U.S. patent application number 16/273613 was filed with the patent office on 2019-08-15 for delivery system for delivering a drug depot to a target site under image guidance and methods and uses of same.
The applicant listed for this patent is Kieran P. MURPHY. Invention is credited to Kieran P. MURPHY.
Application Number | 20190247638 16/273613 |
Document ID | / |
Family ID | 67540678 |
Filed Date | 2019-08-15 |
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United States Patent
Application |
20190247638 |
Kind Code |
A1 |
MURPHY; Kieran P. |
August 15, 2019 |
DELIVERY SYSTEM FOR DELIVERING A DRUG DEPOT TO A TARGET SITE UNDER
IMAGE GUIDANCE AND METHODS AND USES OF SAME
Abstract
A delivery system for delivering a drug depot to a site within a
patient, the system comprising: a cannula; a delivery stylet
configured and dimensioned to be receivable by and slidable
forwardly and backwardly within the cannula including to a position
wherein a distal portion of the stylet protrudes beyond the distal
end of the cannula; a drug depot retainable by the stylet at the
distal end of the stylet, the drug depot being visualizable by a
diagnostic imaging beam or modality; and an actuator for ejecting
the drug depot from the stylet to a site within the body using
fluid pressure. Also disclosed are methods using, and uses of, the
delivery system, including for treating scoliosis.
Inventors: |
MURPHY; Kieran P.; (Toronto,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MURPHY; Kieran P. |
Toronto |
|
CA |
|
|
Family ID: |
67540678 |
Appl. No.: |
16/273613 |
Filed: |
February 12, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62629769 |
Feb 13, 2018 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 17/3403 20130101;
A61M 37/0069 20130101; A61M 5/31565 20130101; A61B 2017/3413
20130101; A61M 5/178 20130101; A61M 5/3129 20130101; A61F
2310/00023 20130101; A61M 2005/311 20130101; A61M 31/002 20130101;
A61K 9/0021 20130101; A61M 5/3297 20130101; A61M 2205/32 20130101;
A61K 9/0085 20130101; A61B 2090/3966 20160201; A61B 2017/00924
20130101; A61B 2090/3925 20160201 |
International
Class: |
A61M 37/00 20060101
A61M037/00; A61K 9/00 20060101 A61K009/00; A61M 31/00 20060101
A61M031/00; A61M 5/31 20060101 A61M005/31; A61B 17/34 20060101
A61B017/34 |
Claims
1. A delivery system for delivering a drug depot to a site within a
patient, the system comprising: a. a hollow cannula having a
proximal end and a distal end; b. a delivery stylet having a
proximal end, a distal end, a lumen extending between the proximal
and distal ends of the delivery stylet, and a distal portion at the
distal end of the delivery stylet, the delivery stylet being
configured and dimensioned to be receivable by and slidable
forwardly and backwardly within the cannula including to a position
wherein said distal portion protrudes beyond the distal end of the
cannula; and c. an actuator for ejecting the drug depot from the
stylet to a site within the body, said actuator having a fluid
delivery mechanism in fluid communication with an interior of the
stylet and being effective to create pressure within the stylet
sufficient to eject the drug depot therefrom.
2. The delivery system of claim 1, further comprising a drug depot
retained by the stylet at the distal end of the stylet, the drug
depot being visualizable by a diagnostic imaging beam or
modality.
3. The delivery system of claim 2, wherein the drug depot has a
portion inside the stylet and a portion protruding from the distal
end of the stylet.
4. The delivery system of claim 2, further comprising a solid
stylet configured and dimensioned to be receivable inside the
cannula to provide rigidity thereto, whereby the cannula, with the
solid stylet received therein, is effective to pierce tissue of a
patient.
5. The delivery system of claim 1, wherein the drug depot comprises
a radiographic marker that allows the drug depot to be visualized
under a diagnostic imaging beam.
6. The delivery system of claim 5, wherein the radiographic marker
is selected from the group consisting of barium, calcium phosphate,
bismuth, iodine, tantalum, tungsten, metal beads, and mixtures
thereof.
7. The delivery system of claim 1, wherein the delivery stylet has
a hub at the proximal end thereof, and the actuator is releasably
attachable to the hub.
8. The delivery system of claim 7, wherein the actuator is a
syringe having a barrel, a plunger slidable within the barrel, and
wherein the barrel has a distal portion configured to be attachable
to the hub of the delivery stylet.
9. The delivery system of claim 8, wherein the syringe is a Luer
lock syringe and the hub of the delivery stylet has external
threads complementary to internal threads of the Luer lock of the
syringe.
10. The delivery system of claim 1, wherein the fluid is a
liquid.
11. The delivery system of claim 10, wherein the liquid comprises
an agent selected from the group consisting of an anaesthetic,
Depo-Medrol (methylprednisolone), dexamethasone, and mixtures
thereof.
12. The delivery system claim 2, wherein the diagnostic imaging
beam or modality is selected from the group consisting of computed
tomography (CT), ultrasound, x-ray, magnetic resonance imaging
(MRI), and fluoroscopy.
13. The delivery system of claim 1, wherein at least one of the
cannula and delivery stylet comprises a radiopaque material or
ultrasound responsive topography to provide increased contrast
relative to the absence of the material or topography under a
diagnostic imaging beam.
14. The delivery system of claim 1 for use in treating
scoliosis.
15. A method of delivering a drug depot to a site within a patient,
the method comprising: a. inserting a cannula with a solid stylet
received into a target tissue of a patient under image guidance; b.
removing the solid stylet from the cannula and inserting a delivery
stylet into the cannula until a distal portion of the delivery
stylet emerges from a distal end of the cannula; c. positioning a
drug depot under image guidance by moving the delivery stylet
forwards and/or backwards until the drug depot is positioned at a
desired location; and d. actuating an actuator to expel the drug
depot from the delivery stylet.
16. The method of claim 15 for treating scoliosis, comprising
delivering a drug depot comprising a therapeutically acceptable
amount of a growth modulator into a first epiphyseal growth plate
of a first vertebra for altering the growth of the first epiphyseal
growth plate to correct or compensate for disproportionate
growth.
17. Use of the delivery system according to claim 1 to treat
scoliosis.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. 62/629,769, filed
Feb. 13, 2018, the entirety of which is incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] The present invention relates to devices or delivery systems
for drug depots and methods for delivering drug depots to inside an
animal, including humans.
BACKGROUND OF THE INVENTION
[0003] Drugs may be delivered to patients by a variety of methods
including oral, intravenous, intramuscular, inhalation, topical,
subcutaneous delivery or delivery directly or locally to the
treatment site (e.g., intrathecally, intraspinally,
intraarticularly, etc.). The method of delivery chosen depends,
among other things, upon the condition being treated, desired
therapeutic concentration of the drug to be achieved in the patient
and the duration of drug concentration that must be maintained.
[0004] Drug depots have been developed which allow a drug to be
introduced or administered to sites beneath the skin of a patient
(e.g., subcutaneously or intramuscularly) so that the drug is
slowly released over a long period of time. Such drug depots allow
the drug to be released from the depot in a relatively uniform dose
over a time period.
[0005] Drug depot delivery devices or systems have been developed
for implanting drug depots. One prior art device has a handle for
one-handed implantation of the drug depot, a small needle
containing the drug depot to be implanted, and a rod positioned
within the needle for pushing the drug depot out of the needle.
Once the needle containing the drug depot has been inserted at the
site of implant, a spring-loaded trigger on the handle is activated
which causes the needle to be automatically withdrawn by a spring
leaving the implanted drug depot in place. Unfortunately, it is not
possible to control the motion of the needle in these devices
because the needle will automatically retract upon activation of
the trigger. The complex spring loaded propelling system and
trigger of these devices increase the chances that the device will
jam and fail to eject the drug depot when required, or deposit the
drug depot in a less than optimal site.
[0006] Other prior art devices also suffer from inaccurate
placement of the drug depot due to the limited control over where
the drug is deposited. Therefore, new drug depot devices or
delivery systems are needed, which can allow more accurate and
precise implantation of a drug depot with minimal physical and
psychological trauma to a patient.
SUMMARY OF THE INVENTION
[0007] Accordingly, the invention provides, according to a first
aspect, a delivery system for delivering a drug depot to a site
within a patient, the system comprising: [0008] a hollow cannula
having a proximal end and a distal end; [0009] a delivery stylet
having a proximal end, a distal end, a lumen extending between the
proximal and distal ends of the delivery stylet, and a distal
portion at the distal end of the delivery stylet, the delivery
stylet being configured and dimensioned to be receivable by and
slidable forwardly and backwardly within the cannula including to a
position wherein said distal portion protrudes beyond the distal
end of the cannula; and [0010] an actuator for ejecting the drug
depot from the stylet to a site within the body, said actuator
having a fluid (e.g. liquid) delivery mechanism in fluid
communication with an interior of the stylet and being effective to
create pressure within the stylet sufficient to eject the drug
depot therefrom.
[0011] In certain embodiments, the delivery system further
comprises a drug depot to be administered to a patient. The drug
depot may be packaged separately or retained by the stylet at the
distal end of the stylet. When retained in the stylet, the drug
depot may have a portion inside the stylet and a portion protruding
from the distal end of the stylet. Furthermore, the drug depot may
be visualizable by a diagnostic imaging beam or modality (e.g.
computed tomography (CT), ultrasound, x-ray, magnetic resonance
imaging (MRI), and fluoroscopy). For example, the drug depot may
incorporate a radiographic marker that allows the drug depot to be
visualized under a diagnostic imaging beam. The radiographic marker
may be selected from the group consisting of barium, calcium
phosphate, bismuth, iodine, tantalum, tungsten, metal beads, and
mixtures thereof.
[0012] In some embodiments, the delivery system may further
comprise a solid stylet configured and dimensioned to be receivable
inside the cannula to provide rigidity thereto, whereby the
cannula, with the solid stylet received therein, is effective to
pierce tissue of a patient, prior to the use of the delivery
stylet.
[0013] The delivery stylet may have a hub at the proximal end
thereof, and the actuator may be releasably attachable to the
hub.
[0014] The actuator of the system may be a syringe having a barrel
with a distal portion thereof configured to be attachable to the
hub of the delivery stylet, and a plunger slidable within the
barrel. In some embodiments, the syringe is a Luer lock syringe and
the hub of the delivery stylet has external threads complementary
to internal threads of the Luer lock of the syringe.
[0015] The fluid (e.g. liquid) delivery mechanism may deliver
liquid selected from the group consisting of an anaesthetic (e.g.
Marcaine), Depo-Medrol (methylprednisolone), dexamethasone, and
mixtures thereof.
[0016] In some embodiments, at least one of the cannula and
delivery stylet comprises a radiopaque material or ultrasound
responsive topography to provide increased contrast relative to the
absence of the material of topography under a diagnostic imaging
beam.
[0017] The invention also provides, in accordance with a second
aspect, a method of delivering a drug depot to a site within a
patient using the delivery system according to the first aspect,
comprising: [0018] a. inserting the cannula with solid stylet
received into a target tissue of a patient under image guidance;
[0019] b. removing the solid stylet from the cannula and inserting
the delivery stylet into the cannula until the distal portion of
the delivery stylet emerges from the distal end of the cannula;
[0020] c. positioning the drug depot under image guidance by moving
the delivery stylet forwards or backwards until the drug depot is
positioned at a desired location; and [0021] d. actuating the
actuator to expel the drug depot from the delivery stylet.
[0022] The method can be used to treat scoliosis according to the
additional teachings of U.S. Pat. No. 9,821,033 for an invention
entitled Method of Treating Scoliosis, the contents of which are
incorporated herein by reference. That is, the present delivery
system can be used to treat scoliosis by delivering a drug depot
comprising a therapeutically effective or acceptable amount of a
growth modulator into a first epiphyseal growth plate of a first
vertebra for altering the growth of the first epiphyseal growth
plate to correct or compensate for disproportionate growth.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] The invention may be better understood with reference to the
following description and drawings in which:
[0024] FIG. 1 shows components of a delivery system for delivering
a drug depot pursuant to one embodiment of the invention;
[0025] FIGS. 2-10 show the system in use at various stages of
delivery of the drug depot to a site near the spinal column of a
patient.
DETAILED DESCRIPTION OF EMBODIMENT
[0026] For the sake of clarity and to avoid ambiguity, certain
terms are defined herein as follows.
[0027] The term "comprising" means "including without limitation."
Thus, a system, device, or component comprising a list of elements
may include additional elements not expressly recited. The term
"consisting of" means "including the listed elements and such
additional elements as may be normally present in the recited
elements." Elements that would normally be present in a recited
element will be apparent to the person of ordinary skill in the
art. For example, a "needle" will necessarily have a proximal and a
distal end. The term "consisting essentially of" means "consisting
of" (as defined herein) the listed elements plus such additional
elements as would not materially affect (positively or negatively)
the basic and novel properties of the invention. By "basic and
novel properties" is meant the ability of the systems, devices and
methods according to the invention to deliver a drug depot to a
desired site within the body.
[0028] The numerical values set forth herein are reported as
precisely as possible. However, any numerical value inherently may
contain errors resulting from the standard deviation found in
standard measurement techniques. Therefore, unless the context
indicates otherwise, all numerical values recited herein are to be
understood as being modified by the term "about." Furthermore, the
numerical parameters set forth herein may vary depending upon the
desired properties sought to be obtained by the present invention.
Without limiting the application of the doctrine of equivalents to
the scope of the claims, each numerical parameter should (at least)
be construed in light of the number of reported significant digits
and ordinary rounding techniques. Moreover, all ranges disclosed
herein are to be understood to encompass any and all subranges
subsumed therein. For example, a range of "1 to 10" includes any
and all subranges having a minimum value of equal to or greater
than 1 and a maximum value of equal to or less than 10, e.g., 2-4,
5.5-10, etc.
[0029] It is noted that, as used in this specification and the
appended claims, the singular forms "a," "an," and "the," include
plural referents unless expressly and unequivocally limited to one
referent. Thus, for example, reference to "a drug depot" includes
one, two, three or more drug depots.
[0030] When used herein, the term "patient" can refer to animals,
including, without limitation, humans.
[0031] The headings below are not meant to limit the disclosure in
any way; embodiments under any one heading may be used in
conjunction with embodiments under any other heading.
[0032] Referring now primarily to FIG. 1, a delivery system 10 for
delivering a drug depot (not shown) to a site within a patient is
shown. The system 10 comprises a hollow cannula 12 having a
proximal end 14 and a distal end 16. A plastic hub 17 is attached
to the cannula 12 at the proximal end 14 to allow a user to grasp
and manipulate the cannula 12. The distal end 16 of the cannula 12
is bevelled to facilitate piercing of tissue, as will be described
below. The cannula 12 is designed to cause minimal physical and
psychological trauma to the patient and made of a low density
material, in this case, carbon fiber, to reduce beam hardening
artifacts when visualized under an imaging beam of a CT scanner
(not shown).
[0033] The system 10 also includes a plastic delivery stylet 18
having a proximal end 20, a distal end 22, a lumen 24 (referenced
in FIGS. 6 and 9) extending between the proximal and distal ends
20, 22. At the proximal end 20 is attached a plastic hub 25 for use
in grasping and manipulating the delivery stylet 18. The delivery
stylet 18 is longer than the cannula 12 and further dimensioned to
be receivable by and slidable forwardly and backwardly within the
cannula 12 including to a position wherein a distal portion 26
protrudes beyond the distal end 16 of the cannula 12 (as will be
described further below).
[0034] As best shown in FIGS. 5 and 6, a drug depot 28 is retained
by the delivery stylet 18 at the distal end 22 of the stylet 18.
Referring to FIG. 6, the drug depot 28 has a portion 30 inside the
delivery stylet 18 and a portion 32 protruding from the distal end
22 of the delivery stylet 18. As will be further described, the
drug depot 28 can be visualized by a diagnostic imaging beam or
modality, which in this embodiment, is a beam of a CT scanner.
[0035] The system 10 further includes an actuator, which, in this
embodiment, is in the form of a syringe 34 comprising a barrel 36
and plunger 38. The plunger 38 is slidable within the barrel 36 to
eject the drug depot 28 from the delivery stylet 18 using a fluid
(in this case a liquid) in the barrel 36 to a site within the body
(as will be further described below). The syringe 34 is a Luer lock
syringe making it releasably attachable to a hub 25 of the delivery
stylet 18 using internal screw threads 42 of the barrel 36 and
external thread 43 of the hub 25.
[0036] The system 10 further comprises a solid plastic stylet 44
having a plastic hub 45 attached to a proximal end 47 thereof for
use in grasping and manipulating the stylet 44. The solid stylet 44
is configured and dimensioned to be receivable inside the cannula
12 to provide additional rigidity thereto, whereby the cannula 12,
with the solid stylet 44 received therein, can be used to pierce
tissue of a patient prior to use of the delivery stylet 18, as will
now be described with reference to FIGS. 2-10.
[0037] As shown in FIG. 2, during a procedure, the cannula 12 with
the solid plastic stylet 44 seated therein is advanced through
tissue of a patient until the distal end 16 of the cannula reaches
a desired location within the patient, but can in other locations,
e.g. along the path of the exiting nerve root or to the rear of the
dorsal root ganglion. In this embodiment, the location is near the
spinal column of the patient. Because of the materials used in the
cannula and solid stylet, the combination can be visualized under
an imaging beam of a CT scanner (not shown) with reduced beam
hardening artifacts. This facilitates accurate placement of the
cannula within the patient. Once the cannula is moved to the
desired location, the solid stylet 44 is withdrawn (as shown in
FIG. 3) and the delivery stylet 18 carrying the drug depot 28 is
inserted into the cannula 12 (shown in FIG. 4) until the distal
portion 26 of the delivery stylet 18 emerges from the distal end of
the cannula 12 (as shown in FIG. 5). Referring to FIG. 7, physical
markers 27 are placed at regular and predetermined, in this case 1
cm, intervals on the delivery stylet 18 and are used to determine
the position of the delivery stylet 18 relative to the cannula 12
by inspecting the location of the markers relative to a proximal
end 50 of the hub 17 of the cannula 12. The markers 27 are placed
to allow the user to determine when the distal end 22 of the
delivery stylet 18 will emerge from the distal end 16 of the
cannula 12.
[0038] The areas denoted by reference numerals 5 and 6 in FIG. 5
are enlarged and shown in FIGS. 5 and 6 to better show the drug
depot 28 carried by the distal end 22 of the delivery stylet 18.
The drug depot 28 is in the form of a biodegradable pellet provided
with a lyophilized powder coating containing a radiographic marker,
in this case iodine, to allow the drug depot 28 to be visualized
under a diagnostic imaging beam of a CT scanner. The coating also
contains a therapeutic agent, in this case, clonidine, for use in
treating pain (amongst other things). The user can position the
drug depot 28 within the patient by moving the delivery stylet 18
back and forth within the cannula 12 until the drug depot 28
reaches the desired location based on the user's view of the drug
depot 28 under the imaging beam. Once the drug depot 28 is in the
desired location, the barrel 36 of the Luer lock syringe 34
carrying liquid, in this case, a saline solution comprising a
mixture of 0.5 g/mL of Marcaine and 40 mg/mL of Depo-Medrol, is
screwed onto the hub 40 of the delivery stylet 18, and the plunger
38 is advanced within the barrel 36 to expel the liquid through the
lumen 24 of the delivery stylet 18 thereby depositing the drug
depot 28 in the desired location in the neural foramen near the
spinal column of the patient--see FIGS. 7, 8 and 9, wherein the
areas denoted by reference numerals 8 and 9 in FIG. 8 are shown
enlarged in FIGS. 8 and * to between show the drug depot 28 being
expelled from the distal end 22 of the delivery stylet 18. The
syringe 34, cannula 12, and delivery stylet 18 are then withdrawn
from the patient leaving the drug depot 28 in place near the spinal
column (as shown in FIG. 10). After deposition, the radiographic
marker of the drug depot 28 can be used to track movement and/or
degradation of the drug depot 28 at the site over time.
[0039] In accordance with another aspect of the invention, there is
provided a method for localized and/or targeted delivery of a drug
to a patient to treat a disease or condition such as for example,
scoliosis, rheumatoid arthritis, osteoarthritis, sciatica, carpal
tunnel syndrome, cancer, inflammation and pain, such as lower back
pain, sciatica, lower extremity pain, upper extremity pain, tissue
pain and pain associated with injury or repair of cervical,
thoracic, and/or lumbar vertebrae or intervertebral discs, rotator
cuff, articular joint, TMJ, tendons, ligaments, muscles, and the
like. The treatment of scoliosis can incorporate methods disclosed
in U.S. Pat. No. 9,821,033 referenced above.
[0040] Treating or treatment of a disease refers to executing a
protocol, which may include administering one or more drugs to a
patient (human or otherwise), in an effort to alleviate signs or
symptoms of the disease. Alleviation can occur prior to signs or
symptoms of the disease appearing, as well as after their
appearance. Thus, "treating" or "treatment" includes "preventing"
or "prevention" of disease. In addition, "treating" or "treatment"
does not require complete alleviation of signs or symptoms, does
not require a cure, and specifically includes protocols that have
only a marginal effect on the patient.
[0041] "Localized delivery" includes delivery to tissue within
close proximity to a target site in the tissue, e.g. within about
10 cm or about 5 cm from the target site. "Targeted delivery"
includes delivery to the target site.
[0042] It will be appreciated that numerous variations can be made
to the embodiment described above as will be described below.
[0043] Cannula and Stylets
[0044] The various embodiments, the materials used to make the
cannula 12, stylets 18, 44 and hubs of the cannula, delivery stylet
and solid stylet 17, 25, 45 may be the same or different materials.
Examples of materials that can be used include but are not limited
to polyurethane, polyurea, polyether(amide), PEBA, thermoplastic
elastomeric olefin, copolyester, and styrenic thermoplastic
elastomer, steel, aluminum, stainless steel, titanium, metal alloys
with high non-ferrous metal content and a low relative proportion
of iron, carbon fiber, glass fiber, plastics, ceramics or
combinations thereof.
[0045] The cannula may include a transparent or translucent portion
that can be visualizable by ultrasound, fluoroscopy, x-ray, or
other imaging techniques. In such embodiments, the transparent or
translucent portion may include a radiopaque material or ultrasound
responsive topography that increases the contrast of the cannula
relative to the absence of the material or topography. To reduce or
minimize beam hardening artifacts under a CT scan, low density
materials (relative to stainless steel or steel) can be used.
[0046] The cannula may also include one or more tapered regions or
have a tip style designed for accurate treatment of the patient
depending on the site for implantation. Examples of tip styles
include, for example, Trephine, Cournand, Veress, Huber, Seldinger,
Chiba, Francine, Bias, Crawford, deflected tips, Hustead, Lancet,
or Tuohey. Ideally, the cannula is packaged together with a sheath
covering the distal end thereof prior to use to avoid unwanted
needle sticks.
[0047] The dimensions of the cannula, among other things, will
depend on the site for implantation. For example, the width of the
epidural space is only about 3-5 mm for the thoracic region and
about 5-7 mm for the lumbar region. Thus, the cannula can be
designed for these specific areas. In various embodiments, the
cannula may be inserted using a transforaminal approach in the
spinal foramen space, for example, along an inflamed nerve root and
the drug depot implanted at this site for treating the condition.
Typically, the transforaminal approach involves approaching the
intervertebral space through the intervertebral foramina and
implanting the drug depot.
[0048] The length of the cannula will vary depending on the
specific application and may range from about 50 to 150 mm. For
example, for epidural use, the cannula may be about 65 mm for use
in children, about 85 mm for use in a standard adult, and about 110
mm for use in an obese adult patient. The thickness of the cannula
will also depend on the specific application, including the site of
implantation. The thickness includes, but is not limited to, from
about 0.05 to about 1.655 mm. The gauge of the cannula may be the
widest or smallest diameter or a diameter in between for insertion
into a patient. The widest diameter is typically about 14 gauge,
while the smallest diameter is about 22 gauge. In various
embodiments, the gauge of the cannula is about 18 to about 22
gauge.
[0049] The delivery stylet and solid stylet will be dimensioned to
be slidable within the cannula. The length of the delivery stylet
will, in all cases be greater than the length of the cannula in
order for the distal portion thereof to protrude from a distal end
of the cannula when fully inserted therein. The markers on the
delivery stylet can be placed at differing intervals, e.g. every 1
mm to 1 cm, along its length or along a portion of its length. For
example, the markers can appear only along a proximal end portion
of the delivery stylet to allow the user to determine the degree to
which the delivery stylet is extending beyond the distal end of the
cannula during a procedure.
[0050] Drug Depot
[0051] The drug depot comprises a physical structure to facilitate
implantation and retention in a desired site (e.g., a synovial
joint, a disc space, a spinal canal, soft tissue surrounding the
spinal canal, or other tissue of the patient, etc.). The drug depot
includes but is not limited to capsules, microspheres, particles,
gels, matrices, wafers, pills, cartridges, pellets or other
pharmaceutical delivery compositions provided that they can be
shaped and sized so as to be receivable by the delivery stylet and
slidable through the cannula of the delivery system of the
invention.
[0052] In various embodiments, the drug depot is in the form of a
pellet. Pellets include, but are not limited to, substantially
spherical, rod shaped, square, oval shaped particles having, in
various embodiments, an aspect ratio (the ratio of the length to
the width of the pellet) which is less than about 4.0 to about
1.0.
[0053] Procedures for making pellets include, but are not limited
to, extrusion-spheroidization, for spherical pellets where the
active pharmaceutical ingredient (API) and any inactive ingredients
(excipients, binders, etc.) are pre-mixed, then wetted with water,
in a high shear mixer to form a damp mass. The damp mass is then
transferred into an extruder where it is forced through a screen or
die plate, where it forms an essentially solid, cylindrical
extrudate of uniform shape and size. The size of the opening in the
screen or die dictate resultant pellet size. The extrudate is fed
onto a rotating disk, which may be smooth or may contain a grid
(waffled, grooved, etc.) and the extrudate breaks into small
cylinders, which in time are rounded into spherically shaped
solids. Subsequently, the pellets are dried to the desired residual
moisture content, typically in a fluid bed dryer. Any oversized or
undersized product is removed by sieving, and the resulting pellets
have a narrow size distribution.
[0054] The drug depot also comprises a therapeutically effective
amount of a drug. The term "drug" as used herein is generally meant
to refer to any substance that alters the physiology of a patient.
The term "drug" may be used interchangeably herein with the terms
"therapeutic agent", and "active pharmaceutical ingredient". It
will be understood that a "drug" formulation may include more than
one therapeutic agent, wherein exemplary combinations of
therapeutic agents include a combination of two or more drugs. The
drug provides a concentration gradient of the therapeutic agent for
delivery to the site. In various embodiments, the drug depot
provides an optimal drug concentration gradient of the therapeutic
agent at a distance of up to about 1 cm, about 5 cm, or about 10
cm, from the implant site. A "therapeutically effective amount" is
an amount such that when administered, the drug results in
alteration of the biological activity, such as, for example,
inhibition of inflammation, reduction or alleviation of pain,
improvement in the condition, etc. The dosage administered to a
patient can be a single dose or multiple doses depending upon a
variety of factors, including the drug's pharmacokinetic
properties, patient conditions and characteristics (sex, age, body
weight, health, size, etc.), extent of symptoms, concurrent
treatments, frequency of treatment and the effect desired.
[0055] Examples of drugs suitable for use in the drug depot,
include, but are not limited to growth modulators (both positive
and negative) such as those disclosed in U.S. Pat. No. 9,821,033,
an anti-inflammatory agent, analgesic agent, or osteoinductive
growth factor or a combination thereof. Anti-inflammatory agents
include, but are not limited to, salicylates, diflunisal,
indomethacin, ibuprofen, naproxen, tolmetin, ketorolac, diclofenac,
ketoprofen, fenamates (mefenamic acid, meclofenamic acid), enolic
acids (piroxicam, meloxicam), nabumetone, celecoxib, etodolac,
nimesulide, apazone, gold, sulindac or tepoxalin; antioxidants,
such as dithiocarbamate, and other compounds such as sulfasalazine
[2-hydroxy-5-[-4-[C2-pyridinylamino)sulfonyl]azo]benzoic acid],
steroids, such as fluocinolone, cortisol, cortisone,
hydrocortisone, fludrocortisone, prednisone, prednisolone,
methylprednisolone, triamcinolone, betamethasone, dexamethasone,
beclomethasone, fluticasone or a combination thereof.
[0056] Suitable anabolic growth or anti-catabolic growth factors
include, but are not limited to, a bone morphogenetic protein, a
growth differentiation factor, a LIM mineralization protein, CDMP
or progenitor cells, mesenchymal stem cells, or a combination
thereof.
[0057] Suitable analgesic agents include, but are not limited to,
acetaminophen, lidocaine, bupivicaine, opioid analgesics such as
buprenorphine, butorphanol, dextromoramide, dezocine,
dextropropoxyphene, diamorphine, fentanyl, alfentanil, sufentanil,
hydrocodone, hydromorphone, ketobemidone, levomethadyl, mepiridine,
methadone, morphine, nalbuphine, opium, oxycodone, papavereturn,
pentazocine, pethidine, phenoperidine, piritramide,
dextropropoxyphene, remifentanil, tilidine, tramadol, codeine,
dihydrocodeine, meptazinol, dezocine, eptazocine, flupirtine or a
combination thereof. Analgesics also include agents with analgesic
properties, such as for example, amitriptyline, carbamazepine,
gabapentin, pregabalin, clonidine, or a combination thereof.
[0058] Other therapeutic agents which can be incorporated into the
drug depot include NSAIDs, anti-tumour necrosis factor (anti-TNF),
interleukins, byname, dexamethasone, and anaesthetic agents.
[0059] In various embodiments, the drug can be layered on the solid
core of the pellet by solution or suspension layering or by powder
layering techniques, as are known in the art.
[0060] The drug depot may comprise a biopolymer that is
biodegradable or non-biodegradable. For example, the drug depot can
comprise a non-biodegradable body in the form of a porous hollow
chamber filled with the therapeutic agent alone or incorporated
into a degradable polymer. It may be desirable to make the body
non-degradable to be able to retrieve it after it has released its
contents. Non-limiting examples of suitable biodegradable materials
for the pellet body include polyorthoesters (POE),
polylacticglycolic acid (PLGA) polysacharides (Saber technology),
polycapralactone, polyfumarate, tyrosine polycarbonate, etc. The
body may be solid, and the therapeutic agent may be dispersed
throughout the material that forms the body. The dispersal of the
therapeutic agent may be even throughout the body. Alternatively,
the concentration of the therapeutic agent may vary throughout the
body. As the biodegradable material of the body degrades at the
site, the therapeutic agent is released.
[0061] The drug depot may also comprise a biopolymer that may
provide for immediate release, sustained release, or controlled
release of the drug(s). Examples of suitable sustained release
biopolymers include but are not limited to poly(alpha-hydroxy
acids), poly(lactide-co-glycolide) (PLGA), polylactide (PLA),
polyglycolide (PG), polyethylene glycol (PEG) conjugates of
poly(alpha-hydroxy acids), polyorthoesters, polyaspirins,
polyphosphagenes, collagen, starch, chitosans, gelatin, alginates,
dextrans, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA,
PEGT-PBT copolymer (polyactive), methacrylates,
poly(N-isopropylacrylamide), PEO-PPO-PEO (pluronics), PEO-PPO-PAA
copolymers, PLGA-PEO-PLGA, or combinations thereof.
[0062] In one embodiment, the pellet is made using a core of
biodegradable material, such as, for example, polyglactin,
polylactone, polylactide, etc. The core is then coated with a thin
layer of the drug, such as an anti-inflammatory agent, analgesic
agent, etc. by solution, suspension, or powdered layering until the
desired potency is achieved.
[0063] In various embodiments, the drug pellets can be different
sizes, for example, from a length of from about 0.5 mm to 5 mm and
have a diameter of from about 0.01 to about 2 mm. The layer or
layers will each have a layer thickness of from about 0.005 to 1.0
mm, such as, for example, from about 0.05 to about 0.75 mm.
[0064] Radiographic markers that can be incorporated in the drug
depot include iodine, barium, calcium phosphate, bismuth, tantalum,
tungsten, metal beads (e.g. gold, silver), and mixtures thereof.
Instead of or in addition to a radiographic marker, the drug depot
can be provided with a certain topography to allow the drug depot
to be visualised under ultrasound. Depending on the nature of the
radiographic marker and/or topography, a variety of diagnostic
imaging procedures can be used including X-ray imaging, magnetic
resonance imaging (MRI), ultrasound and fluoroscopy.
[0065] The fluid used to eject the drug depot can be a gas (eg.
air) or a liquid, including any pharmaceutically acceptable liquid
such as a pharmaceutically acceptable saline solution alone or in
combination with a pharmaceutically effective amount of an
anaesthetic, e.g. Marcaine. Marcaine can be used in an amount of
about 0.5, 1, or 2 v/v%, Depo-Medrol (methylprednisolone) (e.g.
40-80 mg/mL), dexamethasone, and mixtures thereof.
[0066] The system components (e.g., cannula, stylets, syringe,
etc.) may be disposable or sterilisable for re-use. Sterilization
can be done via radiation, e.g. gamma radiation or electronic beam
radiation, or via gas sterilization, such as, for example, with
ethylene oxide or steam sterilization. The radiation can be
performed in a terminal sterilization step in the final packaging
or the individual components can be sterilized separately and the
final package assembled in a sterile environment.
[0067] It will be apparent to those skilled in the art that various
additional modifications and variations can be made to the
embodiments described herein without departing from the invention
as described and claimed.
* * * * *