U.S. patent application number 13/642042 was filed with the patent office on 2013-06-06 for drug delivery devices for delivery of ocular therapeutic agents.
This patent application is currently assigned to Aerie Pharmaceuticals, Inc.. The applicant listed for this patent is Casey Kopczynski, Cheng-Wen Lin, Chris Sutay. Invention is credited to Casey Kopczynski, Cheng-Wen Lin, Chris Sutay.
Application Number | 20130142858 13/642042 |
Document ID | / |
Family ID | 44992020 |
Filed Date | 2013-06-06 |
United States Patent
Application |
20130142858 |
Kind Code |
A1 |
Kopczynski; Casey ; et
al. |
June 6, 2013 |
DRUG DELIVERY DEVICES FOR DELIVERY OF OCULAR THERAPEUTIC AGENTS
Abstract
Drug delivery devices comprising a non-bioabsorbable polymer
structure configured to support a composition comprising an active
agent. The devices include a plurality of portions fused together
and a recess configured to support the composition. At least one of
the portions includes an impermeable polymer and at least one other
portion includes a rate-limiting water-permeable polymer. The
rate-limiting water-permeable polymer allows for transportation of
the active agent to an exterior of the device.
Inventors: |
Kopczynski; Casey; (Chapel
Hill, NC) ; Lin; Cheng-Wen; (Raleigh, NC) ;
Sutay; Chris; (Raleigh, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Kopczynski; Casey
Lin; Cheng-Wen
Sutay; Chris |
Chapel Hill
Raleigh
Raleigh |
NC
NC
NC |
US
US
US |
|
|
Assignee: |
Aerie Pharmaceuticals, Inc.
Research Triangle Park
NC
|
Family ID: |
44992020 |
Appl. No.: |
13/642042 |
Filed: |
May 17, 2011 |
PCT Filed: |
May 17, 2011 |
PCT NO: |
PCT/US11/36806 |
371 Date: |
February 1, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61345547 |
May 17, 2010 |
|
|
|
Current U.S.
Class: |
424/427 ;
514/180; 514/236.2; 514/249; 514/300; 514/432; 514/443; 514/530;
514/571; 514/622; 604/93.01 |
Current CPC
Class: |
A61K 47/36 20130101;
A61F 9/0017 20130101; A61P 27/06 20180101; A61K 31/215 20130101;
A61K 31/00 20130101; A61P 43/00 20180101; A61P 27/02 20180101; A61K
47/32 20130101; A61K 9/0051 20130101 |
Class at
Publication: |
424/427 ;
604/93.01; 514/432; 514/571; 514/443; 514/530; 514/180; 514/249;
514/236.2; 514/622; 514/300 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61F 9/00 20060101 A61F009/00 |
Claims
1. A device for insertion in the eye, the device comprising: a
first portion including a recess configured to support a
composition comprising an active agent, the first portion
comprising an impermeable polymer; and a second portion fused to
the first portion, the second portion comprising a rate-limiting
water-permeable polymer that allows for transportation of the
active agent to an exterior of the device, wherein the
rate-limiting water-permeable polymer includes a thickness in a
range of about 20 .mu.m to about 500 .mu.m.
2. The device set forth in claim 1 further comprising a flange
fused to the second portion.
3. The device set forth in claim 1 wherein the second portion
includes a base and a flange integral with the base.
4. A device for insertion in the eye, the device comprising: a
first portion comprising a rate-limiting water-permeable polymer; a
second portion fused to the first portion, the second portion
including a recess configured to support a composition comprising
an active agent, the second portion comprising a rate-limiting
water-permeable polymer; and a third portion fused to the second
portion, the third portion comprising a rate-limiting
water-permeable polymer, wherein the rate-limiting water-permeable
polymer includes a thickness in a range of about 20 .mu.m to about
500 .mu.m and allows for transportation of the active agent to an
exterior of the device.
5. A device for insertion in the eye, the device comprising: a
non-bioabsorbable polymer structure comprising a rate-limiting
water-permeable polymer; and a composition supported within an
enclosure of the non-bioabsorbable polymer structure, the
composition including an active agent; wherein the
non-bioabsorbable polymer structure includes a thickness in a range
of about 200 .mu.m to about 800 .mu.m, and wherein the thickness is
configured to control an elution rate of the active agent through
the rate-limiting water-permeable polymer, wherein the
rate-limiting water-permeable polymer is a copolymer having both
hydrophobic and hydrophilic monomers.
6. The device set forth in claim 5, wherein the rate-limiting
water-permeable polymer is selected from the group consisting of:
ethylene vinyl acetate with a vinyl acetate content of about 10% to
about 50% by weight (EVA-10-50) and ethylene vinyl alcohol with a
vinyl alcohol content of about 40% to about 80% by weight
(EVOH-40-80).
7. (canceled)
8. The device set forth in claim 5, wherein the active agent is
selected from the group consisting of:
3-hydroxy-2,2-bis(hydroxymethyl)propyl
7-((1R,2R,3R,5S)-2-((R)-3-(benzo[b]thiophen-2-yl)-3-hydroxypropyl)-3,5-di-
hydroxycyclopentyl)heptanoate (AR-102),
7-((1R,2R,3R,5S)-2-((R)-3-(benzo[b]thiophen-2-yl)-3-hydroxypropyl)-3,5-di-
hydroxycyclopentyl)heptanoic acid (AR-102 free acid), dorzolamide,
ethacrynic acid, latanoprost, latanoprost free acid, travoprost,
travoprost free acid, bimatoprost, bimatoprost free acid,
tafluprost, tafluprost free acid, dexamethasone, brimonidine,
timolol, or salts thereof.
9. A method of treating an ocular condition comprising inserting
the device of any one of claims 5, 6, and 8 to the conjunctiva of
the eye.
10. The method of claim 9 wherein the device is inserted into the
upper or lower formix of the eye.
11. A method of treating an ocular condition comprising implanting
episclerally or supraconjunctivally a drug delivery device
comprising an active agent, wherein the active agent is released at
a rate of about 0.0001 to about 200 micrograms/hr.
12. The method of claim 11, wherein the active agent is released at
a rate of about 0.0001 to about 30 micrograms/hr.
13. The method of claim 11, wherein the active agent is released at
a rate of about 0.001 micrograms/hr to about 30 micrograms/hr.
14. The method of claim 11, wherein the active agent is released at
a rate of about 0.001 micrograms/hr to about 10 micrograms/hr.
15. The method of claim 11, wherein the active agent comprises a
prostaglandin active agent, the active agent being implanted
episclerally and being released at a rate of about 0.00025 to about
0.0075 micrograms/hr.
16. The method of claim 15, wherein the active agent comprises
latanoprost, travoprost, bimatoprost, each of their free acids or
salts.
17. The method of claim 11, wherein the active agent comprises a
prostaglandin active agent, the active agent being implanted
supraconjunctivally and being released at a rate of about 0.0005 to
about 0.015 micrograms/hr.
18. The method of claim 17, wherein the active agent comprises
latanoprost, travoprost, bimatoprost, each of their free acids or
salts.
19. The method of claim 11, wherein the active agent comprises a
rho-kinase active agent, the active agent being implanted
episclerally, and being released at a rate of about 0.02 to about
0.6 micrograms/hr.
20. The method of claim 19, wherein the active agent comprises a
Y-39983 salt.
21. The method of claim 11, wherein the active agent comprises a
rho-kinase active agent, the active agent being implanted
supraconjunctivally and being released at a rate of about 0.04 to
about 1.2 micrograms/hr.
22. The method of claim 21, wherein the active agent comprises a
Y-39983 salt.
23. The method of claim 11, wherein the active agent is a
non-prostaglandin and non-rho-kinase active agent, the active agent
being implanted episclerally and being released at a rate of about
0.25 to about 7.5 micrograms/hr.
24. The method of claim 23, wherein the active agent comprises
timolol or a salt thereof.
25. The method of claim 11, wherein the active agent is a
non-prostaglandin and non-rho-kinase active agent, the active agent
being implanted supraconjunctivally and being released at a rate of
about 0.5 to about 15 micrograms/hr.
26. The method of claim 25, wherein the active agent comprises
timolol or a salt thereof.
27. The device set forth in claim 1, wherein the device is
substantially cylindrical-shaped.
28. The device set forth in claim 4, wherein the device is
substantially cylindrical-shaped.
29. The device set forth in claim 5, wherein the device is
substantially cylindrical-shaped.
Description
RELATED APPLICATIONS
[0001] This application in a non-provisional application of and
claims priority to provisional patent application No. 61/345,547,
filed on May 17, 2010, the entire contents of which are
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to a drug delivery device for
sustained delivery of therapeutic agents to target tissues. In
particular, it relates to a non-biodegradable, drug-eluting
removable device for the purpose of treating various diseases and
conditions. More particularly, but not by way of limitation, this
device is well-suited for episcleral or supraconjunctival delivery
of pharmaceutical agents for the treatment of glaucoma and ocular
hypertension.
BACKGROUND OF THE INVENTION
[0003] The delivery of therapeutic and pharmaceutical agents is a
complex problem without a single universal solution. Many chronic
diseases and conditions can be treated effectively by oral
medications, but side effects, patient forgetfulness, and other
factors often produce high rates of noncompliance with the
recommended treatment. In such cases, patient outcomes can be
improved using sustained delivery formulations that simplify the
medication regimen (e.g., Lupron Depot.RTM. for endometriosis).
[0004] Where possible, diseases and conditions that affect only a
single organ or local tissue are preferably treated by a local
application. This allows for a relatively high concentration of the
therapeutic agent at the site where it is most needed, and allows
for minimal systemic exposure. However there are relatively few
tissues that are directly accessible, with skin, hair follicles,
the oral, nasal and genitourinary cavities, and eyes being
candidates for direct application of therapeutic agents. Direct
application of therapeutic agents to internal organs is more
challenging, but has been useful in the treatment of some types of
tumors.
[0005] In the treatment of ocular conditions in particular, many
medications are now delivered topically to the eye as eyedrops.
Despite the success of the eyedrop in treating diseases and
conditions of the eye, treatment with topical eyedrops suffers from
numerous drawbacks.
[0006] A significant drawback of the eyedrop is the requirement
that the pharmaceutical agent be soluble in an isotonic buffered
solution at a therapeutically effective concentration and be
chemically stable in solution for 18 months or longer. However,
solubility of useful therapeutic agents in aqueous formulation is
often well below the concentration needed for effective treatment.
This can sometimes be corrected by the addition of various
excipients, but this increases the complexity of the formulation
and often reduces tolerability of the eyedrop.
[0007] A second limitation of eyedrops is the rapid clearance of
the therapeutic agent via nasolacrimal drainage from the eye
surface. This results in most of the compound being delivered to
the inside of the nose, where it is not needed and where, in fact,
a high concentration of agent might have a detrimental effect.
[0008] A third limitation to the use of eyedrops is the observation
that many therapeutically-valuable agents cause a local irritation
when topically-dosed to the eye. The cornea of the eye is highly
sensitive to the application of chemical agents. This irritation
potential significantly limits the use of many otherwise valuable
therapeutic agents.
[0009] A fourth limitation of eyedrops, which also applies to
systemic drugs taken by oral, sublingual, nasal or rectal delivery
routes, is the need to re-apply the therapeutic agent on a regular
basis. For eyedrops, repeating application as frequently as four
times a day can be necessary, and even the best agents must be
reapplied on a daily basis. For many individuals, in particular the
elderly, this frequent dosing becomes burdensome and leads to
non-compliance with the dosing regimen, lessening the therapeutic
value of the treatment.
[0010] To counter these disadvantages of eyedrop delivery,
researchers have suggested various devices aimed at providing local
delivery over a longer period of time. U.S. Pat. No. 5,824,072 to
Wong discloses a non-biodegradable implant containing a
pharmaceutical agent that diffuses through a water-impermeable
polymer matrix into the target tissue. The implant is placed in the
tear film or in a surgically-induced avascular region, or in direct
communication with the vitreous.
[0011] U.S. Pat. No. 5,476,511 to Gwon et al. discloses a polymer
implant for placement under the conjunctiva of the eye. The implant
is claimed to be useful for the delivery of neovascular inhibitors
for the treatment of age-related macular degeneration (AMD). Again,
the pharmaceutical agent diffuses through a water-impermeable
polymer matrix of the implant.
[0012] U.S. Pat. No. 5,773,019 to Aston et al. discloses a
non-biodegradable implant for the delivery of steroids and
immunosuppressives such as cyclosporine for the treatment of
uveitis, with the drug again diffusing through the
water-impermeable polymer matrix of the implant.
[0013] U.S. Pat. No. 3,854,480 to Zaffaroni discloses a
drug-delivery system with a solid inner matrix formulation
containing solid particles of drug surrounded by an outer polymer
membrane that is permeable to the passage of the drug. While both
the inner matrix and the outer wall are claimed to be permeable to
the passage of drugs, the patent requires that the rate of
diffusion of the outer membrane be not more than 10% of the rate of
the inner matrix.
[0014] Both U.S. Pat. No. 4,281,654 to Shell, et al. and U.S. Pat.
No. 4,190,642 to Gale, et al. disclose matrix polymer systems that
are designed to deliver either beta-blockers or a combination of
epinephrine and pilocarpine to the eye to treat glaucoma. Gale, et
al. micronize their medicaments to a particle size of not more than
100 microns and these are subsequently dispersed throughout the
entire polymer matrix, with no distinct cavity that contains the
drug and no drug-free outer layer. In addition, both Shell and Gale
require the walls surrounding these small depots be ruptured by the
force of the osmotic pressure in order to release the drug by way
of those formed ruptures.
[0015] All of the above-referenced patents and publications are
hereby incorporated herein by reference.
SUMMARY OF THE INVENTION
[0016] In one aspect, the present invention provides an implantable
device comprising a first portion including a recess configured to
support a composition comprising an active agent, the first portion
comprising an impermeable polymer and a second portion fused to the
first portion, the second portion comprising a rate-limiting
water-permeable polymer that allows for transportation of the
active agent to an exterior of the device.
[0017] In one embodiment, the present invention includes a device
for insert in the eye. The device comprises a first portion
including a recess configured to support a composition comprising
an active agent, the first portion comprising an impermeable
polymer; and a second portion fused to the first portion, the
second portion comprising a rate-limiting water-permeable polymer
that allows for transportation of the active agent to an exterior
of the device.
[0018] In another embodiment, the present invention includes a
device for insert in the eye. The device comprises a first portion
including a recess configured to support a composition comprising
an active agent, the first portion comprising an impermeable
polymer; a second portion fused to the first portion, the second
portion comprising a rate-limiting water-permeable polymer that
allows for transportation of the active agent to an exterior of the
device; and a flange fused to the second portion.
[0019] In a further embodiment, the present invention includes a
device for insert in the eye. The device comprises a first portion
including a recess configured to support a composition comprising
an active agent, the first portion comprising an impermeable
polymer; and a second portion fused to the first portion, the
second portion including a base and a flange integral with the
base, the second portion comprising a rate-limiting water-permeable
polymer that allows for transportation of the active agent to an
exterior of the device.
[0020] In yet another embodiment, the present invention includes a
device for insert in the eye. The device comprises a first portion
comprising a rate-limiting water-permeable polymer; a second
portion fused to the first portion, the second portion including a
recess configured to support a composition comprising an active
agent, the second portion comprising a rate-limiting
water-permeable polymer; and a third portion fused to the second
portion, the third portion comprising a rate-limiting
water-permeable polymer. The rate-limiting water-permeable polymer
allows for transportation of the active agent to an exterior of the
device.
[0021] In another embodiment, the present invention includes a
method of treating an ocular condition comprising suturing an
embodiment of one of the devices disclosed herein to the
conjunctiva of the eye.
[0022] In a further embodiment, the present invention includes a
method of treating an ocular condition comprising implanting
episclerally or supraconjunctivally a drug delivery device
comprising an active agent, wherein the active agent is released at
a rate of about 0.0001 to about 200 micrograms/hr.
[0023] Other aspects of the invention will become apparent by
consideration of the detailed description and accompanying
drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] FIG. 1 shows a drug delivery device according to one
embodiment of the present invention.
[0025] FIG. 2 shows a drug delivery device according to one
embodiment of the present invention.
[0026] FIG. 3 illustrates a cross-sectional view of the eye with a
drug delivery device according to one embodiment of the present
invention inserted in the eye.
[0027] FIG. 4 illustrates several drawings of a drug delivery
device according to one embodiment of the present invention.
[0028] FIG. 5 is an exploded view of the drug delivery device
illustrated in FIG. 4.
[0029] FIG. 6 illustrates several drawings of a composition
supported by the drug delivery device illustrated in FIG. 4.
[0030] FIG. 7 illustrates several drawings of a portion of the drug
delivery device illustrated in FIG. 4.
[0031] FIG. 8 illustrates several drawings of a portion of the drug
delivery device illustrated in FIG. 4.
[0032] FIG. 9 illustrates several drawings of a drug delivery
device according to one embodiment of the present invention.
[0033] FIG. 10 is an exploded view of the drug delivery device
illustrated in FIG. 9.
[0034] FIG. 11 illustrates several drawings of a composition
supported by the drug delivery device illustrated in FIG. 9.
[0035] FIG. 12 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 9.
[0036] FIG. 13 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 9.
[0037] FIG. 14 illustrates several drawings of a drug delivery
device according to one embodiment of the present invention.
[0038] FIG. 15 is an exploded view of the drug delivery device
illustrated in FIG. 14.
[0039] FIG. 16 illustrates several drawings of a composition
supported by the drug delivery device illustrated in FIG. 14.
[0040] FIG. 17 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 14.
[0041] FIG. 18 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 14.
[0042] FIG. 19 illustrates several drawings of a drug delivery
device according to one embodiment of the present invention.
[0043] FIG. 20 is an exploded view of the drug delivery device
illustrated in FIG. 19.
[0044] FIG. 21 illustrates several drawings of a composition
supported by the drug delivery device illustrated in FIG. 19.
[0045] FIG. 22 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 19.
[0046] FIG. 23 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 19.
[0047] FIG. 24 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 19.
[0048] FIG. 25 illustrates several drawings of a drug delivery
device according to one embodiment of the present invention.
[0049] FIG. 26 is an exploded view of the drug delivery device
illustrated in FIG. 25.
[0050] FIG. 27 illustrates several drawings of a composition
supported by the drug delivery device illustrated in FIG. 25.
[0051] FIG. 28 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 25.
[0052] FIG. 29 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 25.
[0053] FIG. 30 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 25.
[0054] FIG. 31 illustrates several drawings of a drug delivery
device according to one embodiment of the present invention.
[0055] FIG. 32 is an exploded view of the drug delivery device
illustrated in FIG. 31.
[0056] FIG. 33 illustrates several drawings of a composition
supported by the drug delivery device illustrated in FIG. 31.
[0057] FIG. 34 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 31.
[0058] FIG. 35 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 31.
[0059] FIG. 36 illustrates several drawings of a drug delivery
device according to one embodiment of the present invention.
[0060] FIG. 37 is an exploded view of the drug delivery device
illustrated in FIG. 36.
[0061] FIG. 38 illustrates several drawings of a composition
supported by the drug delivery device illustrated in FIG. 36.
[0062] FIG. 39 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 36.
[0063] FIG. 40 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 36.
[0064] FIG. 41 illustrates several drawings of a drug delivery
device according to one embodiment of the present invention.
[0065] FIG. 42 is an exploded view of the drug delivery device
illustrated in FIG. 41.
[0066] FIG. 43 illustrates several drawings of a composition
supported by the drug delivery device illustrated in FIG. 41.
[0067] FIG. 44 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 41.
[0068] FIG. 45 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 41.
[0069] FIG. 46 illustrates several drawings of a drug delivery
device according to one embodiment of the present invention.
[0070] FIG. 47 is an exploded view of the drug delivery device
illustrated in FIG. 46.
[0071] FIG. 48 illustrates several drawings of a composition
supported by the drug delivery device illustrated in FIG. 46.
[0072] FIG. 49 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 46.
[0073] FIG. 50 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 45.
[0074] FIG. 51 illustrates several drawings of a drug delivery
device according to one embodiment of the present invention.
[0075] FIG. 52 is an exploded view of the drug delivery device
illustrated in FIG. 51.
[0076] FIG. 53 illustrates several drawings of a composition
supported by the drug delivery device illustrated in FIG. 51.
[0077] FIG. 54 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 51.
[0078] FIG. 55 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 51.
[0079] FIG. 56 illustrates several drawings of a drug delivery
device according to one embodiment of the present invention.
[0080] FIG. 57 is an exploded view of the drug delivery device
illustrated in FIG. 56.
[0081] FIG. 58 illustrates several drawings of a composition
supported by the drug delivery device illustrated in FIG. 56.
[0082] FIG. 59 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 56.
[0083] FIG. 60 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 56.
[0084] FIG. 61 illustrates several drawings of a drug delivery
device according to one embodiment of the present invention.
[0085] FIG. 62 is an exploded view of the drug delivery device
illustrated in FIG. 61.
[0086] FIG. 63 illustrates several drawings of a composition
supported by the drug delivery device illustrated in FIG. 61.
[0087] FIG. 64 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 61.
[0088] FIG. 65 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 61.
[0089] FIG. 66 illustrates several drawings of a drug delivery
device according to one embodiment of the present invention.
[0090] FIG. 67 is an exploded view of the drug delivery device
illustrated in FIG. 66.
[0091] FIG. 68 illustrates several drawings of a composition
supported by the drug delivery device illustrated in FIG. 66.
[0092] FIG. 69 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 66.
[0093] FIG. 70 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 66.
[0094] FIG. 71 illustrates several drawings of a drug delivery
device according to one embodiment of the present invention.
[0095] FIG. 72 is an exploded view of the drug delivery device
illustrated in FIG. 71.
[0096] FIG. 73 illustrates several drawings of a composition
supported by the drug delivery device illustrated in FIG. 71.
[0097] FIG. 74 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 71.
[0098] FIG. 75 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 71.
[0099] FIG. 76 illustrates several drawings of a drug delivery
device according to one embodiment of the present invention.
[0100] FIG. 77 is an exploded view of the drug delivery device
illustrated in FIG. 76.
[0101] FIG. 78 illustrates several drawings of a composition
supported by the drug delivery device illustrated in FIG. 76.
[0102] FIG. 79 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 76.
[0103] FIG. 80 illustrates several drawings of a portion of the
drug delivery device illustrated in FIG. 76.
[0104] FIG. 81 shows the release profile for a drug delivery device
according to the present invention.
[0105] FIG. 82 shows the release profile for a drug delivery device
according to the present invention.
[0106] FIG. 83 shows the IOP-lowering effect of a drug delivery
device according to the present invention.
[0107] FIG. 84 shows the release profile of a drug delivery device
according to the present invention.
[0108] FIG. 85 shows the IOP-lowering effect of a drug delivery
device according to the present invention.
[0109] FIG. 86 shows the release profile of a drug delivery device
according to the present invention.
[0110] FIG. 87 shows the IOP-lowering effect of a drug delivery
device according to the present invention.
[0111] FIG. 88 shows the release profile of a drug delivery device
according to the present invention.
[0112] FIG. 89 shows the release profile of a drug delivery device
according to the present invention.
[0113] FIG. 90 shows the release profile of a drug delivery device
according to the present invention.
[0114] FIG. 91 shows the IOP-lowering effect of a drug delivery
device according to the present invention.
[0115] FIG. 92 shows the release profile of a drug delivery device
according to the present invention.
[0116] FIG. 93 shows the release profile of a drug delivery device
according to the present invention.
[0117] FIG. 94 shows the IOP-lowering effect of a drug delivery
device according to the present invention.
[0118] FIG. 95 shows a flowchart for designing drug delivery
devices.
[0119] FIG. 96 shows a flowchart for designing drug delivery
devices.
[0120] FIG. 97 shows solubility characteristics for various active
agents.
DETAILED DESCRIPTION
[0121] Before any embodiments of the invention are explained in
detail, it is to be understood that the invention is not limited in
its application to the details of construction and the arrangement
of components set forth in the following description or illustrated
in the following drawings. The invention is capable of other
embodiments and of being practiced or of being carried out in
various ways. Also, it is to be understood that the phraseology and
terminology used herein is for the purpose of description and
should not be regarded as limiting. The use of "including,"
"comprising," or "having" and variations thereof herein is meant to
encompass the items listed thereafter and equivalents thereof as
well as additional items. Unless specified or limited otherwise,
the terms "mounted," "connected," "supported," and "coupled" and
variations thereof are used broadly and encompass both direct and
indirect mountings, connections, supports, and couplings.
[0122] Although directional references, such as upper, lower,
downward, upward, rearward, bottom, front, rear, etc., may be made
herein in describing the drawings, these references are made
relative to the drawings (as normally viewed) for convenience.
These directions are not intended to be taken literally or limit
the present invention in any form. In addition, terms such as
"first," "second," and "third" are used herein for purposes of
description and are not intended to indicate or imply relative
importance or significance.
[0123] FIG. 1 illustrates a drug delivery device 10 according to
one embodiment of the present invention. The drug delivery device
10 comprises a non-bioabsorbable polymer structure 14 which
encloses a composition 18 comprising an active agent. The active
agent is released through the polymer structure once the drug
delivery device is implanted in the desired portion of the
body.
[0124] The non-bioabsorbable polymer structure 14 comprises, in one
embodiment shown in FIG. 1, a mixture comprising a water-soluble
polymer and a non-water soluble polymer with about 0% to about 50%
by weight of the mixture being the water-soluble polymer or about
10% to about 30% by weight. Suitably, the drug delivery device 10
at least partially bioerodes when implanted in the body as the
water-soluble polymer dissolves leaving a porous non-bioabsorbable
polymer structure through which the active agent is released. The
polymer structure 14 suitably has a thickness of about 20
micrometers to about 800 micrometers or about 40 micrometers to
about 500 micrometers or about 50 micrometers to about 250
micrometers, depending on the overall size and required mechanical
strength of the device 10.
[0125] The non-water soluble polymer may be selected from ethylene
vinyl acetate (EVA), silicon rubber polymers, polydimethylsiloxane
(PDMS), polyurethane (PU), polyesterurethanes, polyetherurethanes,
polyolefins, polyethylenes (PE), low density polyethylene (LDPE),
polypropylene (PP), polyetheretherketone (PEEK), polysulfone (PSF),
polyphenylsulfone, polyacetals, polymethyl methacrylate (PMMA),
polybutymethacrylate, plasticized polyethyleneterephthalate,
polyisoprene, polyisobutylene, silicon-carbon copolymers, natural
rubber, plasticized soft nylon, polytetrafluoroethylene (PTFE), or
combinations thereof. Suitably, the non-water soluble polymer is
EVA. The vinyl acetate content may be from about 9% to about 50% by
weight (EVA-9-50). In one embodiment, the vinyl acetate content is
about 40% by weight (EVA-40). Other suitable non-water soluble
polymers are known to those of ordinary skill in the art.
[0126] The water-soluble polymer may be selected from dextran,
cyclodextrin, poly-(L-lactic acid), polycaprolactone,
poly(lactic-co-glycolic acid), poly(glycolic acid),
poly(trimethylene carbonate), polydioxanone or combinations
thereof. Other suitable water-soluble polymers are known to those
of ordinary skill in the art.
[0127] Alternatively, in an embodiment shown in FIG. 2, the
non-bioabsorbable polymer structure 14 comprises an impermeable
polymer 22 and a partially-bioerodible membrane 26. Suitably, about
0% to about 50% by weight of the polymer structure 14 is the
partially-bioerodible membrane 26 or about 10% to about 30% by
weight of the partially-bioerodible membrane 26. The impermeable
polymer 22 does not allow the passage of the active agent and
provides mechanical strength for the device 10. The impermeable
polymer 22 suitably has a thickness of about 50 micrometers to
about 800 micrometers or about 100 micrometers to about 250
micrometers, depending on the overall size and required mechanical
strength of the device 10. The partially-bioerodible membrane 26
suitably has a thickness of about 20 micrometers to about 800
micrometers or about 40 micrometers to about 500 micrometers,
depending on the overall size and required mechanical strength of
the device 10.
[0128] Suitable impermeable polymers 22 include, but are not
limited to, EVA-9-50, silicon rubber polymers, polydimethylsiloxane
(PDMS), polyurethane (PU), polyesterurethanes, polyetherurethanes,
polyolefins, polyethylenes (PE), low density polyethylene (LDPE),
polypropylene (PP), polyetheretherketone (PEEK), polysulfone (PSF),
polyphenylsulfone, polyacetals, polymethyl methacrylate (PMMA),
polybutylmethacrylate, plasticized polyethyleneterephthalate,
polyisoprene, polyisobutylene, silicon-carbon copolymers, natural
rubber, plasticized soft nylon, polytetrafluoroethylene (PTFE), or
combinations thereof. Other suitable impermeable polymers 22 are
known to those of ordinary skill in the art.
[0129] In some embodiments, the partially-bioerodible membrane 26
comprises an impermeable polymer and a bioerodible polymer.
Suitably, the partially-bioerodible membrane 26 contains about 0%
to about 50% by weight of the bioerodible polymer. Suitable
bioerodible polymers include, but are not limited to, dextran,
cyclodextrin, poly-(L-lactic acid), polycaprolactone,
poly(lactic-co-glycolic acid), poly(glycolic acid),
poly(trimethylene carbonate), polydioxanone, or combinations
thereof. Other suitable bioerodible polymers are known to those of
ordinary skill in the art.
[0130] In another embodiment also encompassed by FIG. 2, the
non-bioabsorbable polymer structure 14 comprises an impermeable
polymer 22 and a rate-limiting water-permeable polymer 30.
Suitably, the polymer structure contains about 0% to about 50% by
weight of the rate-limiting water-permeable polymer or about 10% to
about 30% by weight of the rate-limiting water-permeable polymer.
The impermeable polymer 22 does not allow the passage of the active
agent and provides mechanical strength for the device 10. The
impermeable polymer 22 suitably has a thickness of about 50
micrometers to about 800 micrometers or about 100 micrometers to
about 250 micrometers, depending on the overall size and required
mechanical strength of the device 10.
[0131] Suitable impermeable polymers 22 include, but are not
limited to, EVA-9-50, silicon rubber polymers, polydimethylsiloxane
(PDMS), polyurethane (PU), polyesterurethanes, polyetherurethanes,
polyolefins, polyethylenes (PE), low density polyethylene (LDPE),
polypropylene (PP), polyetheretherketone (PEEK), polysulfone (PSF),
polyphenylsulfone, polyacetals, polymethyl methacrylate (PMMA),
polybutylmethacrylate, plasticized polyethyleneterephthalate,
polyisoprene, polyisobutylene, silicon-carbon copolymers, natural
rubber, plasticized soft nylon, polytetrafluoroethylene (PTFE), or
combinations thereof. Other suitable impermeable polymers 22 are
known to those of ordinary skill in the art.
[0132] The rate-limiting water-permeable polymer 30 is a polymer
that allows for the passage of active agent and water or tissue
fluids. The composition and/or thickness of this polymer determines
the rate of release from the drug delivery device. The
water-permeable polymer 30 has limited water permeability which
only allows water passage into the drug core 18 at a very slow
rate. Once water penetrates the polymer 30 into the enclosed drug
core 18, it then serves as a solvent to dissolve the active agent
to its solubility limit. Therefore, the active agent suitably has
low or moderate solubility. In one embodiment, the majority of the
active agent remains as a solid compressed form and the
concentration of the dissolved aqueous portion remains at its
solubility limit, so that the concentration gradient across the
polymer remains substantially constant, given that the clearance
rate is sufficient in the environment. Without wishing to be bound
by theory, in one embodiment the above described mechanisms allow
this polymer to provide the rate-limiting steps that allow the
active agent to be released at a substantially constant rate until
at least about 70% to at most about 95% of the active agent is
released from the drug delivery device. The rate-limiting
water-permeable polymer 30 suitably has a thickness of about 20
micrometers to about 500 micrometers, depending on the overall size
and required mechanical strength of the device 10.
[0133] Suitable rate-limiting water-permeable polymers 30 may be
selected from ethylene vinyl acetate with a vinyl acetate content
of about 26% to about 80% by weight (EVA-26-80) or ethylene vinyl
alcohol with a vinyl alcohol content of about 40% to about 80% by
weight (EVOH-40-80). Suitable rate-limiting water-permeable
polymers 30 may be copolymers that have both hydrophobic and
hydrophilic monomers where the hydrophilic portion allows the
passage of water or tissue fluids and the hydrophobic portion
limits its water-permeability in order to provide the rate-limiting
barrier. Other suitable rate-limiting water-permeable polymers are
known to those of ordinary skill in the art.
[0134] In some embodiments, the drug delivery device 10 has a
cylindrical structure. Suitably, the cylindrical structure
comprises a cylindrical wall, a top and a bottom. The top and the
bottom are coupled to opposite sides of the cylindrical wall. In
some embodiments, the cylindrical wall and top comprise the
impermeable polymer 22 and the bottom comprises the
partially-bioerodible membrane 26 or rate-limiting water-permeable
polymer 30. In other embodiments, drug delivery device 10 can be
spherical, tubular, rod-shaped, or the like.
[0135] FIG. 3 illustrates one embodiment of a drug delivery device
10 inserted or implanted in the eye. For episcleral implantation, a
small incision (.about.3 mm) is made in the conjunctiva near the
limbus in the superior temporal episcleral zone of the eye, and a
drug delivery device 10 according to one embodiment of the present
invention is introduced through the incision into the sub-Tenon's
space. Closing the conjunctival incision by suture is optional. For
supraconjunctival placement, a drug delivery device 10 according to
one embodiment of the present invention is gently inserted into the
upper or lower formix of the eye. Depending on the size/shape and
desired duration of use, the drug delivery device 10 may be sutured
to the conjunctiva to immobilize such device.
[0136] Although FIG. 3 illustrates one embodiment of a drug
delivery device 10 inserted in the eye, any one of the drug
delivery devices disclosed herein can be inserted or implanted in
the eye as described above.
[0137] FIGS. 4-8 illustrate a drug delivery device 34 according to
another embodiment of the present invention. The drug delivery
device 34 is generally cylindrical-shaped and includes a first
portion 38 and a second portion 42. The first portion 38 includes a
bottom surface 46, a top surface 50, and an outer side surface 54
positioned between and extending around a periphery of the bottom
surface 46 and the top surface 50. The first portion 38 includes a
recess 58 defined by an inner side wall 62 and a bottom surface 66.
The bottom surface 66 is positioned a predetermined distance from
the bottom surface 46.
[0138] The recess 54 is configured to support the composition 18
comprising an active agent (as discussed above). The dimensions of
the recess 58 are similar to the dimensions of the composition 18
such that the composition 18 (in its undissolved state or
pre-insertion state) cannot move freely within the recess 58. The
inner side wall 62 is generally concentric with the outer side
surface 54 and is spaced from the outer side surface 54 around its
entire circumference. The outer side surface 54 includes a first
diameter 70, and the inner side wall 62 includes a second diameter
74. The first diameter 70 is generally greater than the second
diameter 74.
[0139] The second portion 42 includes a bottom surface 78, a top
surface 82, and a side surface 86 positioned between and extending
around a periphery of the bottom surface 78 and the top surface 82.
The bottom surface 78 of the second portion 42 interfaces with the
top surface 50 of the first portion 38 to enclose the composition
18 within the recess 58.
[0140] The first portion 38 comprises an impermeable polymer 22 as
discussed above. The impermeable polymer 22 does not allow the
passage of the active agent and provides mechanical strength for
the device 34. The impermeable polymer 22 suitably has a thickness
of about 50 micrometers to about 800 micrometers or about 100
micrometers to about 250 micrometers, depending on the overall size
and required mechanical strength of the device 34.
[0141] The second portion 42 comprises a rate-limiting
water-permeable polymer 30 as discussed above. The rate-limiting
water-permeable polymer 30 is a polymer that allows for the passage
of the active agent and water or tissue fluids. The composition
and/or thickness of this polymer determines the rate of release
from the drug delivery device. The rate-limiting water-permeable
polymer 30 suitably has a thickness of about 20 micrometers to
about 500 micrometers, depending on the overall size and required
mechanical strength of the device 34.
[0142] FIGS. 9-13 illustrate a drug delivery device 90 according to
another embodiment of the present invention. The drug delivery
device 90 is generally cylindrical-shaped and includes a first
portion 94 and a second portion 98. The first portion 94 includes a
bottom surface 102, a top surface 106, and an outer side surface
110 positioned between and extending around a periphery of the
bottom surface 102 and the top surface 106. The first portion 94
includes a recess 114 defined by an inner side wall 118 and a
bottom surface 122. The bottom surface 122 is positioned a
predetermined distance from the bottom surface 102.
[0143] The recess 114 is configured to support the composition 18
comprising an active agent (as discussed above). The recess 114
includes an axis extending between the bottom surface 122 and the
top surface 106. The dimensions of the recess 114 are similar to
the dimensions of the composition 18, but extra space exists
between the top surface 106 and the composition 18 and/or between
the bottom surface 122 and the composition 18, such that the
composition 18 (in its undissolved state or pre-insertion state)
can move along the axis within the recess 114. The inner side wall
118 is generally concentric with the outer side surface 110 and is
spaced from the outer side surface 110 around its entire
circumference. The outer side surface 110 includes a first diameter
126, and the inner side wall 118 includes a second diameter 130.
The first diameter 126 is generally greater than the second
diameter 130.
[0144] The second portion 98 includes a bottom surface 134, a top
surface 138, and a side surface 142 positioned between and
extending around a periphery of the bottom surface 134 and the top
surface 138. The bottom surface 134 of the second portion 98
interfaces with the top surface 106 of the first portion 94 to
enclose the composition 18 within the recess 114.
[0145] The first portion 94 comprises an impermeable polymer 22 as
discussed above. The impermeable polymer 22 does not allow the
passage of the active agent and provides mechanical strength for
the device 90. The impermeable polymer 22 suitably has a thickness
of about 50 micrometers to about 800 micrometers or about 100
micrometers to about 250 micrometers, depending on the overall size
and required mechanical strength of the device 90.
[0146] The second portion 98 comprises a rate-limiting
water-permeable polymer 30 as discussed above. The rate-limiting
water-permeable polymer 30 is a polymer that allows for the passage
of the active agent and water or tissue fluids. The composition
and/or thickness of this polymer determines the rate of release
from the drug delivery device. The rate-limiting water-permeable
polymer 30 suitably has a thickness of about 20 micrometers to
about 500 micrometers, depending on the overall size and required
mechanical strength of the device 90.
[0147] FIGS. 14-18 illustrate a drug delivery device 146 according
to another embodiment of the present invention. The drug delivery
device 146 is generally cylindrical-shaped and includes a first
portion 150 and a second portion 154. The first portion 150
includes a bottom surface 158, a top surface 162, and an outer side
surface 166 positioned between and extending around a periphery of
the bottom surface 158 and the top surface 162. The first portion
150 includes a recess 170 defined by an inner side wall 174 and a
bottom surface 178. The bottom surface 178 is positioned a
predetermined distance from the bottom surface 158.
[0148] The recess 170 is configured to support the composition 18
comprising an active agent (as discussed above). The dimensions of
the recess 170 are similar to the dimensions of the composition 18
such that the composition 18 (in its undissolved state or
pre-insertion state) cannot move freely within the recess 170. The
inner side wall 174 is generally concentric with the outer side
surface 166 and is spaced from the outer side surface 166 around
its entire circumference. The outer side surface 166 includes a
first diameter 182, and the inner side wall 174 includes a second
diameter 186. The first diameter 182 is generally greater than the
second diameter 186.
[0149] The second portion 154 includes a bottom surface 190, a top
surface 194, and a side surface 198 positioned between and
extending around a periphery of the bottom surface 190 and the top
surface 194. The bottom surface 190 of the second portion 154
interfaces with the top surface 162 of the first portion 150 to
enclose the composition 18 within the recess 170.
[0150] The first portion 150 comprises an impermeable polymer 22 as
discussed above. The impermeable polymer 22 does not allow the
passage of the active agent and provides mechanical strength for
the device 146. The impermeable polymer 22 suitably has a thickness
of about 50 micrometers to about 800 micrometers or about 100
micrometers to about 250 micrometers, depending on the overall size
and required mechanical strength of the device 146.
[0151] The second portion 154 comprises a rate-limiting
water-permeable polymer 30 as discussed above. The rate-limiting
water-permeable polymer 30 is a polymer that allows for the passage
of the active agent and water or tissue fluids. The composition
and/or thickness of this polymer determines the rate of release
from the drug delivery device. The rate-limiting water-permeable
polymer 30 suitably has a thickness of about 20 micrometers to
about 500 micrometers, depending on the overall size and required
mechanical strength of the device 146.
[0152] FIGS. 19-24 illustrate a drug delivery device 202 according
to another embodiment of the present invention. The drug delivery
device 202 is generally cylindrical-shaped and includes a first
portion 206 and a second portion 210. The first portion 206
includes a bottom surface 214, a top surface 218, and an outer side
surface 222 positioned between and extending around a periphery of
the bottom surface 214 and the top surface 218. The first portion
206 includes a recess 226 defined by an inner side wall 230 and a
bottom surface 234. The bottom surface 234 is positioned a
predetermined distance from the bottom surface 214.
[0153] The recess 226 is configured to support the composition 18
comprising an active agent (as discussed above). The dimensions of
the recess 226 are similar to the dimensions of the composition 18
such that the composition 18 (in its undissolved state or
pre-insertion state) cannot move freely within the recess 226. The
inner side wall 230 is generally concentric with the outer side
surface 222 and is spaced from the outer side surface 222 around
its entire circumference. The outer side surface 222 includes a
first diameter 234, and the inner side wall 230 includes a second
diameter 238. The first diameter 234 is generally greater than the
second diameter 238.
[0154] The second portion 210 includes a bottom surface 242, a top
surface 246, and a side surface 250 positioned between and
extending around a periphery of the bottom surface 242 and the top
surface 246. The bottom surface 242 of the second portion 210
interfaces with the top surface 246 of the first portion 206 to
enclose the composition 18 within the recess 226.
[0155] The device 202 also includes a flange 254 such as a surgical
suture tab configured to secure the device to an anchor point with
a surgical suture(s). The flange 254 is connected to the second
portion 210 and extends therefrom. The flange 254 includes a base
258, a first arm 262 extending from the base 258, and a second arm
266 extending from the base 258. The base 258 and the first and
second arms 262, 266 are integrally molded and form a recess 270
configured to receive at least a portion of the second portion 210.
In one construction, the recess 270 is configured to receive about
one-half the circumference of the side surface 250. In other
constructions, the recess 270 can be configured to receive more or
less than one-half the circumference of the side surface 250. The
base 258 can include one or more apertures 274 configured to
receive a surgical suture. The apertures 274 are not necessary,
however, as a surgical suture needle can penetrate the flange 254
to secure the device 202 in a suitable position. The recess 270 of
the flange 254 is connected to side surface 250 of the second
portion 210 in a thermal process that involves the application of
heat to fuse the flange 254 to the side surface 250. A suitable
application of heat is in the range of about 90 degrees C. to about
102 degrees C. to fuse the flange 254 to the side surface 250.
[0156] The first portion 206 comprises an impermeable polymer 22 as
discussed above. The impermeable polymer 22 does not allow the
passage of the active agent and provides mechanical strength for
the device 202. The impermeable polymer 22 suitably has a thickness
of about 50 micrometers to about 800 micrometers or about 100
micrometers to about 250 micrometers, depending on the overall size
and required mechanical strength of the device 202.
[0157] The second portion 210 comprises a rate-limiting
water-permeable polymer 30 as discussed above. The rate-limiting
water-permeable polymer 30 is a polymer that allows for the passage
of the active agent and water or tissue fluids. The composition
and/or thickness of this polymer determines the rate of release
from the drug delivery device. The rate-limiting water-permeable
polymer 30 suitably has a thickness of about 20 micrometers to
about 500 micrometers, depending on the overall size and required
mechanical strength of the device 202.
[0158] FIGS. 25-30 illustrate a drug delivery device 278 according
to another embodiment of the present invention. The drug delivery
device 278 is generally cylindrical-shaped and includes a first
portion 282 and a second portion 286. The first portion 282
includes a bottom surface 290, a top surface 294, and an outer side
surface 298 positioned between and extending around a periphery of
the bottom surface 290 and the top surface 294. The first portion
282 includes a recess 302 defined by an inner side wall 306 and a
bottom surface 310. The bottom surface 310 is positioned a
predetermined distance from the bottom surface 290.
[0159] The recess 302 is configured to support the composition 18
comprising an active agent (as discussed above). The dimensions of
the recess 302 are similar to the dimensions of the composition 18
such that the composition 18 (in its undissolved state or
pre-insertion state) cannot move freely within the recess 302. The
inner side wall 306 is generally concentric with the outer side
surface 298 and is spaced from the outer side surface 298 around
its entire circumference. The outer side surface 298 includes a
first diameter 314, and the inner side wall 306 includes a second
diameter 318. The first diameter 314 is generally greater than the
second diameter 318.
[0160] The second portion 286 includes a bottom surface 322, a top
surface 326, and a side surface 330 positioned between and
extending around a periphery of the bottom surface 322 and the top
surface 326. The bottom surface 322 of the second portion 286
interfaces with the top surface 294 of the first portion 284 to
enclose the composition 18 within the recess 302.
[0161] The device 278 also includes a flange 334 such as a surgical
suture tab configured to secure the device to an anchor point with
a surgical suture(s). The flange 334 is connected to the second
portion 286 and extends therefrom. The flange 334 includes a base
338, a first arm 342 extending from the base 338, and a second arm
346 extending from the base 338. The base 338 and the first and
second arms 342, 346 are integrally molded and form a recess 350
configured to receive at least a portion of the second portion 286.
In one construction, the recess 350 is configured to receive about
one-half the circumference of the side surface 330. In other
constructions, the recess 350 can be configured to receive more or
less than one-half the circumference of the side surface 330. The
base 338 can include one or more apertures 354 configured to
receive a surgical suture. The apertures 354 are not necessary,
however, as a surgical suture needle can penetrate the flange 334
to secure the device 278 in a suitable position. The recess 350 of
the flange 334 is connected to side surface 330 of the second
portion 286 in a thermal process that involves the application of
heat to fuse the flange 334 to the side surface 330. A suitable
application of heat is in the range of about 90 degrees C. to about
102 degrees C. to fuse the flange 334 to the side surface 330.
[0162] The first portion 282 comprises an impermeable polymer 22 as
discussed above. The impermeable polymer 22 does not allow the
passage of the active agent and provides mechanical strength for
the device 278. The impermeable polymer 22 suitably has a thickness
of about 50 micrometers to about 800 micrometers or about 100
micrometers to about 250 micrometers, depending on the overall size
and required mechanical strength of the device 278.
[0163] The second portion 286 comprises a rate-limiting
water-permeable polymer 30 as discussed above. The rate-limiting
water-permeable polymer 30 is a polymer that allows for the passage
of the active agent and water or tissue fluids. The composition
and/or thickness of this polymer determines the rate of release
from the drug delivery device. The rate-limiting water-permeable
polymer 30 suitably has a thickness of about 20 micrometers to
about 500 micrometers, depending on the overall size and required
mechanical strength of the device 278.
[0164] FIGS. 31-35 illustrate a drug delivery device 358 according
to another embodiment of the present invention. The drug delivery
device 358 is generally cylindrical-shaped and includes a first
portion 362 and a second portion 366. The first portion 362
includes a bottom surface 370, a top surface 374, and an outer side
surface 378 positioned between and extending around a periphery of
the bottom surface 370 and the top surface 374. The first portion
362 includes a recess 382 defined by an inner side wall 386 and a
bottom surface 390. The bottom surface 390 is positioned a
predetermined distance from the bottom surface 370.
[0165] The recess 382 is configured to support the composition 18
comprising an active agent (as discussed above). The dimensions of
the recess 382 are similar to the dimensions of the composition 18
such that the composition 18 (in its undissolved state or
pre-insertion state) cannot move freely within the recess 382. The
inner side wall 386 is generally concentric with the outer side
surface 378 and is spaced from the outer side surface 378 around
its entire circumference. The outer side surface 378 includes a
first diameter 394, and the inner side wall 386 includes a second
diameter 398. The first diameter 394 is generally greater than the
second diameter 398.
[0166] The second portion 366 includes a bottom surface 402, a top
surface 406, and a side surface 410 positioned between and
extending around a periphery of the bottom surface 402 and the top
surface 406. The bottom surface 402 of the second portion 366
interfaces with the top surface 374 of the first portion 362 to
enclose the composition 18 within the recess 382. The second
portion 366 includes a base 414 and a portion 418 extending from
the base 414. The portion 418 also at least partially extends
outside of the side surface 378. The portion 418 can include one or
more apertures 422 configured to receive a surgical suture. The
apertures 422 are not necessary, however, as a surgical suture
needle can penetrate the portion 418 to secure the device 358 in a
suitable position. The bottom surface 402 of the second portion 366
is connected to the top surface 374 of the first portion 362 in a
thermal process that involves the application of heat to fuse the
bottom surface 402 to the top surface 374. A suitable application
of heat is in the range of about 90 degrees C. to about 102 degrees
C. to fuse the bottom surface 402 to the top surface 374.
[0167] The first portion 362 comprises an impermeable polymer 22 as
discussed above. The impermeable polymer 22 does not allow the
passage of the active agent and provides mechanical strength for
the device 358. The impermeable polymer 22 suitably has a thickness
of about 50 micrometers to about 800 micrometers or about 100
micrometers to about 250 micrometers, depending on the overall size
and required mechanical strength of the device 358.
[0168] The second portion 366 (including the portion 418) comprises
a rate-limiting water-permeable polymer 30 as discussed above. The
rate-limiting water-permeable polymer 30 is a polymer that allows
for the passage of the active agent and water or tissue fluids. The
composition and/or thickness of this polymer determines the rate of
release from the drug delivery device. The rate-limiting
water-permeable polymer 30 suitably has a thickness of about 20
micrometers to about 500 micrometers, depending on the overall size
and required mechanical strength of the device 358.
[0169] FIGS. 36-40 illustrate a drug delivery device 426 according
to another embodiment of the present invention. The drug delivery
device 426 is generally cylindrical-shaped and includes a first
portion 430 and a second portion 434. The first portion 430
includes a bottom surface 438, a top surface 442, and an outer side
surface 446 positioned between and extending around a periphery of
the bottom surface 438 and the top surface 442. The first portion
430 includes a recess 450 defined by an inner side wall 454 and a
bottom surface 458. The bottom surface 458 is positioned a
predetermined distance from the bottom surface 438.
[0170] The recess 450 is configured to support the composition 18
comprising an active agent (as discussed above). The dimensions of
the recess 450 are similar to the dimensions of the composition 18
such that the composition 18 (in its undissolved state or
pre-insertion state) cannot move freely within the recess 450. The
inner side wall 454 is generally concentric with the outer side
surface 446 and is spaced from the outer side surface 446 around
its entire circumference. The outer side surface 446 includes a
first diameter 462, and the inner side wall 454 includes a second
diameter 466. The first diameter 462 is generally greater than the
second diameter 466.
[0171] The second portion 434 includes a bottom surface 470, a top
surface 474, and a side surface 478 positioned between and
extending around a periphery of the bottom surface 470 and the top
surface 474. The bottom surface 470 of the second portion 434
interfaces with the top surface 442 of the first portion 430 to
enclose the composition 18 within the recess 450. The second
portion 434 includes a base 482 and a portion 486 extending from
the base 482. The portion 486 also at least partially extends
outside of the side surface 446. The portion 486 can include one or
more apertures 490 configured to receive a surgical suture. The
apertures 490 are not necessary, however, as a surgical suture
needle can penetrate the portion 486 to secure the device 426 in a
suitable position. The bottom surface 470 of the second portion 434
is connected to the top surface 442 of the first portion 430 in a
thermal process that involves the application of heat to fuse the
bottom surface 470 to the top surface 442. A suitable application
of heat is in the range of about 90 degrees C. to about 102 degrees
C. to fuse the bottom surface 470 to the top surface 442.
[0172] The first portion 430 comprises an impermeable polymer 22 as
discussed above. The impermeable polymer 22 does not allow the
passage of the active agent and provides mechanical strength for
the device 426. The impermeable polymer 22 suitably has a thickness
of about 50 micrometers to about 800 micrometers or about 100
micrometers to about 250 micrometers, depending on the overall size
and required mechanical strength of the device 426.
[0173] The second portion 434 (including the portion 486) comprises
a rate-limiting water-permeable polymer 30 as discussed above. The
rate-limiting water-permeable polymer 30 is a polymer that allows
for the passage of the active agent and water or tissue fluids. The
composition and/or thickness of this polymer determines the rate of
release from the drug delivery device. The rate-limiting
water-permeable polymer 30 suitably has a thickness of about 20
micrometers to about 500 micrometers, depending on the overall size
and required mechanical strength of the device 426.
[0174] FIGS. 41-45 illustrate a drug delivery device 494 according
to another embodiment of the present invention. The drug delivery
device 494 is generally cylindrical-shaped and includes a base
portion 498, a middle portion 502, and an upper portion 506. The
base portion 498 includes a bottom surface 510, an upper surface
514, and a side wall 518 positioned between the bottom surface 510
and the upper surface 514 and extending around a periphery of the
bottom surface 510 and the upper surface 514. The side wall 518
includes a first diameter 522.
[0175] The middle portion 502 includes a bottom wall 526, a top
wall 528, an outer side wall 530 having a second diameter 534
substantially the same as the first diameter 522, and an inner side
wall 538 having a third diameter 542 less than the second diameter
534. The inner side wall 538 is generally concentric with the outer
side wall 530 and is spaced from the outer side wall 530 around its
entire circumference. The bottom wall 526 rests upon or is in
contact with the upper surface 514 of the base portion 498. The
middle portion 502 includes an aperture 546 in the bottom wall 526
and the top wall 528 and is surrounded by the inner side wall 538.
The aperture 546 (and the upper surface 514) is configured to
support the composition 18 comprising an active agent (as discussed
above).
[0176] The upper portion 506 includes a bottom surface 550, an
upper surface 554, and a side wall 558 positioned between the
bottom surface 550 and the upper surface 554 and extending around a
periphery of the bottom surface 550 and the upper surface 554. The
bottom surface 550 rests on or is in contact with the middle
portion 502 such that the composition 18 is housed within an
enclosure 562 defined at least partially by the upper surface 514,
the inner side wall 538, and at least a portion of the bottom
surface 550. The side wall 558 includes a fourth diameter 566
substantially the same as the first diameter 522. The dimensions of
the enclosure 562 are similar to the dimensions of the composition
18 such that the composition 18 (in its undissolved state or
pre-insertion state) cannot move freely within the enclosure
562.
[0177] The base portion 498, the middle portion 502, and the upper
portion 506 comprise a rate-limiting water-permeable polymer 30 as
discussed above. The rate-limiting water-permeable polymer 30 is a
polymer that allows for the passage of the active agent and water
or tissue fluids. The composition and/or thickness of this polymer
determines the rate of release from the drug delivery device. The
rate-limiting water-permeable polymer 30 suitably has a thickness
of about 20 micrometers to about 500 micrometers, depending on the
overall size and required mechanical strength of the device
494.
[0178] FIGS. 46-50 illustrate a drug delivery device 570 according
to another embodiment of the present invention. The drug delivery
device 570 is generally cylindrical-shaped and includes a base
portion 574, a middle portion 578, and an upper portion 582. The
base portion 574 includes a bottom surface 586, an upper surface
590, and a side wall 594 positioned between the bottom surface 586
and the upper surface 590 and extending around a periphery of the
bottom surface 586 and the upper surface 590. The side wall 594
includes a first diameter 598.
[0179] The middle portion 578 includes a bottom wall 602, a top
wall 604, an outer side wall 606 having a second diameter 610
substantially the same as the first diameter 598, and an inner side
wall 614 having a third diameter 618 less than the second diameter
610. The inner side wall 614 is generally concentric with the outer
side wall 606 and is spaced from the outer side wall 606 around its
entire circumference. The bottom wall 602 rests upon or is in
contact with the upper surface 590 of the base portion 574. The
middle portion 578 includes an aperture 622 in the bottom wall 602
and the top wall 604 and is surrounded by the inner side wall 614.
The aperture 622 (and the upper surface 590) is configured to
support the composition 18 comprising an active agent (as discussed
above).
[0180] The upper portion 582 includes a bottom surface 626, an
upper surface 630, and a side wall 634 positioned between the
bottom surface 626 and the upper surface 630 and extending around a
periphery of the bottom surface 626 and the upper surface 630. The
bottom surface 626 rests on or is in contact with the middle
portion 578 such that the composition 18 is housed within an
enclosure 638 defined at least partially by the upper surface 590,
the inner side wall 614, and at least a portion of the bottom
surface 626. The side wall 634 includes a fourth diameter 642
substantially the same as the first diameter 598. The dimensions of
the enclosure 638 are similar to the dimensions of the composition
18 such that the composition 18 (in its undissolved state or
pre-insertion state) cannot move freely within the enclosure
638.
[0181] The base portion 574, the middle portion 578, and the upper
portion 582 comprise a rate-limiting water-permeable polymer 30 as
discussed above. The rate-limiting water-permeable polymer 30 is a
polymer that allows for the passage of the active agent and water
or tissue fluids. The composition and/or thickness of this polymer
determines the rate of release from the drug delivery device. The
rate-limiting water-permeable polymer 30 suitably has a thickness
of about 20 micrometers to about 500 micrometers, depending on the
overall size and required mechanical strength of the device
570.
[0182] FIGS. 51-55 illustrate a drug delivery device 646 according
to another embodiment of the present invention. The drug delivery
device 646 is generally cylindrical-shaped and includes a base
portion 650, a middle portion 654, and an upper portion 658. The
base portion 650 includes a bottom surface 662, an upper surface
670, and a side wall 674 positioned between the bottom surface 662
and the upper surface 670 and extending around a periphery of the
bottom surface 662 and the upper surface 670. The side wall 674
includes a first diameter 678.
[0183] The middle portion 654 includes a bottom wall 682, a top
wall 684, an outer side wall 686 having a second diameter 690
substantially the same as the first diameter 678, and an inner side
wall 694 having a third diameter 698 less than the second diameter
690. The inner side wall 694 is generally concentric with the outer
side wall 686 and is spaced from the outer side wall 686 around its
entire circumference. The bottom wall 682 rests upon or is in
contact with the upper surface 670 of the base portion 650. The
middle portion 654 includes an aperture 702 in the bottom wall 682
and the top wall 684 and is surrounded by the inner side wall 694.
The aperture 702 (and the upper surface 670) is configured to
support the composition 18 comprising an active agent (as discussed
above).
[0184] The upper portion 658 includes a bottom surface 706, an
upper surface 710, and a side wall 714 positioned between the
bottom surface 706 and the upper surface 710 and extending around a
periphery of the bottom surface 706 and the upper surface 710. The
bottom surface 706 rests on or is in contact with the middle
portion 654 such that the composition 18 is housed within an
enclosure 718 defined at least partially by the upper surface 670,
the inner side wall 694, and at least a portion of the bottom
surface 706. The side wall 714 includes a fourth diameter 722
substantially the same as the first diameter 678. The dimensions of
the enclosure 718 are similar to the dimensions of the composition
18 such that the composition 18 (in its undissolved state or
pre-insertion state) cannot move freely within the enclosure
718.
[0185] The middle portion 654 comprises an impermeable polymer 22
as discussed above. The impermeable polymer 22 does not allow the
passage of the active agent and provides mechanical strength for
the device 646. The impermeable polymer 22 suitably has a thickness
of about 50 micrometers to about 800 micrometers or about 100
micrometers to about 250 micrometers, depending on the overall size
and required mechanical strength of the device 646.
[0186] The base portion 650, the middle portion 654, and the upper
portion 658 comprise a rate-limiting water-permeable polymer 30 as
discussed above. The rate-limiting water-permeable polymer 30 is a
polymer that allows for the passage of the active agent and water
or tissue fluids. The composition and/or thickness of this polymer
determines the rate of release from the drug delivery device. The
rate-limiting water-permeable polymer 30 suitably has a thickness
of about 20 micrometers to about 500 micrometers, depending on the
overall size and required mechanical strength of the device
646.
[0187] FIGS. 56-60 illustrate a drug delivery device 726 according
to another embodiment of the present invention. The drug delivery
device 726 is generally cylindrical-shaped and includes a base
portion 730, a middle portion 734, and an upper portion 738. The
base portion 730 includes a bottom surface 742, an upper surface
746, and a side wall 750 positioned between the bottom surface 742
and the upper surface 746 and extending around a periphery of the
bottom surface 742 and the upper surface 746. The side wall 750
includes a first diameter 754.
[0188] The middle portion 734 includes a bottom wall 758, a top
wall 760, an outer side wall 762 having a second diameter 766
substantially the same as the first diameter 754, and an inner side
wall 770 having a third diameter 774 less than the second diameter
766. The inner side wall 770 is generally concentric with the outer
side wall 762 and is spaced from the outer side wall 762 around its
entire circumference. The bottom wall 758 rests upon or is in
contact with the upper surface 746 of the base portion 730. The
middle portion 734 includes an aperture 778 in the bottom wall 758
and the top wall 760 and is surrounded by the inner side wall 770.
The aperture 778 (and the upper surface 746) is configured to
support the composition 18 comprising an active agent (as discussed
above).
[0189] The upper portion 738 includes a bottom surface 782, an
upper surface 786, and a side wall 790 positioned between the
bottom surface 782 and the upper surface 786 and extending around a
periphery of the bottom surface 782 and the upper surface 786. The
bottom surface 782 rests on or is in contact with the middle
portion 734 such that the composition 18 is housed within an
enclosure 794 defined at least partially by the upper surface 746,
the inner side wall 770, and at least a portion of the bottom
surface 782. The side wall 790 includes a fourth diameter 798
substantially the same as the first diameter 754. The dimensions of
the enclosure 794 are similar to the dimensions of the composition
18 such that the composition 18 (in its undissolved state or
pre-insertion state) cannot move freely within the enclosure
794.
[0190] The base portion 730, the middle portion 734, and the upper
portion 738 comprise a rate-limiting water-permeable polymer 30 as
discussed above. The rate-limiting water-permeable polymer 30 is a
polymer that allows for the passage of the active agent and water
or tissue fluids. The composition and/or thickness of this polymer
determines the rate of release from the drug delivery device. The
rate-limiting water-permeable polymer 30 suitably has a thickness
of about 20 micrometers to about 500 micrometers, depending on the
overall size and required mechanical strength of the device
726.
[0191] FIGS. 61-65 illustrate a drug delivery device 802 according
to another embodiment of the present invention. The drug delivery
device 802 is generally cylindrical-shaped and includes a base
portion 806, a middle portion 810, and an upper portion 814. The
base portion 806 includes a bottom surface 818, an upper surface
822, and a side wall 826 positioned between the bottom surface 818
and the upper surface 822 and extending around a periphery of the
bottom surface 818 and the upper surface 822. The side wall 826
includes a first diameter 830.
[0192] The middle portion 810 includes a bottom wall 834, a top
wall 836, an outer side wall 838 having a second diameter 842
substantially the same as the first diameter 830, and an inner side
wall 846 having a third diameter 850 less than the second diameter
842. The inner side wall 846 is generally concentric with the outer
side wall 838 and is spaced from the outer side wall 838 around its
entire circumference. The bottom wall 834 rests upon or is in
contact with the upper surface 822 of the base portion 806. The
middle portion 810 includes an aperture 854 in the bottom wall 834
and the top wall 836 and is surrounded by the inner side wall 846.
The aperture 854 (and the upper surface 822) is configured to
support the composition 18 comprising an active agent (as discussed
above).
[0193] The upper portion 814 includes a bottom surface 858, an
upper surface 862, and a side wall 866 positioned between the
bottom surface 858 and the upper surface 862 and extending around a
periphery of the bottom surface 858 and the upper surface 862. The
bottom surface 858 rests on or is in contact with the middle
portion 810 such that the composition 18 is housed within an
enclosure 870 defined at least partially by the upper surface 822,
the inner side wall 846, and at least a portion of the bottom
surface 858. The side wall 866 includes a fourth diameter 874
substantially the same as the first diameter 830. The dimensions of
the enclosure 870 are similar to the dimensions of the composition
18 such that the composition 18 (in its undissolved state or
pre-insertion state) cannot move freely within the enclosure
870.
[0194] The base portion 806, the middle portion 810, and the upper
portion 814 comprise a rate-limiting water-permeable polymer 30 as
discussed above. The rate-limiting water-permeable polymer 30 is a
polymer that allows for the passage of the active agent and water
or tissue fluids. The composition and/or thickness of this polymer
determines the rate of release from the drug delivery device. The
rate-limiting water-permeable polymer 30 suitably has a thickness
of about 20 micrometers to about 500 micrometers, depending on the
overall size and required mechanical strength of the device
802.
[0195] FIGS. 66-70 illustrate a drug delivery device 880 according
to another embodiment of the present invention. The drug delivery
device 880 is generally elliptical-shaped and is adapted to conform
to the curvature of the eye. The materials of the drug delivery
device 880 include suitable properties that provide flexibility to
allow the device 880 to flex and conform to the curvature or shape
of the eye. The drug delivery device 880 includes a base portion
884, a middle portion 888, and an upper portion 892. The base
portion 884 includes a bottom surface 896, an upper surface 900,
and a side wall 904 positioned between the bottom surface 896 and
the upper surface 900 and extending around a periphery of the
bottom surface 896 and the upper surface 900.
[0196] The middle portion 888 includes a bottom wall 908, a top
wall 910, an outer side wall 912, and an inner side wall 916. The
inner side wall 916 is spaced from the outer side wall 912. The
bottom wall 908 rests upon or is in contact with the upper surface
900 of the base portion 884. The middle portion 888 includes an
aperture 920 in the bottom wall 908 and the top wall 910 and is
surrounded by the inner side wall 916. The aperture 920 (and the
upper surface 900) is configured to support the composition 18
comprising an active agent (as discussed above). The aperture 920
is generally circular-shaped as illustrated, however the aperture
920 may have a different but suitable shape to accommodate the
shape of the composition 18. For example, the aperture 920 may be
elliptical-shaped similar to the outer side wall 912. The aperture
920 may be concentric or non-concentric with the outer side wall
912.
[0197] The upper portion 892 includes a bottom surface 924, an
upper surface 928, and a side wall 932 positioned between the
bottom surface 924 and the upper surface 928 and extending around a
periphery of the bottom surface 924 and the upper surface 928. The
bottom surface 924 rests on or is in contact with the middle
portion 888 such that the composition 18 is housed within an
enclosure 936 defined at least partially by the upper surface 900,
the inner side wall 916, and at least a portion of the bottom
surface 924. The dimensions of the enclosure 936 are similar to the
dimensions of the composition 18 such that the composition 18 (in
its undissolved state or pre-insertion state) cannot move freely
within the enclosure 936.
[0198] The base portion 884, the middle portion 888, and the upper
portion 892 comprise a rate-limiting water-permeable polymer 30 as
discussed above. The rate-limiting water-permeable polymer 30 is a
polymer that allows for the passage of the active agent and water
or tissue fluids. The composition and/or thickness of this polymer
determines the rate of release from the drug delivery device. The
rate-limiting water-permeable polymer 30 suitably has a thickness
of about 20 micrometers to about 500 micrometers, depending on the
overall size and required mechanical strength of the device
880.
[0199] FIGS. 71-75 illustrate a drug delivery device 950 according
to another embodiment of the present invention. The drug delivery
device 950 is generally elliptical-shaped and is adapted to conform
to the curvature of the eye. The materials of the drug delivery
device 950 include suitable properties that provide flexibility to
allow the device 950 to flex and conform to the curvature or shape
of the eye. The drug delivery device 950 includes a base portion
954, a middle portion 958, and an upper portion 962. The base
portion 954 includes a bottom surface 966, an upper surface 970,
and a side wall 974 positioned between the bottom surface 966 and
the upper surface 970 and extending around a periphery of the
bottom surface 966 and the upper surface 970.
[0200] The middle portion 958 includes a bottom wall 978, a top
wall 980, an outer side wall 982, a first inner side wall 986 and a
second inner side wall 990. The first and second inner side walls
986, 990 are spaced from the outer side wall 982. The bottom wall
978 rests upon or is in contact with the upper surface 970 of the
base portion 954. The middle portion 958 includes a first aperture
994 and a second aperture 998 in the bottom wall 978 and the top
wall 980 and is surrounded by the first inner side wall 986 and the
second inner side wall 990, respectively. The apertures 994, 998
(and the upper surface 970) are configured to support one or more
of the composition 18 comprising an active agent (as discussed
above). Each of the compositions 18 can comprise the same agents or
different agents or other types of elements that comprise the
composition(s) 18. The apertures 994, 998 are generally
circular-shaped as illustrated, however one or more of the
apertures 994, 998 may have a different but suitable shape to
accommodate the shape of the composition(s) 18. For example, one or
both of the apertures 994, 998 may be elliptical-shaped similar to
the outer side wall 982. One or both of the apertures 994, 998 may
be concentric or non-concentric with the outer side wall 982.
[0201] The upper portion 962 includes a bottom surface 1002, an
upper surface 1006, and a side wall 1010 positioned between the
bottom surface 1002 and the upper surface 1006 and extending around
a periphery of the bottom surface 1002 and the upper surface 1006.
The bottom surface 1002 rests on or is in contact with the middle
portion 958 such that the compositions 18 are housed within a first
enclosure 1014 and a second enclosure 1018 defined at least
partially by the upper surface 970, the inner side walls 986, 990,
and at least a portion of the bottom surface 1002. The dimensions
of the enclosures 1014, 1018 are similar to the dimensions of the
compositions 18 such that the compositions 18 (in its undissolved
state or pre-insertion state) cannot move freely within the
enclosures 1014, 1018.
[0202] The base portion 954, the middle portion 958, and the upper
portion 962 comprise a rate-limiting water-permeable polymer 30 as
discussed above. The rate-limiting water-permeable polymer 30 is a
polymer that allows for the passage of the active agent and water
or tissue fluids. The composition and/or thickness of this polymer
determines the rate of release from the drug delivery device. The
rate-limiting water-permeable polymer 30 suitably has a thickness
of about 20 micrometers to about 500 micrometers, depending on the
overall size and required mechanical strength of the device
950.
[0203] FIGS. 76-80 illustrate a drug delivery device 1030 according
to another embodiment of the present invention. The drug delivery
device 1030 is generally elliptical-shaped and is adapted to
conform to the curvature of the eye. In this construction, the ends
of the device 1030 are rounded in comparison to the device 880
described (and illustrated in FIGS. 66-70) above. The materials of
the drug delivery device 1030 include suitable properties that
provide flexibility to allow the device 1030 to flex and conform to
the curvature or shape of the eye. The drug delivery device 1030
includes a base portion 1034, a middle portion 1038, and an upper
portion 1042. The base portion 1034 includes a bottom surface 1046,
an upper surface 1050, and a side wall 1054 positioned between the
bottom surface 1046 and the upper surface 1050 and extending around
a periphery of the bottom surface 1046 and the upper surface
1050.
[0204] The middle portion 1038 includes a bottom wall 1058, a top
wall 1062, an outer side wall 1066, and an inner side wall 1070.
The inner side wall 1070 is spaced from the outer side wall 1066.
The bottom wall 1058 rests upon or is in contact with the upper
surface 1050 of the base portion 1034. The middle portion 1038
includes an aperture 1074 in the bottom wall 1058 and the top wall
1062 and is surrounded by the inner side wall 1070. The aperture
1074 (and the upper surface 1050) is configured to support the
composition 18 comprising an active agent (as discussed above). The
aperture 1074 is generally circular-shaped as illustrated, however
the aperture 1074 may have a different but suitable shape to
accommodate the shape of the composition 18. For example, the
aperture 1074 may be elliptical-shaped similar to the outer side
wall 1066. The aperture 1074 may be concentric or non-concentric
with the outer side wall 1066.
[0205] The upper portion 1042 includes a bottom surface 1078, an
upper surface 1082, and a side wall 1086 positioned between the
bottom surface 1078 and the upper surface 1082 and extending around
a periphery of the bottom surface 1078 and the upper surface 1082.
The bottom surface 1078 rests on or is in contact with the middle
portion 1038 such that the composition 18 is housed within an
enclosure 1090 defined at least partially by the upper surface
1050, the inner side wall 1070, and at least a portion of the
bottom surface 1078. The dimensions of the enclosure 1090 are
similar to the dimensions of the composition 18 such that the
composition 18 (in its undissolved state or pre-insertion state)
cannot move freely within the enclosure 1090.
[0206] The base portion 1034, the middle portion 1038, and the
upper portion 1042 comprise a rate-limiting water-permeable polymer
30 as discussed above. The rate-limiting water-permeable polymer 30
is a polymer that allows for the passage of the active agent and
water or tissue fluids. The composition and/or thickness of this
polymer determines the rate of release from the drug delivery
device. The rate-limiting water-permeable polymer 30 suitably has a
thickness of about 20 micrometers to about 500 micrometers,
depending on the overall size and required mechanical strength of
the device 1030.
[0207] In some embodiments, the non-bioabsorbable polymer structure
contains a pigment. The pigment is optionally placed into the
impermeable polymer. Suitable pigments include, but are not limited
to, inorganic pigments, organic lake pigments, pearlescent
pigments, fluorescein, and mixtures thereof. Inorganic pigments
useful in this invention include those selected from the group
consisting of rutile or anatase titanium dioxide, coded in the
Color Index under the reference CI 77,891; black, yellow, red and
brown iron oxides, coded under references CI 77,499, 77,492 and,
77,491; manganese violet (CI 77,742); ultramarine blue (CI 77,007);
chromium oxide (CI 77,288); chromium hydrate (CI 77,289); and
ferric blue (CI 77,510) and mixtures thereof.
[0208] The organic pigments and lakes useful in this invention
include those selected from the group consisting of D&C Red No.
19 (CI 45,170), D&C Red No. 9 (CI 15,585), D&C Red No. 21
(CI 45,380), D&C Orange No. 4 (CI 15,510), D&C Orange No. 5
(CI 45,370), D&C Red No. 27 (CI 45,410), D&C Red No. 13 (CI
15,630), D&C Red No. 7 (CI 15,850), D&C Red No. 6 (CI
15,850), D&C Yellow No. 5 (CI 19,140), D&C Red No. 36 (CI
12,085), D&C Orange No. (CI 45,425), D&C Yellow No. 6 (CI
15,985), D&C Red No. 30 (CI 73,360), D&C Red No. 3 (CI
45,430), the dye or lakes based on Cochineal Carmine (CI 75,570)
and mixtures thereof.
[0209] The pearlescent pigments useful in this invention include
those selected from the group consisting of the white pearlescent
pigments such as mica coated with titanium oxide, bismuth
oxychloride, colored pearlescent pigments such as titanium mica
with iron oxides, titanium mica with ferric blue, chromium oxide
and the like, titanium mica with an organic pigment of the
above-mentioned type as well as those based on bismuth oxychloride
and mixtures thereof.
[0210] In a further embodiment, the drug delivery device comprises
a composition comprising an active agent at least partially
encompassed by an impermeable membrane and a permeable membrane,
wherein the permeable membrane controls release of the active agent
episclerally over time.
[0211] About 70% to about 90% of the active agent is suitably
released from the drug delivery device over a period of about 30
days to about 5 years. Alternatively, about 70% to about 90% of the
active agent is released over a period of about 30 days to about 2
years or about 30 days to about 1 year or about 30 days to about 90
days or about 1 year to about 5 years or about 1 year to about 2
years.
[0212] In some embodiments, the active agent is released from any
one of the drug delivery devices at a rate of about 0.0003
micrograms/hr or from about 0.0001 micrograms/hr to about 200
micrograms/hr, or from about 0.0001 micrograms/hr to about 30
micrograms/hr, or from about 0.001 micrograms/hr to about 30
micrograms/hr, or from about 0.001 micrograms/hr to about 10
micrograms/hr.
[0213] Suitably, the rate of release of the active agent does not
deviate substantially from linearity (i.e., does not deviate from
linearity more than about 5%) until at least about 70% and at most
about 95% of the active agent is released from the drug delivery
device.
[0214] Alternatively, about 2% to about 90% of the active agent is
released from the drug delivery device with a coefficient of
determination, R-squared or R2, of the linear regression is at
least about 0.95.
[0215] Dosages may be varied based on the active agent being used,
the patient being treated, the condition being treated, the
severity of the condition being treated, the route of
administration, etc. to achieve the desired effect.
[0216] The drug delivery devices of the present invention can be
used to treat various conditions including, ocular conditions (such
as glaucoma, ocular hypertension, ocular inflammation, uveitis,
macular degenerative conditions, retinal degenerative conditions,
ocular tumors, ocular allergy, and dry eye), topical fungal
infections, topical bacterial infections, dermatitis, peripheral
neuropathy, allergic and other rashes, and topical eruptions of
t-cell lymphoma. Some of the drug delivery devices of the present
invention are also useful in decreasing intraocular pressure. In
addition to treatment of ocular conditions, the present invention
can be used for local delivery of therapeutics to various types of
solid tumors, including tumors of the lung, pancreas, liver,
kidney, colon and brain.
[0217] The device can also be implanted subcutaneously,
intramuscularly or intraperitoneally for systemic delivery of
therapeutics, including delivery of contraceptive agents and agents
to treat cardiovascular, metabolic, immunological and neurological
disorders. The drug delivery device may be implanted at or near a
tissue affected by the condition. The drug delivery devices of the
present invention are suitably implanted in ocular tissues. In some
embodiments, the drug delivery devices are implanted episclerally
(inserted between the conjunctiva and sclera) with the permeable
portion of the polymer structure facing the sclera. The drug
delivery devices of the present invention may also be used as
supraconjunctival inserts. In some embodiments, the drug delivery
devices are placed on top of the bulbar conjunctiva near the
conjunctival formix. A suture may be used to immobilize the
insert.
[0218] In some embodiments, the present invention is a method of
treating an ocular condition comprising episcleral or
supraconjunctival placement of a drug delivery device containing a
composition comprising an active agent, wherein the active agent is
released at a rate of
Q=0.001.times.L.times.N.times.C
wherein C is the optimal topically effective concentration (in
micrograms/mL) of the active agent, L is the placement constant,
and N is the composition constant in mL/hour. L is 1 or 2 when the
drug delivery device is placed episclerally or supraconjunctivally,
respectively. N=0.005 to 0.15 for prostaglandins in their ester,
amide, free acid or salt form, N=0.02-0.6 for rho-kinase inhibitors
in their salt or free base form, and N=0.05 to 1.5 for any other
active agents. Using the equation, a prostaglandin active agent
with a topical effective concentration of 0.05 milligrams/mL (e.g.,
latanoprost) may be designed to release at a rate of about 0.00025
to about 0.0075 micrograms/hr or about 0.0005 to about 0.015
micrograms/hr when the drug delivery device is placed episclerally
or supraconjunctivally, respectively. Using a similar approach, a
rho-kinase active agent with a topical effective concentration of 1
milligram/mL (e.g., a Y-39983 salt) may be designed to release at a
rate of about 0.02 to about 0.6 micrograms/hr or about 0.04 to
about 1.2 micrograms/hr when the drug delivery device is placed
episclerally or supraconjunctivally, respectively. Again, using a
similar approach, a non-prostaglandin, non-rho-kinase, active agent
with a topical effective concentration of 5 milligrams/mL (e.g., a
timolol salt) may be designed to release at a rate of about 0.25 to
about 7.5 micrograms/hr or about 0.5 to about 15 micrograms/hr when
the drug delivery device is placed episclerally or
supraconjunctivally, respectively.
[0219] Brimonidine or its salts may be designed to release at a
rate of about 0.05 to about 60 micrograms/hr, about 0.75 to about
7.5 micrograms/hr, about 0.05 to about 10 micrograms/hr, about 0.05
to about 5 micrograms/hr, about 0.05 to about 4 micrograms/hr,
about 0.3 to about 60 micrograms/hr, 0.1 to about 10 micrograms/hr,
or 0.7 to about 2.5 micrograms/hr. Brimonidine free base may be
designed to release at a rate of about 0.05 to about 4
micrograms/hr, 0.7 to about 2.5 micrograms/hr, or 0.7 to about 2.5
micrograms/hr. Brimonidine tartrate may be designed to release at a
rate of about 0.3 to about 60 micrograms/hr, or 0.1 to about 10
micrograms/hr.
[0220] Timolol or its salts may be designed to release at a rate of
about 0.1 to about 50 micrograms/hr, about 1 to about 50
micrograms/hr, about 2.5 to about 20 micrograms/hr, about 0.1 to
about 20 micrograms/hr, about 0.5 to about 5 micrograms/hr, or
about 12 to about 18 micrograms/hr. Timolol maleate may be designed
to release at a rate of about 1 to about 50 micrograms/hr, about
0.5 to about 5 micrograms/hr, or about 12 to about 18
micrograms/hr.
[0221] Latanoprost, latanoprost free acid, or its salts may be
designed to release at a rate of about 0.0001 to about 5
micrograms/hr, about 0.0005 to about 0.025 micrograms/hr, about
0.04 to about 5 micrograms/hr, about 0.0001 to about 0.05
micrograms/hr, about 0.001 to about 0.05 micrograms/hr, or about
0.04 to about 5 micrograms/hr. Latanoprost arginine salt may be
designed to release at a rate of about 0.04 to about 5
micrograms/hr, or about 0.0001 to about 0.05 micrograms/hr.
Latanoprost (the isopropyl ester of latanoprost fee acid) may be
designed to release at a rate of about 0.001 to about 0.05
micrograms/hr.
[0222] Travoprost, travoprost free acid, or its salts may be
designed to release at a rate of about 0.0001 to about 0.05
micrograms/hr, about 0.0004 to about 0.02 micrograms/hr, about
0.0001 to about 0.05 micrograms/hr, or about 0.001 to about 0.02
micrograms/hr. Travoprost (the isopropyl ester of travoprost free
acid) may be designed to release at a rate of about 0.001 to about
0.02 micrograms/hr.
[0223] Dorzolamide or its salts may be designed to release at a
rate of about 0.1 to about 2 micrograms/hr.
[0224] Ethacrynic acid or its salts may be designed to release at a
rate of about 5 to about 50 micrograms/hr.
[0225] AR-102, AR-102 free acid or its salts may be designed to
release at a rate of about 0.0005 to about 0.7 micrograms/hr, about
0.04 to about 0.7 micrograms/hr, or about 0.0005 to about 0.1
micrograms/hr. AR-102 free acid may be designed to release at a
rate of about 0.04 to about 0.7 micrograms/hr, or about 0.0005 to
about 0.1 micrograms/hr.
[0226] Dexamethasone or its salts may be designed to release at a
rate of about 0.1 to about 200 micrograms/hr, about 0.1 to about 3
micrograms/hr, about 0.1 to about 5 micrograms/hr, or about 2 to
about 200 micrograms/hr. Dexamethasone sodium phosphate may be
designed to release at a rate of about 2 to about 200
micrograms/hr, or about 0.1 to about 5 micrograms/hr.
[0227] Bimatoprost, bimatoprost free acid or its salts may be
designed to release at a rate of about 0.0005 to about 0.1
micrograms/hr, or about 0.002 to about 0.1 micrograms/hr.
[0228] The active agent may be any active agent suitable to treat
the desired condition. In various embodiments, the active agent may
be of one of low solubility, moderate solubility or high
solubility. "Low solubility" means a solubility of less than or
equal to 300 micrograms/mL in phosphate buffered saline (PBS) at
pH=7.2-7.4. Examples include, but are not limited to, cyclosporin
A, lovastatin, atorvastatin, dexamethasone, and travoprost
isopropyl ester, latanoprost isopropyl ester. "Moderate solubility"
means a solubility of greater than 300 micrograms/mL, but less than
1000 micrograms/mL in PBS at pH=7.2-7.4. Examples include, but are
not limited to, latanoprost free acid (0.8 mg/mL in PBS),
brimonidine tartrate (0.6 mg/mL in water at pH 7.7) and brimonidine
free base (0.36 mg/mL in PBS). "High solubility" means a solubility
of greater than or equal to 1000 micrograms/mL in PBS at
pH=7.2-7.4. Examples include, but are not limited to,
acetazolamide, dorzolamide HCl, timolol maleate, and ethacrynic
acid sodium salt.
[0229] For ocular conditions, the active agent is suitably
3-hydroxy-2,2-bis(hydroxymethyl)propyl
7-((1R,2R,3R,5S)-2-((R)-3-(benzo[b]thiophen-2-yl)-3-hydroxypropyl)-3,5-di-
hydroxycyclopentyl)heptanoate (AR-102),
7-((1R,2R,3R,5S)-2-((R)-3-(benzo[b]thiophen-2-yl)-3-hydroxypropyl)-3,5-di-
hydroxycyclopentyl)heptanoic acid (AR-102 free acid), dorzolamide,
ethacrynic acid, latanoprost, latanoprost free acid, travoprost,
travoprost free acid, bimatoprost, bimatoprost free acid,
tafluprost, tafluprost free acid, dexamethasone, brimonidine,
timolol, or salts thereof. Other suitable ocular active agents are
known to those of ordinary skill in the art, such as other
prostaglandins and other G-protein coupled receptor ligands,
antifungals, antibiotics, enzyme inhibitors including kinase
inhibitors, channel blockers, reuptake inhibitors and transporter
inhibitors.
##STR00001##
[0230] In some embodiments, the composition consists essentially of
the active agent. In other embodiments, the composition also
includes excipients such as the carriers and other components
discussed below. The composition may be in the form of a single
compressed pellet. In another embodiment, the composition may be in
the form of a matrix of an active agent and a non-water soluble
polymer.
[0231] Techniques and compositions for making dosage forms useful
in the methods of this invention are described in the following
references: Modern Pharmaceutics, Chapters 9 and 10, Banker &
Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms:
Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage
Forms, 2nd Ed., (1976). Examples of pharmaceutically acceptable
carriers and excipients can, for example, be found in Remington
Pharmaceutical Science, 16th Ed.
[0232] Suitable carriers include, but are not limited to, phosphate
buffered saline (PBS), isotonic water, deionized water,
monofunctional alcohols, symmetrical alcohols, aloe vera gel,
allantoin, glycerin, vitamin A and E oils, mineral oil, propylene
glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil,
combinations thereof, and the like.
[0233] The composition may also contain one or more of the
following: a) diluents, b) binders, c) antioxidants, d) solvents,
e) wetting agents, f) surfactants, g) emollients, h) humectants, i)
thickeners, j) powders, k) sugars or sugar alcohols such as
dextrans, particularly dextran 70, l) cellulose or a derivative
thereof, m) a salt, n) disodium EDTA (Edetate disodium), and o)
non-water soluble polymers.
[0234] Ingredient a) is a diluent. Suitable diluents for solid
dosage forms include, but are not limited to sugars such as
glucose, lactose, dextrose, and sucrose; diols such as propylene
glycol; calcium carbonate; sodium carbonate; sugar alcohols, such
as glycerin; mannitol; and sorbitol. The amount of diluent in the
composition is typically about 0 to about 90%.
[0235] Ingredient b) is a binder. Suitable binders for solid dosage
forms include, but are not limited to, polyethylene oxide (PEO),
polyvinyl pyrrolidone; magnesium aluminum silicate; starches such
as corn starch and potato starch; gelatin; tragacanth; and
cellulose and its derivatives, such as sodium
carboxymethylcellulose, ethyl cellulose, methylcellulose,
microcrystalline cellulose, and sodium carboxymethylcellulose. The
amount of binder in the composition is typically about 0 to about
25%.
[0236] Ingredient c) is an antioxidant such as butylated
hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT"), vitamin C
and vitamin E. The amount of antioxidant in the composition is
typically about 0 to about 15%.
[0237] Ingredient d) is a solvent such as water, ethyl alcohol,
isopropanol, castor oil, ethylene glycol monoethyl ether,
diethylene glycol monobutyl ether, diethylene glycol monoethyl
ether, dimethylsulfoxide, dimethyl formamide, and combinations
thereof. The amount of ingredient d) in the composition is
typically about 0% to about 95%. While a solvent may be used, one
discovery of the present invention is that a solvent is generally
not needed to ensure substantially linear delivery of the active
agent.
[0238] Ingredient e) is a wetting agent such as sodium lauryl
sulfate, polyoxyethylene sorbitan fatty acid esters,
polyoxyethylene alkyl ethers, sorbitan fatty acid esters,
polyethylene glycols, polyoxyethylene castor oil derivatives,
docusate sodium, quaternary ammonium compounds, sugar esters of
fatty acids and glycerides of fatty acids.
[0239] Ingredient f) is a surfactant such as lecithin, Polysorbate
80, and sodium lauryl sulfate, and the TWEENS.RTM. from Atlas
Powder Company of Wilmington, Del. Suitable surfactants include,
but are not limited to, those disclosed in the C.T.F.A. Cosmetic
Ingredient Handbook, 1992, pp. 587-592; Remington's Pharmaceutical
Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume 1,
Emulsifiers & Detergents, 1994, North American Edition, pp.
236-239. The amount of surfactant in the composition is typically
about 0% to about 5%.
[0240] Ingredient g) is an emollient. Suitable emollients include,
but are not limited to, stearyl alcohol, glyceryl monoricinoleate,
glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil,
cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl
palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate,
hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol,
cetyl palmitate, di-n-butyl sebacate, isopropyl myristate,
isopropyl palmitate, isopropyl stearate, butyl stearate,
polyethylene glycol, triethylene glycol, lanolin, sesame oil,
coconut oil, arachis oil, castor oil, acetylated lanolin alcohols,
petroleum, mineral oil, butyl myristate, isostearic acid, palmitic
acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl
oleate, myristyl myristate, and combinations thereof. The amount of
emollient in the composition is typically about 0% to about
50%.
[0241] Ingredient h) is a humectant. Suitable humectants include,
but are not limited to, glycerin, sorbitol, sodium
2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate,
gelatin, and combinations thereof. The amount of humectant in the
composition is typically about 0% to about 50%.
[0242] Ingredient i) is a thickener. The amount of thickener in the
composition is typically about 0% to about 50%.
[0243] Ingredient j) is a powder. Suitable powders include, but are
not limited to, chalk, talc, fullers earth, kaolin, starch, gums,
colloidal silicon dioxide, tetra alkyl ammonium smectites, trialkyl
aryl ammonium smectites, chemically-modified magnesium aluminum
silicate, organically-modified montmorillonite clay, hydrated
aluminum silicate, fumed silica, sodium carboxymethyl cellulose,
ethylene glycol monostearate, and combinations thereof. The amount
of powder in the composition is typically about 0% to about
50%.
[0244] Ingredient k) is a sugar or sugar alcohol. Suitable sugars
or sugar alcohols include, but are not limited to, dextrans,
dextran 70, beta-cyclodextrins, and hydroxypropyl cyclodextrins.
The amount of sugars or sugar alcohols in the composition is
typically about 0% to about 60%.
[0245] Ingredient l) is a cellulose derivative. Suitable cellulose
derivatives include, but are not limited to, sodium
carboxymethylcellulose, ethylcellulose, methylcellulose, and
hydroxypropyl-methylcellulose, particularly,
hydroxypropylmethylcellulose.
[0246] Ingredient m) is a salt. Suitable salts include, but are not
limited to, mono-, di- and trisodium phosphate, sodium chloride,
potassium chloride, and combinations thereof.
[0247] Ingredient n) is disodium EDTA (Edetate disodium). The
amount of disodium EDTA in the composition is typically about 0% to
about 1%.
[0248] Ingredient o) is a non-water soluble polymer. The non-water
soluble polymer may be selected from ethylene vinyl acetate (EVA),
silicon rubber polymers, polydimethylsiloxane (PDMS), polyurethane
(PU), polyesterurethanes, polyetherurethanes, polyolefins,
polyethylenes (PE), low density polyethylene (LDPE), polypropylene
(PP), polyetheretherketone (PEEK), polysulfone (PSF),
polyphenylsulfone, polyacetals, polymethyl methacrylate (PMMA),
polybutymethacrylate, plasticized polyethyleneterephthalate,
polyisoprene, polyisobutylene, silicon-carbon copolymers, natural
rubber, plasticized soft nylon, polytetrafluoroethylene (PTFE), or
combinations thereof. Suitably, the non-water soluble polymer is
EVA. The vinyl acetate content may be from about 9% to about 50% by
weight (EVA-9-50). In one embodiment, the vinyl acetate content is
about 40% by weight (EVA-40). Other suitable non-water soluble
polymers are known to those of ordinary skill in the art.
[0249] The drug delivery devices of the present invention may be
included in kits, which include the drug delivery devices and
information, instructions, or both for use of the kit to provide
treatment for medical conditions in mammals (particularly humans).
The information and instructions may be in the form of words,
pictures, or both, and the like.
[0250] The use of the terms "a" and "an" and "the" and similar
referents in the context of describing the invention are to be
construed to cover both the singular and the plural, unless
otherwise indicated herein or clearly contradicted by context. The
terms "comprising," "having," "including," and "containing" are to
be construed as open-ended terms (i.e., meaning "including, but not
limited to,") unless otherwise noted. Recitation of ranges of
values herein are merely intended to serve as a shorthand method of
referring individually to each separate value falling within the
range, unless otherwise indicated herein, and each separate value
is incorporated into the specification as if it were individually
recited herein. All methods described herein can be performed in
any suitable order unless otherwise indicated herein or otherwise
clearly contradicted by context. The use of any and all examples,
or exemplary language (e.g., "such as") provided herein, is
intended merely to better illuminate the invention and does not
pose a limitation on the scope of the invention unless otherwise
claimed. No language in the specification should be construed as
indicating any nonclaimed element as essential to the practice of
the invention.
[0251] Preferred embodiments of this invention are described
herein, including the best mode known to the inventors for carrying
out the invention. Variations of those preferred embodiments may
become apparent to those of ordinary skill in the art upon reading
the foregoing description. The inventors expect skilled artisans to
employ such variations as appropriate, and the inventors intend for
the invention to be practiced otherwise than as specifically
described herein. Accordingly, this invention includes all
modifications and equivalents of the subject matter recited in the
claims appended hereto as permitted by applicable law. Moreover,
any combination of the above-described elements in all possible
variations thereof is encompassed by the invention unless otherwise
indicated herein or otherwise clearly contradicted by context.
EXAMPLES
[0252] The invention will be further explained by the following
illustrative examples that are intended to be non-limiting.
[0253] Procedures for preparation of the drug delivery devices are
described in the following examples. All temperatures are given in
degrees Centigrade. Reagents were purchased from commercial sources
(given) or prepared following literature procedures.
Example 1
Drug Delivery Device Containing Dorzolamide HCl (a High Solubility
Drug)
Parameters Tested
[0254] Thickness of permeable EVA film: 40-250 micrometers Elution
rate: 0.1-2 micrograms/hr
[0255] 30 mg of dorzolamide HCl (which has high solubility) was
compressed at 1000 psi to form a compressed drug pellet with a
diameter of 5 mm and a thickness of 1 mm. Next, 15 mg of EVA-25
(vinyl acetate content of 25%; Sigma Chemical Company, St. Louis,
Mo.) was loaded into a custom-made die set and heated to
100.degree. C. for 1 minute. The polymer was compressed at 100 psi
and allowed to cool to room temperature. When prepared in this
manner, this EVA-25 polymer membrane is impermeable to water. The
molded polymer cup was removed from the die set and the compressed
drug pellet was loaded into the cup with the top side
uncovered.
[0256] EVA-40 (Sigma Chemical Company, St. Louis, Mo.) was loaded
into a film maker (International Crystal Laboratory) with a
150-micrometer spacer and heated to 75.degree. C. for 4 minutes.
The polymer was compressed at 1500 psi for 1 minute and allowed to
cool to room temperature. The polymer membrane thus created with a
thickness of 150 micrometers was removed from the base and cut into
a discshaped membrane with a diameter of 6 mm using a biopsy punch.
This polymer membrane is permeable to water when prepared in this
manner. The disc-shaped, permeable membrane was placed on the
exposed side of the drug pellet in contact with the EVA-25 "cup",
and the two polymers were heat-sealed at 90.degree. C. using a
custom-made die set and allowed to cool to room temperature.
[0257] In summary, this drug delivery device was composed of a 30
mg core of dorzolamide HCl, the top and sides were composed of the
impermeable EVA-25 polymer membrane, and the bottom of the drug
delivery device was a 150 micrometer rate-limiting water-permeable
membrane composed of EVA-40. The average elution rate in this
particular design was 0.66.+-.0.05 micrograms/hr (R2=0.9999) (FIG.
81).
Example 2
Drug Delivery Device Containing Ethacrynic Acid Sodium Salt (a High
Solubility Drug)
Parameters Tested
[0258] Thickness of EVA film: 100-500 micrometers Elution rate:
5-50 micrograms/hr
[0259] 30 mg of ethacrynic acid sodium salt (Sigma Chemical
Company, St. Louis, Mo.) (which has high solubility), was
compressed at 1000 psi to form a compressed drug pellet with a
diameter of 5 mm and a thickness of 1 mm. 15 mg of EVA-25 (Sigma
Chemical Company, St. Louis, Mo.) was loaded into a custom-made die
set and heated to 100.degree. C. for 1 minute. The polymer was
compressed at 100 psi and allowed to cool to room temperature. When
prepared in this manner, this polymer membrane was impermeable to
water. The molded polymer cup was removed from the die set and the
compressed drug pellet was loaded into the cup with the top side
uncovered.
[0260] EVA-40 (Sigma Chemical Company, St. Louis, Mo.) was loaded
into a film maker (International Crystal Laboratory) with a
25-micrometer spacer and heated to 75.degree. C. for 4 minutes. The
polymer was compressed at 200 psi for 1 minute and allowed to cool
to room temperature. The thus created polymer membrane with a
thickness of 75 micrometers was removed from the base and cut into
a disc-shaped membrane with a diameter of 6 mm using a biopsy
punch. This polymer membrane was permeable to water when prepared
in this manner. The disc-shaped, permeable membrane was placed on
the exposed side of the drug pellet in contact with the EVA-25
"cup", and the two polymers were heat-sealed at 90.degree. C. using
a custom-made die set and allowed to cool to room temperature.
[0261] In summary, this drug delivery device was composed of a 30
mg core of ethacrynic acid sodium salt, the top and sides were
composed of an impermeable EVA-25 polymer membrane, and the bottom
of the drug delivery device was a 75 micrometer rate-limiting
water-permeable membrane composed of EVA-40. The elution rate in
this particular design was 27 micrograms/hr with a zero-order
release profile for up to 90% of the contained agent (R2=0.9997)
(FIG. 82).
[0262] Ethacrynic acid sodium salt drug delivery devices falling
within the above parameters with an elution rate of approximately
20 micrograms/hr were inserted episclerally in the right eye of
Dutch-belted rabbits and the contralateral eye was used as an
untreated control. The intraocular pressure was measured at regular
intervals. As shown in FIG. 83, the devices provided a sustained
IOP-lowering effect for approximately 30 days with >90% elution
of the agent achieved.
Example 3
Drug Delivery Device Containing AR-102 Free Acid (a Moderately
Soluble Drug)
Parameters Tested
[0263] Thickness of EVA film: 120-250 micrometers Elution rate:
0.04-0.7 micrograms/hr
[0264] 4 mg of AR-102 free acid (which has moderate solubility) was
compressed at 1000 psi to form a compressed drug pellet with a
diameter of 3 mm and a thickness of 1 mm. 8 mg of EVA-25 (Sigma
Chemical Company, St. Louis, Mo.) was loaded into a custom-made die
set and heated to 100.degree. C. for 1 minute. The polymer was
compressed at 100 psi and allowed to cool to room temperature. This
was the impermeable polymer. The molded polymer cup was removed
from the die set and the compressed drug pellet was loaded into the
cup with the top side uncovered.
[0265] EVA-40 (Sigma Chemical Company, St. Louis, Mo.) was loaded
into a film maker (International Crystal Laboratory) with a
200-micrometer spacer and heated to 75.degree. C. for 4 minutes.
The polymer was compressed at 200 psi for 1 minute and allowed to
cool to room temperature. The polymer membrane with a thickness of
250 micrometers was removed from the base and cut into a
disc-shaped membrane with a diameter of 4 mm using a biopsy punch.
This polymer membrane was permeable to water when prepared in this
manner. The disc-shaped, permeable membrane was placed on the
exposed side of the drug pellet in contact with the EVA-25 "cup",
and the two polymers were heat-sealed at 90.degree. C. using a
custom-made die set and allowed to cool to room temperature.
[0266] In summary, this device was composed of a 4 mg core of
AR-102 free acid. The impermeable polymer was EVA-25. The
rate-limiting water-permeable polymer was EVA-40, and the thickness
of the water-permeable membrane was 250 micrometers. The elution
rate in this particular design was 0.16 micrograms/hr (R2=0.9998)
(FIG. 84).
[0267] AR-102 free acid drug delivery devices falling within the
above parameters with an elution rate of approximately 0.03
micrograms/hr were inserted episclerally in the right eye of
Dutch-belted rabbits and the contralateral eye was used as an
untreated control. The intraocular pressure was measured at regular
intervals. As shown in FIG. 85, the devices provided a sustained
IOP-lowering effect with a theoretical duration in vivo of
approximately 7 years.
Example 4
Drug Delivery Device Containing Latanoprost Arginine Salt (a
Moderately Soluble Drug)
Parameters Tested
[0268] Thickness of EVA film: 40-300 micrometers Elution rate:
0.04-5 micrograms/hr
[0269] 4 mg of latanoprost arginine salt (which has moderate
solubility) was compressed at 1000 psi to form a compressed drug
pellet with a diameter of 3 mm and a thickness of 1 mm. 8 mg of
EVA-25 (Sigma Chemical Company, St. Louis, Mo.) was loaded into a
custom-made die set and heated to 100.degree. C. for 1 minute. The
polymer was compressed at 100 psi and allowed to cool to room
temperature. This was the impermeable polymer. The molded polymer
cup was removed from the die set and the compressed drug pellet was
loaded into the cup with the top side uncovered.
[0270] EVA-40 (Sigma Chemical Company, St. Louis, Mo.) was loaded
into a film maker (International Crystal Laboratory) with a
150-micrometer spacer and heated to 75.degree. C. for 4 minutes.
The polymer was compressed at 400 psi for 1 minute and allowed to
cool to room temperature. The polymer membrane with a thickness of
160 micrometers was removed from the base and cut into a
disc-shaped membrane with a diameter of 4 mm using a biopsy punch.
This polymer membrane was permeable to water when prepared in this
manner. The disc-shaped, permeable membrane was placed on the
exposed side of the drug pellet in contact with the EVA-25 "cup",
and the two polymers were heat-sealed at 90.degree. C. using a
custom-made die set and allowed to cool to room temperature.
[0271] In summary, this device was composed of a 4 mg core of
latanoprost arginine salt. The impermeable polymer was EVA-25. The
rate-limiting waterpermeable polymer was EVA-40, and the thickness
of the water-permeable membrane was 160 micrometers. The elution
rate in this particular design was approximately 0.01 micrograms/hr
(R2=0.9977) (FIG. 86).
[0272] A latanoprost free acid arginine salt drug delivery device
falling within the above parameters with an elution rate of
approximately 0.01 micrograms/hr was inserted episclerally in the
right eye of Dutch-belted rabbits and the contralateral eye was
used as an untreated control. The intraocular pressure was measured
at regular intervals. As shown in FIG. 87, the device provided a
sustained IOP-lowering effect for approximately 30 days with a
theoretical duration in vivo of approximately 30 years.
Example 5
Drug Delivery Device Containing Dexamethasone (a Low Solubility
Drug)
Parameters Tested
[0273] Thickness of EVA film: 40-150 micrometers Elution rate:
0.1-3 micrograms/hr
[0274] 30 mg of dexamethasone (which has low solubility) was
compressed at 1000 psi to form a compressed drug pellet with a
diameter of 5 mm and a thickness of 1 mm. 15 mg of EVA-25 (Sigma
Chemical Company, St. Louis, Mo.) was loaded into a custom-made die
set and heated to 100.degree. C. for 1 minute. The polymer was
compressed at 100 psi and allowed to cool to room temperature. This
was the impermeable polymer. The molded polymer cup was removed
from the die set and the compressed drug pellet was loaded into the
cup with the top side uncovered.
[0275] EVA-40 (Sigma Chemical Company, St. Louis, Mo.) was loaded
into a film maker (International Crystal Laboratory) with a
50-micrometer spacer and heated to 75.degree. C. for 4 minutes. The
polymer was compressed at 200 psi for 1 minute and allowed to cool
to room temperature. The polymer membrane with a thickness of 75
micrometers was removed from the base and cut into a disc-shaped
membrane with a diameter of 6 mm using a biopsy punch. This polymer
membrane is permeable to water when prepared in this manner. The
disc-shaped, permeable membrane was placed on the exposed side of
the drug pellet, and the two polymers were heatsealed at 90.degree.
C. using a custom-made die set and allowed to cool to room
temperature.
[0276] In summary, this device was composed of a 30 mg core of
dexamethasone. The impermeable polymer was EVA-25. The
rate-limiting waterpermeable polymer was EVA-40, and the thickness
of the water-permeable membrane was 75 micrometers. The elution
rate in this particular design was 0.25 micrograms/hr (R2=0.9999)
(FIG. 88).
Example 6
Ethylene Vinyl Acetate/Dextran Film
Standard Methods for Making EVA/Dextran Film
[0277] Dextran with an average molecular weight of 5,000-670,000
Daltons (Fluka) was desiccated under vacuum overnight to purge
excess moisture. EVA pellets with selected vinyl acetate ratios
from 0 to 40% were ground into fine pieces to increase surface
area. Dextran and EVA-0-40 were then measured out at a selected
weight ratio in a sealed glass vial. Dichloromethane was
incrementally added to the dextran/EVA mixture and the mixture was
vigorously shaken to prevent clumping of dextran. The mixture was
then gently heated to 50.degree. C. and shaken in quick succession
to aid EVA-25 dissolution. The mixture was then placed in an
ultrasonic bath for 2 minutes. The mixture was allowed to cool to
room temperature and inspected for undesirable air bubble
formation.
[0278] A glass plate or silicon wafer was used as a casting
substrate for the evaporative casting of the film. The mixture was
uncapped and quickly decanted onto the substrate. Typical drying
time was at least 4 hours under low humidity conditions to limit
moisture uptake by the hygroscopic dextran. The cast film was then
placed in a negative pressure rated flask and the atmosphere was
flushed with high purity Argon gas. Air was then evacuated under a
high vacuum overnight. The dried film was grounded into fine
powder, and a dextran/EVA film with desired thickness was made by
heat compression in a film maker. A digital micrometer was used to
verify the final film thickness.
Example 7
Drug Delivery Device Containing Dexamethasone Sodium Phosphate (a
High Solubility Drug)
Parameters Tested
[0279] Dextran molecular weight: 5-12 kDa Weight ratio of
Dextran/EVA film: 1:20 to 1:4 Thickness of Dextran/EVA film: 40-150
micrometers Elution rate: 2-200 micrograms/hr
[0280] 30 mg of dexamethasone sodium phosphate (which has high
solubility) was compressed at 1000 psi to form a compressed drug
pellet with a diameter of 5 mm and a thickness of 1 mm. 15 mg of
EVA-25 (Sigma Chemical Company, St. Louis, Mo.) was loaded into a
custom-made die set and heated to 100.degree. C. for 1 minute. The
polymer was compressed at 100 psi and allowed to cool to room
temperature. This was the impermeable polymer. The molded polymer
cup was removed from the die set and the compressed drug pellet was
loaded into the cup with the top side uncovered.
[0281] A mixture of EVA-25 (Sigma Chemical Company, St. Louis, Mo.)
and dextran with an average molecular weight of 5 kDa was loaded
into a film maker (International Crystal Laboratory) with a
100-micrometer spacer and heated to 100.degree. C. for 4 minutes.
The weight ratio of the dextran/EVA film was 1:19. The polymer was
compressed at 200 psi for 1 minute and allowed to cool to room
temperature. The polymer membrane with a thickness of 120
micrometers was removed from the base and cut into a disc-shaped
membrane with a diameter of 6 mm using a biopsy punch. This was the
partially-bioerodible membrane. The disc-shape,
partially-bioerodible membrane was placed on the exposed side of
the drug pellet in contact with the EVA-25 "cup", and the two
polymers were heat-sealed at 90.degree. C. using a custom-made die
set and allowed to cool to room temperature.
[0282] In summary, this device was composed of a 30 mg core of
dexamethasone sodium phosphate. The impermeable polymer was EVA-25.
The partially-bioerodible membrane was dextran with an average
weight molecular of 5 kDa and EVA-25 at a weight ratio of 1:19, and
the thickness of the partially bioerodible membrane was 120
micrometers. The elution rate in this particular design was
approximately 14 micrograms/hr (R2=0.9954) (FIG. 89).
Example 8
Drug Delivery Device Containing Brimonidine Free Base (a Low
Solubility Drug)
Parameters Tested
[0283] Dextran molecular weight: 12-670 kDa Weight ratio of
Dextran/EVA film: 1:4 to 1:3 Thickness of Dextran/EVA film: 40-150
micrometers Elution rate: 0.05-4 micrograms/hr
[0284] 20 mg of brimonidine free base (which has low solubility)
was compressed at 1000 psi to form a compressed drug pellet with a
diameter of 5 mm and a thickness of 1 mm. 15 mg of EVA-25 (Sigma
Chemical Company, St. Louis, Mo.) was loaded into a custom-made die
set and heated to 100.degree. C. for 1 minute. The polymer was
compressed at 100 psi and allowed to cool to room temperature. This
was the impermeable polymer. The molded polymer cup was removed
from the die set and the compressed drug pellet was loaded into the
cup with the top side uncovered.
[0285] A mixture of EVA-25 (Sigma Chemical Company, St. Louis, Mo.)
and dextran with an average molecular weight of 270 kDa was loaded
into a film maker (International Crystal Laboratory) with a
50-micrometer spacer and heated to 75.degree. C. for 4 minutes. The
weight ratio of the dextran/EVA film was 1:4. The polymer was
compressed at 400 psi for 1 minute and allowed to cool to room
temperature. The polymer membrane which had a thickness of 65
micrometers was removed from the base and cut into a disc-shaped
membrane with a diameter of 6 mm using a biopsy punch. This was the
partially-bioerodible membrane. The disc-shaped, partially
bioerodible membrane was placed on the exposed side of the drug
pellet in contact with the EVA-25 "cup", and the two polymers were
heat-sealed at 90.degree. C. using a custom-made die set and
allowed to cool to room temperature.
[0286] In summary, this device was composed of a 20 mg core of
brimonidine free base. The impermeable polymer was EVA-25. The
partially-bioerodible membrane was synthesized using dextran with
an average molecular weight of 270 kDa and EVA-25 at a weight ratio
of 1:4, and the thickness of the partially-bioerodible membrane was
65 micrometers. The elution rate in this particular design was 0.7
micrograms/hr (R2=0.9997) (FIG. 90).
[0287] Brimonidine free base drug delivery devices falling within
the above parameters using a similar design with elution rates of
0.7-2.5 micrograms/hr were inserted below the sclera in the right
eye of Dutch-belted rabbits and the contralateral eye was used as
an untreated control. The intraocular pressure was measured at
regular intervals. As shown in FIG. 91, the device provided a
sustained IOP-lowering effect for approximately 38 days with an
expected duration in vivo of at least 7 months.
Example 9
Drug Delivery Device Containing Brimonidine D-Tartrate Salt (a High
Solubility Drug)
Parameters Tested
[0288] Dextran molecular weight: 5-270 kDa Weight ratio of
Dextran/EVA film: 1:20 to 1:4 Thickness of Dextran/EVA film: 95-150
micrometers Elution rate: 0.3-60 micrograms/hr
[0289] 30 mg of brimonidine D-tartrate salt (which has high
solubility) was compressed at 1000 psi to form a compressed drug
pellet with a diameter of 5 mm and a thickness of 1 mm. 15 mg of
EVA-25 (Sigma Chemical Company, St. Louis, Mo.) was loaded into a
custom-made die set and heated to 100.degree. C. for 1 minute. The
polymer was compressed at 100 psi and allowed to cool to room
temperature. This was the impermeable polymer. The molded polymer
cup was removed from the die set and the compressed drug pellet was
loaded into the cup with the top side uncovered.
[0290] A mixture of EVA-25 (Sigma Chemical Company, St. Louis, Mo.)
and dextran with an average molecular weight of 270 kDa was loaded
into a film maker (International Crystal Laboratory) with a
100-micrometer spacer and heated to 100.degree. C. for 4 minutes.
The weight ratio of the dextran/EVA film was 1:4. The polymer was
compressed at 200 psi for 1 minute and allowed to cool to room
temperature. The polymer membrane which had a thickness of 125
micrometers was removed from the base and cut into a disc-shaped
membrane with a diameter of 6 mm using a biopsy punch. This was the
partially-bioerodible membrane. The disc-shaped, partially
bioerodible membrane was placed on the exposed side of the drug
pellet in contact with the EVA-25 "cup", and the two polymers were
heat-sealed at 90.degree. C. using a custom-made die set and
allowed to cool to room temperature.
[0291] In summary, this device was composed of a 30 mg core of
brimonidine D-tartrate salt. The impermeable polymer was EVA-25.
The partially-bioerodible membrane was dextran with an average
molecular weight of 270 kDa and EVA-25 at a weight ratio of 1:4,
and the thickness of the partially-bioerodible membrane was 125
micrometers. The elution rate in this particular design was
approximately 34 micrograms/hr with a zero-order release profile
for up to 95% (R2=0.9948) (FIG. 92).
Example 10
Drug Delivery Device Containing Timolol Maleate Salt (a High
Solubility Drug)
Parameters Tested
[0292] Dextran molecular weight: 5-670 kDa Weight ratio of
Dextran/EVA film: 1:20 to 1:3 Thickness of Dextran/EVA film: 40-150
micrometers Elution rate: 1-50 micrograms/hr
[0293] 30 mg of timolol maleate (which has high solubility) was
compressed at 1000 psi to form a compressed drug pellet with a
diameter of 5 mm and a thickness of 1 mm. 15 mg of EVA-25 (Sigma
Chemical Company, St. Louis, Mo.) was loaded into a custom-made die
set and heated to 100.degree. C. for 1 minute. The polymer was
compressed at 100 psi and allowed to cool to room temperature. This
was the impermeable polymer. The molded polymer cup was removed
from the die set and the compressed drug pellet was loaded into the
cup with the top side uncovered.
[0294] A mixture of EVA-25 (Sigma Chemical Company, St. Louis, Mo.)
and dextran with an average molecular weight of 5 kDa was loaded
into a film maker (International Crystal Laboratory) with a
100-micrometer spacer and heated to 75.degree. C. for 4 minutes.
The weight ratio of the dextran/EVA film was 1:9. The polymer was
compressed at 1500 psi for 1 minute and allowed to cool to room
temperature. The polymer membrane which had a thickness of 100
micrometers was removed from the base and cut into a disc-shaped
membrane with a diameter of 6 mm using a biopsy punch. This was the
partially-bioerodible membrane. The disc-shape, partially
bioerodible membrane was placed on the exposed side of the drug
pellet in contact with the EVA-25 "cup", and the two polymers were
heat-sealed at 90.degree. C. using a custom-made die set and
allowed to cool to room temperature.
[0295] In summary, this device was composed of a 30 mg core of
timolol maleate salt. The impermeable polymer was EVA-25. The
partially-bioerodible membrane was dextran with an average
molecular weight of 5 kDa and EVA-25 at a weight ratio of 1:9, and
the thickness of the partially-bioerodible membrane was 100
micrometers. The elution rate in this particular design was
approximately 15 micrograms/hr with a zero-order release profile
for up to 90% of the enclosed agent (R2=0.9986) (FIG. 93).
[0296] Timolol maleate salt drug delivery devices falling within
the above parameters with elution rates of about 12 to 18
micrograms/hr were inserted below the sclera in the right eye of
Dutch-belted rabbits and the contralateral eye was used as an
untreated control. The intraocular pressure was measured at regular
intervals. As shown in FIG. 94, the device provided a sustained
IOP-lowering effect for approximately 90 days with complete elution
achieved.
Example 11
Drug Delivery Device Containing Albumin (a High Molecular Weight,
High Solubility Compound)
Parameters Tested
[0297] Dextran molecular weight: 270-670 kDa Weight ratio of
Dextran/EVA film: 1:20 to 1:3 Thickness of Dextran/EVA film: 40-150
micrometers
[0298] 30 mg of albumin (average molecular weight of approximately
67 kDa) that had been labeled with fluorescein isothiocyanate
(BSA-FITC, Fluka) (which has high solubility) was mixed with
unlabeled albumin at weight ratio of 1:9 and compressed at 1000 psi
to form a compressed drug pellet with a diameter of 5 mm and a
thickness of 1 mm. 15 mg of EVA-25 (Sigma Chemical Company, St.
Louis, Mo.) was loaded into a custom-made die set and heated to
100.degree. C. for 1 minute. The polymer was compressed at 100 psi
and allowed to cool to room temperature. This was the impermeable
polymer. The molded polymer cup was removed from the die set and
the compressed drug pellet was loaded into the cup with the top
side uncovered.
[0299] A mixture of EVA-25 (Sigma Chemical Company, St. Louis, Mo.)
and dextran with an average molecular weight of 670 kDa was loaded
into a film maker (International Crystal Laboratory) with a
50-micrometer spacer and heated to 100.degree. C. for 4 minutes.
The weight ratio of dextran/EVA film was 1:4. The polymer was
compressed at 150 psi for 1 minute and allowed to cool to room
temperature. The polymer membrane which had a thickness of 85
micrometers was removed from the base and cut into a disc-shaped
membrane with a diameter of 6 mm using a biopsy punch. This was the
partially-bioerodible membrane. The disc-shaped,
partially-bioerodible membrane was placed on the exposed side of
the drug pellet in contact with the EVA-25 "cup", and the two
polymers were heat-sealed at 90.degree. C. using a custom-made die
set and allowed to cool to room temperature.
[0300] In summary, this device was composed of a 30 mg core of
albumin with 10% of the core consisting of FITC-labeled albumin.
The impermeable polymer was EVA-25. The partially-bioerodible
membrane was dextran with an average molecular weight of 670 kDa
and EVA-25 at a weight ratio of 1:4, and the thickness of the
partially-bioerodible membrane was 85 micrometers. The data showed
that albumin was released from the permeable polymer at a
controlled rate.
Example 12
General Methods of In Vitro Elution Rate Determination
[0301] A drug delivery device, containing a known active agent of
interest, is placed in a 20-mL Class A clear borosilicate glass
vial with PTFE threaded lid. To the vial is then added 10 mL of
sterile 1.times. phosphate-buffered saline (PBS) without calcium
and magnesium salts (Mediatech). The 20-mL glass vial is placed
onto a tight fitting polymer rack. The polymer rack is then placed
on an adjustable orbital platform shaker set to 60 Hz with infinite
duration in a 37.degree. C. incubator. At predetermined time
points, 1-2 ml of the incubated solution is transferred from the
vial to a sampling vial, and the rest of the solution is aspirated.
The predetermined time intervals are usually 48 or 72 hours, and
are subject to change based on the target elution rate and the
maximum solubility of the active agent in PBS. 10 mL of fresh PBS
is added to the 20-mL vial, and the vial is placed back to the
incubator. In general, the concentration of active agent in
solution is maintained at less than 10% of its maximum solubility
in PBS to ensure the near-sink conditions.
[0302] The concentration of the solution in the sampling vial is
determined using a standard curve obtained from several (usually
more than 8) different known concentrations of the same active
agent. The total amount of active agent eluted is determined from
the original volume of the incubating solution and the elution rate
is calculated based on the incubation time.
Example 13
Drug Delivery Device Containing Bimatoprost (a Low Solubility
Drug)
Suggested Parameters
[0303] Thickness of EVA film: 40-500 micrometers Elution rate:
0.005-0.3 micrograms/hr Preferred elution rate: 0.002-0.1
micrograms/hr
[0304] 4 mg of bimatoprost (which has low solubility) is compressed
at 1000 psi to form a compressed drug pellet with a diameter of 3
mm and a thickness of 1 mm. 8 mg of EVA-25 (Sigma) is loaded into a
custom-made die set and heated to 100.degree. C. for 1 minute. The
polymer is compressed at 100 psi and allowed to cool to room
temperature. This is the impermeable polymer. The molded polymer
cup is removed from the die set and the compressed drug pellet is
loaded into the cup with the top side uncovered.
[0305] EVA-40 is loaded into a film maker with a suitable spacer
and heated to 75.degree. C. for 4 minutes. The polymer is
compressed at constant pressure for 1 minute and allowed to cool to
room temperature. The polymer membrane with a thickness of 40-500
micrometers is removed from the base and cut into a disc-shaped
membrane with a diameter of 4 mm using a biopsy punch. This polymer
membrane is permeable to water when prepared in this manner. The
disc-shaped, permeable membrane is placed on the exposed side of
the drug pellet in contact with the EVA-25 "cup", and the two
polymers are heat-sealed at 90.degree. C. using a custom-made die
set and allowed to cool to room temperature.
[0306] In summary, this device is composed of a 4 mg core of
bimatoprost. The top and sides are composed of an impermeable
EVA-25 polymer membrane, and the bottom of the drug delivery device
is a 40-500 micrometer permeable membrane composed of EVA-40. The
elution rate in this design can be adjusted to the desired elution
rate by changing the thickness of the permeable polymer.
Example 14
Drug Delivery Device Containing Latanoprost Isopropyl Ester (a Low
Solubility Drug)
Suggested Parameters
[0307] Thickness of EVA film: 300-1000 micrometers Elution rate:
0.005-0.3 micrograms/hr Preferred elution rate: 0.001-0.05
micrograms/hr
[0308] 8 mg of EVA-25 is loaded into a custom-made die set and
heated to 100.degree. C. for 1 minute. The polymer is compressed at
100 psi and allowed to cool to room temperature. This is the
impermeable polymer. The molded polymer cup is removed from the die
set and 4 mg of latanoprost isopropyl ester (which has low
solubility) is loaded into the EVA-25 cup.
[0309] EVA-40 is loaded into a film maker with a suitable spacer
and heated to 75.degree. C. for 4 minutes. The polymer is
compressed at constant pressure for 1 minute and allowed to cool to
room temperature. The polymer membrane with a thickness of 300-800
micrometers is removed from the base and cut into a disc-shaped
membrane with a diameter of 4 mm using a biopsy punch. This polymer
membrane is permeable to water when prepared in this manner. The
disc-shaped, permeable membrane is placed on the exposed side of
the drug pellet in contact with the EVA-25 "cup," and the two
polymers are heat-sealed at 90.degree. C. using a custom-made die
set and allowed to cool to room temperature.
[0310] In summary, this device is composed of a 4 mg core of
latanoprost isopropyl ester. The top and sides are composed of an
impermeable EVA-25 polymer membrane, and the bottom of the drug
delivery device is a 40-500 micrometer permeable membrane composed
of EVA-40. The elution rate in this design can be adjusted to
desired elution rate by changing the thickness of the permeable
polymer.
Example 15
Drug Delivery Device Containing Travoprost Isopropyl Ester (a Low
Solubility Drug)
Suggested Parameters
[0311] Thickness of EVA film: 300-750 micrometers Elution rate:
0.001-0.04 micrograms/hr Preferred elution rate: 0.001-0.02
micrograms/hr
[0312] 8 mg of EVA-25 is loaded into a custom-made die set and
heated to 100.degree. C. for 1 minute. The polymer is compressed at
100 psi and allowed to cool to room temperature. This is the
impermeable polymer. The molded polymer cup is removed from the die
set and 4 mg of travoprost isopropyl ester (which has low
solubility) is loaded into the EVA-25 cup.
[0313] EVA-40 is loaded into a film maker (International Crystal
Laboratory) with a suitable spacer and heated to 75.degree. C. for
4 minutes. The polymer is compressed at constant pressure for 1
minute and allowed to cool to room temperature. The polymer
membrane with a thickness of 300-800 micrometers is removed from
the base and cut into a disc-shaped membrane with a diameter of 4
mm using a biopsy punch. This polymer membrane is permeable to
water when prepared in this manner. The disc-shaped, permeable
membrane is placed on the exposed side of the drug pellet in
contact with the EVA-25 "cup," and the two polymers are heat-sealed
at 90.degree. C. using a custom-made die set and allowed to cool to
room temperature.
[0314] In summary, this device is composed of a 4 mg core of
travoprost isopropyl ester. The top and sides are composed of an
impermeable EVA-25 polymer membrane, and the bottom of the drug
delivery device is a 40-500 micrometer permeable membrane composed
of EVA-40.
Example 16
Drug Delivery Device Containing Non-Steroidal Anti-Inflammatory
Drugs
[0315] A drug delivery device of the invention can be designed to
release a selected active agent at a predetermined rate using the
flowcharts and table in FIGS. 95-97. Suitably, one would start with
EVA-40 as the water permeable membrane and EVA-25 as the water
impermeable membrane, or using partially-bioerodible membranes if
the active agent may not release at the predetermined rate. For
those skilled in the art, the composition and thickness of the
membrane can readily be identified using similar experimental
procedures illustrated above.
Example 17
Drug Delivery Device Containing Latanoprost Arginine Salt (a
Moderately Soluble Drug)
Parameters Tested
[0316] Thickness of EVA film: 40-300 micrometers Elution rate:
0.00025-0.025 micrograms/hr Preferred elution rate: 0.00025-0.0075
micrograms/hr
[0317] The drug core film was prepared using a solvent casting
technique. 50 mg of latanoprost arginine salt and 200 mg of EVA-40
(Sigma Chemical Company, St. Louis, Mo.) were dissolved in 3 mL of
dichloromethane (DCM). The polymer solution was cast on a
custom-made polydimethylsiloxane (PDMS) substrate, and the cast
film was dried at ambient temperature in a fume hood for 2 days.
The drug core film with a thickness of 100-125 micrometers was
removed from the base and cut into disc-shaped pieces with a
diameter of 2 mm using a biopsy punch.
[0318] EVA-25 (Sigma Chemical Company, St. Louis, Mo.) was loaded
into a film maker (International Crystal Laboratory) with a
100-micrometer spacer and heated to 95.degree. C. for 4 minutes.
The polymer was compressed at 400 psi for 1 minute and allowed to
cool to room temperature. The polymer membrane with a thickness of
125 micrometers was removed from the base and cut into disc-shaped
membranes with a diameter of 4 mm using a biopsy punch. This
polymer membrane was permeable to water when prepared in this
manner. Some of these 4-mm membranes were subsequently manufactured
to donut-shaped rings with an outer diameter of 4 mm and an inner
diameter of 2 mm. This polymer membrane is the "spacer ring" (FIGS.
46-65). A 2-mm drug core film containing latanoprost arginine salt
and EVA-40 was then inserted into the void of a spacer ring, and
both sides of the composite film were covered by a 4-mm EVA-25 film
(the permeable membrane). The four-piece assembly (2 EVA-25
permeable membranes, 1 spacer ring, and 1 drug core film) was then
heat-sealed at 90.degree. C. using a custom-made die set and
allowed to cool to room temperature.
[0319] In summary, this device was composed of a drug core film of
20% latanoprost arginine salt and 80% of EVA-40. The rate-limiting
water permeable polymer was EVA-25, and the thickness of the
water-permeable membranes was 125 micrometers. The elution rate in
this particular design was approximately 0.005 micrograms/hr.
Example 18
Drug Delivery Device Containing Bimatoprost (a Low Solubility
Drug)
Suggested Parameters
[0320] Thickness of EVA film: 40-300 micrometers Elution rate:
0.003-0.3 micrograms/hr Preferred elution rate: 0.002-0.1
micrograms/hr
[0321] The drug core film was prepared using a solvent casting
technique. 50 mg of bimatoprost and 200 mg of EVA-40 (Sigma
Chemical Company, St. Louis, Mo.) were dissolved in 3 mL of
dichloromethane (DCM). The polymer solution was cast on a
custom-made polydimethylsiloxane (PDMS) substrate, and the cast
film was dried at ambient temperature in a fume hood for 2 days.
The drug core film with a thickness of 100-125 micrometers was
removed from the base and cut into disc-shaped pieces with a
diameter of 2 mm using a biopsy punch.
[0322] EVA-25 (Sigma Chemical Company, St. Louis, Mo.) was loaded
into a film maker (International Crystal Laboratory) with a
100-micrometer spacer and heated to 95.degree. C. for 4 minutes.
The polymer was compressed at 400 psi for 1 minute and allowed to
cool to room temperature. The polymer membrane with a thickness of
125 micrometers was removed from the base and cut into disc-shaped
membranes with a diameter of 4 mm using a biopsy punch. This
polymer membrane was permeable to water when prepared in this
manner. Some of these 4-mm membranes were subsequently manufactured
to donut-shaped rings with an outer diameter of 4 mm and an inner
diameter of 2 mm. This polymer membrane is the "spacer ring" (FIGS.
46-65). A 2-mm drug core film containing bimatoprost and EVA-40 was
then inserted into the void of a spacer ring, and both sides of the
composite film were covered by a 4-mm EVA-25 film (the permeable
membrane). The four-piece assembly (2 EVA-25 permeable membranes, 1
spacer ring, and 1 drug core film) was then heat-sealed at
90.degree. C. using a custom-made die set and allowed to cool to
room temperature.
[0323] In summary, this device was composed of a drug core film of
20% bimatoprost and 80% of EVA-40. The rate-limiting water
permeable polymer was EVA-25, and the thickness of the
water-permeable membranes was 125 micrometers. The elution rate in
this particular design was approximately 0.015-0.020
micrograms/hr.
Example 19
Drug Delivery Device Containing Y-39983 Free Base (a Moderately
Soluble Drug)
Parameters Tested
[0324] Thickness of EVA film: 40-300 micrometers Elution rate:
0.01-1.0 micrograms/hr Preferred elution rate: 0.04-0.6
micrograms/hr
[0325] The drug core film was prepared using a solvent casting
technique. 100 mg of Y-39983 free base and 100 mg of EVA-40 (Sigma
Chemical Company, St. Louis, Mo.) were dissolved in 3 mL of
dichloromethane (DCM). The polymer solution was cast on a
custom-made polydimethylsiloxane (PDMS) substrate, and the cast
film was dried at ambient temperature in a fume hood for 2 days.
The drug core film with a thickness of 75-90 micrometers was
removed from the base and cut into disc-shaped pieces with a
diameter of 2.5 mm using a biopsy punch.
##STR00002##
[0326] EVA-40 (Sigma Chemical Company, St. Louis, Mo.) was loaded
into a film maker (International Crystal Laboratory) with a
50-micrometer spacer and heated to 75.degree. C. for 4 minutes. The
polymer was compressed at 300 psi for 1 minute and allowed to cool
to room temperature. The polymer membrane with a thickness of 90
micrometers was removed from the base and cut into disc-shaped
membranes with a diameter of 4 mm using a biopsy punch. This
polymer membrane was permeable to water when prepared in this
manner. Some of these 4-mm membranes were subsequently manufactured
to donut-shaped rings with an outer diameter of 4 mm and an inner
diameter of 2.5 mm. This polymer membrane is the "spacer ring"
(FIGS. 46-65). A 2.5-mm drug core film containing Y-39983 free base
and EVA-40 was then inserted into the void of a spacer ring, and
both sides of the composite film were covered by a 4-mm EVA-40 film
(the permeable membrane). The four-piece assembly (2 EVA-40
permeable membranes, 1 spacer ring, and 1 drug core film) was then
heat-sealed at 75.degree. C. using a custom-made die set and
allowed to cool to room temperature.
[0327] In summary, this device was composed of a drug core film of
50% Y-39983 free base and 50% EVA-40. The rate-limiting water
permeable polymer was EVA-40, and the thickness of the
water-permeable membranes was 90 micrometers. The elution rate in
this particular design was approximately 0.015-0.020
micrograms/hr.
Example 20
Drug Delivery Device Containing Latanoprost Arginine Salt (a
Moderately Soluble Drug)
Parameters Tested
[0328] Thickness of EVA film: 40-300 micrometers Elution rate:
0.0005-0.03 micrograms/hr Preferred elution rate: 0.0005-0.015
micrograms/hr
[0329] The drug core film was prepared using a solvent casting
technique. 50 mg of latanoprost arginine salt and 200 mg of EVA-40
(Sigma Chemical Company, St. Louis, Mo.) were dissolved in 3 mL of
dichloromethane (DCM). The polymer solution was cast on a
custom-made polydimethylsiloxane (PDMS) substrate, and the cast
film was dried at ambient temperature in a fume hood for 2 days.
The drug core film with a thickness of 90-100 micrometers was
removed from the base and cut into disc-shaped pieces with a
diameter of 2 mm using a biopsy punch.
[0330] EVA-40 (Sigma Chemical Company, St. Louis, Mo.) was loaded
into a film maker (International Crystal Laboratory) with a
50-micrometer spacer and heated to 75.degree. C. for 4 minutes. The
polymer was compressed at 300 psi for 1 minute and allowed to cool
to room temperature. The polymer membrane with a thickness of 100
micrometers was removed from the base and cut into oval-shaped
membranes with an aspect ratio of 7.5 mm.times.3 mm using a biopsy
punch. This polymer membrane was permeable to water when prepared
in this manner. Some of these 7.5 mm.times.3 mm oval-shaped
membranes were subsequently manufactured to eye-shaped rings with a
void of 2 mm at the center of the membrane. This polymer membrane
is the "spacer ring" (FIGS. 66-75). A 2-mm drug core film
containing latanoprost arginine salt and EVA-40 was then inserted
into the void of a spacer ring, and both sides of the composite
film were covered by a 7.5 mm.times.3 mm EVA-40 film (the permeable
membrane). The four-piece assembly (2 EVA-40 permeable membranes, 1
spacer ring, and 1 drug core film) was then heat-sealed at
75.degree. C. using a custom-made die set and allowed to cool to
room temperature.
[0331] In summary, this device was composed of a drug core film of
20% latanoprost arginine salt and 80% of EVA-40. The rate-limiting
water permeable polymer was EVA-40, and the thickness of the
water-permeable membranes was 100 micrometers. The elution rate in
this particular design was approximately 0.012 micrograms/hr.
[0332] Various features and advantages of the invention are set
forth in the following claims.
* * * * *