soluble polymer is polyvinylpyrollidone, polyvinylpyrollidone
co-vinyl acetate, polyvinyl alcohol, polyethylene glycol and/or
polyethylene oxide.
60. The composition of claim 56 wherein the surface barrier coating
comprises a biodegradable polymer and the biodegradable polymer is
polyhydroxybutyrate, polydioxanone, polyorthoester,
polycaprolactone, polycaprolactone copolymer,
polycaprolactone-polyethylene glycol copolymer, polylactic acid,
polyglycolic acid, polylactic-glycolic acid copolymer, acid
terminated polylactic-glycolic acid copolymer, and/or
polylactic-glycolic acid-ethylene oxide copolymer.
61. The composition of claim 56 wherein the surface barrier coating
comprises a biological material and the biological material is
gelatin, collagen, glycosoaminoglycan, cellulose, chemically
modified cellulose, dextran, alginate, chitin, chemically modified
chitin, lipid, fatty acid and/or sterol.
62. The composition of claim 56 wherein the barrier coating has a
higher partition coefficient than the active agent or less water
solubility than the active agent.
63. The composition of claim 62 where the barrier coating comprises
a hydrophobic polymer, fatty acid, lipid and/or sterol.
64. The composition of claim 63 where the lipid or fatty acid
comprises capric acid, erucic acid,
1,2-dinervonoyl-sn-glycero-3-phosphocholine,
1,2-dimyristoyl-sn-glycero-3-phosphocholine, or
1,2-dipentadecanoyl-sn-glycero-3-phosphocholine.
65. The composition of claim 46 wherein the excipient is a
biodegradable or bioerodible material and the biodegradable or
bioerodible material is polyhydroxybutyrate, polydioxanone,
polyorthoester, polycaprolactone, polycaprolactone copolymer,
polycaprolactone-polyethylene glycol copolymer, polylactic acid,
polyglycolic acid, polylactic-glycolic acid copolymer, acid
terminated poly lactic-glycolic acid copolymer, or
polylactic-glycolic acid-ethylene oxide copolymer, gelatin,
collagen, glycosoaminoglycan, cellulose, chemically modified
cellulose, dextran, alginate, chitin, chemically modified chitin,
lipid, fatty acid or sterol.
66. The composition of claim 65 wherein the active agent is
dispersed in the biodegradable or bioerodible material as a
plurality of active agent crystals or particles.
67. The composition of 66 wherein the active agent crystals or
particles additionally comprise a barrier coating.
68. The composition of any one of claim 45 to claim 67 wherein the
active agent is a steroid, non-steroidal anti-inflammatory agent, a
VEGF inhibitor, an anti-TNF alpha agent, an mTOR inhibitor, cell
therapy, nucleic acid based therapeutic and/or a
neuroprotectant.
69. The composition of claim 68 wherein the steroid is
dexamethasone, fluocinolone, loteprednol, difluprednate,
fluorometholone, prednisolone, medrysone, triamcinolone,
betamethasone or rimexolone.
70. The composition of claim 68 wherein the non-steroidal
anti-inflammatory agent is bromfenac, diclofenac, flurbiprofen,
ketorolac tromethamine or nepafenac.
71. The composition of claim 68 wherein the anti-TNF alpha agent is
infliximab, etanercept, adalimumab, certolizumab or golimumab.
72. The composition of claim 68 wherein the mTOR inhibitor is
sirolimus, Everolimus, Temsirolimus or a mTOR kinase inhibitor.
73. The composition of claim 68 wherein the cell therapy inhibitor
is mesenchymal cells or cells transfected to produce a therapeutic
compound.
74. The composition of claim 68 wherein the neuroprotective agent
is an antioxidant, calcineurin inhibitor, NOS inhibitor, sigma-1
modulator, AMPA antagonist, calcium channel blocker or
histone-deacetylases inhibitor.
75. The composition of claim 68 wherein the nucleic acid based
therapeutic is a gene vector, plasmid or siRNA.
Description
CROSS REFERENCE TO OTHER APPLICATIONS
[0001] This application claims priority of U.S. Provisional
Application No. 62/309,350, filed 16 Mar., 2016. The following
patent applications are incorporated by reference:
PCT/EP2015/071520, PCT/EP2015/071522.
BACKGROUND OF INVENTION
[0002] Due to the unique anatomy and physiology of the eye,
multiple barriers exist that prevent significant transport of drugs
to ocular tissues. The blood vessels of the eye have restricted
permeability due to the blood-ocular barriers that regulate
intraocular fluid. Due to these blood-ocular barriers, systemically
administered drugs do not reach significant concentration in ocular
tissues. Drugs in topical drops administered to the corneal surface
are mostly washed out by tears into the naso-lacrimal duct. While
in the tear film, drugs have limited time to penetrate the cornea
to reach the intraocular space. Some drugs may be delivered to the
front, anterior portion of the eye by drops, but reaching
significant therapeutic concentrations in the posterior portion of
the eye and the retina is generally not achieved with topical
methods of administration.
[0003] Many diseases that result in visual loss involve the
posterior retina where color vision and reading occur. To treat the
posterior portion of the eye and the posterior retina typically
drugs are injected into the eye. Sub-conjunctival injections are
used to place a drug depot under the outer layer of the eye,
however the very high lymphatic flow in the conjunctiva leads to
rapid transport of the drug away from the eye. Sub-conjunctival
injections are typically not effective to achieving high drug
levels in the posterior portion of the eye.
[0004] Sub-Tenon's injections are sometimes used to place the drug
under the conjunctiva and Tenon's capsule of the eye in a more
posterior location to deliver drug to the posterior region of the
eye. Sub-Tenon's injections have been demonstrated to be useful for
the administration of steroids, however many drugs do not achieve
significant drug levels in the retinal tissues from sub-Tenon's
injection. The tip of the injection needle is placed deep into the
posterior shell of the eye where the tip of the needle cannot be
directly observed. The technique requires experience and careful
technique to avoid physical injury to the eye or misplacement of
drug.
[0005] Intravitreal injections are given to place drug directly
into the vitreous chamber, and typically require a smaller quantity
of drug as compared to sub-Tenon's injections. The half-life of the
drug is limited due to the fluid in the vitreous which continuously
moves forward toward the anterior chamber. This vitreous flow
washes out the drug over time and contacts the drug to other
tissues of the eye in the flow path. Intravitreally administered
drugs such as steroids are associated with complications of
cataract progression due to drug exposure to the lens and increased
intraocular pressure from drug exposure to the trabecular meshwork
during anterior flow from the vitreous chamber.
[0006] The suprachoroidal space between the choroid and sclera and
the supraciliary space between the ciliary body and sclera are more
difficult to locate but also can be used for the injection of
drugs. Unlike intravitreal injections, the fluid in the
suprachoroidal space and supraciliary space flows posteriorly. This
flow may assist drugs injected into the suprachoroidal space or the
supraciliary space to reach the posterior tissues and posterior
retina. Small drug particle sizes are ideal for migration in the
suprachoroidal space or supraciliary space, however small drug
particles release drug at a much faster rate thereby reducing the
longevity of the drug treatment.
[0007] One potential problem with all injections of drug into the
eye beneath the sclera is increased intraocular pressure (IOP)
caused by the additional volume introduced into the eye. The
increased IOP may cause pain and potential damage to the optic
nerve. For highly active drugs a small injection volume may be used
without significant acute IOP increase, for example 0.05 ml of
anti-VEGF drugs. However, for larger volumes such as 0.1 ml with
steroids, IOP increase may be significant and may cause an acute
period of pain and loss of vision.
SUMMARY OF THE INVENTION
[0008] In keeping with the foregoing discussion, the present
invention provides a device designed for the delivery or
implantation of a solid material comprising an active agent shaped
as an elongated body. The delivery device comprises an elongated
barrel with a hollow needle at the distal end, where the lumen of
the needle serves as the reservoir for the elongated body and a
plunger or push rod with a force element such as a spring or gas
reservoir that provides a delivery force to the elongated body. The
elongated body is sized with a diameter less than or equal to the
inner diameter of the needle lumen. In one embodiment, the delivery
device also comprises a distal element comprising a tissue
interface with a distal seal secured to the distal end of the
delivery device thereby sealing the needle lumen during application
of the delivery force. The distal seal is penetrable by the distal
tip of the needle by the application of pressure on the tissue
surface with the distal end of the delivery device and the
penetrated distal element becomes slidable on the needle to allow
advancement of the needle into tissue. Penetration of the distal
seal opens a path for delivery of the material for administration
from the distal end of the needle. The delivery device with a force
element is activated prior to or simultaneous with penetration of
the distal seal by the needle and advancement of the needle tip
into tissues, thereby enabling simple one-handed operation of the
delivery device to administer the active agent containing
composition shaped as an elongated body to an eye. In one
embodiment, the distal tip of the needle is curved or incorporates
an inner deflecting element in the needle lumen to direct the solid
element at an angle from the long axis of the needle during
delivery. In one embodiment, the active agent containing
composition is directed at an angle from the long axis of the
needle during delivery in a posterior direction. In one embodiment,
the active agent containing composition shaped as an elongated body
is preloaded in the delivery device, whereby the delivery device
serves as the storage container for the active agent containing
composition prior to use. In one embodiment, the preloaded device
is sterilized for use after placement and sealing of the elongated
body in the delivery device.
[0009] The present invention provides a device designed for the
administration of a semisolid material comprising an active agent.
The delivery device comprises an elongated barrel with a hollow
needle at the distal end, and a reservoir in the elongated body
containing the semisolid material and a plunger or push rod with a
force element such as a spring or gas reservoir that provides a
delivery force on the semisolid material. In one embodiment, the
semisolid material is designed to flow under delivery pressure
provided by the force element and plunger or push rod, resulting in
flow through the distal needle into tissues, but the active agent
containing composition sets as a semisolid to remain at the
administration site during and immediately after administration. In
one embodiment, the semisolid comprises particles or microparticles
comprising an active agent, whereby the dissolution of the
semisolid at the administration site over time allows natural
physiological flow within a tissue space such as the suprachoroidal
or supraciliary space to direct the particles posteriorly. In one
embodiment, the delivery device also comprises a distal element
comprising a tissue interface with a distal seal secured to the
distal end of the delivery device thereby sealing the needle lumen
during application of the delivery force. The distal seal is
penetrable by the distal tip of the needle by the application of
pressure on the tissue surface with the distal end of the delivery
device and the penetrated distal element becomes slidable on the
needle to allow advancement of the needle into tissue. Penetration
of the distal seal opens a path for delivery of the material for
administration from the distal end of the needle. The force element
of the delivery device is activated prior to or simultaneous with
penetration of the distal seal by the needle and advancement of the
needle tip into tissues, thereby enabling simple one-handed
operation of the delivery device to administer the semisolid
composition to an eye. In one embodiment, the distal tip of the
needle is curved or incorporates an inner deflecting element in the
needle lumen to direct the semisolid material at an angle from the
long axis of the needle during delivery. In one embodiment, the
semisolid material is directed at an angle from the long axis of
the needle during delivery in a posterior direction. In one
embodiment, the semisolid material is preloaded in the delivery
device, whereby the delivery device serves as the storage container
for the active agent containing composition prior to use. In one
embodiment, the semisolid material is preloaded in the delivery
device in a dry form whereby the delivery device serves as the
storage container for the active agent containing composition and
the semisolid material is hydrated in the delivery device prior to
use. In one embodiment, the preloaded device is sterilized for use
after placement and sealing of the semisolid material in the
delivery device.
[0010] The present invention provides a device designed for the
delivery of a controlled amount of gas to facilitate the
administration of a material comprising an active agent to the
suprachoroidal space or supraciliary space. The delivery device
comprises a gas reservoir and a flow path between the reservoir and
the needle lumen, where the gas is introduced to the needle lumen
proximal to the distal seal. The gas is pressurized with a force
element such as a spring, compressed bladder or expanding element.
The gas reservoir is activated prior to or simultaneous with
penetration of the distal seal by the needle and advancement of the
needle tip into tissues. The flow path for the gas may comprise the
needle lumen, a portion of the needle lumen or a separate lumen. In
one embodiment, the flow path comprises an outer sleeve that is
coaxial to the needle and the needle has at least one hole along
the shaft of the needle within the coaxial outer sleeve. The gas
flows from the gas reservoir through the outer sleeve and into the
needle lumen through the hole and into the eye from the distal tip
of the needle. The resultant gas flow path bypasses the active
agent containing composition in the proximal end of the needle to
provide an unrestricted flow path to the distal end of the needle.
Subsequent to the delivery of the gas, the active agent containing
composition is administered through the needle to the
suprachoroidal space or supraciliary space. The delivery of the
active agent containing composition may be triggered manually after
gas delivery or the device may incorporate a mechanism to
administer the active agent containing composition after all or a
portion of the gas has been delivered through the needle to provide
a sequential delivery process for the gas and active agent
containing composition. In one embodiment, the delivery device has
a first reservoir for the delivery of gas, a second reservoir for
the delivery of the active agent containing composition and a force
element to deliver both the gas and the active agent containing
composition. In one embodiment, the delivery device has a first
reservoir for the delivery of gas, a second reservoir for the
delivery of the active agent containing composition, a force
element to deliver both the gas and the active agent containing
composition and a flow path for the gas delivery comprising an
outer sleeve that is coaxial to the needle. In one embodiment, the
delivery device has a first reservoir for the delivery of gas, a
second reservoir for the delivery of the active agent containing
composition, a force element to deliver both the gas and the active
agent containing composition, a flow path for the gas delivery
comprising an outer sleeve that is coaxial to the needle and at
least one hole in the shaft of the needle in the region of the
outer sleeve for gas flow to the lumen of the needle. In one
embodiment, the delivery device has a first reservoir and force
element for the delivery of gas and a second reservoir and force
element for the delivery of the active agent containing
composition. In one embodiment, the delivery device has a first
reservoir and force element for the delivery of gas and a second
reservoir and force element for the delivery of the active agent
containing composition and a flow path for the gas delivery
comprising an outer sleeve that is coaxial to the needle. In one
embodiment, the delivery device has a first reservoir and force
element for the delivery of gas and a second reservoir and force
element for the delivery of the active agent containing
composition, a flow path for the gas delivery comprising a hollow
member that is external to the needle and the needle has at least
one hole in the shaft in communication with the external hollow
member for gas flow into the needle lumen. In one embodiment, the
delivery device has a first reservoir and force element for the
delivery of gas and a second reservoir and force element for the
delivery of the active agent containing composition, a flow path
for the gas delivery comprising an outer sleeve that is coaxial to
the needle and the needle has at least one hole in the shaft in the
region of the outer sleeve for gas flow into the needle lumen. In
one embodiment, the device comprises a gas reservoir, a flow path
for the delivery of gas, a second reservoir for an active agent
containing composition and a force element for the delivery of the
active agent containing composition through a needle with an inner
deflecting element.
[0011] The present invention provides an active agent containing
composition for delivery to the suprachoroidal space, supraciliary
space or other tissue spaces of the eye such as the vitreous
cavity, subconjunctival space, sub-Tenon's space and sub-retinal
space. The active agent containing composition is in the form of a
semisolid material whereby the material flows under pressure in a
delivery device, but sets into a semisolid once exiting the distal
tip of the needle to remain at the administration site. In one
embodiment, the active agent containing composition comprises a
plurality of drug-containing particles and at least one excipient
to form the drug particles into a semisolid. In one embodiment, the
active agent containing composition comprises a plurality of
drug-containing particles and at least one excipient to form the
drug particles into a slurry or suspension. In one embodiment, the
excipient comprises a substance that undergoes dissolution in the
physiological conditions of the tissue space after delivery to
allow the drug-containing particles to disperse and migrate in the
tissue space. In one embodiment, the active agent containing
composition is in a dry form that is rehydrated prior to
administration.
[0012] In one embodiment, the drug-containing particles are in the
form of drug crystals. In one embodiment, the drug-containing
particles are in the form of microspheres. The microspheres may
have a coating and/or be made with a biodegradable or bioerodible
polymer component to modify the rate of drug release. Similarly,
the excipient material may be chosen to control the rate of drug
release.
[0013] These and other aspects of the invention will be made
apparent from consideration of the following detailed description
in conjunction with the accompanying drawing figures.
BRIEF DESCRIPTION OF THE DRAWINGS:
[0014] FIG. 1 depicts one embodiment of a solid material delivery
device.
[0015] FIG. 2 depicts one embodiment of a distal tip of a solid
material delivery device.
[0016] FIG. 3 depicts one embodiment of a semisolid material
delivery device.
[0017] FIG. 4 depicts one embodiment of a distal tip of a semisolid
material delivery device.
[0018] FIG. 5 depicts one embodiment of a distal tip of a delivery
device with a collapsible element.
[0019] FIG. 6 depicts magnified detail of one embodiment of a
distal tip of a delivery device with a collapsible element.
[0020] FIG. 7 depicts one embodiment of a distal tip of a delivery
device in an uncollapsed state.
[0021] FIG. 8 depicts one embodiment of a delivery device in a
collapsed state.
[0022] FIG. 9 depicts one embodiment of a delivery device needle
with a curved distal tip to direct the delivered material at an
angle from the long axis of the needle.
[0023] FIG. 10 depicts one embodiment of a delivery device needle
with an inner deflecting element in the needle lumen at the distal
tip to direct the delivered material at an angle from the long axis
of the needle.
[0024] FIG. 11 depicts one embodiment of a delivery device needle
with a protrusion in the needle lumen at the distal tip to fragment
a solid element delivered through the needle.
[0025] FIG. 12 depicts a delivery device expelling a semisolid
material for administration with a plurality of drug-containing
particles.
[0026] FIGS. 13A and 13B depict a formed solid material for
administration with a plurality of drug-containing particles.
[0027] FIG. 14 is a graph of test results of the tissue interface
minimum sealing force.
[0028] FIG. 15A depicts one embodiment of a delivery device with a
gas delivery mechanism comprising a gas reservoir, a force element
to pressurize the gas and gas flow path to the needle lumen.
[0029] FIG. 15B depicts the embodiment of FIG. 15A further
comprising a coaxial outer sleeve and a needle with a hole along
the shaft of the needle within the outer sleeve to allow for the
passage of a gas from the gas reservoir into the needle lumen.
[0030] FIG. 16 depicts one embodiment of a delivery device with a
gas delivery mechanism with a manually triggered delivery mechanism
for a solid active agent containing composition.
[0031] FIG. 17A through 17F depicts one embodiment of a delivery
device with a gas reservoir coaxial to a push rod for delivery of
an active agent containing composition with a mechanism to provide
sequential gas delivery and active agent containing composition
delivery.
[0032] FIG. 18A through 18E depicts one embodiment of a delivery
device with a gas reservoir, a gas reservoir force element, a
reservoir for the active agent containing composition and a force
element for the active agent containing composition with a
mechanism to provide sequential gas delivery and active agent
containing composition delivery.
[0033] FIG. 19 depicts one embodiment of a delivery device with a
gas delivery mechanism incorporating a vent hole.
DESCRIPTION OF THE INVENTION
[0034] To place an active agent containing composition for
administration into a tissue space of an eye, the composition is
placed in a delivery device. In the present application, the terms
delivery is used to describe the administration or implantation of
a variety of materials by the invention to various tissues of an
eye. The device comprises an elongated body with a hollow needle at
the distal end, a slidable plunger or push rod at the proximal end,
and a reservoir for the material to be administered residing
between the distal tip of the needle and the plunger or push rod.
In the present application, the term plunger is used to indicate an
elongated mechanical element with a seal to provide an interference
fit with the inner surface of a reservoir. With some materials for
administration such as a solid or sufficiently cohesive semi-solid
material for administrations, a seal may not be required for
delivery of the material for administration and either a plunger or
a push rod without a seal may be used to apply a delivery force to
the material for administration. The reservoir is configured to
receive a material for administration to be delivered through the
lumen of the needle. In particular, the material for administration
is a semisolid or solid active agent containing composition. The
active agent may be a substance that provides a therapeutic or
diagnostic effect for treatment of an eye. The active agent may
comprise a drug, a diagnostic agent, gene therapy agents,
therapeutic cells or means for physical tissue repair.
[0035] The plunger or push rod acts to push the material for
administration through the needle to the desired tissue location. A
plunger or push rod with a force element is configured to provide a
delivery force to the material for administration. The force
element may comprise a spring mechanically coupled to a plunger or
push rod. The force element may be at least partially located
within the elongated body of the device. The plunger or push rod is
mechanically coupled to a source of force such as a spring or
pressurized gas reservoir such that a delivery force is applied to
the material for administration within the device after the
material for administration is placed in the reservoir and prior to
insertion of the distal end of the needle into ocular tissues to
deliver the material for administration into an eye. Secured to the
distal end of the needle is a distal element comprising a distal
seal, which also acts as a tissue interface. The distal element is
moveably secured to the distal tip of the needle where it serves to
close off the distal end of the needle to close or block the path
of the material for administration from the needle tip. In some
embodiments the distal element has a lumen to fit over the outer
diameter of the needle. In some embodiments the distal element is
secured to the distal tip of the needle through other means. The
distal seal of the distal element is distal to the tip or lumen of
the needle and is configured to be penetrated by the needle as the
distal tip of the device is placed on the surface of the eye and
the needle is advanced into the eye by the user. The needle
penetrates the distal seal and is inserted into ocular tissue,
thereby opening a flow path or path of delivery of the material for
administration from the reservoir, through the needle and into the
eye. The resulting self-actuating delivery mechanism insures
opening of the delivery path for the material for administration
immediately when the needle is placed in tissue, regardless of the
orientation and speed of needle insertion.
[0036] In one embodiment, the distal element comprises a tissue
interface and distal seal mounted on a tubular distal housing. The
tubular distal housing is fit to the exterior of the needle and may
be sealed to the surface of the needle at some point along its
length. In one embodiment the housing may be sealed by means of an
elastomeric element which is compressed between the housing and the
needle. The elastomeric element may therefore be annular. In one
embodiment, the elastomeric element may be compressed between the
housing and the body of the device. The elastomeric element may
reside at or near the proximal end of the housing. In one
embodiment the elastomeric element serves as a seal between the
housing and the needle. In one embodiment the elastomeric element
serves as a frictional element or component which limits the
housing travel in the proximal direction to thereby apply a force
against the tissue surface by the tissue interface as the needle
penetrates the tissues. In some embodiments, the distal element
comprises a tissue interface and a distal seal and is slidably
attached to the exterior of the needle without a distal
housing.
[0037] The distal element, which comprises a tissue interface with
a distal seal, or a tissue interface with a distal seal and an
attached housing, is attached to the distal tip of the needle but
is not freely movable or slidable proximally from the end of the
needle due to the closed distal seal. After the material for
administration is loaded into the device and the device is
activated for use, the material comes under pressure from the
source of force but cannot move through the distal seal. The tissue
interface is placed on the surface of the eye and the device is
manually advanced, thereby forcing the needle through the distal
seal and then through the external surface of the eye into
underlying tissues. The distal element, after penetration of the
distal seal, becomes slidable in the proximal direction from the
end of the needle to retain the tissue interface on the surface of
the eye during advancement of the needle into tissue. When the
distal tip of the needle penetrates through the distal seal, the
source of force immediately allows for expression of the material
for administration from the needle tip and into the tissues.
[0038] In one embodiment the tissue interface and distal seal is
secured to a housing disposed about the needle. The housing may be
comprised of a cylindrical element which is secured to the distal
end of the body of the device at the proximal end of the housing.
The housing may contain collapsible, distortable or deformable
elements which allow the distal end of the housing to retract
slidably along the needle, which in turn allows the needle tip to
penetrate the distal seal. In some embodiments the distal element
is secured to the distal tip of the needle through other means.
[0039] In one embodiment, the device comprises an elongated barrel
with a hollow needle at the distal end and a slidable plunger or
push rod at the proximal end. The lumen of the needle serves as the
reservoir for the material for administration shaped as an
elongated body with a diameter less than or equal to the inner
lumen of the needle. The plunger or push rod can be actuated either
manually or with a force element such as a spring or pressurized
gas source, to push the plunger or push rod and eject the material
for administration into the tissue space when the distal tip of the
device reaches the space.
[0040] In one embodiment, the device comprises an elongated barrel
with a hollow needle at the distal end, a slidable plunger or push
rod at the proximal end and a reservoir for the material to be
administered residing between the needle and the plunger or push
rod. The reservoir of the device contains a liquid or semisolid
composition as the material for administration. The plunger or push
rod can be actuated either manually or with a force element such as
a spring or pressurized gas source, to push the plunger or push rod
and eject the material for administration into the tissue space
when the distal tip of the device reaches the space.
[0041] Operation of the device mechanism opens the path for the
material for administration to move out from the tip of the needle
immediately upon penetration through the distal seal which occurs
just prior to the entry of the needle into the target tissue. Since
the material for administration is under pressure prior to or
simultaneous with penetration of the distal seal by the needle tip,
the delivery is triggered solely by placement and subsequent
advancement of the needle through the tissue interface. This allows
precise and automatic control of the timing of the delivery action
solely due to the needle tip entering the target tissue. The
resultant self-actuated mechanism obviates the need for a separate
control mechanism, for example a valve or trigger on the body of
the delivery device, and hence allows for administration of the
material for administration without the need for special
positioning of the fingers or the use of the second hand. The
device thereby enables an administration to be performed with a
single hand, allowing the other hand of the physician to stabilize
the eye or perform other actions to facilitate administration. The
self-actuating delivery mechanism also eliminates the need for the
user to determine when to begin administration which is especially
useful when the target tissue space is difficult to locate due to
small target size, lack of visualization and anatomic variability
such as the suprachoroidal space or supraciliary space.
[0042] The device allows precise control of the position of the
needle by the user during use. The needle is fixed to the body of
the device to allow direct control of the distal tip of the needle
when the device is held by the body. Since the delivery force is
provided by the force element, the plunger or push rod of the
device does not have to be held, triggered or actuated by the hand
holding the device, allowing the device to be held and used in a
natural, highly controllable position such as with a writing
instrument or scalpel. Generally, the needle is arranged parallel
to the elongated body or barrel of the device.
[0043] Once the flow path from the distal end of the needle is
opened by penetration of the distal seal and insertion into the
eye, the material for administration cannot flow or move into the
eye until a space to accept the material for administration is
reached by the distal end of the needle. Scleral tissue in
particular is very resilient and effectively seals the needle tip
during passage of the needle tip to the suprachoroidal or
supraciliary space, hence the unique properties of the sclera do
not allow for the material for administration to enter the sclera.
Once an underlying space such as the suprachoroidal space or the
supraciliary space is reached by the needle tip, the material for
administration is able to flow or move out of the needle and be
delivered to the space. By this mechanism the material for
administration is directed to a location that can accept the
material for administration at the distal tip of the needle. The
delivery of the material for administration may be further directed
by the tissue interface. The tissue interface may optionally apply
a force to the surface of the eye to aid sealing of the needle
tract at the surface of the eye. With an appropriate needle length
and orientation, the device may be used to deliver into the
sub-conjunctival space, sub-Tenon's space, suprachoroidal space,
supraciliary space, sub-retinal space, the vitreous cavity, or the
anterior chamber.
[0044] In one embodiment, the material for administration is a
solid or semisolid material. The material for administration may be
loaded into the distal end of the needle lumen. The needle may
extend proximally in the body of the device to provide an extended
length for the material for administration. A plunger or push rod
is inserted into the proximal end of the needle and the distal end
of the plunger or push rod is put into contact with the proximal
end of the material for administration. After placement of the
plunger or push rod, a force element such as a compression spring
acting on the plunger or push rod provides a delivery force on the
material prior to or simultaneous with contact of the device with
the surface of an eye. In one embodiment, the force element is
self-contained in the device or is integrated on the body of the
device. In one embodiment, the material for administration is a
fluid or semisolid material that flows under pressure. The material
for administration may be pre-loaded in the device during
manufacture. The material for administration may be placed into the
reservoir portion of the device by the user, in a manner similar to
a syringe, through a connector, valve or septum in fluid connection
to the reservoir. The device may be configured to preload a force
element such as a compression spring acting on the plunger or push
rod providing a delivery force on the material for administration
in the reservoir upon placement of the material for administration
in the device. Other mechanisms may be provided for activating or
priming the delivery force. For example, the delivery force may be
activated by a mechanism to compress the force element from the
exterior of the device. In another option, the delivery force may
be activated by mechanically releasing a constrained force element
or gas prior to use. A trigger, latch or other control means for
the activation of the device can be located at various locations on
the device.
[0045] The size of the reservoir, needle and plunger or push rod
may be sized appropriately for the volume of material for
administration to be delivered. For the solid or semisolid material
for administration of the invention, the needle and potentially an
extension of the needle into the body of the device may act as the
reservoir. The needle, reservoir and plunger or push rod may be
sized for solid or semisolid delivery volumes ranging from, for
example, 0.1 microliters to 100 microliters.
[0046] The needle comprises a stiff material with a diameter to
allow the material for administration to pass through the lumen of
the needle, typically in the range of 20 gauge to 40 gauge (for
example, less than 0.91 mm outer diameter/0.6 mm inner diameter),
where the length of the needle is suitable to both reach the
intended tissue and provide sufficient volume for the desired dose
of the composition to be administered. The needle is fixed to the
body or barrel of the device and generally does not slide or move
in relation to the body to provide precise control of needle depth
during penetration of tissues. The needle may extend proximally
into the body of the delivery device to provide sufficient volume
for the material for administration. If additional volume is
required for delivery of a semi-solid active agent containing
composition, the proximal end of the needle may interface to a
small reservoir within the body of the device that is pressurized
by the delivery force element.
[0047] The distal tip of the needle may be beveled or sharpened to
aid penetration. The bevel angle may be designed to facilitate
entry into a specific target. For example, a short bevel of 18
degree bevel angle may be used to deliver into narrower spaces such
as the subconjunctival or sub-Tenon's space. A medium bevel needle
of 15 degree bevel angle may be used to deliver into spaces such as
the suprachoroidal or supraciliary space. Longer bevels, such as 12
degree bevel angle may be used to deliver into the anterior or
posterior chambers.
[0048] In one embodiment, the distal element is designed with a
complementary bevel in a lumen of the distal element to provide
close apposition of the distal seal to the needle bevel. The bevel
of the needle is in alignment with the bevel in a lumen of the
distal element. The most distal portion of the distal element may
be flat or beveled to aid orientation of the needle during tissue
penetration to aid reaching certain delivery targets. For example,
a beveled or angled tissue contacting surface of the distal element
may aid targeting of administration into the tissue targets with
less depth such as the subconjunctival space, sub-Tenon's space and
in some regions of the suprachoroidal space. The angle of the
tissue contacting surface of the distal element may range from 90
degrees from the axis of the distal element for perpendicular
insertion, to 45 degrees from the axis.
[0049] In some applications of the invention, it may be desired for
the distal tip of the needle to direct the material for
administration at an angle from the long axis of the needle. Such a
design reduces force of the material for administration on the
underlying tissues such as the ciliary body or choroid and may also
be used to direct the material for administration in a desired
direction such as toward the posterior region of the suprachoroidal
space near the macular region of the retina. In one embodiment, the
distal tip of the needle may be curved in the range of 5 to 60
degrees to direct the material for administration. In one
embodiment, the distal tip of the needle may have an inner
deflecting element in the lumen of the needle in the region of the
bevel of the needle. The inner deflecting element may be a
protrusion, a sloped surface or a ramp to direct the material for
administration away from the long axis of the needle. The inner
deflecting element may be located along the entire length of the
needle bevel or in a discrete location. In one embodiment, the
inner deflecting element is positioned at a specific distance from
the proximal end of the bevel where the distance is 20% to 80% of
the length of the needle bevel, 25% to 75% of the length of the
needle bevel or 30% to 60% of the length of the needle bevel. The
inner deflection element may have a width equal to the inner
diameter of the needle, 75% to 50% of the inner diameter or 50% to
20% of the inner diameter. The inner deflection element may have a
height of 75% to 50% of the inner diameter, 50% to 25% of the inner
diameter or less than 25% of the inner diameter. The inner
deflecting element may be formed by mechanical or thermal
deformation of a region of the needle wall. The inner deflecting
element may be formed by insertion and bonding of a shaped element
within the lumen of the needle. In one embodiment, the inner
deflecting element may be a protrusion that acts to fragment a
solid material for administration at the needle distal tip to
promote distribution of the material for administration in a tissue
space such as the supraciliary space or suprachoroidal space.
[0050] The needle may be constructed from a metal, ceramic, high
modulus polymer or glass. The length of the needle in tissue is
selected to match the target location for the administration and
the variation in target location due to anatomical variability. The
effective full length of the needle is the length of the needle
distal tip to the distal surface of the tissue interface, when the
distal element has achieved full proximal travel. The distal
element moves slidably on the needle during needle advancement,
allowing for progressive increase in the length of needle
protruding through the distal element during advancement into
tissue. The material for administration is delivered automatically
once the needle reaches the appropriate location which may be less
than the effective full length of the needle. The release of force
and resultant time for administration occurs quickly, in
approximately 0.1 to 2 seconds depending on the properties of the
material for administration and the amount of force from the
plunger force element. The time for administration may also be
controlled by a damping or frictional mechanism coupled to
advancement of the plunger or push rod to limit the speed of the
plunger. The release of force from the force element communicates
to the physician with visible and tactile feedback that there is no
need for additional advancement of the needle. The rapid delivery
event gives the physician sufficient time to halt needle
advancement, resulting in an effective variable needle length to
accommodate patient to patient differences in tissue thickness. The
variable needle length and self-actuation of administration is
especially useful for administration into spaces that are not
normally open spaces, such as the subconjunctival space,
sub-Tenon's space, suprachoroidal space and supraciliary space. For
the subconjunctival space and sub-Tenon's space the needle
effective full length is in the range of 0.35 mm to 2 mm depending
on the angle of needle insertion. For the suprachoroidal space and
supraciliary space, the needle effective full length is in the
range of 1 mm to 4 mm depending on the angle of insertion. For the
vitreous cavity, the needle effective full length is in the range
of 10 to 15 mm. The effective full needle length may, for example,
be 0.3 mm to 3 mm, 0.35 to 2 mm, 1 mm to 4 mm, 10 to 15 mm.
[0051] In one embodiment, the distal element applies a distally
directed sealing force against the tissue surface to maintain a
seal on the surface of the eye. The sealing force is designed to be
sufficient to seal the flow of the material for administration from
the needle track during needle insertion into tissue. The sealing
force is minimized to prevent compression of the tissues of a
normally closed space or nearly closed space such as the
suprachoroidal space or supraciliary space at the site of
administration that would prevent delivery into the space or
increasing the intraocular pressure that would restrict delivery of
the material for administration into the space. In one embodiment,
the distal element maintains contact with the tissue surface but
does not apply a distally directed sealing force against the tissue
surface to maintain a seal on the surface of the eye. In one
embodiment, the distal element contacts the surface of the eye
during penetration of the distal seal of the distal element by the
distal tip of the needle but does not maintain contact with the
surface of the eye after needle penetration through the distal seal
and into ocular tissue. The tissue interface and distal seal may
comprise a soft polymer, rubber or other material that allows
needle penetration without coring of the material. The tissue
interface and distal seal material is selected to provide
compliance to both seal to the surface of the eye during insertion
of the needle into ocular tissue and also to seal the delivery
pathway from the needle until the needle is advanced through the
distal seal. Once the needle penetrates the distal seal, the needle
is advanced through the outer ocular tissues to reach the desired
administration site. The tissue interface and distal seal remain on
the surface of the eye. The distal seal is sufficiently resilient
to prevent rupture by the material for administration under
pressure prior to advancement of the needle through the distal
seal. The portion of the distal seal in the path of the needle is
also sufficiently thin to allow penetration by the needle without
undue application of force. The distal seal is typically in the
range of 250 to 1500 microns in thickness in the region that is
penetrated by the needle.
[0052] In one embodiment a sealing force is provided by a
compressible or collapsible element between the body of the device
and the proximal end of the distal element or distal housing. In
one embodiment, the tissue interface provides a sealing force by
compression of the tissue interface or elastically compressible
elements in the distal element. In one embodiment, the distal
element is configured to allow an elastic reduction in length
during needle advancement to apply a sealing force. In one
embodiment, a friction element disposed in or about the distal
element increases the force required to move the distal element
proximally thereby promoting contact of the tissue interface with
the surface of the eye and maintaining a seal against the eye
surface during needle advancement. The friction of the distal
element against the needle may be tailored in relation to the
proximal movement of the distal element during needle advancement.
An increase in friction may be obtained by increased contact or
surface texture between the distal element and the external surface
of the needle or through a decrease in the durometer of the distal
element in order to tailor the amount of force applied by the
tissue interface during proximal travel of the interface along the
needle length. The friction may be varied along the path of travel
of the distal element along the needle. High friction may be
provided during the initial path of travel of the distal element to
promote contact of the tissue interface to the surface of the eye
during initial insertion of the needle into ocular tissues, the
friction may be reduced after a length of the needle corresponding
to the length of the needle bevel is inserted into ocular tissue.
The length of travel of the distal element under the influence of
the region of high friction is in the range of 0.3 mm to 2 mm.
[0053] In one embodiment, the distal element is attached to the
body of the device by one or more collapsible elements. The
collapsible element is configured to not allow an increase in
length to prevent the distal seal from being displaced from the tip
of the needle due to the delivery force applied to the material for
administration prior to penetration of the distal seal. The
collapsible element allows a reduction in length, thereby allowing
proximal travel of the distal element during advancement of the
needle into tissues. In one embodiment, the collapsible element
comprises one or more elongated struts that may deform, bend or
fold away from the needle during proximal travel of the distal
element. In one embodiment, the collapsible element comprises a
section of tubing concentric to the needle that has been cut to
form openings along the axial length of the tubing to form
collapsible struts. The shape and configuration of the collapsible
struts may be tailored to provide a desired force-displacement
characteristic of the collapsible element. The force versus
displacement may be linear or non-linear. In one embodiment the
material for administration is a gas, fluid or semisolid and the
collapsible element provides a sealing force which transitions from
an increasing spring like force per unit displacement to a constant
force independent of displacement to keep the tissue interface and
distal seal in sealing contact to the eye surface without undue
application of force with further needle advancement into the eye.
Application of force above 80 to 100 grams-force may limit the
ability of the material for administration to enter a closed space
such as the suprachoroidal or supraciliary space. In one
embodiment, the tissue interface applies a sealing force in the
range of 40 to 80 gram force. The transition to a constant force is
designed to occur after a length of the needle bevel is inserted
into ocular tissue, corresponding to a compression or collapse of
the collapsible element of 0.3 mm to 2 mm. In one embodiment the
material for administration is a solid and the collapsible element
provides for contact of the tissue interface to the surface of the
eye during initial insertion of the needle into ocular tissue, but
collapses to provide little or no resistance to proximal movement
of the distal element along the needle after the bevel of the
needle is fully inserted into tissue. The collapsible element may
be assembled from components in a tubelike configuration or
alternatively cut from a segment of tubing such as a laser machined
nickel titanium alloy (e.g. Nitinol) tube. The collapsible element
may be disposed between the elongate body and the distal element,
such as between the barrel and the housing of the distal element
(if present). The collapsible element may be fixed to the body of
the device and to the distal element such that the distal element
is proximally slidable on the needle but will not travel distally
from its initial position to maintain the position of the distal
seal while under delivery pressure.
[0054] In some embodiments the tissue interface provides a sealing
function. The sealing force provided by the tissue interface is
within a range to provide sealing of the needle tract, but less
than the force that would close the tissue space to impede movement
of the material for administration into the space. A tissue
interface with a tissue contacting surface area in the range of
0.45 to 5.07 mm.sup.2 is suitable for sealing of the needle tract.
Suitable materials for the tissue interface and distal seal
include, but are not limited to, natural rubbers, silicone rubbers
and thermoplastic elastomers such as polyurethanes. The stiffness
of the rubber or elastomer may be selected to provide the
appropriate combination of conformance to the tissue surface and
sealing of the lumen of the distal end of the needle. The selection
of the material of the tissue interface may also minimize the
sealing force that might impede movement of the material for
administration into the tissue space. The rubber or elastomer must
also be capable of penetration by the distal tip of the needle to
trigger release of the material for administration. Rubbers or
elastomers with a Shore A durometer of 10 to 70, 10 to 50 or 10 to
30 are suitable for use as the sealing element. Suitable materials
for a distal housing include, but are not limited to,
polypropylene, polyethylene, polycarbonate, polysulfone,
polyetheretherketone, acrylonitrile butadiene styrene, polystyrene,
polyamide, and polyurethanes. Suitable materials for a distal
collapsible element include, but are not limited to, stainless
steel, spring temper steel, super-elastic nickel titanium alloys,
cobalt chrome alloys, oil-tempered chrome silicon, polyimide, and
polyetherimide. In one embodiment, the barrel of the device
contains the reservoir and provides an external surface for holding
the device during use.
[0055] The reservoir may comprise a tubular cylinder attached on
the distal end to the proximal end of the needle, with a plunger
slidably disposed in the lumen of the tubular body. The reservoir
may also provide for insertion of a cartridge containing the
material for administration where the plunger or push rod of the
device moves a slidable seal in the proximal end of the cartridge
to deliver the material for administration. The body may be
fabricated from a variety of thermoplastic materials suitable for
medical use such as polypropylene, polyamide, polycarbonate,
polysulfone, polyethylene, cyclic polyolefins, polystyrene and
polymethylmethacryate. The body may incorporate external features
such as textures or finger indentations to allow a user to more
ergonomically grip and use the device. The body may incorporate
index or measurement markings to provide an indication of the
amount of material being delivered or to indicate that
administration is complete. The body may incorporate transparent
materials or a section of transparent material to allow the
visualization of the material for administration in the reservoir
or movement of the plunger or push rod to visually indicate the
administration event. The plunger or push rod may have markings to
aid visualization of reservoir loading and release of material for
administration. The body may incorporate a label or indicator to
provide the user with the orientation to the direction of the
delivery, for instance a notation of the orientation of the needle
bevel or the direction in which a deflection element will deflect
the material for administration.
[0056] In embodiments of the invention, the device comprises a
means for providing a delivery force. The means as described herein
could be, for example, a syringe with a compressible reservoir that
can be "squeezed" or compressed by a user (directly or indirectly)
to effect delivery of the material for administration.
Alternatively, in a preferred embodiment, the means is a plunger or
push rod with a biasing means or force element (such as a
compression spring or a pressurized gas).
[0057] The device may be disposable and/or for single use.
Alternatively, the device may be reusable.
[0058] In some embodiments of the delivery device, the device
provides for the delivery of a controlled amount of gas as a first
material for administration to facilitate the subsequent
administration of an active agent containing composition to the
suprachoroidal space or supraciliary space. A small amount of gas
has been found to aid opening of a normally closed space near the
needle tip, while the compressible nature of the gas minimizes
potential trauma and pain. The delivery device comprises a gas
reservoir and a flow path between the reservoir and the needle
lumen, where the gas is introduced to the needle lumen proximal to
the distal seal. The gas is pressurized with a force element such
as a spring, compressed bladder, or expanding element. The gas
reservoir is separate from the reservoir for the delivery of the
active agent containing composition to prevent mixing of the gas
with the active agent composition and to provide independent
delivery characteristics. The gas reservoir may use the same force
element as used for the delivery of the active agent containing
composition or may have a separate, independent force element. The
gas may comprise air, nitrogen, carbon dioxide, argon or a
fluorocarbon. The gas may be selected for its solubility in the
physiological environment to tailor the residence time of the gas.
Generally, a fast dissolving gas such as air, nitrogen or carbon
dioxide is used to minimize physical perturbation to the eye. The
gas reservoir and gas flow path is configured to deliver gas
volumes of 10 to 200 microliters, 20 to 150 microliters, 30 to 100
microliters, or 40 to 75 microliters of gas at standard temperature
and pressure. The gas may be pressurized in a range of 0.1 to 2.0
bar, 0.15 to 1.6 bar or 0.2 to 1.0 bar gauge pressure. The volume
and pressure of the gas, and the flow resistance of the gas flow
path may be adjusted to tailor the timing of gas delivery from 0.1
to 2 seconds, 0.2 to 1.5 seconds, 0.3 to 1 seconds, 0.5 to 0.75
seconds.
[0059] The gas reservoir is activated prior to or simultaneous with
penetration of the distal seal by the needle and advancement of the
needle tip into tissues. The gas reservoir is activated by
compression of the volume of gas in the gas reservoir by the action
of a force element onto a plunger acting on the gas volume. The
force element may be a spring or an expansive gas. The flow path
for the gas may comprise the needle lumen, a portion of the needle
lumen or a separate lumen. In one embodiment, the flow path
comprises a hollow member external to the needle and the needle has
at least one hole along the shaft of the needle that is in
communication with the external hollow member to allow the gas to
flow from through the hollow member and into the needle lumen. In
one embodiment, the flow path comprises an outer sleeve that is
coaxial to the needle and the needle has at least one hole along
the shaft of the needle within the coaxial outer sleeve. The gas
flows from the gas reservoir through the outer sleeve and into the
needle lumen through the hole or multiple holes and out from the
distal tip of the needle. Holes in the needle are located
approximately 4 to 10 mm from the tip of the needle. Each hole may
have a variety of shapes, including circular, polygonal or
rectangular. The effective cross-sectional area of each hole may be
from 0.05 to 2.0 mm.sup.2. The coaxial outer sleeve may comprise a
metal such as stainless steel or a plastic such as polypropylene,
polyethylene, polycarbonate, polysulfone, polyethylene
teraphthalate, polyetheretherketone, acrylonitrile butadiene
styrene, polystyrene, polyamide, and polyurethanes. The coaxial
outer sleeve is dimensioned to provide a gap between the inner
surface of the sleeve and the outer surface of the needle for gas
flow, where the gap is in the range of 0.1 to 2.5 mm. The length of
the coaxial outer sleeve is configured to be compatible with the
effective needle length of the device and may be in the range of 2
to 20 mm. The hole or holes may be made in the needle by laser
machining, grinding, or punching.
[0060] The resultant gas flow path through the coaxial outer sleeve
and into a needle hole bypasses any active agent containing
composition in the proximal end of the needle to provide an
unrestricted gas flow path to the distal end of the needle. A
distal seal, tissue interface and distal element as described for
the delivery of an active agent containing composition may be
configured on the delivery device to facilitate the self-actuated
delivery of the gas prior to the delivery of the active agent
containing composition. Subsequent to the delivery of the gas, the
active agent containing composition is administered through the
needle to the suprachoroidal space or supraciliary space. In one
embodiment, the plunger or push rod for the active agent containing
material is incorporated into the plunger for the gas compression.
In one embodiment, the plunger or push rod for the active agent
containing material is separate from the plunger for the gas
compression. The delivery of the active agent containing
composition may be triggered manually after gas delivery or the
device may incorporate a mechanism to administer the active agent
containing composition after all or a portion of the gas has been
delivered through the needle. The mechanism may comprise means to
block or inactivate the delivery mechanism for the active agent
containing composition by the gas pressure in the device in a
primed or activated state, and release of the gas pressure by the
delivery of gas releases the delivery mechanism for the active
agent containing composition. The mechanism may comprise a
mechanical linkage from the force element mechanism for gas
compression to the force element mechanism for delivery of the
active agent containing composition, a linkage from the gas
compression plunger to the force element mechanism for delivery of
the active agent containing composition or a linkage from the gas
compression plunger to the plunger or push rod for delivery of the
active agent containing composition.
[0061] The distal seal acts to prevent escape of the material for
administration whether gas or active agent containing composition,
from the needle or reservoir when the device is primed by
activation of the delivery force before the distal seal is
penetrated by the needle. This can be achieved by a seal between
the needle lumen and the outside of the device. This seal may be
achieved by the seal being in direct contact with the needle tip or
may be achieved by using a distal element housing that is suitably
sized to provide a liquid and gas tight seal around the needle
shaft when placed over the needle tip. For example, the outer
diameter of the needle may be complimentary to the inner diameter
of the housing to provide a seal. In one embodiment for delivery of
a solid material, the seal may only block enough of the needle
lumen so as to prevent the material from being expelled until the
seal is moved proximally, thereby exposing the opening of the
lumen.
[0062] The person skilled in the art will appreciate the difference
between flowable, semisolid and solid materials for administration.
Any material for administration may be described as flowable if,
for example, the kinematic viscosity of the material is less than
about 0.002 m.sup.2/sec at 20.degree. C. A material for
administration may be described as semisolid if, for example, the
kinematic viscosity of the material is greater than about 0.002
m.sup.2/sec at 20.degree. C.
[0063] Generally speaking, and as described above, the device is
primed or activated when a pressure or force is placed on the
material for administration, whether gas or an active agent
containing composition, such that once the distal seal is
penetrated by the needle and the needle reaches the desired site of
delivery in the eye (such as the suprachoroidal space or
supraciliary space), the material for administration is
automatically released. The device is primed prior to or
simultaneous with penetration of the distal seal. In this way, the
device can be operated with one hand. The only force that needs to
be applied by the user is the penetration force to allow the needle
to penetrate the distal seal and then the eye tissue. The needle
length can be suitably designed to target specific administration
sites at corresponding depths in the eye. In some embodiments, the
device may comprise a retaining means to retain the distal element
on the needle once the device is primed.
[0064] Prior to delivery of the active agent containing composition
or gas prior to the active agent containing composition, the distal
element will generally not be in direct physical contact with the
elongate body or the barrel. In fact, the distance between the
proximal end of the distal element and distal end of the elongate
body or barrel (and design of any compressible or collapsible
element that may be present) can be arranged to determine the
maximum depth of needle penetration. For example, during operation
of the device, as the distal seal is pressed against the eye, the
distal element and elongate body or barrel will move towards each
other. It is this motion that advances the needle tip towards and
through the distal seal/tissue interface and into the patient's
eye. Once the proximal end of the distal element abuts against the
distal end of the elongate body or barrel (or once the compressible
or collapsible element does not permit further motion), continued
advancement of the needle is prevented. Hence, the distance between
the proximal end of the distal element and distal end of the
elongate body or barrel may be equal to the maximum depth of needle
penetration. Account may need to be taken for any distance between
the needle tip and the distal seal/tissue interface and/or the use
of any compressible element. In particular, the maximum depth of
needle penetration may be determined by the distance between the
proximal end of the distal element and distal end of the elongate
body or barrel less the distance between the needle tip and the
distal seal/tissue interface. Thus, the position and sizes of the
distal element, needle, and distance between the needle tip and
distal seal/tissue interface (if any) can be configured to
determine a maximum needle penetration depth. The skilled person
could design the device accordingly based on the present
disclosure.
[0065] In this way the device may comprise a means for determining
a maximum needle penetration depth to control the depth of
penetration of the needle into the eye. The means can be a set
distance between the proximal end of the distal element and distal
end of the elongate body or barrel (as determined by the relative
size of the distal element, the needle, the distance of the needle
tip from the distal seal/tissue interface, and the shape and
configuration of any compressible or collapsible element present).
Alternatively, the needle may comprise a separate element that
halts advancement of the distal element along the needle during
operation (such as an element present on the needle disposed
between the distal element and the elongate body or barrel, for
example an annular ridge or clamp). In some embodiments, this
element to prevent further advancement of the distal element along
the needle during operation may be movable such that the maximum
needle penetration depth can be determined by the user. In such an
embodiment, the needle may comprise markings to allow the use to
select an appropriate maximum needle penetration depth. In another
embodiment, the maximum depth of needle penetration may be
determined by the compressible element, for example the
compressible element only allowing the desired needle penetration
depth by way of increasing rigidity as the element is compressed,
or by other mechanical means, such as entrapment of the
compressible element between the proximal end of the distal element
and distal end of the elongate body or barrel. The present
invention therefore provides devices having fixed maximum needle
penetration depths suitable for targeting the tissue space of
interest. Suitable designs to achieve a fixed maximum needle
penetration depth would be apparent to the skilled person based on
this disclosure. Of course, the maximum depth of needle penetration
can be within certain tolerances. Maximum needle penetration depth
is also referred to herein as effective needle length.
[0066] In one embodiment, the active agent containing composition
is preloaded in the delivery device, whereby the delivery device
serves as the storage container for the composition prior to use.
In one embodiment, the preloaded device is sterilized for use after
placement and sealing of the active agent containing composition in
the delivery device. The sterilization may be accomplished by
established methods of sterilization such as heat or ionizing
radiation. In one embodiment the active agent containing
composition is preloaded in the device as a dry material that is
reconstituted with a liquid that is introduced into the device
prior to use. The delivery device may contain a port or connector
in fluid communication with the device reservoir to facilitate
reconstitution of the active agent containing composition within
the delivery device.
[0067] In one embodiment, the device is configured to deliver a
material for administration, where the material for administration
is an elongated solid material, semisolid material or implant
within the lumen of the needle. Referring to the device depicted in
FIG. 1 and the distal tip detail of the device in FIG. 2, the
device comprises a hollow barrel 1, with a proximal barrel end cap
2. A plunger 3 slidably passes through the end cap. The plunger has
a proximal end 4 which is sealed. A push rod guide tube 6 is
slidably disposed in a lumen in the plunger 3, which provides
support for a push rod 7 to prevent the push rod 7 from buckling
during delivery. A plunger compression spring 5, provides a
distally directed force on the plunger 3 and push rod 7. A beveled
needle 8 is attached and fixed to the distal end of the barrel 1
such that the needle 8 does not move in relation to the barrel 1 to
provide direct control of the location of the needle 8 tip when
manipulating the position of the barrel 1. The distal end of the
push rod 7 resides within the lumen of the needle 8 and moves
distally when the tissue interface and distal seal 11 is opened by
the distal tip of the needle 8. The distal element for the needle 8
comprises a tubular distal housing 10 surrounding the distal end of
the needle 8. The tissue interface and distal seal 11 is attached
to the distal end of the distal housing 10. A collapsible element
is comprised of a distal housing spring 9 and is placed between the
distal end of the barrel and the proximal end of the distal housing
10 to provide a distally directed force on the distal housing 10
thereby pressing the tissue interface and distal seal 11 onto the
tissue surface.
[0068] As the needle 8 is advanced to penetrate the tissue
interface and distal seal 11, the distal housing 10 moves
proximally toward the barrel 1 while the needle 8 is advanced into
tissue. The distal housing spring 9 acts to maintain pressure of
the tissue interface and distal seal 11 as the needle 8 is advanced
into tissue. While the tip of the needle 8 is passing through the
outer tissues of the eye, the material for administration 12 within
the lumen of the needle 8 is under pressure from compression spring
5 and the path from the distal tip of the needle 8 has been opened,
but there is no tissue space for the material for administration 12
to be delivered from the needle tip. Once the distal tip of the
needle reaches the desired space such as the suprachoroidal space
or the supraciliary space, the material for administration 12 can
exit from the needle and is expelled into the space. FIGS. 1 and 2
show the distal segment of the device in an uncompressed state. The
tissue interface and distal seal 11 and the distal housing 10 are
disposed at the end of the uncompressed distal spring 9. The distal
spring 9 is anchored to the barrel 1. As the device is deployed,
the distal segment of the device transitions to a compressed state.
The force of advancing the device into the tissue causes the distal
spring 9 to compress, allowing the distal housing 11 and distal
seal and interface 11 to slide proximally along the needle 8. The
distal tip of the needle 8 penetrates the tissue interface and
distal seal 11.
[0069] In one embodiment, the device is configured to deliver a
material for administration where the material for administration
is a fluid or flowable semisolid material. Referring to the device
depicted in FIG. 3 and the distal tip detail of the device in FIG.
4, the device comprises a hollow barrel 13, with a proximal barrel
end cap 14. A plunger 3 slidably passes through the end cap and has
a plunger seal 19 within the barrel 13. The plunger seal 19
prevents leakage of material for administration between the plunger
3 and the barrel 13 inner wall. The distal end of the plunger 3
forms the proximal end of the reservoir 24. The shaft of plunger 3
has a flow path from the distal end, through the plunger seal 19
into the reservoir 24. The proximal end of the flow path is
connected to a female Luer fitting 17. A one-way check valve 16 is
placed between the female Luer fitting 17 and the proximal end of
the flow path in shaft of plunger 3. A beveled needle 8 is attached
and fixed to the distal end of barrel 13 such that the needle 8
does not move in relation to the barrel 13 to provide direct
control of the location of the needle 8 tip when manipulating the
position of the barrel 13. The plunger 3 moves distally when the
tissue interface and distal seal 11 is opened by the distal tip of
the needle 8. The distal element of the device comprises a tubular
housing 22 surrounding the distal end of the needle 8. The tissue
interface and distal seal 11 is attached to the distal end of the
distal housing 22. A frictional element in the shape of a tube 20
is disposed in the proximal end of the housing 22 to contact the
exterior of the needle 8 and provide means for the tissue interface
and distal seal 11 to provide sealing at the administration site.
To use the device, the fluid or flowable material to be delivered
is placed into the device through the female Luer fitting 17 into
reservoir 24. As the fluid or flowable semisolid material is placed
in the reservoir 24, the plunger travels proximally, compressing
the compression spring 18. The plunger compression spring 18,
provides a distally directed force on the fluid or flowable
semisolid material, pressurizing the reservoir 24. The check valve
16 provides a proximal seal to the flow path in the shaft of
plunger 3 preventing flow out of the female Luer fitting 17. As the
needle 8 is advanced to penetrate the tissue interface and distal
seal 11, the distal housing 22 moves proximally toward the barrel
13. The tissue interface and distal seal 11 is placed on the
surface of an eye and the device is advanced toward the eye. The
tissue interface and distal seal 11 is compressed on the surface of
the eye and the distal end of the needle 8 is advanced through the
distal seal. While the tip of the needle 8 is passing through the
outer tissues of the eye, the pressurized material for
administration in the reservoir 24 has no tissue space to exit the
needle tip. Once the distal tip of the needle reaches the target
which allows for material flow into a tissue space, such as the
suprachoroidal space or supraciliary space, the material can exit
from the tip of the needle 8 and is expelled from the reservoir 24
into the space or cavity.
[0070] In one embodiment, the distal tip of the device is comprised
of collapsible elements. Referring to the device depicted in FIG. 5
and the magnified device distal tip detail in FIG. 6, the distal
tip is comprised of distal segment, a central collapsible segment
and a proximal segment. The tissue interface and distal seal 11 is
disposed about a distal tubular shaft 26. The inner lumen of the
distal tubular shaft 26 contains an internal seal 25 which seals
the space between the tubular distal shaft 25 and the beveled
needle 8. The central segment is comprised one or more segments 27
which function as collapsible elements that can impart a force
against the tissue surface during use. The collapsible elements 27
are attached or integral to the distal tubular shaft 26 and
proximal tubular shaft 28. The proximal tubular shaft 28 is
connected to the barrel 13 of the device providing an anchor point
for the collapsible element and preventing distal movement of the
tissue interface and distal seal 11. FIG. 7 shows the distal
segment of the device in an uncollapsed state. The tissue interface
and distal seal 11 and the distal tubular shaft 26 are disposed at
the end of the collapsible elements 27. The proximal tubular shaft
28 is anchored to the barrel 13. FIG. 8 shows the distal segment of
the device in a collapsed state. The force of advancing the device
into the tissue causes the collapsible elements 27 to deform,
allowing the distal tubular shaft 26 and tissue interface and
distal seal 11 to slide proximally along the needle 8. The distal
tip of the needle 8 has penetrated the tissue interface and distal
seal 11.
[0071] In some embodiments, the distal tip of the needle is
configured to direct the material for administration at an angle
from the long axis of the needle. Referring to the needle tip
depicted in FIG. 9, the distal tip of the needle 29 may be curved
to direct the material for administration. Referring to the needle
tip depicted in FIG. 10, the distal tip of the needle 30 may have
an inner deflecting element 31 in the lumen of the needle in the
region of the bevel of the needle. Referring to the needle tip
depicted in FIG. 11, inner deflecting element may be a protrusion
32 that acts to fragment a solid material for administration at the
needle distal tip 33 to promote distribution of the material for
administration in a tissue space, such as the supraciliary or
suprachoroidal space.
[0072] In some embodiments, the delivery device is designed for
delivery of a controlled amount of gas to facilitate the
administration of a material comprising an active agent to the
suprachoroidal space or supraciliary space. The delivery device
comprises a gas reservoir and a flow path between the reservoir and
the needle lumen, where the gas is introduced to the needle lumen
proximal to the distal seal.
[0073] In one embodiment of the device depicted in FIGS. 15A and
15B, a needle assembly, a gas reservoir with a plunger element and
a force element with a push rod element which are coaxially
configured. FIG. 15A depicts a schematic of the device with a
distal segment consisting of a needle 8 with a distal seal 11,
attached to the body 50 of the device and in communication with the
gas reservoir 51. A solid material for administration 52 resides
within the lumen of the needle 8. The body 50 contains a gas
reservoir mechanism and a force element mechanism 53. The gas
reservoir mechanism comprises a tubular barrel section 54 within
which resides a sliding gas plunger 55. The plunger 55 is sealed
about the inner surface of the tubular barrel 54 and contains a
through hole 56 on the central axis which is sized to allow a gas
tight seal on a push rod 7. When the plunger 55 is moved distally,
the sealed plunger acts to compress any gas within the lumen of the
barrel 54 thereby pressurizing the device for delivery of the gas.
A distal locking pin 57 serves to hold the plunger 55 in place to
maintain pressurization during preparation and use of the
device.
[0074] The force element mechanism 53 is located in the tubular
barrel section 54 and sized to allow free passage within the gas
reservoir 51 in the barrel 54. The distal end of the force element
53 is attached to the proximal end of the gas reservoir plunger 55.
The force element 53 is mechanically coupled to the push rod 7
attached to a sliding plunger 3 at the proximal end. The push rod 7
traverses through the gas reservoir plunger 55 and extends distally
to align with the lumen of the needle 8. A compression spring 18 is
placed over the sliding plunger 3 to provide the motive force for
the push rod 7 to expel the material for administration 52. A
proximal locking pin 58 is attached to a finger-actuated lever 59
and serves to hold the force element spring 18 in a compressed
state during preparation of the device for use.
[0075] FIG. 15B depicts the distal end of a device according to
FIG. 15A further comprising an outer sleeve 60 or jacket which
allows for gas passage along the outside of the needle shaft 8. The
needle 8 contains one or more holes 61 in the outer wall of the
needle which allow the gas to enter the needle lumen near the
distal tip of the needle 8. A gap 62 exists between the inner
surface of the sleeve and the outer surface of the needle 8. The
gap is sufficient to allow for unimpeded gas flow to the needle
holes. The sleeve 60 is sealed against the needle 8 at the distal
end 63 and is in open communication with the gas reservoir 51 at
the proximal end 64.
[0076] In one embodiment depicted in FIG. 16 a device consists of a
distal needle 8 and outer sleeve 60, a gas reservoir 51 and a force
element mechanism 53. The needle, outer sleeve and gas reservoir
are as depicted in FIGS. 15A and 15B. The mechanism for the force
element to deliver a material for administration comprises a push
rod 7 attached to a plunger 3 within a tubular barrel 54. The
plunger 3 is slidably sealed against the inner surface of the
barrel 54. The proximal end of the barrel 54 is configured to allow
the attachment of tubing 65 which is connected to a plunger driven
syringe reservoir 66. The syringe reservoir 66, tubing 65 and
proximal end of the force element barrel 53 are filled with a
non-compressible fluid such as water or oil 67. The gas in the gas
reservoir 51 is compressed and delivered to through the lumen of
the needle 8. Subsequently, the plunger of the syringe reservoir 66
is activated, the hydraulic mechanism serves to advance the force
element plunger 3 and therefore the push rod 7 to expel the
material for administration from the distal tip of the needle 8.
The syringe reservoir 66 may be mounted on a syringe pump 68 that
is manually activated by means of a button or foot switch 69 in
order to trigger delivery of the material for administration. The
rate of hydraulic advancement of the force element plunger 3 and
push rod 7 may be adjusted to provide the rate of delivery of the
material for administration from the distal tip of the needle
8.
[0077] In one embodiment of the device depicted in FIGS. 17A to
17F, the reservoir for gas delivery 51 is coaxial to the push rod 7
that applies a force on active agent containing composition 12
within the needle 8. The gas delivery portion of the device
comprises a plunger seal 19 that moves to compress a volume of gas
in the gas reservoir 51 between a distal seal 11 and the plunger
seal 19. FIG. 17A depicts the device in a standby state prior to
activation where the plunger rod 3 either does not yet have force
applied to it or has a plunger stop feature 15 resisting the
applied force to prevent the push rods axial movement towards the
active agent containing composition 12. In this embodiment the user
is able to remove a plunger stop feature 15 which allows the
compression spring 5 to extend, displacing the plunger seal 19. The
displacement of the plunger seal 19 compresses the enclosed gas
volume in the gas reservoir 51 between the plunger seal 19 and the
distal seal 11 until the plunger seal 19 reaches the equilibrium
position as depicted in FIG. 17B. The plunger seal 19 stops at an
equilibrium position once the compressed gas pressure exerts a
force that equals the force applied by the compression spring 5
minus any friction (i.e. forces are balanced). The device is now
activated to self-actuate the delivery of gas once the tip of the
needle 8 has passed through the distal seal 11.
[0078] For use, the distal seal 11 of the device is placed at the
administration site against the surface of the outer layers of an
eye 70. By advancing the device toward the eye the needle 8 pierces
through the distal seal 11 and at least partially through the outer
layers of the eye 70 to reach the stage shown in FIG. 17C. For
suprachoroidal or supraciliary administration the outer layers 70
would represent the conjunctiva and sclera, while the secondary
layer 71 would represent the choroid or ciliary body. At the stage
in FIG. 17C the gas in the enclosed volume remains at an elevated
pressure and remains sealed by the outer layers 70 and/or the
distal seal 11. By advancing the needle further into the eye, the
needle 8 penetrates deeper through the outer layers 70 until the
pressurized gas in the enclosed gas reservoir 51 is able to pass
through the needle 8 and inflate the space between tissue layers 70
and 71. The expansion of this gas allows the plunger seal 19 to
advance, as the pressure in gas reservoir 51 has now reduced
allowing the spring 5 to extend. The device incorporates a needle
stop face 21 to prevent the user from pushing the needle further
through the outer layers 70. FIG. 17D shows the stage in which a
portion of the gas has been delivered to separate the tissue layers
70 and 71. The plunger seal 19 has moved beyond a gas bypass
feature 23 and is no longer sealing the enclosed gas reservoir 51
to allow a small volume of gas to be delivered before allowing a
longer plunger and push rod translation for administration of the
active agent containing composition to occur without continued gas
delivery, this also eliminates the plunger seal friction for the
remaining travel. Alternatively, maintaining a near constant
cross-section (and therefore seal) throughout the travel of the
plunger seal 19 without a bypass feature 23 enables larger volumes
of gas to be delivered and a continuation of gas delivery during
the active agent composition delivery.
[0079] The time during or after gas delivery that the active agent
containing composition 12 is delivered is able to be controlled by
the length and positioning of the active agent containing solid or
semi-solid elongated body 48 and push rod 7. FIG. 17E depicts the
push rod 7 contacting the proximal end of the active agent
containing composition 12. FIG. 17F shows the push rod 7 advanced
further down the needle 8 bore to deliver the entirety of the
active agent containing composition 12 to the space between the
outer layers 70 and the secondary layer 71.
[0080] In one embodiment, the gas delivery portion of the device is
configured to be independent of the push rod and delivery mechanism
for the active agent containing composition. FIG. 18A depicts the
device in standby configuration, where the plunger seal 19 for the
gas delivery is uncoupled from the push rod 7 for delivery of the
active agent containing composition. In this example, the gas
compression spring 59 is being held in a compressed state by an
activation latch 35. The drive spring 5 to deliver the active agent
containing composition is being held in a compressed state by a
mechanical couple, shown here as a bent metal wire 69 that has a
position that is dependent on the travel of the plunger seal 19
and/or the gas plunger rod 55. The wire is biased away from the
push rod 7 but in FIG. 18A it is shown to be initially held in this
position by a loop around the gas plunger rod 55. The wire 69 could
essentially be any feature that obstructs the elongation of the
drive spring 5 until the plunger seal 19 has reached a displacement
that allows the obstruction to be removed. Releasing the gas
compression spring 59 by removing activation latch 35 compresses
the enclosed volume to reach an equilibrium position shown in FIG.
18B where the force from the gas pressure acting on the plunger
seal 19 plus friction is equal to the force from the gas
compression spring 59. The pressurized gas reservoir 51 volume is
enclosed by the distal seal 11, the plunger seal 19 and a push rod
seal 34 which forms a seal between the push rod 7 and the proximal
end of the needle lumen.
[0081] With the device in its equilibrium state the distal seal 11
is placed against the administration site on the surface of an eye.
Advancing the device into the eye causes the needle 8 to pierce
through the distal seal 11 and the outer layer of the eye 70. In
the position shown in FIG. 18C the outer layers of the eye 70 and
distal seal 11 are maintaining a seal on the enclosed gas reservoir
51 volume. Advancing the needle 8 further through the distal seal
11 and the outer layers 70 allows the pressurized gas in enclosed
gas reservoir 51 to expand, travel down the needle 8 and inflate
the space between layers 70 and 71 as is shown in FIG. 18D. The
expansion of the gas reduces the gas pressure in gas reservoir 51
which allows the gas spring 59 to elongate displacing the plunger
seal 19 and delivering a further volume of gas. The gas plunger rod
55 is attached to the plunger seal 19 and as this moves it reaches
an unlatch point where the biased feature of the mechanical couple
69 is able to deflect out of the way so that it no longer obstructs
the movement of the plunger 3 attached to the push rod 7 to deliver
the active agent containing composition. This mechanism could be
achieved in a number of ways but the critical aspect is that the
displacement of plunger seal 19 removes an obstruction that is
preventing the drive spring 5 elongation. FIG. 18E shows that the
plunger seal 19 has reached the end of its travel and finished
delivering gas. The push rod 7 has pushed the active agent
containing composition 12 out of the needle 8 and into the space
between layers 70 and 71.
[0082] In one embodiment of the device depicted in FIG. 19, the gas
reservoir comprises a vent hole as a form of gas plunger seal
bypass. A vent hole 36 is open from gas reservoir 51 to atmosphere,
allowing the device internals to remain at atmospheric pressure
between manufacture and use which may alleviate issues such as
pressure changes during transit. The vent hole 36 can also be used
to set the starting position for when the gas in reservoir 51
begins to be compressed. This enables the plunger seal 19 to move
from any position in the standby state and the volume of gas that
will be compressed and later delivered to the administration site
is not compressed until the plunger seal 19 passes vent hole 36 and
completes the seal on gas reservoir 51. The plunger seal 19 must
pass the vent hole 36 between the standby state and the equilibrium
position. Optionally the vent hole 36 can incorporate a filter to
maintain sterility within the gas reservoir 51.
[0083] The described embodiments of the device may be used in
combination to deliver a fluid, semisolid or solid. The
configuration of the distal portion of the device comprises the
distal element which functions as a tissue interface and distal
seal on the distal end of the needle. The use of a distal
compression spring, frictional element, a collapsible element, or a
combination of such elements in conjunction with the distal element
may be used for delivery of a material for administration where the
material is a gas, fluid, semisolid, solid or implant.
[0084] For use in the device, a lubricant may be used to aid
delivery. The lubricant may be used to coat the material for
administration or the needle lumen. The lubricant may also be
placed in the lumen of the distal element to coat the tip of the
material for administration and the outer surface of the needle as
it passes into tissue. Suitable lubricants include, but are not
limited to, oils, waxes, lipids, fatty acids and low molecular
weight polymers. Low molecular weight polymers include, but are not
limited to, polyethylene glycol and polysiloxane.
[0085] The material for administration may be a fluid, solid or
semisolid composition of an active agent for delivery into the
suprachoroidal space, supraciliary space or other spaces of the eye
such as the vitreous cavity, subconjunctival space, sub-Tenon's
space and sub-retinal space. The active agent may be solubilized in
the fluid, semisolid or solid composition, or alternatively
distributed in the composition as particles. In one embodiment, the
composition comprises a plurality of drug-containing particles 45
formed into a semisolid composition 46 as a material for
administration, shown schematically in FIG. 12. For delivery of the
semisolid composition in the suprachoroidal space or supraciliary
space, the composition is placed into the eye from the outer
surface of the eye through a needle to preferentially locate the
material in the suprachoroidal space or supraciliary space near the
administration site. After placement in the suprachoroidal space or
the supraciliary space, the semisolid composition transforms,
degrades or dissolves into individual drug-containing particles
that may migrate in the space. The semisolid mass of drug particles
allows a large amount of drug to be administered in a very small
volume to prevent an acute increase of intraocular pressure such as
occurs with administration of an equivalent amount of drug
suspended in a fluid. The semisolid formulation enables an
effective amount of drug to be delivered in the range of 5 to 100
microliters, 10 to 75 microliters or 20 to 50 microliters.
[0086] In one embodiment, the material for administration comprises
a plurality of drug containing particles 47 formed into a formed
elongated solid or semi-solid body 48, shown schematically in FIG.
13A and FIG. 13B. The formed elongated solid or semi-solid body 48
comprising the plurality of drug containing particles 47 may be in
the shape of an elongated body such as a plug, tube or cylinder.
The elongated body may be molded, machined, printed or extruded
from the material for administration. In one embodiment, the formed
elongated solid is an elongated body with a diameter approximately
the inside diameter of the needle used for placement of the formed
solid in the tissue space. The diameter may range from 0.60 mm,
corresponding to a 20 gauge needle, to 0.159 mm, corresponding to a
30 gauge needle. Depending on the dose of drug and drug content of
the particles, the formed solid may have a length ranging from 1 mm
to 50 mm (for example 1 mm to 25 mm). After placement in the
suprachoroidal space or the supraciliary space, the formed solid
composition transforms, degrades or dissolves into individual drug
containing particles that may migrate in the space. The formed
solid mass of drug containing particles allows a large amount of
drug to be administered in a very small volume to prevent an acute
increase of intraocular pressure such as occurs with administration
of an equivalent amount of drug suspended in a fluid. The volume of
the delivered formed elongated solid may range from 0.1 microliters
to 10 microliters (for example 0.1 to 5 microliters).
[0087] The drug containing particles may be in the form of a
selected size range of crystals of the drug. The drug containing
particles may be in the form of microspheres by fabrication of the
drug into the form of spherical particles or by the formulation of
the drug with an excipient such as a polymer and fabricating
microspheres from the combination. Microspheres containing drug may
be fabricated by any of the known means for microsphere fabrication
such as by spray drying, coacervation or emulsion processes. The
use of a non-toxic polymer to hold drug within microspheres allows
tailoring of the drug release rate by the polymer composition, drug
content and size of the microspheres. Microspheres with a drug
content of 10-90 weight % drug may provide appropriate drug
release. The use of polymers of selected solubility allows both
water soluble and water insoluble drugs to be incorporated into
microspheres. Suitable polymers include, but are not limited to,
non-toxic water soluble polymers such as polyvinylpyrrolidone,
polyvinylpyrrolidone co-vinyl acetate, polyvinyl alcohol,
polyethylene glycol and polyethylene oxide, biodegradable polymers
such as polyhydroxybutyrate, polydioxanone, polyorthoester,
polycaprolactone, polycaprolactone copolymers, poly lactic acid,
poly glycolic acid, poly lactic-glycolic acid copolymers and poly
lactic-glycolic acid-ethylene oxide copolymers, and biological
polymers such as gelatin, collagen, glycosoaminoglycans, cellulose,
chemically modified cellulose, dextran, alginate, chitin and
chemically modified chitin.
[0088] Alternatively, drug containing particles of approximately
spherical shape or other uniform shapes may be prepared by milling
of larger drug particles or by controlled crystallization. Drug
particles and drug-containing microspheres may also be individually
coated with a polymer layer to form drug particles with an external
surface coating or barrier coating. The coatings may comprise
non-toxic water soluble polymers including, but not limited to,
polyvinylpyrrolidone, polyvinylpyrrolidone co-vinyl acetate,
polyvinyl alcohol, polyethylene glycol and polyethylene oxide,
biodegradable polymers such as polyhydroxybutyrate, polydioxanone,
polyorthoester, polylactic acid, polyglycolic acid, poly
lactic-glycolic acid copolymers, acid terminated
polylactic-glycolic acid copolymers, polylactic-glycolic
acid-ethylene oxide copolymers, polylactic acid-polyethylene glycol
copolymers, polycaprolactone, polycaprolactone copolymers and
polycaprolactone-polyethylene glycol copolymers, and biological
materials such as gelatin, collagen, glycosoaminoglycans,
cellulose, chemically modified cellulose, dextran, alginate,
chitin, chemically modified chitin, lipids, fatty acids and
sterols.
[0089] In one embodiment, the plurality of drug containing
particles is formed into a solid or semisolid with an excipient.
Suitable excipients include, but are not limited to, non-toxic
water soluble polymers such as polyvinylpyrrolidone,
polyvinylpyrrolidone co-vinyl acetate, polyvinyl alcohol,
polyethylene glycol and polyethylene oxide, biodegradable polymers
such as polyhydroxybutyrate, polydioxanone, polyorthoester,
polycaprolactone, polycaprolactone copolymers, polylactic acid,
polyglycolic acid, polylactic-glycolic acid copolymers and
polylactic-glycolic acid-ethylene oxide copolymers, and biological
materials such as gelatin, collagen, glycosoaminoglycans,
cellulose, chemically modified cellulose, dextran, alginate, chitin
and chemically modified chitin. The solid or semisolid composition
may be formulated with a mixture of different excipients. The drug
containing particles are mixed with the excipient in a suitable
solvent that dissolves or forms a dispersion of the excipient, but
does not extract the drug from the particles or dissolve the
particles. In one embodiment, a semisolid composition is delivered
as a mixture, dispersion or suspension with a solvent. In one
embodiment, the solid or semisolid composition is formed in a mold
or extruded and allowed to dry to form a solid of desired
dimensions for delivery. Ideal for delivery of the formed solid or
semisolid composition is an elongated shape with an outer diameter
sized to fit within the lumen of a small gauge needle, 20 gauge or
smaller, corresponding to 0.60 mm diameter or smaller. In one
embodiment, the formed solid or semisolid composition has an outer
diameter sized to fit within the lumen of a 25 gauge or smaller
needle, corresponding to a 0.26 mm diameter or smaller.
[0090] In one embodiment, the semisolid composition is dried, such
as by lyophilization, critical point drying or air drying for
rehydration prior to delivery. The semisolid composition may have
excipients to aid reconstitution such as salts, sugars, water
soluble polymers and surfactants.
[0091] In one embodiment, the drug containing particles are sized
smaller than the inner diameter of the delivery needle to allow
close packing of the drug containing particles within a formed
solid or semisolid to enhance mechanical properties. Such drug
containing particles would have an average diameter in the range of
4 to 100 microns, for example 4 to 25 microns, and may comprise a
mixture of diameters to facilitate close packing. The mean or
median diameter of the particles may be in the range of 2 to 100
microns, for example 2 to 50 microns, 2 to 40 microns, 2 to 30
microns or 2 to 20 microns.
[0092] The dispersion and migration of the drug containing
particles are desired to promote a uniform distribution of the
particles in the eye. The dissolution of the excipient and
resultant release of drug containing particles may be triggered by
the absorption of fluid from the tissue space, for example due to
the ionic environment or the temperature of the environment. In one
embodiment, the excipient comprises a lipid or fatty acid with a
melting temperature between room temperature and the temperature of
the ocular tissues space, approximately 37 degrees centigrade (for
example, a melting temperature between 21 and 37 degrees
centigrade, between 25 and 37 degrees centigrade, or between 30 to
35 degrees centigrade). The rate of release of the individual drug
containing particles from the solid or semisolid composition may be
tailored by the addition of hydrophilic or amphiphilic agents that
increase the dissolution rate of the excipients of the solid or
semisolid composition. The release of the drug containing particles
may occur over hours, days or weeks, depending on the amount and
composition of the material for administration. For example, a
maximum (or minimum, depending on the formulation) of 50% of the
drug containing particles may be released after 1 hour, 6 hours, 12
hours, 1 day, 3 days or 1 week.
[0093] The solid or semisolid composition may act by the ionic
environment of the tissue space to provide dissolution, which may
be provided by ionically crosslinked polymers such as sodium
alginate. The solid or semisolid composition may be triggered for
dissolution in the tissue space by temperature, such as with lipids
and fatty acids with a melt transition temperature greater than
room temperature, approximately 20 degrees centigrade, and less
than or equal to the temperature within the ocular tissue space,
approximately 37 degrees centigrade. Such lipids and fatty acids
include, but are not limited to, capric acid, erucic acid,
1,2-dinervonoyl-sn-glycero-3-phosphocholine,
1,2-dimyristoyl-sn-glycero-3-phosphocholine, and
1,2-dipentadecanoyl-sn-glycero-3-phosphocholine and mixtures
thereof.
[0094] Due to the small size of the drug containing particles, drug
release from the particles may be too rapid to provide sustained
drug effect after administration to the eye. It is an object of the
invention to provide drug containing particles with prolonged
release kinetics (i.e. controlled release formulations). In one
embodiment the drug is incorporated into a polymer matrix that
creates a poor diffusion path for the drug thereby slowing drug
release as compared to the drug without a polymer matrix. In one
embodiment, the drug containing particle is coated with a barrier
such as a polymer or other compound. The barrier material typically
has different chemical properties than the drug so that the drug is
not readily soluble through the barrier coating and is slowed in
drug release as compared to the drug particle without a barrier
coating. One method for selection of the barrier coating is a
material with a different partition coefficient or log P than the
drug, with an increased difference providing an increased barrier
to drug release. In one embodiment, the individual particles of a
drug, are coated with a barrier coating of increased water
solubility or decreased log P compared to the drug to form a
barrier coating on each particle. Barrier materials may include,
but are not limited to, acid terminated poly lactic-glycolic acid
copolymers, polylactic acid-polyethylene glycol copolymers
polycaprolactone-polyethylene glycol copolymers, polyethylene
oxide, polyvinylalcohol, hydroxyethylmethacrylate, alginate,
gelatin, chitin and glycosoaminoglycans. In one embodiment, the
individual particles of a drug are coated with a barrier coating of
decreased water solubility or increased log P compared to the drug
to form a barrier coating on each particle including, but not
limited to, a hydrophobic polymer, lipid, fatty acid or sterol.
Drug particles may be coated by any of the known means for particle
coating, for example, spray drying, electrostatic spraying or
chemical deposition. In one embodiment, shown schematically in FIG.
13A and FIG. 13B, the formed solid or semisolid material 48
comprises a plurality of drug containing particles 47 encapsulated
or coated with a barrier material 49, such as a soluble polymer or
other coating, to modify the drug release characteristics and/or
the mechanical properties.
[0095] While the drug of the composition is primarily contained in
the plurality of particles, some drug may also be formulated into
the excipient. The drug in the excipient may act to prevent
extraction or diffusion of drug from the particles during
processing or storage. The drug in the excipient may also act to
provide a rapid release component to the drug formulation to
initiate therapeutic effect of the drug while allowing the drug in
the particles to provide a sustained delivery to maintain the
treatment effect.
[0096] In one embodiment, the active agent containing composition
comprises a drug and an excipient comprising a biodegradable or
bioerodible material. The biodegradable or bioerodible material may
be comprised of, for example but not limited to,
polyhydroxybutyrate, polydioxanone, polyorthoester,
polycaprolactone, polycaprolactone copolymer,
polycaprolactone-polyethylene glycol copolymer, polylactic acid,
polyglycolic acid, polylactic-glycolic acid copolymer, acid
terminated polylactic-glycolic acid copolymer, or
polylactic-glycolic acid-ethylene oxide copolymer, gelatin,
collagen, glycosoaminoglycan, cellulose, chemically modified
cellulose, dextran, alginate, chitin, chemically modified chitin,
lipid, fatty acid or sterol. The drug may be dispersed in the
biodegradable or bioerodible material as an amorphous solid
dispersion. The drug may be dispersed in the biodegradable or
bioerodible material as a plurality of drug crystals. The drug may
be dispersed in the biodegradable or bioerodible material as both
an amorphous solid dispersion and as drug crystals. The active
agent containing composition is shaped as an elongate solid body
for delivery into the ocular tissue space. Release of the drug from
the elongated body allows the drug to diffuse into the tissues of
the eye and may be assisted by the flow of fluid in the tissue
space. In the case where the drug is in the form of a solid
amorphous dispersion, the biodegradable or bioerodible material is
selected to provide the desired drug loading and release
characteristics of the drug. In the case where the drug is in the
form of dispersed drug crystals, the amount of drug, the
biodegradable or bioerodible material characteristics and the
crystal form of the drug may be selected to provide the desired
drug loading and release characteristics of the drug. The drug
crystals may also be coated with an excipient to reduce the drug
release rate of the active agent containing composition. In one
embodiment, the composition has an extended release of the active
agent or drug. The drug elution from the composition may have a
half-life in the range of 14 to 180 days, 21 to 90 days or 30 to 45
days.
[0097] A variety of active agents and drugs may be delivered by the
present invention to the eye for the treatment of ocular diseases
and conditions including inflammation, infection, macular
degeneration, retinal degeneration, neovascularization,
proliferative vitreoretinopathy, glaucoma and edema. Useful drugs
include, but are not limited to, steroids, non-steroidal
anti-inflammatory agents, antibiotics, VEGF inhibitors, PDGF
inhibitors, anti-TNF alpha agents, mTOR inhibitors, cell therapies,
neuroprotective agents, anti-hypertensive agents, antihistamines,
aminosterols and nucleic acid based therapeutics. The active agents
and drugs may be in the form of soluble solutions, suspensions,
gels, semisolids, microspheres, formed solids or implants.
[0098] In one embodiment, the material for administration is
preloaded in the device during the time of manufacture prior to
use. The source of force to provide a delivery force to the
material for administration may be activated just prior to use. In
one embodiment the activation is achieved by a mechanism to preload
the force element, such as compressing a spring, from the exterior
of the device such as by a movable proximal handle attached to the
plunger. In one embodiment, the source of force is preloaded during
manufacture when the drug is placed in the device and the preloaded
force is stabilized by means of a stop mechanism. Prior to use, the
stop mechanism is released, thereby placing the force on the
material for administration prior to or simultaneous with contact
of the eye and the delivery is triggered by the advancement of the
needle through the tissue interface and distal seal as with the
previous embodiments of the invention. In one embodiment, the
material for administration comprises a volume of gas prior to
delivery of an active agent containing composition. Activation of
the delivery mechanism for the active agent containing composition
is triggered by the delivery of gas from a gas reservoir in the
device immediately prior to the delivery of the active agent
containing composition.
[0099] As noted, a variety of active agents and drugs may be
delivered by the present invention to the eye for the treatment of
a variety of ocular diseases and conditions including inflammation,
infection, macular degeneration, retinal degeneration,
neovascularization, proliferative vitreoretinopathy, glaucoma, and
edema. Useful drugs include, but are not limited to, steroids such
as corticosteroids including dexamethasone, fluocinolone,
loteprednol, difluprednate, fluorometholone, prednisolone,
medrysone, triamcinolone, betamethasone and rimexolone;
non-steroidal anti-inflammatory agents such as salicylic-, indole
acetic-, aryl acetic-, aryl propionic- and enolic acid derivatives
including bromfenac, diclofenac, flurbiprofen, ketorolac
tromethamine and nepafenac; antibiotics including azithromycin,
bacitracin, besifloxacin, ciprofloxacin, erythromycin,
gatifloxacin, gentamicin, levofloxacin, moxifloxacin, ofloxacin,
sulfacetamide and tobramycin; VEGF inhibitors such as tyrosine
kinase inhibitors, antibodies to VEGF, antibody fragments to VEGF,
VEGF binding fusion proteins; PDGF inhibitors, antibodies to PDGF,
antibody fragments to PDGF, PDGF binding fusion proteins; anti-TNF
alpha agents such as antibodies to TNF-alpha, antibody fragments to
TNF-alpha and TNF binding fusion proteins including infliximab,
etanercept, adalimumab, certolizumab and golimumab; mTOR inhibitors
such as sirolimus, sirolimus analogues, Everolimus, Temsirolimus
and mTOR kinase inhibitors; cell therapies such as mesenchymal
cells or cells transfected to produce a therapeutic compound;
neuroprotective agents such as antioxidants, calcineurin
inhibitors, NOS inhibitors, sigma-1 modulators, AMPA antagonists,
calcium channel blockers and histone-deacetylases inhibitors;
antihypertensive agents such as prostaglandin analogs, beta
blockers, alpha agonists, and carbonic anhydrase inhibitors;
aminosterols such as squalamine; antihistamines such as H1-receptor
antagonists and histamine H2-receptor antagonists; and nucleic acid
based therapeutics such as gene vectors, plasmids and siRNA.
[0100] In one embodiment of the invention, there is provided the
active agent containing composition of the invention for use in
medicine, in particular for use in ocular medicine. In a further
embodiment of the invention, there is provided the active agent
containing composition of the invention for use in the treatment of
an ocular disease or condition. The ocular disease or condition may
be inflammation, infection, macular degeneration, retinal
degeneration, neovascularization, proliferative vitreoretinopathy,
glaucoma or edema. The active agent containing composition is
generally for administration by delivery through a delivery device
of the present invention.
[0101] In one embodiment there is provided a method of treating an
ocular disease or condition by administration of the active agent
containing composition of the invention to the eye, for example to
the suprachoroidal space or to the supraciliary space. The active
agent containing composition may dissolve or transform into a
plurality of spherical drug-containing particles that migrate from
the site of administration (for example the suprachoroidal space or
supraciliary space) after delivery. The active agent containing
composition may be administered through a needle. In some
embodiments, the active agent containing composition may be
administered using the device described herein. The ocular disease
or condition may be inflammation, infection, macular degeneration,
retinal degeneration, neovascularization, proliferative
vitreoretinopathy, glaucoma or edema.
[0102] One aspect includes the use of an active agent in the
treatment of an ocular disease or condition. Such uses therefore
also include the use of an active agent in the manufacture of a
medicament for treating an ocular disease or condition.
[0103] In one embodiment there is provided a method of treating an
ocular disease or condition by administration of a controlled
amount of gas prior immediately prior to administration of an
active agent containing composition of the invention to the eye,
for example to the suprachoroidal space or to the supraciliary
space.
[0104] In another embodiment of the invention there is provided a
kit of parts comprising the delivery device described herein and
the active agent containing composition of the invention. The
active agent containing composition may be provided preloaded into
the delivery device. Alternatively, the active agent containing
composition may be provided as a plurality of discrete dosage forms
suitable for insertion into the delivery device. Therefore a kit
may also provide the active agent containing composition of the
invention in the form of a plurality of discrete dosage forms along
with the delivery device.
[0105] Preferred features of the second and subsequent embodiments
of the invention are as for the first embodiment mutatis
mutandis.
[0106] The invention will now be described in reference to a number
of examples, which are provided for illustrative purposes and are
not to be construed as limiting on the scope of the invention.
EXAMPLES
Example 1: Solid Material Delivery Device with Inner Deflecting
Element
[0107] A device according to an embodiment of the invention was
fabricated to administer a solid or semisolid material into the
suprachoroidal or supraciliary space of the eye. A barrel element
was fabricated by cutting off the proximal end of a 0.5 ml insulin
syringe to a barrel length of 30 mm. The integral needle was
removed from the barrel to allow the attachment of standard Luer
hub needles. The distal tip of the barrel was cut off leaving a
remaining section of Luer taper capable of securely holding a Luer
hub needle. A barrel end cap was fabricated from a nylon 10-32
socket head cap screw with a thread length of 4.5 mm. A through
hole of 1.86 mm diameter was drilled through the end cap to allow
the plunger to freely slide through the end cap. A plunger shaft
was fabricated from a tubular Teflon coated stainless steel rod
with an outer diameter of 1.8 mm and an inner diameter of 0.8 mm
and a length of 43 mm. The distal end of the shaft was turned down
to a diameter of 1.74 mm and a stainless steel washer of 4.1 mm
outer diameter, 1.70 mm inner diameter and 0.5 mm thickness was
press-fit onto the rod to provide a distal stop for the plunger
spring. The proximal end of the rod was drilled out to 1.55 mm
diameter.
[0108] A polyetheretherketone (PEEK) monofilament 0.25 mm diameter
and 80 mm long was used as a push rod element to expel the
delivered material from the device. A segment of PEEK capillary
tubing with an outer diameter of 1.57 mm, an inner diameter of 0.25
mm and a length of 2.25 mm was fabricated as a securement for the
PEEK push rod. The lumen of the PEEK securement tube was
sufficiently tight enough on the push rod to hold it securely in
place under normal use, but allowed the push rod to be slidably
adjusted. The push rod was inserted through the PEEK securement
tube and then the assembly was press-fit into the drilled out
proximal end of the plunger shaft with the push rod extending
distally through the lumen of the plunger rod. A stainless steel
hypodermic support tube with an inner diameter of 0.30 mm and an
outer diameter of 0.61 mm was placed over the push rod in order to
prevent kinking of the push element during deployment. The support
tube was slidably disposed within the inner diameter of the plunger
shaft. A compression spring with an outer diameter of 3.1 mm and a
wire diameter of 0.18 mm and a length of 31.8 mm was placed over
the shaft of the plunger and the barrel end cap was then slid over
the plunger shaft proximal to the spring. The plunger and push rod
assembly was placed into the barrel housing with the push rod
extending through the distal tip of the barrel. The end cap was
press fit into the barrel proximal end securing the plunger
assembly within the barrel.
[0109] A safety mechanism was incorporated into the device to
prevent premature activation of the plunger by the plunger spring
force. Two shallow grooves 180 degrees apart and perpendicular to
the axis of the plunger were made in the plunger at a distance of
19 mm from the distal tip. The distance between the groove faces
was 1.5 mm. A securement clip was fabricated from brass sheet with
a width of 6.3 mm and a length of 18 mm. A slot with a width of 1.6
mm and a length of 8.8 mm was machined into the securement clip.
The slot was cut in the center of the short side of the securement
clip and traversing in the long axis direction.
[0110] A needle was fabricated to allow a solid element to be
delivered at an angle from the axis of the needle lumen. The needle
was fabricated from 27 gauge ultra-thin walled hypodermic tubing
with an inner diameter of 0.29 mm and an outer diameter of 0.41 mm.
The needle was adhesively bonded into a standard female Luer needle
hub. An inner deflecting element was fabricated in the needle by
inserting a length of polyimide tubing with an inner diameter of
0.26 mm and an outer diameter of 0.28 mm. The segment of the
polyimide tubing that extended out from the beveled tip of the
needle was bent at a 90 degree angle to the axis of the needle
lumen and then adhesively bonded in place. After the adhesive had
cured, the polyimide tube was skived along the face of the needle
bevel. The remaining curved tip of the polyimide tube allowed a
solid material to exit the tubing at an angle of approximately 20
degrees from the axis of the needle.
[0111] A molded cylindrical tissue interface and distal seal
element was fabricated from 70 Shore A durometer silicone rubber.
The distal element had a length of 3.7 mm and a diameter of 1.75
mm. The distal element had a lumen of 2.7 mm length and 0.38 mm
diameter. The distal end of the lumen of the distal element was
configured with a beveled shape which conformed to the bevel on the
distal end of a 27 gauge needle. The distal element was attached to
the distal tip of the needle such that the needle bevel was in
contact with the lumen bevel in order to seal the distal tip of the
needle. The non-beveled section of the lumen acted as a slidable
seal on the shaft of the needle and provided enough frictional
force against the needle shaft to maintain the distal tip against
the eye surface during advancement of the needle through the distal
seal of 1 mm thickness.
[0112] For use, the plunger was retracted thereby compressing the
plunger spring until the plunger grooves were exposed proximally to
the end cap. The securement clip was placed over the plunger such
that the slot on the securement clip engaged the grooves on the
plunger shaft. The securement clip then was held against the
proximal end surface of the end cap by the spring force, preventing
movement of the plunger. The needle assembly was removed and a
solid material was inserted into the proximal end of the polyimide
insert tubing. The push rod was aligned in the insert tubing and
advanced, pushing the solid material towards the distal end of the
needle. The needle and barrel assembly were mated yielding a device
ready for use.
Example 2: Use of Solid Material Delivery Device with Inner
Deflection Element
[0113] A device according to Example 1 was fabricated. A solid
element for delivery was fabricated by extruding a slurry comprised
of drug loaded microspheres in a carrier material. The drug loaded
microspheres comprised polylactic-glycolic acid copolymer spherical
particles in the range of 10 to 20 microns in diameter. The
microspheres were loaded with 25 weight % fluocinolone acetonide, a
corticosteroid. A slurry for extrusion was formulated using 85
weight % microspheres and 15 weight % binder. The binder was
formulated from 92 weight % high molecular weight, K90
polyvinylpyrrolidone and 8 weight % low molecular weight, K12
polyvinylpyrrolidone, which was in a solution of 25 weight %
concentration in de-ionized water. The slurry was dispensed using a
0.3 ml syringe with a distal needle of 0.25 mm inner diameter at a
pump speed of 50 microliters/min using a syringe pump to extrude
filaments of similar diameter to the inner diameter of the
dispensing needle deflection element. The filaments were allowed to
dry at ambient conditions prior to further processing. The
microsphere-containing filament was cut to a length of 10 mm and
loaded into the delivery device as described in Example 1.
[0114] A cadaver porcine eye was prepared by inflating the
posterior chamber to a pressure of approximately 20 mm Hg. A target
location 5 mm posterior of the limbus of the eye was chosen for
administration. The securement clip was removed from the plunger
shaft. The tissue interface and distal seal was placed against the
scleral surface and the needle tip was then advanced through the
distal seal and into the tissues with the needle bevel oriented
towards the posterior of the eye. Once the needle lumen reached the
suprachoroidal space, the segmented solid element was free to exit
the needle and was expelled by the push rod under the plunger
spring force. The delivery of the solid element was confirmed by
manually excising a flap in the sclera to expose the suprachoroidal
space. A sample of the fluid in the suprachoroidal space was taken
and placed on a microscope slide. Examination of the slide under
the microscope at 100.times. magnification revealed numerous
microspheres that had been released from the solid element
administered into the suprachoroidal space.
Example 3
[0115] A solid active agent containing composition was fabricated
for delivery in the form of an elongated body or filament. Two
binder materials were prepared, polyethylene oxide (PolyOx WSR-301)
of 7 million Daltons average molecular weight dispersed in
deionized water at a concentration of 2.5% and K90
polyvinylpyrrolidone of 360,000 Daltons average molecular weight
dissolved in deionized water at a concentration of 40%. The binders
were mixed in a ratio of 66% polyethylene oxide and 33%
polyvinylpyrrolidone. Microspheres with average diameter of 15
microns were mixed into the binder formulation at a concentration
of 93.7 wt %. The microsphere contained 50 wt % dexamethasone and
50 wt % polylactic-glycolic acid copolymer. The composition was
loaded into a 0.3 ml syringe with a modified distal tip. The distal
tip comprised a polyimide tube with a lumen inner diameter of 0.24
mm. The syringe was placed on a syringe pump and the composition
was extruded as a filament. The filament was allowed to dry at
ambient conditions then cut to desired length. A coating material
was prepared by dissolving K12 polyvinylpyrrolidone of 40,000
Daltons average molecular weight in ethanol at a concentration of
25 wt %. The lengths of filament were dipped into the coating
dispersion and slowly removed then allowed to dry. Two dip coating
layers were applied to the filaments. Once dry, the filaments were
then cut to a final length of 20 mm appropriate for loading into
the delivery device.
[0116] A delivery device was fabricated comprising a distal needle
assembly, a gas reservoir portion and a force element.
[0117] The distal needle assembly comprised a 27 gauge thin walled
needle with a deflecting feature coined into the wall of the needle
opposite of the lumen of the needle. The deflecting feature was
located approximately 0.6 mm proximal of the tip of the needle and
extended approximately 1/2 the diameter of the lumen or 0.1 mm. The
deflecting feature was configured to both deploy the filament off
axis from the needle axis and to fracture the filament as it
traversed passed the feature. The needle had a 15.degree. bevel
with a standard three bevel hypodermic configuration. Two oval side
holes 0.5 mm long and 0.18 mm wide were placed approximately 7 mm
proximal from the needle tip. The holes were laser cut through the
wall of the needle tubing and were 180.degree. apart. An outer
sleeve was fabricated from nylon tubing 1.1 mm inner diameter and
1.3 mm outer diameter. The outer sleeve was bonded to the needle,
distal to the side holes such that approximately 3 mm of needle
extended beyond the sleeve. The gap between the sleeve and the
needle allowed for the free flow of gas from the reservoir to the
needle side holes and then to the needle tip. This assembly was
bonded within a female Luer hub modified to accept the jacket outer
diameter. A distal seal and tissue interface consisting of a Shore
50 A durometer solid silicone rod segment 3 mm long and 0.75 mm in
diameter was placed over the tip of the needle. The seal was gas
tight and prevented premature expelling of the gas in the gas
reservoir when pressurized. A length of filament was inserted into
the proximal end of the needle lumen.
[0118] The main body of the device comprised a 6 ml polycarbonate
syringe body as a gas reservoir and a 1 ml polycarbonate syringe as
a housing for the force element. The distal end of the syringe
comprised a male Luer lock connection. The 6 ml syringe rubber
plunger tip was removed from the plunger shaft and mounted on a
machined plastic body configured to hold the plunger tip on the
distal end and to receive the distal end of the 1 ml syringe on the
proximal end. In this manner, the 1 ml syringe was mounted
coaxially within the 6 ml gas reservoir syringe.
[0119] The 1 ml syringe was configured as the force element section
of the device. A stainless steel wire 0.23 mm in diameter was
mounted to the tip of a plunger rod as a push rod. The plunger rod
consisted of a polytetrafluoroethylene coated stainless steel tube
with an outer diameter of 1.8 mm. A flange was fixed to the distal
end of the plunger rod as the distal spring perch. A compression
spring was placed over the proximal end of the plunger rod, which
acted as the motive force for the deployment of the filament. The
spring was fabricated from stainless steel wire 0.24 mm in diameter
with a spring diameter of 2.6 mm, a free length of 80 mm and a
compressed length of 18 mm. A cap was attached to the proximal end
of the 1 ml syringe to provide the proximal spring perch. A through
hole in the cap allowed the plunger rod to extend proximally so
that it could be pulled rearward to compress the spring in
preparation for use.
[0120] An external finger controlled lever was attached to the
syringe body. The lever comprised a distal section, a proximal
section and a central pivot area. The proximal section of the lever
acted as an activation mechanism for a release pin. The release pin
held the force element plunger, with the spring compressed, in
preparation for use. When the plunger rod was pulled rearward to
compress the spring, the release pin freely fell into place thereby
holding the plunger rod from moving. The distal section of the
lever comprised a through hole through which a gas reservoir
locking pin was placed and was freely slidable within the hole. The
reservoir locking pin fell into place when the gas reservoir
plunger was pushed fully distally thereby pressurizing the system.
Pressing the distal end of the lever raised the release pin
allowing the force element to activate and the device to deploy the
filament.
[0121] The device was activated by pulling the gas reservoir
plunger distally until 100 to 150 microliters of air was held in
the gas reservoir. The end of the plunger rod was then pulled
rearward compressing the spring then the release pin was inserted
to hold the spring compressed. The distal needle assembly which was
loaded with the filament was tightly assembled onto the distal end
of the device body. The plunger assembly was then advanced distally
compressing the air within the main body and the reservoir locking
pin was pushed into place to maintain pressure.
[0122] A porcine eye was prepared as described in Example 2. The
distal tip of the device was pressed against the surface of the eye
and advanced. The needle tip penetrated the distal seal and
remained sealed as it entered the scleral tissues. Once the tip of
the needle lumen entered the suprachoroidal space the air was
released from the pressurized gas reservoir into the space. The gas
delivery was confirmed through the change in tone in the eye by a
finger resting on the surface of the eye. As soon as the air
delivery was confirmed the lever was depressed thereby pulling the
release pin, activating the spring force element and deploying the
filament into the space. The device was then removed from the site.
A scleral flap was made over the administration site and the sclera
peeled back exposing the suprachoroidal space. The filament was
observed and was consistently fractured into segments of
approximately 0.5 mm length.
Example 4. Low Sealing Force Tissue Interface
[0123] Tissue interfaces were fabricated in a manner similar to
those described in Example 1 and Example 3. Two different outer
diameters of tissue interface were fabricated: 1.75 mm diameter and
2.50 mm diameter. Samples of each diameter tissue interface were
fabricated using four different durometers of liquid silicone
elastomer, Shore 10 A, 30 A, 50 A and 70 A.
[0124] A test method was prepared to determine the sealing force of
the various samples of the tissue interface. A segment of PEEK
tubing 8.3 mm long was placed over a 27 gauge.times.13 mm thin
walled hypodermic needle to serve as a stop so as not to allow the
tissue seals to travel proximally during the test. A tissue seal
being tested was then placed over the needle tip. The length of the
PEEK tubing was sized so as to allow approximately one-half of the
needle bevel section to protrude through the tissue interface
distal surface. A test surface was used which consisted of a
silicone elastomer pad with a durometer of Shore 50 A and 3.2 mm
thick. The needle was mounted to a tee-fitting which in turn was
mounted on the shaft of a digital force gauge with a 250N capacity
mounted on a motorized test stand. The side leg of the tee-fitting
was attached to a length of tubing and then to a Luer fitting and a
three-way valve. A 10 cc syringe filled with water was attached to
the valve. The syringe was held vertically using a ring stand.
Tests were conducted using two different constant pressures which
were generated by applying fixed weights of 1030 and 1656 grams
respectively to the finger flange of the syringe plunger. The
inside of the syringe had a cross-sectional area of 1.64.times.10-4
m2 which corresponded to fluid pressures of 6.18.times.104 Pa and
9.93.times.104 Pa respectively.
[0125] To perform a test, the needle tip was traversed down until
the tissue interface was close to touching the silicone test pad.
The test stand motor was jogged downward until approximately 30
grams-force of pressure was being applied to the tissue interface.
The three-way valve was opened and the periphery of the tissue
interface observed for water leakage. The valve was closed and then
the needle was moved downward until approximately 35 grams-force of
pressure was being applied. The valve was opened and the tissue
interface observed for leakage. The tissue interface pressure on
the test pad was increased in 5 gram-force increments in this
manner until no leakage was observed, e.g. a seal was achieved and
the force was recorded. The test was repeated with the second
syringe pressure weight. The testing was performed on the two
different tissue interface diameters and the four different
durometers (Table 1 and FIG. 14). Two samples of each tissue
interface were tested three times each for a total of six data
points for each test condition. The silicone test pad was moved
after each test so that each needle penetration was at a new site.
FIG. 14 shows a tissue interface minimum sealing force graph
grouped by diameter & fluid pressure, as a function of
durometer. Table 1 shows the minimum Sealing Force in Grams-Force
for Tissue Interface Test Samples (Average and Standard Deviation)
grouped by Tissue Interface Diameter and Fluid Pressure, as a
Function of Durometer.
TABLE-US-00001 TABLE 1 1.8 mm 1.8 mm 2.5 mm 2.5 mm Diameter
Diameter Diameter Diameter 6.18 .times. 9.93 .times. 6.18 .times.
9.93 .times. Durometer 10.sup.4 Pa 10.sup.4 Pa 10.sup.4 Pa 10.sup.4
Pa 10 43.3 .+-. 5.2 77.5 .+-. 2.7 66.7 .+-. 4.1 81.7 .+-. 4.1 30
40.8 .+-. 5.8 58.3 .+-. 5.2 66.7 .+-. 5.2 110.0 .+-. 4.5 50 50.8
.+-. 7.4 64.2 .+-. 4.9 78.3 .+-. 2.6 97.5 .+-. 2.7 70 53.3 .+-. 6.1
63.3 .+-. 6.1 69.2 .+-. 10.7 89.2 .+-. 10.2
Example 5. Semisolid Active Agent Containing Composition
[0126] A semisolid active agent containing composition was
prepared. A 1.5 wt % of polyethylene oxide (PolyOx WSR-303) of 7
million Daltons average molecular weight was dispersed in deionized
water. Microspheres with average diameter of 15 microns were mixed
into the polyethylene oxide dispersion at a concentration of 2.5 wt
%. The microsphere contained 50 wt % dexamethasone and 50 wt %
polylactic-glycolic acid copolymer. The semisolid composition was
stained with sodium fluorescein for observation.
[0127] A delivery device according to one embodiment of the
invention was fabricated to administer the semisolid composition
into the suprachoroidal space of an eye. A body and attached needle
was fabricated by cutting off the proximal end of a 1.0 ml insulin
syringe with 12.7 mm long 27 gauge integral needle to a barrel
length of 32 mm. The proximal open end of the syringe barrel was
tapped for a 10-32 thread. A barrel end cap was fabricated from
plastic with a through hole sized to fit the plunger shaft and an
external thread of 10-32. A plunger was fabricated from a metal
tube with an outer diameter of 2.4 mm and an inner diameter of 0.4
mm. The distal end of the plunger comprised two flanges welded to
the end and with a gap of 1.3 mm between them. A silicone O-ring
seal was placed between the flanges. A compression spring with a
spring force of 0.98 N/mm, an outer diameter of 4.6 mm and a wire
diameter of 0.4 mm was placed over the shaft of the plunger, and
the barrel end cap was then slid over the plunger shaft proximal to
the spring. The proximal end of the plunger comprised a larger
diameter tube sized to allow the insertion of a rubber duck-bill
style check valve which was welded to the plunger shaft after
assembly of the plunger spring and end cap. The valve was inserted
into the larger tube and a female Luer lock fitting was attached
over the tube and valve.
[0128] A housing 9.5 mm long with a 1.5 mm outer diameter and a
0.35 mm inner diameter, was fabricated from polycarbonate tubing,
with a sealing element disposed in the proximal end of the housing.
The housing length was such that the distal tip of the housing
extended 2 mm beyond the tip of the needle when assembled. A molded
tissue interface and distal seal element 3.5 mm long with an outer
diameter of 1.9 mm and an inner diameter of 0.9 mm was fabricated
from 50 Shore A durometer silicone. The tissue interface and distal
seal was placed over the distal end of the housing. A housing
compression spring of 0.08 N/mm spring force, an outer diameter of
1.5 mm and a wire diameter of 0.1 mm was placed over the needle to
provide sealing force against the tissues. The housing compression
spring had a free length of 4.8 mm and a compressed length of 0.8
mm. The spring was placed over the needle, then the housing and
tissue interface and distal seal were placed over the needle and
the spring was adhesively bonded to the proximal end of the housing
at one end and the syringe barrel at the other end.
[0129] One hundred microliters of the semisolid active agent
containing composition was placed into the delivery device through
the female Luer lock fitting, thereby placing a delivery pressure
on the composition. An enucleated porcine eye was prepared by
infusion to 20 mm Hg. The distal tip of the device was placed on
the pars plana region of the eye and advanced into the eye. The
delivery of material was observed to occur once the tip of the
needle reached the appropriate depth to deliver the composition to
the suprachoroidal space. After delivery, indirect ophthalmoscopy
was performed, showing none of the composition in the vitreous
cavity. Dissection of the sclera overlying the administration site
revealed the semisolid composition in the suprachoroidal space,
extending to approximately 4 mm from the administration site. A
second porcine eye was prepared for administration. After
administration, indirect ophthalmoscopy showed none of the
composition in the vitreous cavity. The eye was perfused with
phosphate buffered saline through a 30 gauge needle at a pressure
of 20 mm Hg. After 18 hours, the perfusion was discontinued and the
sclera at the posterior pole of the eye dissected to reveal the
suprachoroidal space. A swab of the suprachoroidal space 9 mm
posterior to the administration site was performed and rubbed
against a glass slide for microscopic examination at 100.times. and
200.times. magnification. Microscopy demonstrated a plurality of
microspheres retrieved from the posterior region of the
suprachoroidal space.
Example 6
[0130] A delivery device according to an embodiment of this
invention was fabricated. The device consisted of a distal
assembly, a gas reservoir portion and force element to deliver the
material for administration.
[0131] The distal assembly comprised a 27 gauge thin walled
hypodermic needle with a 15 degree beveled tip. A deflecting
feature was created in the wall of the needle by mechanically
deforming the wall of the tube opposite the bevel using a circular
punch. The deflecting feature was located 0.63 mm from the distal
tip and had a height inside the needle lumen of 0.11 mm. Two oval
side holes of 0.18 mm width and 0.5 mm length were cut by laser
through the wall of the needle tubing. The holes were 180.degree.
apart and located 5.5 mm from the distal tip of the needle. An
outer jacket for the needle was fabricated from PET tubing with an
inner diameter of 0.94 mm and an outer diameter of 2.0 mm. The
jacket element was bonded to the needle distally of the needle side
holes. The gap between in the inner diameter of the jacket element
allowed for the passage of gas from the gas reservoir into the
needle lumen through the laser cut side holes. A distal seal and
tissue interface was molded from silicone elastomer of 50 A
durometer. The seal was 3.0 mm long and had an outer diameter of
0.76 mm and an inner lumen of 0.30 mm diameter. The distal end of
the seal was solid in order to provide a seal against the passage
of the gas and the material for administration after activation of
the device. The needle/jacket assembly was bonded into a female
Luer lock fitting for attachment to the body of the device. An open
passage existed through the Luer fitting and into the ID of the
needle jacket to allow for gas flow from the gas reservoir, through
the needle side holes and into the lumen of the needle.
[0132] The gas reservoir portion of the device was fabricated from
a polypropylene 3 ml syringe barrel. The stock rubber syringe
plunger tip was removed from the stock plunger and mounted on the
distal end of a machined plunger with a length of 10 mm. The
machined plunger contained a through hole of 0.38 mm diameter sized
to slidably fit the plunger rod. The proximal end of the machined
plunger was sized to fit the distal end of the force element
portion of the device. A locking tab in the body of the 3 ml
syringe was created by cutting a three sided rectangle in the
plastic of the syringe. The locking tab was positioned such that
when the plunger of the gas reservoir portion was advanced to the
end of the barrel, the distal end of the tab could be depressed,
thereby holding the plunger in place. In this manner, the plunger
was used to pressurize the gas charge in the reservoir and the
locking tab used to maintain the pressure for use. The distal end
of the barrel incorporated a male Luer lock configuration for
mounting of the distal assembly of the device.
[0133] A force element portion of the device was fabricated using a
polypropylene 1 ml syringe barrel. The syringe barrel was mounted
in a reverse configuration in the device, i.e. with the barrel
proximal end directed to the device distal end. The proximal end of
the barrel was modified in order to provide a friction fit to the
machined plunger in the gas reservoir, thereby becoming the distal
end of the force element portion. The distal end of the barrel
retained the male Luer lock configuration for attachment to the
force mechanism, thereby becoming the proximal end of the portion.
The syringe plunger shaft was modified by cutting it to a length of
3 mm. A push rod of 60 mm length and 0.23 mm diameter was mounted
to the plunger extending distally. The push rod was inserted
through the gas reservoir machined plunger and plunger tip and
extended sufficiently to engage the proximal end of the needle
lumen. The plunger stopper provided a distal seal to the proximal
segment of the syringe barrel which was used as a fluid reservoir
for the force producing mechanism.
[0134] A hydraulic system was configured to produce the force for
advancing the push rod in the force element portion of the device.
A hydraulic system was used in order to allow for varying the speed
of the push rod actuation. The hydraulic mechanism consisted of a
syringe pump, syringe and tubing configured to attach to the Luer
lock on the distal end of the force element. A 6 ml syringe fluid
reservoir was mounted on a programmable syringe pump. A length of
PTFE tubing with Luer fittings at each end was attached to the
fluid reservoir and to a three-way Luer stopcock. The Luer stopcock
was attached to the proximal Luer connection on the force element
syringe. The fluid reservoir was filled with water. The stopcock
position was adjusted to open the side port and the syringe pump
was activated to fill the tubing and stopcock with water. The
proximal lumen of the force element portion was manually filled
with water such that there was no air bubble in the line between
the fluid reservoir syringe and the force element plunger. In this
manner the force element could be advanced by activation of the
syringe pump. A foot pedal control was attached to the syringe pump
to allow for manual activation of the deployment of the drug
composition. The gas reservoir portion and the force element
portion were assembled together, thereby creating a unified
assembly as the main body of the device.
[0135] Prior to use, the force element portion was pulled rearward,
sliding the gas reservoir plunger shaft proximally until a set
volume of gas (air) was present in the gas reservoir. A volume of
air in the range of 100-150 microliters was used, with an expected
actual delivery of air being in the range of 75-100 microliters due
to the dead volume of the system. A filament of a solid material
for administration consisting of microparticles in a binder
formulation was inserted into the proximal end of the needle lumen.
The distal needle, jacket, Luer hub assembly with the material for
administration was then attached to the main body, aligning the
distal end of the push rod within the lumen of the needle. The
force element portion was then pushed forward, moving the gas
reservoir plunger until it stopped and the locking tab was pushed
downward thereby maintaining the position of the gas reservoir
plunger. In this manner, the air in the distal end of the device
was pressurized with the distal seal on the needle tip preventing
premature release of the air.
[0136] The distal tip of the device was pressed against the pars
plana region of a cadaver porcine eye at an angle approximately 45
degrees from the normal vector from the surface of the eye. The
device was advanced forcing the needle tip to penetrate through the
distal seal and into the tissues of the eye. When the needle tip
reached the suprachoroidal space, the pressurized air was released
into the space thereby opening up the space to allow for the
delivery of the drug composition. During placement and advancement
of the device, the user held a finger against the eye to assist in
maintaining stability. The air delivery was confirmed by the change
in tone in the eye under the stabilizing finger. Immediately upon
confirmation of the air delivery, the syringe foot pedal was
activated which started the hydraulic system to advance the push
rod and deliver the filament into the suprachoroidal space. After
activation, the device was removed. A scleral flap was cut into the
eye, revealing the suprachoroidal space and the microparticles of
the drug composition was observed in the space.
Example 7: Sequential Automatic Gas and Solid Material Delivery
Device
[0137] A device according to an embodiment of the invention was
fabricated and tested for its ability to successfully deliver
sequential gas and drug into the suprachoroidal space or
supraciliary space of the eye. The device was configured so that
the gas delivery portion of the device was independent of the push
rod and delivery mechanism for the active agent containing
composition.
[0138] A plastic distal chassis was manufactured by 3D printing
from an acrylic polymer blend (Objet Inc., VeroWhite). The distal
chassis was configured such that it held two 1 ml Luer
polycarbonate syringes parallel to each other, 12.5 mm axis to axis
apart and in a matching orientation.
[0139] The first syringe formed the gas reservoir and was
fabricated by cutting off the proximal end of a 1 ml polycarbonate
syringe and retaining the distal Luer end with an internal barrel
length of 28.5 mm and an internal barrel diameter of 4.7 mm. A hole
of 1.5 mm diameter was drilled radially into the side of the gas
reservoir at a position such that once the stopper seal past the
distal edge of the hole this sealed the syringe barrel from
atmosphere and had a capacity of 110 microliters.
[0140] The inner surface of the proximal end of the gas reservoir
was tapped with an M5 metric thread for an axial length of 5 mm. A
plunger rod was turned from stainless steel; its diameter being
substantially 1.6 mm. A modified elastomeric stopper (wherein one
sealing face was removed to reduce the stopper friction), removed
from the original plunger rod of the 1 ml syringe, was push fitted
onto retaining features at the distal end of the turned stainless
steel plunger rod. The stopper remaining distal circumferential
seal had an axial length of approximately 0.5 mm. This plunger rod
and stopper assembly was placed into the gas reservoir. A
compression spring with a spring rate of 0.032 N/mm, free length of
31.75 mm and external diameter of 3.18 mm was positioned over the
turned plunger rod. A 1.8 mm diameter hole was drilled axially
along the entire axis of an M5.times.5.5 mm countersunk socket head
screw; this screw was placed over the proximal end of the plunger
rod, then screwed into the proximal end of the gas reservoir,
thereby compressing the spring and biasing the plunger rod and
stopper to the distal end of the syringe barrel. An activation
latch was fabricated by cutting a "U" shaped section of 0.5 mm
thick sheet metal with a central slot 1 mm wide. The stainless
steel plunger rod had a notch of 0.9 mm diameter by 1 mm cut in 5
mm from the proximal end of the rod. The slot in the activation
latch was fitted into the notch of the plunger rod to hold the
compression spring at a compressed height of 10 mm with the
activation latch butting into the countersunk screw at the proximal
end of the cut syringe.
[0141] The second 1 ml Luer syringe, called the drive syringe, was
assembled into the distal chassis in coaxial configuration with the
device needle. A slot was cut longitudinally into one side of this
syringe; the slot being 3 mm wide and 15 mm long, running axially
in a proximal direction from a position 27.5 mm proximal from the
distal internal end of the syringe barrel. The slot in the drive
syringe was oriented to face directly toward the gas reservoir.
[0142] A cantilever spring was fabricated by bending 0.8 mm
diameter spring steel wire. The form of this was such that the
cantilever spring was affixed into a 0.8 mm diameter blind hole in
the distal chassis and was bent around the exposed proximal end of
the stainless steel gas plunger rod and entered in through the slot
in the drive syringe. In this position the cantilever spring was
configured to exert a force of 1.4 N on the turned gas plunger rod
and was biased away from the drive syringe.
[0143] A plastic push rod holder was fabricated with a diameter
substantially 2.7 mm and a total length of 97 mm; the distal end of
the push rod holder had a diameter of 4.45 mm for an axial length
of 1.5 mm. The center of the distal end face of the push rod holder
was drilled with a 0.5 mm diameter by 5 mm deep hole. A 0.2 mm
diameter straight tungsten wire as a push rod was glued coaxially
into this hole such that the wire extended 52 mm beyond the distal
end face of the push rod holder. This push rod and push rod holder
assembly was inserted into this drive syringe so that the push rod
extended distally of the syringe Luer taper. A compression spring
(the drive spring) was placed over the push rod holder; the spring
had a rate of 0.02 N/mm, a free length of 180 mm and an outer
diameter of 4.1 mm. The cantilever spring that extended radially
inwards of the drive syringe inner wall obstructs the push rod
assembly from moving distally.
[0144] The proximal chassis was fabricated as a plastic 3D printed
part which was secured at the proximal end of the device. The
proximal chassis had the functions of providing an end stop for the
180 mm long drive spring in the drive syringe and provided features
for mounting a rotary damper. This proximal chassis was attached to
a proximal end face of the 3D printed chassis by means of a single
M5 by 12 mm cap head socket screw and an M5 nut; interlocking
features prevented relative rotation of the 3D printed parts. By
connecting the proximal and distal chassis the drive spring was
compressed to a length of 44 mm. A rotary damper with a damping
torque of 0.20 N-cm was attached via bolts to the proximal chassis;
the damper comprised a fixed part and a 7.2 mm outer diameter ten
toothed gear (module 0.6). An 80 mm long toothed module 0.6 plastic
rack compatible with gear of the rotary damper engaged with the
teeth of the rotary damper and was affixed to the proximal end of
the push rod holder so that any axial translation in the push rod
was resisted by the rotation of the rotary damper.
[0145] A needle assembly was fabricated with a 3D printed needle
hub that housed a 27 gauge thin walled, 32 mm long needle with a
15.degree. bevel. The needle was adhered in to the hub at the
distal end with 3 mm of needle extending from the hub; the adhesive
formed a gas tight seal. The needle had two oval side holes of 0.18
mm width and 0.5 mm length were cut by laser through the wall of
the needle tubing. The holes were 180.degree. apart and located 5.5
mm from the distal tip of the needle. A length of 24 mm long, 0.020
in internal diameter and 1/16 in outer diameter microbore tubing
was inserted over the needle to fill the void between the needle
shaft and the 3D printed needle hub which also assisted in
retaining the needle concentricity with the hub. The microbore
tubing was positioned to not obscure the laser cut holes through
the side of the needle. Extending through the wall of the needle
hub was a 6 mm long length of 25 gauge stainless steel hypodermic
tubing which was connected to a 0.19 mm internal diameter by 50 mm
long length of flexible microbore tubing which at the opposing end
was attached to a 25 gauge Luer needle to connect the gas syringe
flow path to the needle lumen via the laser cut holes in the side
of the needle. The Luer needle had o-ring inserts into the Luer end
to reduce the dead volume of the assembly.
[0146] A length of 15 mm by approximately 0.2 mm diameter of an
active agent containing composition in the form of an elongated
body or filament was loaded from the proximal end into the needle
lumen so that it was not blocking the laser cut holes in the side
of the needle. The filament comprised 85.6 wt % of 9 micron PLGA
microspheres containing 24.5 wt % difluprednate, bound together by
13.2 wt % polyvinylpyrrolidone K90 and 1.2 wt %
polyvinylpyrrolidone K12. A 1 mm thick by 4.5 mm diameter section
of 60 shore A silicone was placed against the proximal end of the
needle which was approximately coplanar with the rear face of the
needle hub. The external face of the needle hub was 6.35 mm in
diameter and had a 1/4-28 UNF thread cut 12 mm from the proximal
end. This thread engaged with a mating thread on an adaptor (female
thread to female Luer adaptor) to compress the silicone seal,
forming a gas tight annular seal on the needle hub. The Luer
adaptor was attached to the drive syringe with the push rod pierced
through the silicone seal to form a gas tight seal around the push
rod preventing pressure loss out of the needle hub. The needle on
the distal end of the device was a 27 gauge thin walled hypodermic
needle with a 15 degree beveled tip. A deflecting feature was
created in the wall of the needle by mechanically deforming the
wall of the tube opposite the bevel using a circular punch. The
deflecting feature was located 0.63 mm from the distal tip and had
a height inside the needle lumen of 0.11 mm. A distal seal and
tissue interface was molded from silicone elastomer of 50 A
durometer. The seal was 3.0 mm long and had an outer diameter of
0.76 mm and an inner lumen of 0.30 mm diameter. The distal end of
the seal was solid in order to provide a seal against the passage
of the gas and the material for administration after activation of
the device. The distal seal was placed on the distal end of the
needle to complete sealing of the gas flow path. The entire gas
reservoir and flow path had a dead volume of approximately 20 .mu.l
in addition to the volume in the gas syringe.
[0147] A cadaver porcine eye was prepared by inflating the
posterior chamber to a pressure of approximately 20 mm Hg. A target
administration location 5 mm posterior of the limbus of the eye was
chosen for administration. The activation latch was removed from
the gas plunger rod which allowed the gas spring to extend until
the internal air compressed to reach an equilibrium position where
the force exerted from the gas pressure on the plunger seal and the
seal friction was equal to that of the gas spring. The distal seal
was placed against the scleral surface and the needle tip was then
advanced through the distal seal and into the tissues with the
needle bevel oriented towards the posterior of the eye. Once the
needle lumen pierced through the distal seal and outer eye tissues,
the compressed air entered the suprachoroidal space via the needle
lumen and the expansion of the air volume caused the air pressure
to drop and allowed the gas plunger rod to advance. The translation
of the gas plunger rod allowed the cantilevered spring to extend
away from the push rod. With the cantilevered spring no longer
blocking the push rod holder the drive spring was able to extend at
a reduced speed due to the rotary damper and delivered the solid
active agent containing composition over a duration of
approximately one second. This functionality ensured that a
substantial volume of the compressed air entered the eye before the
solid element of drug began to be ejected. The delivery of the
solid element was confirmed by manually excising a flap in the
sclera to expose the suprachoroidal space. A sample of the fluid in
the suprachoroidal space was taken and placed on a microscope
slide. Examination of the slide under the microscope at 100.times.
magnification revealed numerous microspheres that had been released
from the filament administered into the suprachoroidal space.
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