U.S. patent application number 10/096990 was filed with the patent office on 2002-07-11 for device and method for treating urinary incontinence in females.
Invention is credited to Kay, Martha Francine, Koelmel, Donald F., Mahashabde, Anu.
Application Number | 20020090390 10/096990 |
Document ID | / |
Family ID | 24119337 |
Filed Date | 2002-07-11 |
United States Patent
Application |
20020090390 |
Kind Code |
A1 |
Mahashabde, Anu ; et
al. |
July 11, 2002 |
Device and method for treating urinary incontinence in females
Abstract
Provided herein is a novel and useful device and method for
locally delivering and controllably releasing oxybutynin in the
cervical region of a female. A device of the invention comprises a
ring comprising trifluoropropylmethyl/dimethyl siloxane elastomer.
A pharmaceutical composition comprising oxybutynin and an excipient
is placed within a bore located in the ring, wherein the bore runs
from the surface of the ring into the ring. The ring has a
sufficient size such that it can be inserted into the vaginal canal
of a female. A cap comprising is placed over the bore at the
surface of the ring in order to contain the pharmaceutical
composition within the bore. When the ring is inserted into the
vaginal canal, the trifluoropropylmethyl/dimethyl siloxane
elastomer controllably releases and locally delivers a
therapeutically effective amount of oxybutynin to the detrusor
muscle to treat the female's urinary incontinence.
Inventors: |
Mahashabde, Anu; (Kendall
Park, NJ) ; Kay, Martha Francine; (Lawrence Township,
NJ) ; Koelmel, Donald F.; (Union Township,
NJ) |
Correspondence
Address: |
GIBBONS, DEL DEO, DOLAN, GRIFFINGER & VECCHIONE
1 RIVERFRONT PLAZA
NEWARK
NJ
07102-5497
US
|
Family ID: |
24119337 |
Appl. No.: |
10/096990 |
Filed: |
March 13, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10096990 |
Mar 13, 2002 |
|
|
|
09531856 |
Mar 21, 2000 |
|
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|
Current U.S.
Class: |
424/425 ;
514/540 |
Current CPC
Class: |
A61P 13/02 20180101;
A61K 9/0036 20130101; A61P 7/12 20180101; A61P 13/00 20180101; A61K
31/216 20130101; A61P 13/12 20180101 |
Class at
Publication: |
424/425 ;
514/540 |
International
Class: |
A61K 031/24 |
Claims
What is claimed is:
1. A method of treating urinary incontinence in a female in need of
such treatment comprising providing a single application which
controllably administers a therapeutically effective amount of
oxybutynin intravaginally over a period of at least seven days.
2. A method in accordance with claim 1, wherein said
therapeutically effective amount of oxybutynin is administered
intravaginally over a period of from seven to about twenty-eight
days.
3. A method in accordance with claim 1, wherein said
therapeutically effective amount of oxybutynin is administered
intravaginally over a period of at least twenty-eight days.
4. A method in accordance with claim 1, wherein oxybutynin is
administered at the rate of about 0.5 to about 5.0 mg/day.
5. A method in accordance with claim 2, wherein oxybutynin is
administered at the rate of about 0.5 to about 5.0 mg/day.
6. A method in accordance with claim 3, wherein oxybutynin is
administered at the rate of about 0.5 to about 5.0 mg/day.
7. A method in accordance with claim 3, wherein said oxybutynin is
administered via a ring having a surface and a bore which runs from
said surface into said ring, said bore containing a pharmaceutical
composition comprising oxybutynin, said ring comprising
trifluoropropylmethyl/dimethy- l siloxane elastomer that
controllably releases a therapeutically effective amount of
oxybutynin by passage from said bore through said elastomer, said
ring having a sufficient size such that it can be inserted into the
vaginal canal of said female.
8. A method of simultaneously treating urinary urge incontinence
and urinary stress incontinence in a female in need of such
treatment comprising placing in the vagina of said female, in a
single application, a pessary device with a suitable size and shape
for treating urinary stress incontinence said device controllably
releasing a therapeutically effective amount of oxybutynin over a
period of at least seven days to treat urinary urge
incontinence.
9. A method in accordance with claim 8, wherein said device
comprises a ring having a surface and a bore which runs from said
surface into said ring, said bore containing a pharmaceutical
composition comprising oxybutynin, said ring comprising
trifluoropropylmethyl/dimethyl siloxane elastomer that controllably
releases a therapeutically effective amount of oxybutynin by
passage from said bore through said elastomer.
10. A method in accordance with claim 8, wherein said device
controllably administers a therapeutically effective amount of
oxybutynin intravaginally over a period of seven to about
twenty-eight days.
11. A method in accordance with claim 8, wherein said device
controllably administers a therapeutically effective amount of
oxybutynin intravaginally over a period of at least twenty-eight
days.
12. A method in accordance with claim 9, wherein said
pharmaceutical composition comprises about 60% by weight oxybutynin
and about 40% by weight of an excipient, wherein the excipient
comprises tin catalyzed silicone polymer.
13. A method in accordance with claim 8, wherein said
therapeutically effective amount of oxybutynin is about 0.5 to
about 5.0 mg/day.
14. A method in accordance with claim 10, wherein said
therapeutically effective amount of oxybutynin is about 0.5 to
about 5.0 mg/day.
15. A method in accordance with claim 11, wherein said
therapeutically effective amount of oxybutynin is about 0.5 to
about 5.0 mg/day.
16. A device for locally delivering and controllably releasing
oxybutynin to the cervical region of a female to treat urinary
incontinence for an extended period in a single application, said
device comprising: (a) a ring having a surface, and a bore which
runs from said surface into said ring, wherein said ring comprises
trifluoropropylmethyl/dimethyl siloxane elastomer, and is of a
sufficient size such that it can be inserted into the vaginal canal
of said female; (b) a pharmaceutical composition located within
said bore, wherein said pharmaceutical composition comprises
oxybutynin and an excipient; whereupon, upon insertion of said ring
into said vaginal canal, an amount of oxybutynin therapeutically
effective to treat urinary incontinence is controllably released
from the ring for a period of at least twenty eight days.
17. A device in accordance with claim 16, wherein oxybutynin is
released therefrom at the rate of about 0.5 to about 5.0 mg. per
day.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 09/531,856, filed on Mar. 21, 2000 which is
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to a new and useful device and
method that utilizes trifluoropropylmethyl/dimethyl siloxane
elastomer to locally deliver oxybutynin in a controlled manner for
treating urinary incontinence for up to twenty-eight contiguous
days, or as needed.
BACKGROUND OF THE INVENTION
[0003] Urinary incontinence is a debilitating disorder which
afflicts at least 15% of the elderly population, and is present in
approximately 50% of institutionalized elderly persons. Indeed,
many elderly people are institutionalized because of their urinary
incontinence. The costs for caring for such patients is extremely
high, particularly since they require constant monitoring and
changing of their clothes and bedding.
[0004] The elderly, however, are not the only group of the
population that suffers from urinary incontinence. This disorder is
also prevalent in postmenopausal women. In particular, pelvic
relaxation due to childbirth can cause uterine prolapse and
cystocele, which allows descent of the normal urethrovesical angle
and contributes to urinary incontinence. The ramifications of the
natural aging process in women, such as decreased levels of
estrogen, also may result in urinary incontinence.
[0005] The therapeutic effect of oxybutynin
(4-diethylamino-2-butynylpheny- lcyclohexylglycolate), which is
described in the 1992 Physician's Desk Reference, pages 1332-1333
(with reference to the drug "DITROPAN" manufactured by Marion
Merrill Dow), is well documented [Yarker, Y. E., Goe, K. L. &
Fitton, A., Oxybutynin: A Review of its Pharmacodynamic and
Pharmacokinetic Properties, and its Therapeutic Use in Detrusor
Stability. Drugs & Aging 6(3):243-265 (1995)]. In particular,
oxybutynin has an anticholinergic and spasmolytic effect on the
bladder that leads to relaxation of the detrusor muscle, fewer
spontaneous contractions, a decrease in the frequency and urge to
urinate, and increased bladder-filling capacity. Traditionally,
oxybutynin has been administered orally at relatively high doses (5
mg tablets taken two to four times a day). Oxybutynin has also been
incorporated into tablets, capsules, granules and pills containing
1-5 mg, preferably 5 mg of oxybutynin chloride, and syrups
containing 1-5 mg, preferably 5 mg of oxybutynin chloride per 5 ml,
and transdermal compositions (creams or ointments) containing 1-10
weight percent (wt %) oxybutynin chloride. Such administration
techniques inherently permit oxybutynin to circulate throughout the
body. Unfortunately however, oxybutynin has deleterious side
effects when administered systemically. More specifically,
anticholinergic side effects such as dry mouth, dry eyes, blurred
vision, constipation, and headaches have been observed when
oxybutynin is orally delivered. Moreover, N-desethyloxybutynin, a
metabolite of oxybutynin produced in the liver, has similar
antimuscarinic activity, and hence can have much of the same
effects as oxybutynin both on the bladder's detrusor muscle and in
other organs [Yarker, et al; Westlin, L., Anticholinergic Effects
of Two Metabolites of Oxybutynin, Research Report No. 840625F, data
on file, Smith and Nephew Pharmaceuticals, Ltd., 1985; Hughes, K.
M., Lang, J. C. T., Lazare, R., et al., Measurement of Oxybutynin
and its N-desethyl metabolite in Plasma, and its Application to
Pharmacokinetic Studies in Young, Elderly and Frail Volunteers.
Xenobiotica 22(7):859-69 (1992); Waldeck, K., Larsson, B.,
Andersson, K. E., Comparison of Oxybutynin and its Active
Metabolite, N-desethyloxybutynin, in the Human Detrusor and Parotid
Gland. Jnl. Of Urology 157:1093-97 (1997)]. Oral administration in
particular has been shown to result in peak blood concentrations of
the metabolite that are 6-9 times higher than the concentration of
oxybutynin itself. Furthermore, the area under the plasma time
concentration curve (or AUC, which measures the gross amount of
drug present over time) is also higher for the metabolite (10-12
times) than for oxybutynin.
[0006] In order to ameliorate the effects of oxybutynin in the body
and to limit the production of metabolite, efforts have been made
to administer oxybutynin intravesically. Such delivery has
demonstrated that oxybutynin can be delivered directly to the
bladder of a patient, limit the circulation of oxybutynin in the
body, and the deleterious side effects. However, intravesical
delivery possesses inherent limitations. Initially, intravesical
administration occurs through a catheter 3-4 times a day, and
therefore is a cumbersome modality suited only to relatively
immobile patients. Another limitation is that such delivery is
uncomfortable to the patient. A major limitation of intravesical
administration is that this method is simply not suited to
frequent, long term use for most incontinence suffers. Accordingly,
what is needed is a new and useful device which delivers oxybutynin
locally, i.e., directly to the detrusor muscle, in a controlled
manner, and does not rely solely upon the body's circulatory system
for such delivery. As a result, systemic circulation of oxybutynin
and its metabolite to other body sites can be limited.
[0007] What is also needed is a new and useful device which is
capable of locally delivering and controllably releasing a
therapeutically effective amount of oxybutynin to a patient's
detrusor muscle for up to twenty-eight (28) contiguous days.
[0008] The citation of any reference herein should not be construed
as an admission that such reference is available as "Prior Art" to
the instant application.
SUMMARY OF THE INVENTION
[0009] There is provided, in accordance with the present invention,
a device and method for locally delivering and controllably
releasing a therapeutically effective amount of oxybutynin to the
detrusor muscle in order to treat urinary incontinence in a
female.
[0010] Broadly, the present invention extends to a device for
locally delivering and controllably releasing oxybutynin to the
cervical region of a female to treat urinary incontinence, wherein
the device comprises a ring having a surface, and a bore running
from the surface into the ring, wherein the ring comprises
trifluoropropylmethyl/dimethyl siloxane elastomer. The ring of a
device of the invention has a sufficient size such that it can be
inserted into the vaginal canal of the female. Furthermore, a
device of the invention comprises a pharmaceutical composition
located within the bore, wherein the pharmaceutical composition
comprises oxybutynin and an excipient. A device of the present
invention also comprises a cap on the bore at the surface of the
ring, wherein the cap prevents the pharmaceutical composition from
diffusing out of the bore at the surface of the ring. Upon
insertion of the ring into the vaginal canal, oxybutynin is
controllably released from the ring in a therapeutically effective
amount to treat the urinary incontinence.
[0011] A ring of a device of the invention can further comprise a
first portion comprising trifluoropropylmethyl/dimethyl siloxane
elastomer having a bore therein, and a second portion comprising a
material into which oxybutynin is insoluble, such as a barium
sulfate composite. A ring of a device of the invention can also
comprise a first portion comprising trifluoropropylmethyl/dimethyl
siloxane elastomer having a bore running from the surface of the
first portion into the first portion, a second portion comprising
polydimethylsiloxane elastomer, or a barium sulfate composite, and
at least two shields located between the first and second portions,
wherein the at least two shields comprise a material into which
oxybutynin is insoluble, e.g., a barium sulfate composite or
polytetrafluorethylene (PTFE). The two shields intersect the first
and second portions, and prevent contact between the first and
second portions. In a particular embodiment, the one bore
intersects the surface of the first portion twice, and is capped at
both ends with caps described above. As a result, the
trifluoropropylmethyl/dimethyl siloxane elastomer of the first
portion controllably releases oxybutynin contained within the bore,
and the barium sulfate composite shields prevent diffusion of
oxybutynin to other parts of the ring. In another embodiment,
wherein the first and second portions comprise
trifluoropropylmethyl/dimethyl siloxane elastomer, the bore
comprises a first bore which runs from the surface of the first
portion into the first portion, and a second bore running from the
surface of the second portion into the second portion. Optionally
the bores can intersect the surface of the ring at two different
points. Naturally, the cap of the invention comprises a sufficient
number of caps to cover both bores, so that the pharmaceutical
composition within the bore(s) is prevented from diffusing
uncontrollably from the bore at the surface of the ring.
[0012] Alternatively, a ring of a device of the invention comprises
four portions and four shields such that each shield intersects two
portions, and each portion is prevented from contacting any other
portion. At least one of the portions comprises
trifluoropropylmethyl/dimethyl siloxane elastomer having a bore
running from the surface of the portion into the portion. Other
portions of the ring can comprise polydimethylsiloxane, barium
sulfate composite, or a combination thereof.
[0013] In addition, the present invention extends to a device for
locally delivering and controllably releasing oxybutynin as
described above, wherein the amount of oxybutynin in the
pharmaceutical composition can vary, depending upon the desired
dose to be administered to the patient. In a particular embodiment,
the pharmaceutical composition comprises about 60% by weight
oxybutynin and about 40% by weight an excipient, e.g., tin
catalyzed silicone polymer. Naturally, the oxybutynin can be in a
free base form, a salt, or a mixture thereof. Optionally, the
pharmaceutical composition comprises a rod which is inserted into
the one bore(s) of the ring. Methods of producing such rods are
described infra. A therapeutically effective amount of oxybutynin
that can be locally delivered with a device of the invention ranges
from about 0.5 mg/day to about 5.0 mg/day as needed. In a
particular embodiment, a device of the present invention can
locally deliver a therapeutically effective amount of oxybutynin
for up to twenty-eight contiguous days.
[0014] Moreover, the present invention extends to a device as
described above, wherein caps are placed over the bore at the
surface of the ring. Consequently, an oxybutynin pharmaceutical
composition can be held within the bore of a ring of a device of
the invention, and come into direct contact with the
trifluoropropylmethyl/dimethyl siloxane elastomer of the ring, and
be contained within the bore. Numerous materials can serve as caps
in a ring of a device of the invention. Particular examples of such
materials include, but certainly are not limited to
trifluoropropylmethyl/dimethyl siloxane elastomer, and
polydimethylsiloxane (PDMS), to name only a few. In another
embodiment, the present invention extends to a device for locally
delivering and controllably releasing oxybutynin to the cervical
region of a female to treat urinary incontinence, wherein the
device comprises:
[0015] (a) a ring having a surface, and a bore which runs from the
surface into the ring, wherein the ring comprises
trifluoropropylmethyl/dimethyl siloxane elastomer, and the ring has
a sufficient size such that it can be inserted into the vaginal
canal of the female;
[0016] (b) a pharmaceutical composition located within the bore,
wherein the pharmaceutical composition comprises 60% by weight
oxybutynin and 40% by weight tin catalyzed silicone polymer;
[0017] (c) a cap which covers the bore at the surface of the ring,
wherein the cap comprises polydimethylsiloxane, such that upon
insertion of the ring into the vaginal canal, the oxybutynin is
controllably released from the ring in a therapeutically effective
amount to treat the urinary incontinence. Optionally, the bore
intersects the surface of the ring twice, and thus requires two
caps, one to cover the bore at each point it intersects the surface
of the ring.
[0018] The present invention further extends to a method for
locally delivering and controllably releasing a therapeutically
effective amount of oxybutynin in the cervical region of a female
to treat urinary incontinence. An initial step of a method of the
invention comprises providing a ring having a surface, and a bore
running from the surface into the ring. A pharmaceutical
composition comprising oxybutynin and an excipient is located
within the bore. Moreover, the ring comprises of
trifluoropropylmethyl/dimethyl siloxane elastomer, which
controllably releases oxybutynin, and has a sufficient size such
that it can be inserted into the vaginal canal of the female.
Furthermore, a ring of a method of the invention comprises a cap
which covers the bore at the surface of the ring, so that the
pharmaceutical composition is contained within the bore. The ring
is then inserted into the vaginal canal of the female. Once in the
vaginal canal, a therapeutically effective amount of oxybutynin is
controllably released from the ring, and treats the female's
urinary incontinence.
[0019] In addition, the present invention extends to a method of
treating urinary incontinence in a female as described above,
wherein the ring comprises a first portion comprising
trifluoropropylmethyl/dimethyl siloxane elastomer, a second portion
comprising a barium sulfate composite or polydimethylsiloxane, and
the bore runs from the surface of the first portion into the first
portion of the ring.
[0020] The present invention further extends to a method of
treating urinary incontinence in a female, wherein the ring
comprises at a first portion comprising
trifluoropropylmethyl/dimethyl siloxane elastomer, a second portion
comprising trifluoropropylmethyl/dimethyl siloxane elastomer, a
barium sulfate composite or polydimethylsiloxane, and at least two
shields comprising a material into which oxybutynin is insoluble,
e.g., a barium sulfate composite or polytetrafluoroethylene,
wherein the at least two shields are located between the first and
second portions and prevent contact between the first and second
portions. The bore runs from the surface of the first portion into
the first portion. Furthermore, a method of the invention extends
to a ring comprising a first bore running from the surface of the
first portion into the first portion, and intersecting the surface
of the first portion twice. Additionally, in a ring in which the
second portion comprises trifluoropropylmethyl/dimethyl siloxane
elastomer, the ring further comprises a second bore which runs from
the surface of the second portion into the second portion.
Optionally, the second bore intersects the surface of the second
portion twice. Naturally, a sufficient number of caps comprising a
material such as trifluoropropylmethyl/dimethyl siloxane elastomer,
polydimethylsiloxane, polytetrafluoroethylene, etc. are used in a
ring of a method of the invention to cover the bore(s) at
intersection points with the surface of the ring so that the
pharmaceutical composition is contained within the bore(s).
[0021] As explained above, a pharmaceutical composition of a method
of the invention comprises oxybutynin and an excipient, such as tin
catalyzed silicone polymer. The therapeutically effective amount of
oxybutynin locally delivered and controllably released with a
method or device of the invention can vary, depending upon the
particular needs of the patient. In a particular embodiment, the
pharmaceutical composition comprises about 60% by weight oxybutynin
and about 40% by weight excipient, such as tin catalyzed silicone
polymer. Such a composition can be used to locally deliver and
controllably release a therapeutically effective amount of
oxybutynin ranging from about 0.5 mg/day to about 5 mg/day, for up
to 28 days. Data of delivery of oxybutynin for 28 contiguous days
is set forth in FIG. 5.
[0022] In another embodiment, the present invention extends to a
method for locally delivering and controllably releasing a
therapeutically effective amount of oxybutynin in the cervical
region of a female to treat urinary incontinence, comprising the
steps of:
[0023] (a) providing a ring comprising polydimethylsiloxane,
trifluoropropylmethyl/dimethyl siloxane elastomer, a barium sulfate
composite, or a combination thereof, wherein the ring has a
sufficient size such that it can be inserted into the vaginal canal
of the female, and comprises a bore in the
trifluoropropylmethyl/dimethyl siloxane elastomer which runs from
the surface of the ring into the ring,
[0024] (b) inserting a pharmaceutical composition comprising
oxybutynin and an excipient weight tin catalyzed silicone polymer
within the bore;
[0025] (c) placing a cap on the bore at the surface of the ring;
and
[0026] (d) inserting the ring into the vaginal canal of the
female.
[0027] Once in the vaginal canal, a therapeutically effective
amount of oxybutynin ranging from about 0.5 mg/day to about 5
mg/day is controllably released from the ring for up to twenty
eight days. A ring having applications herein can comprise a first
portion comprising trifluoropropylmethyl/dimethyl siloxane
elastomer, and a second portion comprising a barium sulfate
composite, polydimethylsiloxane or trifluoropropylmethyl/dimethyl
siloxane elastomer, wherein the bore runs from the surface of the
first portion into the first portion. Optionally, the bore
intersects the surface of the first portion twice. Furthermore, in
a ring comprising a second portion which comprises
trifluoropropylmethyl/dimethyl siloxane elastomer, the bore further
comprises a second bore which runs from the surface of the second
portion into the second portion. Pharmaceutical composition is
contained within both bores. Optionally, the second bore intersects
the surface of the second portion twice. Naturally, a ring of a
device of the invention comprises a sufficient number of caps to
cover the points of intersection between the surface and the
bore(s) so that the pharmaceutical composition is contained within
the bore(s).
[0028] Moreover, a ring having applications in a method of the
invention can comprise a first and a second portion, and at least
two shields comprising a pharmaceutically acceptable inert material
into which oxybutynin is insoluble, such as a barium sulfate
composite or polytetrafluoroethylene. At least two shields are
located between the first and second portions, and prevent contact
between these two portions. In a particular embodiment, the first
portion comprises trifluoropropylmethyl/dimethyl siloxane
elastomer, and the second portion comprises
trifluoropropylmethyl/dimethyl siloxane elastomer,
polydimethylsiloxane, or a barium sulfate composite. The bore
comprises a first bore located in the first portion. Optionally,
the first bore intersects the surface of the first portion twice.
Furthermore, if the second portion comprises
trifluoropropylmethyl/dimethyl siloxane elastomer, the bore further
comprises a second bore which runs from the surface of the second
portion into the second portion. Optionally, the second bore
intersects the surface of the second portion twice. Naturally, a
sufficient number of caps are used to cover the intersection points
of the bore(s) and the surface of the ring in order to contain the
pharmaceutical composition within the bore(s).
[0029] Furthermore, the present invention extends to a method for
locally delivering and controllably releasing a therapeutically
effective amount of oxybutynin in the cervical region of a female
to treat urinary incontinence, as described above, wherein the ring
comprises first and second portions, and at least two shields into
which oxybutynin is insoluble. The at least two shields are located
between the first and second portions of the ring, and prevent
contact between the first and second portions. Examples of
substances which form such shields include a barium sulfate
composite or polytetrafluoroethylene, to name only a few. Either
the first portion, the second portion or both portions of the ring
can comprise trifluoropropylmethyl/dimethyl siloxane elastomer.
Moreover, when the second portion of the ring also comprises
trifluoropropylmethyl/dimethyl siloxane elastomer, the bore further
comprises a second bore which runs from the surface of the second
portion into the second portion. Optionally, the bore intersects
the first portion twice, and the second bore intersects the surface
of the second portion twice. Naturally, a sufficient number of caps
as described above are used to cover the intersection points of the
bore(s) and the surface of the ring in order to contain the
pharmaceutical composition within the bore(s).
[0030] The present invention further extends to a method for
locally delivering and controllably releasing a therapeutically
effective amount of oxybutynin in the cervical region of a female
to treat urinary incontinence, as described above, wherein the
pharmaceutical composition comprises about 60% by weight oxybutynin
and about 40% by weight an excipient, preferably tin catalyzed
silicone polymer. In a particular embodiment, the pharmaceutical
composition is in the shape of a rod, which is inserted into the
bore of the ring.
[0031] Accordingly, it is a principal object of the present
invention to provide a device and method for treating urinary
incontinence which locally delivers and controllably releases
oxybutynin in the cervical region of a female so that the
oxybutynin can diffuse directly to, and interact with the detrusor
muscle.
[0032] It is another object of the present invention to utilize the
heretofore unknown ability of trifluoropropylmethyl/dimethyl
siloxane elastomer to controllably release oxybutynin.
[0033] It is still another object of the invention to provide a
device and method for treating urinary incontinence which locally
delivers and controllably releases a therapeutically effective
amount of oxybutynin to the female for up to twenty-eight
contiguous days.
[0034] It is yet another object of the invention to provide a
device and method for treating urinary incontinence wherein the
therapeutically effective amount of oxybutynin delivered to the
patient can be tailored to the patient's needs.
[0035] These and other aspects of the present invention will be
better appreciated by reference to the following drawings and
Detailed Description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0036] FIG. 1A is a schematical cross sectional view of a ring of a
device of the invention.
[0037] FIG. 1B is a schematical cross sectional view of a portion
of a ring of a device of the invention, wherein the portion
comprises a bore which runs from the surface of the portion, into
the ring, and intersects the surface of the portion twice.
[0038] FIG. 2 is a graph of the comparison of the release profiles
between an oxybutynin insert Ring and an insert segment.
[0039] FIG. 3 is a graph of the drug release profile data from
trifluoropropylmethyl/dimethyl siloxane elastomer segments that
deliver about 0.5 mg/day of oxybutynin.
[0040] FIG. 4 is a graph of the drug release profile data from
trifluoropropylmethyl/dimethyl siloxane elastomer segments that
deliver about 1.0 mg/day of oxybutynin.
[0041] FIG. 5 is a graph of the drug release profile data from
trifluoropropylmethyl/dimethyl siloxane elastomer rings that
deliver about 0.5 mg/day of oxybutynin over 28 contiguous days.
[0042] FIG. 6A is a schematical cross sectional view of a ring of a
device of the invention comprising one portion
trifluoropropylmethyl/dimethyl siloxane elastomer, and one portion
polydimethysiloxane, wherein the bore is located in the
trifluoropropylmethyl/dimethyl siloxane elastomer portion.
[0043] FIG. 6B is a schematical cross sectional view of a ring of a
device of the invention comprising one portion
trifluoropropylmethyl/dimethyl siloxane elastomer, and one portion
polydimethylsiloxane, wherein the bore comprises a first bore
located in the trifluoropropylmethyl/dimethyl siloxane elastomer
portion, and a second bore located in the polydimethylsiloxane
portion.
[0044] FIG. 7A is a schematical view of a ring of the invention
comprising two shields into which oxybutynin is insoluble.
[0045] FIG. 7B is a schematical view of a ring of a device of the
invention comprising 4 shields into which oxybutynin is
insoluble.
[0046] FIG. 8A is a schematical cross sectional view of a ring of a
device of the invention comprising a first portion of
trifluoropropylmethyl/dime- thyl siloxane elastomer, a second
portion comprising PDMS, and shields comprising a barium sulfate
composite, wherein the shields located between the first and second
portions, which prevent contact between the first and second
portions.
[0047] FIG. 8B is a schematical cross sectional view of a ring of a
device of the invention comprising a first portion of
trifluoropropylmethyl/dime- thyl siloxane elastomer, a second
portion comprising PDMS, and first and second shields between the
first and second portions that prevent contact between the first
and second portions.
[0048] FIG. 9 is a schematical cross sectional view of a ring of a
device of the invention comprising a first portion of
trifluoropropylmethyl/dime- thyl siloxane elastomer and a second
portion comprising a barium sulfate composite, wherein the at least
one bore comprises a bore in the first portion.
[0049] FIG. 10A is a schematical cross sectional view of a portion
of a ring of a device of the invention schematically showing a
pharmaceutical composition comprising oxybutynin and a silicone
excipient in a bore in the ring, wherein the pharmaceutical
composition contains sufficient oxybutynin to deliver about 0.5
mg/day.
[0050] FIG. 10B is a schematical cross sectional view of a portion
of a ring of a device of the invention schematically showing a
pharmaceutical composition comprising oxybutynin and a silicone
excipient in a bore in the ring, wherein the pharmaceutical
composition contains sufficient oxybutynin to deliver about 1.0
mg/day.
[0051] FIG. 11: Effect of the Oxybutynin implants on the rabbit and
bladder weight. Each bar is the mean SEM of 3 individual
rabbits.
[0052] FIG. 12: Effect of different oxybutynin-doses on cystometric
pressures. Each point is the mean of cystometric curves performed
on three individual rabbits.
[0053] FIG. 13: Cystometry performed on rabbits with placebo
inserts. Each point is the mean of cystometric curves performed on
three individual rabbits.
[0054] FIG. 14: Effect of the Oxybutynin implants on micturition
pressure. Each bar is the mean +/-SEM of three individual rabbits.
*=significantly different from placebo.
[0055] FIG. 15: Plasma values for rabbits with 0.5 mg/day inserts.
Each bar is the mean +/-SEM of three individual rabbits.
[0056] FIG. 16: Plasma values for rabbits with 1.0 mg/day inserts.
Each bar is the mean +/-SEM of three individual rabbits
significantly different from day 1.
[0057] FIG. 17: Plasma values for oxybutynin and desethyloxybutynin
in rabbits with 5.0 mg/day inserts. Each bar is the mean +/-SEM of
three individual rabbits.
[0058] FIG. 18: Plasma values for rabbits with vaginal inserts
after 7 days. Each bar is the mean +/-SEM of three individual
rabbits. *=significantly different from 0.5 mg/day group;
**=significantly different from 0.5 and 1.0 mg/day groups.
DETAILED DESCRIPTION OF THE INVENTION
[0059] The present invention is based upon the discovery that
surprisingly and unexpectedly, trifluoropropylmethyl/dimethyl
siloxane elastomer controllably releases oxybutynin when an
oxybutynin pharmaceutical composition is inserted within
trifluoropropylmethyl/dimethyl siloxane elastomer. Thus, a device
comprising, inter alia, trifluoropropylmethyl/d- imethyl siloxane
elastomer surrounding oxybutynin, that is inserted into the vaginal
canal of the female, controllably releases and locally delivers a
therapeutically effective of amount of oxybutynin to the detrusor
muscle of a female for up to 28 contiguous days. As a result,
circulation of oxybutynin and its metabolite N-desethyloxybutynin
throughout the body is largely avoided, along with the side effects
that have traditionally been associated with such circulation.
[0060] In particular, the present invention extends to a device for
locally delivering and controllably releasing oxybutynin to the
cervical region of a female to treat urinary incontinence,
comprising:
[0061] (a) a ring having a bore running from the surface of the
ring, wherein the ring comprises trifluoropropylmethyl/dimethyl
siloxane elastomer, and has a sufficient size such that it can be
inserted into the vaginal canal of the female;
[0062] (b) a pharmaceutical composition located within the bore,
wherein the pharmaceutical composition comprises oxybutynin and an
excipient; and
[0063] (c) a cap placed on the bore at the surface of the ring so
that the pharmaceutical composition is contained within the
bore,
[0064] such that upon insertion of the ring into the vaginal canal,
oxybutynin is controllably released from the ring in a
therapeutically effective amount, and locally delivered to treat
urinary incontinence.
[0065] Furthermore, the present invention extends to a device for
locally delivering and controllably releasing oxybutynin to the
cervical region of a female to treat urinary incontinence, the
device comprising:
[0066] (a) a ring having a bore running from the surface of the
ring, wherein the ring comprises a pharmaceutically acceptable
inert material that controllably releases oxybutynin, and has a
sufficient size such that it can be inserted into the vaginal canal
of the female; and
[0067] (b) a pharmaceutical composition rod comprising oxybutynin
and an excipient, wherein the rod is inserted into the bore,
[0068] (c) a cap comprising the pharmaceutically acceptable inert
material that is placed on the bore at the surface of the ring so
that the pharmaceutical composition is contained within the
bore,
[0069] such that upon insertion of the ring into the vaginal canal,
oxybutynin is controllably released from the ring in a
therapeutically effective amount, and locally delivered to treat
urinary incontinence.
[0070] Furthermore, the present invention extends to a method for
locally delivering and controllably releasing a therapeutically
effective amount of oxybutynin in the cervical region of a female
to treat urinary incontinence, comprising the steps of:
[0071] (a) providing a ring having at least one bore running from
the surface of the ring, wherein the ring comprises
trifluoropropylmethyl/dim- ethyl siloxane elastomer which
controllably releases oxybutynin, and has a sufficient size such
that it can be inserted into the vaginal canal of the female;
[0072] (b) inserting a pharmaceutical composition comprising
oxybutynin and excipient into the bore;
[0073] (c) placing a cap on the bore at the surface of the ring so
that the pharmaceutical composition is contained within the bore,
and
[0074] (d) inserting the ring into the vaginal canal,
[0075] so that a therapeutically effective amount of oxybutynin is
controllably released from the ring to treat the urinary
incontinence.
[0076] Numerous terms and phrases are used regularly throughout the
instant specification and appending claims. Accordingly, as used
herein, the term "oxybutynin" refers to oxybutynin the base,
optically resolved oxybutynin, and related compounds (e.g., salts)
thereof. Oxybutynin is a base capable of forming salts with organic
and mineral acids, for example, with hydrochloric acid to form
oxybutynin chloride. A particular form of oxybutynin having
applications in a device and method of the present invention is
oxybutynin base.
[0077] As used herein, the term "excipient" refers to a
pharmaceutically acceptable diluent, adjuvant, carrier, or vehicle
with which oxybutynin is administered. Such excipients can be
sterile liquids, including those of petroleum, animal, vegetable or
synthetic origin, such as peanut oil, soybean oil, mineral oil,
sesame oil and the like. A particular example of an excipient
having applications herein comprises tin catalyzed silicone
polymer.
[0078] As used herein, the singular forms "a," "an" and "the"
include plural referents unless the context clearly dictates
otherwise.
[0079] As used herein, the phrase "at least one" means one or more
than one.
[0080] As used herein, the phrase "vaginal canal" refers to a canal
which runs from the hymenal ring to the cervix of a female (also
referred to as the vagina) and the fornices surrounding the
vagina.
[0081] As used herein, the term "biocompatible" refers to a
material having the property of being biologically compatible by
not producing a toxic, injurious, or immunological response in
living tissue.
[0082] As used herein, the phrase "pharmaceutically acceptable"
refers to molecular entities, excipients, and compositions that are
physiologically tolerable and do not typically produce an allergic
or similar untoward reaction, such as gastric upset, dizziness and
the like, when administered to a human. Preferably, as used herein,
the term "pharmaceutically acceptable" means approved by a
regulatory agency of the Federal or a state government or listed in
the US Pharmacopoeia or other generally recognized pharmacopoeia
for use in animals, and more particularly in humans.
[0083] The phrase "therapeutically effective amount" as used herein
refers to an amount of oxybutynin sufficient to alleviate urinary
incontinence by at least about 15 percent, preferably by at least
50 percent, more preferably by at least 90 percent, and most
preferably prevent urinary incontinence in the patient.
[0084] As used herein, the phrase "locally deliver" refers to
delivering oxybutynin directly to the cervical region of the female
so that it can interact with the detrusor muscle. Such delivery is
not dependent upon the patient's circulatory or digestive
systems.
[0085] As used herein, the phrase "controllably released" refers
generally to the release of oxybutynin from a ring of the
invention, wherein the excipient and/or the
trifluoropropylmethyl/dimethyl siloxane elastomer of the ring
retard the release of oxybutynin in order to prevent immediate
release of all the oxybutynin in the pharmaceutical composition to
the cervical region. In a particular embodiment, the release of
oxybutynin ranges from about 0.5 mg/day to about 5 mg/day for up to
twenty-eight contiguous days.
[0086] As used herein, the term "detrusor muscle" refers to the
external longitudinal layer of the muscular coat of the bladder.
Contraction of the detrusor muscle is involved in emptying of the
bladder and urination. Relaxation of the detrusor permits the
bladder to fill with urine prior to urination.
[0087] As used herein, the phrase "urinary incontinence" refers to
the disorder of lacking normal voluntary control of excretory
urinary functions. Urinary incontinence includes: overflow
incontinence, which involves contractile dysfunction of the
detrusor muscle and results in large bladder volumes and urinary
dribbling; stress incontinence, wherein patients lose small volumes
of urine as a result of temporarily increased abdominal pressure;
and functional incontinence, which is present in normally continent
individuals as a result of physical or cognitive problems, or
various medications, e.g., diuretics. A device or method of the
present invention can readily be used to treat any of these
particular types of urinary incontinence.
[0088] As used herein, the phrase "barium sulfate composite" refers
a composite comprising barium sulfate and a siloxane polymer. A
particular example of a barium sulfate composite having
applications herein comprises about 48% by weight barium sulfate
(BaSO.sub.4) and about 52% by weight polydimethylsiloxane
(PDMS).
[0089] As used herein, the phrase "trifluoropropylmethyl/dimethyl
siloxane elastomer" refers to an elastomer having a chemical
formula of: 1
[0090] As explained above, a device of the invention comprises a
ring having a bore in the surface of the ring. FIG. 1A
schematically shows a ring (1) of a device of the invention in
which the bore comprises two bores which run from the surface of
the ring into the ring, and intersect the surface of the ring
twice. In particular, ring (1) comprises a surface (2). A first
bore (3) runs from surface (2) into ring (1). Furthermore, bore (3)
intersects surface (2) of ring (1) at points a and b. A second bore
(4) also runs from surface (2) of ring (1) into ring (1). Also,
just as with bore (3), bore (4) intersects surface (2) twice, i.e,
at c and d. As explained above, ring (1) comprises a
pharmaceutically acceptable inert material that controllably
releases oxybutynin, such as trifluoropropylmethyl/dimethyl
siloxane elastomer. A device of the invention also comprises
pharmaceutical composition comprising oxybutynin and an excipient,
which is placed within bore (3) and/or (4). The oxybutynin can be
in a free base form, a salt form, or a mixture thereof. In a
particular embodiment, the pharmaceutical composition comprises
about 60% by weight oxybutynin, and about 40% by weight excipient.
Furthermore, a particular excipient having applications herein
comprises tin catalyzed silicone polymer. Caps (not shown)
comprising trifluoropropylmethyl/dimethyl siloxane elastomer,
polydimethylsiloxane, or polytetrafluoroethylene are placed on the
bores at points a-d after the pharmaceutical composition is placed
in the bores, and prior to insertion of the ring into the vaginal
canal.
[0091] FIG. 1(b) schematically shows a cross section of a portion
of ring (1) which comprises bore (4). As explained above, a device
of the invention has applications in a variety of females,
including, but not limited to human, bovine, feline, canine, equine
or porcine females, to name only a few. Thus, the size and
dimensions of the ring and the bore(s) will vary, so that the ring
has sufficient size to be inserted into the vaginal canal of the
female. FIG. 1(b) schematically shows a ring of a particular
embodiment of a device of the invention, wherein the female is a
human. The cross-sectional diameter of ring (1) is about 8.5
mm.+-.0.5 mm. Moreover, bore (3) has an outer diameter of about 3.2
mm, and a length of about 2.2 cm.
[0092] FIG. 6A is a schematical view of a ring of a device of the
invention, wherein ring (5) comprises a first portion (6)
comprising trifluoropropylmethyl/dimethyl siloxane elastomer, and a
second portion (7) comprising polydimethylsiloxane. The bore (8)
runs from surface (9) of first portion (6) into first portion (6)
of the ring. In a particular embodiment as schematically shown in
FIG. 6, bore (8) runs from surface (9) of first portion (6) into
first portion (6), and intersects surface (9) at a and b.
Furthermore, the present invention extends to a device for locally
delivering and controllably releasing oxybutynin in the vaginal
canal of a female as described above, wherein a ring of a device of
the invention comprises, inter alia, a first portion, a second
portion, and at least two shields comprising a material into which
oxybutynin is substantially insoluble. The at least two shields lie
between the first and second portions, and prevent contact between
the first and second portions. FIGS. 7A and 7B provide schematical
cross sectional views of such rings. In particular, ring (12) of
FIG. 7A comprises a first portion (13), a second portion (14) and
two shields (15) and (16). Bore (17) runs from the surface of first
portion (13) into first portion (13) and intersects the surface of
portion (13) at two places. Portion (13) comprises a
pharmaceutically acceptable inert material that controllably
releases oxybutynin, e.g., trifluoropropylmethyl/dimethyl siloxane
elastomer. Portion (14) can be comprised of a variety of materials,
including but not limited to polydimethylsiloxane,
polytetrafluoroethylene, trifluoropropylmethyl/dime- thyl siloxane
elastomer, a barium sulfate composite, or a mixture thereof.
Shields (15) and (16), located between portions (13) and (14),
prevent contact between portions (13) and (14). When a
pharmaceutical composition comprising oxybutynin and an excipient
is placed within bore (17), shields (15) and (16) substantially
limit diffusion of oxybutynin into ring (12) beyond portion (13).
Thus, when ring (12) is inserted into the vaginal canal of a
female, the trifluoropropylmethyl/dimethyl siloxane elastomer
portion of the ring controllably releases oxybutynin to treat
incontinence.
[0093] FIG. 7(B) schematically shows another embodiment of a ring
of a device of the invention. In particular, ring (18) of FIG. 7B
comprises first portion (19) with a first bore (20) in first
portion (19), and a second portion (21) with bore (22) therein.
Ring (18) further comprises portions (27) and (28), four shields
(23), (24), (25), and (26). Shields (23)-(26) are located between
first and second portions (19) and (21) respectively, and prevent
contact between first and second portions (19) and (20). As
explained above, ring (18) can be comprised of numerous materials,
including, but not limited to polydimethylsiloxane,
polytetrafluoroethylene, trifluoropropylmethyl/dimethyl siloxane
elastomer, a barium sulfate composite, or a combination thereof, to
name just a few. In the embodiment schematically shown in FIG. 7B,
portions (19) and (21) comprise trifluoropropylmethyl/dimethyl
siloxane elastomer, and portions (27) and (28) comprise
trifluoropropylmethyl/dimethyl siloxane elastomer,
polytetrafluoroethylene, polydimethylsiloxane, a barium sulfate
composite, or a combination thereof. The cross-sectional diameter
of ring (18) is about 8.5 mm.+-.0.5 mm. Moreover, bores (20) and
(22) have an outer diameter of about 3.2 mm, and a length of about
2.2 cm.
[0094] Referring again to FIG. 7(B), shields (23)-(26) comprise
polytetrafluoroethylene. A pharmaceutical composition comprising
oxybutynin and a tin catalyzed silicone polymer excipient is placed
within bores (20) and/or (22) of ring (18). Caps (not shown) are
then placed over the bores at the surface of the ring in order to
contain the pharmaceutical composition within the bore. Ring (18)
is then inserted into the vaginal canal of a female. Oxybutynin
diffuses from the pharmaceutical composition and then through the
trifluoropropylmethyl/dim- ethyl siloxane elastomer portion of the
ring, which in turn controllably releases the oxybutynin in order
to alleviate the female's urinary incontinence.
[0095] FIG. 8A and B schematically show other embodiments or a ring
of a device of the invention, wherein the ring comprises two
portions and at least two shields located between the portions.
Oxybutynin is substantially insoluble in the shields. Thus, the
shields prevent contact between the portions and limit any
diffusion of oxybutynin from the portion of the ring with the bore
containing the pharmaceutical composition to other portions of the
ring. As schematically shown in FIG. 8A, ring (27) comprises
trifluoropropylmethyl/dimethyl siloxane elastomer. Thus, first
portion (30) and second portion (31) comprise
trifluoropropylmethyl/dimethyl siloxane elastomer. A first shield
(28) and a second shield (29) comprising a barium sulfate composite
lie between lie between first portion (30) and second portion (31)
of ring (27), and prevent contact between portions (30) and (31). A
bore (32) is located in first portion (31) and intersects with the
surface of first portion (31) twice. As a result, ring (27)
comprises a combination of trifluoropropylmethyl/dimethyl siloxane
elastomer and a barium sulfate composite. A pharmaceutical
composition comprising oxybutynin and an excipient, e.g., tin
catalyzed silicone polymer is placed within bore (32). Caps (not
shown) are then placed over the points of intersection of the bores
and the outer surfaces of the ring. These caps can be comprised of
numerous materials, including trifluoropropylmethyl/dimethyl
siloxane elastomer, polytetrafluoroethylene, or
polydimethylsiloxane. In a particular embodiment, the caps comprise
polydimethylsiloxane. Since oxybutynin is substantially insoluble
in barium sulfate composite shields (28) and (29), it is
sequestered in first portion (30), and is unable to diffuse
throughout ring (27). When ring (27) is inserted into the vaginal
canal of a female, the trifluoropropylmethyl/dimethyl siloxane
elastomer controllably releases oxybutynin. The controllably
released oxybutynin interacts with the female's detrusor muscle,
and treats the female's urinary incontinence.
[0096] FIG. 8B schematically shows a ring of a device of the
invention which comprises a combination of materials. In
particular, ring (33) schematically shown in FIG. 8B comprises a
first portion (34) of trifluoropropylmethyl/dimethyl siloxane
elastomer, a second portion (35) comprising polydimethylsiloxane,
and two barium sulfate composite shields (36) and (37) located
between first portion (34) and second portion (35). Shields (36)
and (37) prevent contact between first and second portions (34) and
(35). A bore (38), located in first portion runs from the surface
of first portion (34) into portion (34), and intersects the surface
of first portion (34) at a and b. A pharmaceutical composition
comprising oxybutynin and tin catalyzed silicone polymer excipient
is then placed in bore (38). When ring (33) is inserted into the
vaginal canal of a female, oxybutynin is controllably released from
the ring and interacts with the female's detrusor muscle.
[0097] As explained above, a device of the invention can be used to
treat urinary incontinence in a variety of females, including, but
not limited to human, bovine, porcine, equine, canine, and feline
females, to name only a few. In a particular embodiment, the female
is human. Thus, when used in a human female, a ring of a device of
the invention would have a cross sectional diameter of about 8.5
mm.+-.0.5 mm, and a ring diameter of about 5.5.+-.0.1 cm. The outer
diameter and length of a bore of a ring of the invention, such as
the bore schematically shown in FIGS. 8A and 8B for example, is
about 3.2 mm and about 2.2 cm respectively.
[0098] FIG. 9 schematically shows another example of a ring of a
device of the invention comprising a combination of materials. More
specifically, FIG. 9 schematically shows a cross sectional view of
ring (39) which comprises a first portion (40) of
trifluoropropylmethyl/dimethyl siloxane elastomer and a second
portion (41) comprising a barium sulfate composite. A bore (42),
located in first portion (40), intersects the surface of first
portion (40) twice, and runs into first portion (40). A
pharmaceutical composition comprising about 60% by weight
oxybutynin and about 40% tin catalyzed silicone polymer excipient
is then inserted into bore (42). In a particular embodiment, the
pharmaceutical composition is formed into a rod as described infra.
The rod is then inserted into bore (42). The amount of
pharmaceutical composition placed in bore (42) can vary, depending
upon the desired therapeutically effective amount of oxybutynin to
be delivered.
[0099] FIG. 10 provides a schematical cross sectional view of a
portion of a ring of the invention comprising
trifluoropropylmethyl/dimethyl siloxane elastomer, wherein the
portion comprises a bore and a pharmaceutical composition
comprising about 60% by weight oxybutynin and about 40% by weight
tin catalyzed silicone polymer excipient in the bore. Numerous
methods for preparing a pharmaceutical composition comprising
oxybutynin and tin catalyzed silicone polymer excipient are readily
available to one of ordinary skill in the art, and have
applications in a device of the present invention. A particular
method of the present invention comprises forming rods of the
pharmaceutical composition. In particular, polytetrafluoroethylene
tubing having a diameter of about 3.2 mm is provided. Slits are
then put into the tubing. Examples of such slits are schematically
shown in FIGS. 10D and 10E. After the slits are placed in the
tubing, the tubing is filled with a pharmaceutical composition
comprising oxybutynin and tin catalyzed silicone polymer as an
excipient. The pharmaceutical composition within the tubing is then
cured at about room temperature for about twenty-four (24)
hours.
[0100] After curing, the polytetrafluoroethylene tubing is removed,
leaving a pharmaceutical composition rod comprising oxybutynin and
tin catalyzed silicone polymer that can readily be inserted into a
bore in a ring of a device of the invention. Such rods also permit
medical providers to place an appropriate amount of pharmaceutical
composition into a bore in a ring of a device of the invention in
order to locally deliver and controllably release a particular
therapeutically effective amount of oxybutynin. More specifically,
FIGS. 10A-C schematically show a trifluoropropylmethyl/dimethyl
siloxane elastomer portion (44) of a ring for use in a human
female, wherein the ring has a cross sectional diameter of about
8.5 mm.+-.0.5 mm, and a ring diameter of about 5.5.+-.0.1 cm. A
bore (44) runs from the surface of portion (44) into portion (44),
and intersects the surface of portion (44) twice. The diameter of
bore (44) is about 3.2 mm, and bore (44) has a length of about 2.2
cm. Pharmaceutical composition (45) comprising about 60% by weight
oxybutynin and about 40% by weight tin catalyzed silicone polymer
that was formed into a rod as described above, is inserted into
bore (44). In FIG. 10A, approximately 0.55 cm of a rod of
pharmaceutical composition is schematically shown inserted into
bore (44). This length of rod has been determined sufficient to
locally deliver and controllably release approximately 0.5 mg/day
of oxybutynin in the vaginal canal of a human female for up to
twenty-eight days. Likewise, FIGS. 10(A) and 10(B) respectively
schematically show that approximately 1.65 cm of pharmaceutical
composition of rod inserted into bore (44) delivers about 1.0
mg/day of oxybutynin, and 2.2 cm of pharmaceutical composition rod
delivers approximately 5.0 mg/day of oxybutynin.
[0101] The present invention may be better understood by reference
to the following non-limiting Examples, which are provided as
exemplary of the invention. The following examples are presented in
order to more fully illustrate the preferred embodiments of the
invention. They should in no way be construed, however, as limiting
the broad scope of the invention.
EXAMPLES
[0102] Urinary incontinence is a debilitating disorder that causes
unwanted suffering and embarrassment to its victims. Oxybutynin, a
drug used to treat urinary incontinence has traditionally been
delivered via oral ingestion, and transdermally. However, such
methods have inherent limitations, particularly since these methods
are dependent upon a patient's gastrointestinal, and/or circulatory
systems to deliver oxybutynin to the bladder, the site of its
activity in treating urinary incontinence. Set forth herein is a
new and useful device and method for locally delivering and
controllably releasing a therapeutically effective amount of
oxybutynin ranging from 0.5 to 5.0 mg/day for up to twenty-eight
contiguous days. In particular, a device of the instant invention
is based upon the discovery that surprisingly and unexpectedly,
trifluoropropylmethyl/dimethyl siloxane elastomer controls the
release of oxybutynin, and thus can be used to controllably release
oxybutynin. Particular methods of producing rings having
applications in a device or method of the present invention are set
forth infra.
Example 1
Preparation of a Two-Bore, Trifluoropropylmethyl/dimethyl Siloxane
Elastomer Ring as Schematically Shown in FIG. 1A
[0103] 40 g part A and 40 g part B trifluoropropylmethyl/dimethyl
siloxane elastomer formation (NuSil Technology, CF2-3521 grade)
were weighed into a 100 g capacity Hauschild mixing cup and
subsequently mixed for 10 seconds in a Hauschild Model 501 T speed
mixer. A metal spatula was then used to scrape down the sides of
the mixing cup and further blend the two starting components. A
final 14-second speed mixer cycle was supplied to ensure blend
uniformity.
[0104] Both halves of an insert mold with key bore and insert
dimensions as follows were lightly coated in an ethanol/water
solution of DARVAN WAQ (R. T. Vanderbilt Co.) and allowed to air
dry; outer diameter=5.5.+-.0.1 cm, cross-section
diameter=8.5.+-.0.5 mm, insert bore length=2.2.+-.0.1 cm, insert
bore diameter 3.2.+-.0.1 cm. Between 12-15 grams of the 1:1 part
A:part B blend were manually placed via metal spatula into the pin
containing half of the mold. The insert pins were positioned in the
filled portion of the mold and matched unfilled mold half was mated
into place.
[0105] The filled mold assembly was then compressed between the
unheated platens of a Kuntz injection molding machine in order to
discharge excess polymer blend from the mold. During this
compression step, the insert pins were manually held in place to
avoid ejection by the applied air pressure. The discharged blend
material was removed from the outside of the mold assembly and
discarded.
[0106] The compressed, filled mold assembly was then placed between
the preheated platens of a model 3912 Carver press. A pressure of
5,000 psi was applied and heating of the assembly for 15 minutes at
150.degree. C. was performed to affect elastomer cure. During
approximately the first 5 minutes of this curing step, the insert
pins were physically held in place to avoid ejection from the
mold.
[0107] After 15 minutes at 150.degree. C., the mold was removed
from the Carver press and cooled on the Kuntz machine's chiller for
a sufficient time to allow easy separation of the mold halves and
facilitate manual handling. The cured ring was separated from the
mold by hand. The insert pins were then carefully removed from the
molded part by gently pulling them out without tearing or otherwise
deforming the insert bore.
Example 2
Preparation of an Insert Segment as Schematically Shown in FIG.
1B
[0108] Insert segments of the following dimensions were prepared
from molded insert rings prepared as discussed in Example 1 above,
by cutting out the insert bore portion of an insert ring with a
sharp instrument: length=3.5.+-.0.1 cm, cross sectional
diameter=8.5.+-.0.5 mm. Such segments are schematically shown in
FIG. 1B.
Example 3
Preparation of a Trifluoropropylmethyl/Dimethyl Siloxane Elastomer
Insert Rings Containing One Oxybutynin Filled Bore
[0109] Using a syringe, one bore of a ring produced pursuant to
Example 1 above, was completely filled with a 200:1 blend of
R2602:CAT-02 (both from NuSil Technology) condensation cure
silicone sealant. The insert ring's other bore was partially (about
3 mm) filled with this sealant. The sealant was allowed to cure for
5 minutes.
[0110] 96 grams of PLY-7610 (NuSil Technology) and 4 grams of
CAT-01 (NuSil Technology) were weighed into a 40 gram capacity
Hauschild mixing cup. Three 26 second spin cycles in a Hauschild
model AM 501 T speed mixer were conducted to blend these materials.
The resulting blend was labeled CAT-22 (and is hereinafter
referenced as such).
[0111] 1 gram CAT-22, 8 grams of R2602 and 13.5 grams of oxybutynin
base were mixed for 26 seconds in the Hauschild model AM 501 T
speed mixer. A sufficient amount of the resulting paste was
injected via syringe into a partially filled insert ring bore to
give a 1-1.5 cm long drug containing section. After its addition,
the paste was compacted with a small glass stirring rod so it
contacted the initially injected 200:1 R2602:CAT-02 silicone
sealant layer. The remainder of this insert bore was finally filled
with a layer of the 200:1 R2602-02 sealant. The ring was given 24
hours at ambient conditions to allow the bore sealants to fully
cure. By calculation, based on weights before and after additions,
about 18 mg of oxybutynin were present in the ring.
Example 4
Preparation of Trifluoropropylmethyl/Dimethyl Siloxane Elastomer
Insert Segments Containing Oxybutynin
[0112] 16 grams of R2602 (NuSil Technology) and 2 grams of
previously described CAT-22 were weighed into a 40 gram capacity
Hauschild mixing cup. Two 16 second spin cycles in a Hauschild
model AM 501 T speed mixer were conducted to blend these
materials.
[0113] Using a syringe fitted with an 18 gauge needle, the bore of
a trifluoropropylmethyl/dimethyl siloxane elastomer insert segment,
from Example 2 above, was filled to one third volume with the 8:1
R2602:CAT-22 condensation cure silicone sealant. The sealant was
allowed to cure for 24 hours.
[0114] 2 grams of R2602, 0.25 grams of CAT-22 and 3.4 grams of
oxybutynin base were weighed into a 40 gram capacity Hauschild
mixing cup. Two 16 second spin cycles in a Hauschild model AM 501 T
speed mixer were performed to blend these materials. About 30 mg of
this paste was injected, via syringe, into the insert segment's
bore and subsequently compacted so that it contacted the initially
injected 8:1 R2602:CAT-22 condensation cure silicone sealant layer.
The remainder of the bore was then filled with 8:1 R2602:CAT-22
sealant. Cure of the bore's contents was achieved at ambient
conditions overnight. By calculation, based weights before and
after additions, about 18 mg of oxybutynin were present in the
segment.
Example 5
In Vitro Drug Release Testing of Ring Segments
[0115] Seven day in vitro oxybutynin release profiles were
generated from rings and segments produced pursuant to Examples 3
and 4. The datapoints for both ring and segment devices in FIG. 2
represent the average of three samples per type.
[0116] In vitro testing of rings produced pursuant to Example 3 was
performed by immersing individual rings in 300 ml of 0.05 M, pH 6.5
Sodium Dodecyl Sulfate (SDS) solution within 500 ml capacity
"NALGENE" screw cap bottles. The plastic containers were shaken at
about 140 RPM in a 37.degree. C. water bath. Aliquots of receptor
media were withdrawn at 1, 3, 5 and 7 days and individually
analyzed by reverse phase HPLC. For the HPLC analyses, a C.sub.8, 5
micron, 4.6.times.150 mm Kromasil column was employed. The buffer
was 32:68 mixture of acetonitrile: (0.01 M KH.sub.2PO.sub.4, 0.05 M
Dimethyl Octyl Amine (DMOA), with pH=2). The average amount of drug
released at each Potassium Phosphate Monobasic timepoint was
plotted vs. time, as indicated in FIGS. 2-5.
[0117] In vitro testing of segments from such rings was conducted
in a 500 ml capacity DISTEK USP dissolution baths at 37.degree. C.
Individual segments were suspended in basket holder and immersed in
500 ml of 6.5 pH. 0.05 M SDS solution. The basket holders were
rotated at 100 rpm. Aliquots of receptor media were withdrawn at 1,
3, 5 and 7 days and individually analyzed by reverse phase HPLC.
The HPLC conditions were the same as described in the previous
paragraph. The average amount of drug released at each timepoint
was plotted versus time. As shown in FIGS. 2-5 oxybutynin can be
released from trifluoropropylmethyl/dimethyl siloxane elastomer in
a controlled manner.
Example 6
Preparation of Trifluoropropylmethyl/dimethyl Siloxane Elastomer
Insert Segments Containing Sufficient Oxybutynin to Deliver About
0.5 mg/day in vitro Over 7 Days
[0118] 8 grams of R2602 (NuSil Technology) and 1 gram of previously
described CAT-22 were weighed into a 40 gram capacity Hauschild
mixing cup. A 22 second spin cyclein in a Hauschild model AM 501 T
was performed to blend these materials.
[0119] Using a syringe fitted with an 18 gauge needle, the bore of
a trifluoropropylmethyl/dimethyl silicone elastomer insert segment,
from Example 3, was filled with the 8:1 R2602:CAT-22 condensation
cured silicone sealant to about 1/8.sup.th of its length.
[0120] 8 grams of R2602, 1 gram of CAT-22 and 13.5 grams of
oxybutynin base were weighed into a 40 gram capacity Hauschild
mixing cup. Two 16 second spin cycles in a Hauschild model AM 501 T
speed mixer was performed to blend these materials. About 50 mg of
the resulting paste was injected, via syringe, into the insert
segment's bore. This amount of drug containing paste filled about
3/4 of the bore's length. The remainder of the bore was then filled
with 8:1 R2602:CAT-22 sealant. Cure of the bore's contents was
achieved at ambient conditions over the course of 48 hours. By
calculation, based on weights before and after additions, about 32
mg of oxybutynin were present in the segment.
Example 7
In vitro Drug Release Testing of Segments of Rings Comprising
Trifluoropropylmethyl/dimethyl Siloxane Elastomer Insert Segments
Containing Sufficient Oxybutynin to Deliver About 0.5 mg/day in
vitro Over 7 Days
[0121] Seven day in vitro oxybutynin release profiles were
generated from segments of rings described in Example 6 above. The
datapoints for segments of rings comprising
trifluoropropylmethyl/dimethyl siloxane elastomer insert segments
containing sufficient oxybutynin to deliver about 0.5 mg/day in
vitro over 7 days in FIG. 3 represent an average of three
samples.
[0122] In vitro testing of these segments of rings was conducted in
500 ml capacity "DISTEK USP" dissolution baths at 37.degree. C.
Individual segments were suspended in basket holders and immersed
in 500 ml of 6.5 pH. 0.05 M SDS solution. The basket holders were
rotated at 100 rpm. Aliquots of receptor media were withdrawn at 1,
3, 5 and 7 days and individually analyzed by reverse phase HPLC.
For the HPLC analyses, a C.sub.8, 5 micron, 4.6.times.150 mm
Kromasil column was employed. The buffer was 32:68 mixture of
acetonitrile: (0.01 M KH.sub.2PO.sub.4, 0.05 M DMOA, with
pH=2).
[0123] The average drug released from these segments was plotted
versus time and compared to the release data generated for
previously described ring segments. This comparison is presented in
FIG. 3. The data in FIG. 3 show that the segments of such rings
released on average, close to 0.5 mg of oxybutynin per day. FIG. 3
also demonstrates that oxybutynin can be released from
trifluoropropylmethyl/dimethyl siloxane elastomer in a controlled
manner.
Example 8
Preparation of Trifluoropropylmethyl/Dimethyl Siloxane Elastomer
Insert Segments Designed to Deliver Oxybutynin at a Rate of 1.0
mg/day Over 7 Days
[0124] 8 grams of R2602 (NuSil Technology) and 1 gram of previously
described CAT-22 were mixed as described above.
[0125] 2 grams of R2602, 0.25 gram of CAT-22 and 3.38 grams of
oxybutynin base were weighed into a 40 gram capacity Hauschild
mixing cup. Two 16 second spin cycles in a Hauschild model AM 501 T
speed mixer was performed to blend these materials. Using a cuvette
stirrer, about 125 mg of the resulting paste was compacted into the
middle of the bore of an Example 1 trifluoropropylmethyl/dimethyl
siloxane elastomer insert segment. The top and bottom portions of
the bore were then filled with a very small amount of 8:1
R2602:CAT-22 sealant, applied via syringe. Cure of the bore's
contents was achieved at ambient conditions over the course of 24
hours. By calculation, based on weights before and after each
addition to the bore, about 75 mg of oxybutynin were present in the
segment.
Example 9
Preparation of Trifluoropropylmethyl/Dimethyl Siloxane Elastomer
Insert Segments Containing Sufficient Oxybutynin to Deliver Between
1.0 and 1.5 mg/day in vitro Over 7 Days.
[0126] 8 grams of R2602 (NuSil Technology and 1 gram of previously
described CAT-22 were weighed into a 40 gram capacity Hauschild
mixing cup. Two 16 second spin cycles in a Hauschild model AM 501 T
speed mixer were performed to blend these materials.
[0127] 8 grams of R2602, 1 gram of CAT-22 and 4.8 grams of
oxybutynin base were weighed into a 40 gram capacity Hauschild
mixing cup. Two 16 second spin cycles in a Hauschild model AM 501 T
speed mixer were performed to blend these materials. About 191 mg
of the resulting paste was injected, via syringe, into the bore of
trifluoropropylmethyl/dimethyl siloxane elastomer insert segment,
described above. The top portion of the bore was then filled with a
very small amount of 8:1 R2602:CAT-22 sealant, applied via syringe.
Cure of the bore's contents was achieved at ambient conditions over
the course of 48 hours. By calculation, based on weights before and
after additions, about 67 mg of oxybutynin were present in the
segment.
Example 10
Preparation of Trifluoropropylmethyl/Dimethyl Siloxane Elastomer
Insert Segments Containing Sufficient Oxybutynin to Deliver Between
1.5 and 2.0 mg/day in vitro Over 7 Days
[0128] 8 grams of R2602 (NuSil Technology) and 1 gram of previously
described CAT-22 were mixed as described above.
[0129] 8 grams of R2602, 1 gram of CAT-22 and 9 grams of oxybutynin
base were weighed into a 40 gram capacity Hauschild mixing cup. Two
16 second spin cycles in a Hauschild model AM 501 T speed mixer
were performed to blend these materials. About 240 mg of the
resulting paste was injected, via syringe, into the bore of a
trifluoropropylmethyl/dimethyl siloxane elastomer insert segment,
from Example 2. The amount of drug and containing paste filled
nearly the entire bore. The top portion of the bore was then filled
with a very small amount of the 8:1 R2602:CAT-22 sealant, applied
via syringe. Cure of the bore's contents was achieved at ambient
conditions overnight. By calculation, based on weights before and
after additions, about 120 mg of oxybutynin was present in the
segment.
Example 11
Preparation of a Single Bore Insert Ring Comprised of Separate,
Continuous PDMS and Trifluoropropylmethyl/dimethyl Siloxane
Elastomer Sections
[0130] 30 grams part A and 30 grams of part B
trifluoropropylmethyl/dimeth- yl siloxane elastomer formulation
(NuSil Technology, CF2-3521 grade) were weighed into a 100 gram
capacity Hauschild mixing cup and subsequently mixed for 16 seconds
in a Hauschild model AM 501 T speed mixer. A metal spatula was then
used to scrape down the sides of the mixing cup and further blend
the two starting components. A final 16-second speed mixer cycle
was applied to ensure blend uniformity.
[0131] Continuous sections of matching halves of the insert mold
from Example 2 were manually filled with the uncured
trifluoropropylmethyl/dim- ethyl siloxane elastomer mix such that
one of the pin insert portions of the mold contained this material.
Approximately 50% of the mold's volume was filled in this manner.
An insert pin was then positioned in the partially filled mold.
[0132] 30 grams part A and 3.0 grams of part B dimethyl siloxane
elastomer formulation (NuSil Technology, MED-4210 grade) were
weighed into a 100 gram capacity Hauschild mixing cup and
subsequently mixed for two 16 second cycles in a Hauschild model AM
501 T speed mixer. The unfilled matching halves of the partially
filled mold described above were manually filled with this uncured
dimethyl siloxane mix. No insert pin was positioned in this section
of the mold, however.
[0133] The entire mold was next assembled, placed between the
unheated platens of a model 3912 Carver press, and compressed to
5,000 psi in order to discharge excess polymer blend from the mold.
The excess material was removed from the outside of the mold
assembly and discarded. The filled mold was then transferred to the
pre-heated (150.degree. C.) platens of a model 284-1 Kuntz
injection molding machine and held there for 15 minutes to affect
cure. The mold was cooled to room temperature and disassembled.
Careful manual removal of the lone insert pin yielded the single
bore insert ring comprised of separate, continuous PDMS and
trifluoropropylmethyl/dimethyl siloxane elastomer sections that is
depicted in FIG. 6A.
Example 12
Preparation of a Two Bore Ring Comprised of Separate, Continuous
PDMS and Trifluoropropylmethyl/Dimethyl Siloxane Elastomer Sections
(corresponds to FIG. 6B)
[0134] The two bore insert ring schematically shown in FIG. 1 was
prepared using nearly the same procedure described in immediately
above, the only difference being that an additional insert pin was
positioned in the uncured dimethyl siloxane mix filled portion of
the mold prior to curing on the Kuntz machine.
Rings Comprising at Least Two Shields Into Which Oxybutynin is
Insoluble
[0135] Another design of a ring having applications herein
comprises two portions and at least two shields located between the
portions, wherein oxybutynin is substantially insoluble in the at
least two shields. The shields prevent contact between the two
portions, and thus prevent migration of the oxybutynin into the
ring. Based on the segment release data, and the comparison of the
release from rings vs. segments, it was determined minimal
diffusion of oxybutynin into the ring may occur when a
pharmaceutical composition comprising oxybutynin and tin catalyzed
silicone polymer excipient was placed into an at least one bore in
the TFP portion of the ring. To limit such diffusion, at least two
shields comprising polytetrafluoroethylene or a barium sulfate
composite were placed in the rings between a first portion
comprising trifluoropropylmethyl/dimethyl siloxane elastomer having
at least one bore and a second portion. Since oxybutynin is
substantially insoluble in polytetrafluoroethylene and a barium
sulfate composite, these shields prohibit the diffusion of
oxybutynin from the trifluoropropylmethyl/dimet- hyl siloxane
elastomer portion to other parts of the ring. As a result, a
substantial portion of the oxybutynin initially placed in the at
least one bore is controllably released and locally delivered to
the cervical region, and thus is available to treat the female's
urinary incontinence. Rings having only one
trifluoropropylmethyl/dimethyl siloxane elastomer portion with at
least one bore therein use only two shields. Similarly, rings
comprising two trifluoropropylmethyl/dimethyl siloxane elastomer
portions having at least one bore utilize four shields. To prepare
the rings, PTFE disks, cut to the about 8 mm in diameter, were
placed in a mold at 90.degree. angles. At least one pin was then
set in the mold and fixed in place. The pin would be located in a
portion of the mold that was between two shields. FIGS. 7A and 7B
schematically show the location of such shields in a ring of a
device of the invention. After placement of the shields and the
pin(s), trifluoropropylmethyl/dimethyl siloxane elastomer was
poured into the mold. Then, the mold was sealed and heated to cure
the polymer. Particular methods of producing such rings is set
forth infra.
Example 13
Preparation of a Two Bore Insert Ring Comprised of Separate,
Continuous PDMS Sections and Trifluoropropylmethyl/Dimethyl
Siloxane Elastomer, and Containing Four Drug Impermeable PTFE
shields Between These Sections
[0136] 30 grams part A and 30 grams part B of
trifluoropropylmethyl/dimeth- yl siloxane elastomer formulation
(NuSil Technology, CF2-3521 grade) were weighed into a 100 gram
capacity Hauschild mixing cup and subsequently mixed for 16 seconds
in a Hauschild model AM 501 T speed mixer. A metal spatula was then
used to scrape down the sides of the mixing cup and further blend
the two starting components. A final 16-second speed mixer cycle
was applied to ensure blend uniformity.
[0137] Continuous sections of matching halves of the insert mold
from Example 2 were manually filled with the uncured
trifluoropropylmethyl/dim- ethyl siloxane elastomer mix such that
one of the pin insert portions of the mold contained this material.
Approximately 50% of the mold's volume was filled in this manner.
An insert pin was then positioned in the partially filled mold. Two
8 mm diameter, 2 mm thick PTFE disks were manually situated in an
upright position within the uncured polymer mix several millimeters
from both the distal and proximal ends of the insert pin.
[0138] 30 grams part A, 3 gram part B of dimethyl siloxane
elastomer formulation (NuSil Technology, MED-4210 grade) were
weighed into a 100 gram capacity Hauschild mixing cup and
subsequently mixed for two 16 second cycles in a Hauschild model AM
501 T speed mixer. The unfilled matching halves of the partially
filled mold described above were manually filled with this uncured
dimethyl siloxane mix. An insert pin was then positioned in this
section of the mold. Two 8 mm diameter, 2 mm thick PTFE disks were
manually placed in a perpendicular manner within the uncured
polymer mix several millimeters from both the distal and proximal
ends of the insert pin.
[0139] The entire mold was next carefully assembled, placed between
the unheated platens of a model 3912 Carver press and compressed at
5000 psi in order to discharge excess polymer blend from the mold.
The excess material was removed from the outside of the mold
assembly and discarded. The filled mold was then transferred to the
pre-heated (150.degree. C.) platens of a model 284-1 Kuntz
injection molding machine and held there for 15 minutes to affect
cure. The mold was cooled to room temperature and disassembled.
Careful manual removal of the insert pins yielded the two bore
insert ring comprised of separate, continuous PDS and
trifluoropropylmethyl/dimethyl siloxane elastomer sections and
containing four drug impermeable PTFE barriers between these
sections that is shown in FIG. 7B.
Example 14
Preparation of a Single Bore Insert Ring Comprising Separate,
Continuous PDMS and Trifluoropropylmethyl/Dimethyl Siloxane
Elastomer Sections, and Two Drug Impermeable PTFE Barriers Between
These Sections
[0140] 30 grams part A and 30 grams part B of
trifluoropropylmethyl/dimeth- yl siloxane elastomer formulation
(NuSil Technology, CF2-3521 grade) were weighed into a 100 gram
capacity Hauschild mixing cup and subsequently mixed for 16 seconds
in a Hauschild model AM 501 T speed mixer. A metal spatula was then
used to scrape down the sides of the mixing cup and further blend
the two starting components. A final 16-second speed mixer cycle
was applied to ensure blend uniformity.
[0141] Continuous sections of matching halves of the insert mold
from Example 2 were manually filled with the uncured
trifluoropropylmethyl/dim- ethyl siloxane elastomer mix such that
one of the pin insert portions of the mold contained this material.
Approximately 50% of the mold's volume was filled in this manner.
An insert pin was then positioned in the partially filled mold. Two
8 mm diameter, 2 mm thick PTFE disks were manually situated in an
upright position within the uncured polymer mix several millimeters
from both the distal and proximal ends of the insert pin.
[0142] 30 grams part A, 3 grams part B of dimethyl siloxane
elastomer formulation (NuSil Technology, MED-4210 grade) were
weighed into a 100 gram capacity Hauschild mixing cup and
subsequently mixed for two 16 second cycles in a Hauschild model AM
501 T speed mixer. The unfilled matching halves of the partially
filled mold described above were manually filled with this uncured
dimethyl siloxane mix. However, no insert pin was positioned in
this section of the mold, however.
[0143] The entire mold was next carefully assembled, placed between
the unheated platens of a model 3912 Carver press and compressed at
5000 psi in order to discharge excess polymer blend from the mold.
The excess material was removed from the outside of the mold
assembly and discarded. The filled mold was then transferred to the
pre-heated (150.degree. C.) platens of a model 284-1 Kuntz
injection molding machine and held there for 15 minutes to affect
cure. The mold was cooled to room temperature and disassembled.
Careful manual removal of the insert pin yielded the single bore
insert ring comprised of separate, continuous PDMS and
trifluoropropylmethyl/dimethyl siloxane elastomer sections and
containing two drug impermeable PTFE barriers between these
sections, such as schematically shown in FIG. 7.
Rings With at Least Two Barium Sulfate Composite Shields
[0144] Another ring having applications herein comprises two
portions and at least two oxybutynin impermeable barium sulfate
(BaSO.sub.4) composite shields located between the two portions.
These shields prevent contact between the two portions and
diffusion of oxybutynin to other portions of the ring. Barium
sulfate composites have been used on numerous occasions to control
the release of various drugs through silicone.
[0145] BaSO.sub.4 composite shields have ready applications in
rings wherein the portion comprising the at least one bore
comprises trifluoropropylmethyl/dimethyl siloxane elastomer. Such
shields can also be readily used in rings comprising a combination
of materials, e.g., rings comprising TFP and PDMS. Examples of such
rings are schematically shown in FIGS. 7 and 8. Particular methods
of making such rings, which are schematically shown in FIGS. 7-8
are set forth below:
Example 15
Preparation of a Single Bore Insert Ring Comprised of Separate,
Continuous PDMS and Trifluoropropylmethyl/Dimethyl Siloxane
Elastomer Sections Separated by Two Drug Impermeable Barium Sulfate
Composite Regions
[0146] 30 grams part A and 30 grams part B of
trifluoropropylmethyl/dimeth- yl siloxane elastomer formulation
(NuSil Technology, CF2-3521 grade) were weighed into a 100 gram
capacity Hauschild mixing cup and subsequently mixed for 16 seconds
in a Hauschild model AM 501 T speed mixer. A metal spatula was then
used to scrape down the sides of the mixing cup and further blend
the two starting components. A final 16-second speed mixer cycle
was applied to ensure blend uniformity.
[0147] Continuous sections of matching halves of the insert mold
from Example 2 were manually filled with the uncured
trifluoropropylmethyl/dim- ethyl siloxane elastomer mix such that
one of the pin insert portions of the mold contained this material.
Approximately 40% of the mold's volume was filled in this manner.
An insert pin was then positioned in this portion of the mold.
[0148] 10 grams part A, 1 gram part B of dimethyl siloxane
elastomer formulation (NuSil Technology, MED-4210 grade) and 10.2
grams of BaSO4 were weighed into a 40 gram capacity Hauschild
mixing cup and subsequently mixed for one 16-second cycle in a
Hauschild model AM 501 T speed mixer. A metal spatula was then used
to scrape down the sides of the mixing cup and further blend the
two starting components. A final 16-second speed mixer cycle was
applied. Sufficient amounts of this barrier mix were manually
placed in the mold adjacent to both ends of the uncured
trifluoropropylmethyl/dimethyl siloxane elastomer section such that
an unfilled gap of about 1.5 mm was created between each BaSO.sub.4
barrier and the uncured trifluoropropylmethyl/dimethyl siloxane
elastomer section. These gaps insured formation of distinct, but
continuous sections upon subsequent compression and cure. The
length of both BaSO.sub.4 barrier areas was roughly 1 cm.
[0149] 50 grams part A, 5 grams part B of dimethyl siloxane
elastomer formulation (NuSil Technology, MED-4210 grade) were
weighed into a 100 gram capacity Hauschild mixing cup and
subsequently mixed for two 16 second cycles in a Hauschild model AM
501 T speed mixer. The remaining unfilled matching halves of the
partially filled mold described above were manually filled with
this uncured dimethyl siloxane mix. In the mold, this blend was
allowed to contact the two BaSO.sub.4 barrier areas so that there
were no gaps between this component's area and the two BaSO.sub.4
barrier areas. No insert pin was positioned in this section of the
mold.
[0150] The entire mold was next carefully assembled, transferred to
the pre-heated (150.degree. C.) platens of a model 284-1 Kuntz
injection molding machine and held there for 18 minutes to affect
cure. The mold was cooled to room temperature and disassembled.
Careful manual removal of the lone insert pin yielded the single
bore insert ring comprised of continuous PDMS and
trifluoropropylmethyl/dimethyl siloxane elastomer sections that
were separated by two BaSO4 composite sections, as schematically
shown in FIG. 8B.
Example 16
Half-TFP, Half-Barium Sulfate Composite Rings
[0151] 30 grams part A and 30 grams part B of
trifluoropropylmethyl/dimeth- yl siloxane elastomer formulation
(NuSil Technology, CF2-3521 grade) were weighed into a 100 gram
capacity Hauschild mixing cup and subsequently mixed for 16 seconds
in a Hauschild model AM 501 T speed mixer. A metal spatula was then
used to scrape down the sides of the mixing cup and further blend
the two starting components. A final 16-second speed mixer cycle
was applied to ensure blend uniformity.
[0152] Continuous sections of matching halves of the insert mold
from Example 2 were manually filled with the uncured
trifluoropropylmethyl/dim- ethyl siloxane elastomer mix such that
one of the pin insert portions of the mold contained this material.
Approximately 40% of the mold's volume was filled in this manner.
An insert pin was then positioned in this portion of the mold.
[0153] 10 grams part A, 1 gram part B of dimethyl siloxane
elastomer formulation (NuSil Technology, MED-4210 grade) and 10.2
grams of BaSO4 were weighed into a 40 gram capacity Hauschild
mixing cup and subsequently mixed for one 16-second cycle in a
Hauschild model AM 501 T speed mixer. A metal spatula was then used
to scrape down the sides of the mixing cup and further blend the
two starting components. A final 16-second speed mixer cycle was
applied. The unfilled matching halves of the partially filled mold
described above were manually filled with this uncured dimethyl
siloxane/barium sulfate composite. No insert pin was positioned in
this section of the mold, however.
[0154] The entire mold was next carefully assembled, transferred to
the preheated (150.degree. C.) platens of a model 284-1 Kuntz
injection molding machine and held there for 18 minutes to affect
cure. The mold was cooled to room temperature and disassembled.
Careful manual removable of the lone insert pin yielded the single
bore insert ring comprised of separate, continuous
trifluoropropylmethyl/dimethyl siloxane elastomer and PDMS/barium
sulfate composite sections, as shown in FIG. 9.
Example 17
Formation of Pharmaceutical Composition for Insertion Into a Bore
of a Ring
[0155] As explained above, a device of the invention can locally
deliver, and controllably release from about 0.5 mg/day to about
5.0 mg/day of oxybutynin for up to twenty-eight days, or as needed.
Preferred dosages are about 0.5 mg/day, about 1.0 mg/day and about
5.0 mg/day for up to twenty-eight days. All three dosages make use
of a pharmaceutical composition comprising about 60% by weight
oxybutynin and about 40% by weight silicone excipient. To determine
the dosage for a particular duration, the amount of pharmaceutical
composition placed into the bores of the rings was varied. For
example, to make a 0.5 mg/day ring or segment, approximately 55-57
mg of pharmaceutical composition was added to the insert. This
55-57 mg of pharmaceutical composition results in approximately
32-35 mg oxybutynin available for local delivery. Similarly, to
prepare a 1.0 mg/day ring or segment thereof, approximately 120-125
mg of the pharmaceutical composition is required to make about
72-75 mg oxybutynin available for local delivery. This amount of
pharmaceutical composition fills about 3/4 of the volume of a bore
in the ring, wherein the bore has a diameter of about 3.2 mm, and a
length of about 1.65 cm. In order for a ring or segment thereof to
locally deliver and controllably release about 5.0 mg/day of
oxybutynin, approximately 200-205 mg of pharmaceutical composition
is required. This amount of pharmaceutical composition results in
120-123 mg oxybutynin available for delivery, and uses the entire
volume of the bore.
[0156] As explained above, the required amounts of pharmaceutical
composition in the bore to deliver a particular amount of
oxybutynin is known, the volume of the bore the each particular
amount of pharmaceutical composition occupies is known, and the
concentration of oxybutynin in the pharmaceutical composition is
known. With this information, rods of the pharmaceutical
composition can be produced, and the amount of oxybutynin in a
particular length of rod can be readily determined. As a result,
once the rods are formed, a medical provider administering a device
of the invention can merely cut a portion of the rod which has the
correct amount of pharmaceutical composition, and insert that
portion into the bore of the ring.
[0157] Numerous methods readily available to the skilled artisan
can be used to form rods of a pharmaceutical composition comprising
oxybutynin and an excipient. A particular method involves using
polytetrafluoroethylene (PTFE) tubing having an inner diameter of
3.2 mm. Initially, slits are made in the PTFE tubing. These slits
can be either parallel to the tubing, as schematically set forth in
FIG. 10D, or perpendicular to the tubing, as schematically shown in
FIG. 1E. Then, a pharmaceutical composition comprising about 60% by
weight oxybutynin, and about 40% by weight tin catalyzed silicone
polymer excipient is placed in the tubing. The tube's contents are
then permitted to cure for about 24 hours at room temperature.
[0158] Once cured, the PTFE tubing is peeled off, leaving a rod of
the pharmaceutical composition. The rods can be cut to a size which
corresponds to the dosage to be delivered, and inserted into the
bore of the ring. These rods can be prepared days, weeks or even
months prior to their actual use.
Example 18
Animal Studies
[0159] The urinary bladder is a smooth muscle organ whose function
is to collect and store urine at low intravesical pressure; then,
periodically, to expel the urine via a highly coordinated sustained
contraction through a relaxed urethra. Efficient emptying requires
contraction of the bladder body smooth muscle elements coordinated
with relaxation of the bladder neck and urethra (A, B). Continence,
especially in women, depends upon the maintenance of tonic tension
within the urethra and a stable detrusor muscle (C, D). Increases
in bladder pressure such as those that occur in unstable bladders
or hyperreflexia can result in incontinence (C, D).
[0160] Pharmacologically, the bladder can be separated into two
parts, body and base. Both, responses to autonomic agonists and
receptor distribution characterize this division (E). Muscarinic
receptor density and contractile responses to cholinergic
stimulation are greatest in the bladder body and weakest in the
base. Similarly, .alpha.-adrenergic receptor density and relaxant
response to stimulation are greatest in the body and weakest in the
base; whereas-adrenergic receptor density and contractile responses
to stimulation are greatest in the base and weakest in the body
(E). Both unstable bladder contractions and hyperreflexia are
mediated by cholinergic mechanisms, and thus the administration of
agents that can both, relax the bladder and inhibit these
cholinergic spikes would be of therapeutic benefit in the treatment
of incontinence (C, D).
[0161] One agent that has proven to be clinically effective in the
treatment of incontinence is oxybutynin (6-9). Oxybutynin relaxes
the bladder by muscarinic inhibition and by direct relaxation of
smooth muscle. Although the therapeutic effects of oxybutynin make
it the most useful drug for inhibition of unstable bladder and
bladder relaxation for more than 20 years [1,2], the side effects
associated with oral medication can be uncomfortable and
significantly influence the patients compliance. Oxybutynin has a
short half-life and a low systemic bioavailability after oral
administration because of extensive first-pass metabolism, which
also causes typical plasma concentration-time profile peaks and
troughs. The duration of symptom relief often is not satisfying.
This combination of side-effects under peak plasma concentrations
and short symptom relief can cause the discontinuance of
treatment
[0162] The development of a vaginal system for continuous
medication would be of great value in producing a prolonged and
continuous therapeutic blood level. It could allow a much longer
application-free interval and improve the patients convenience and
compliance. Additionally, the constant release would prevent the
peaks and troughs of oral medication, and reduce the level and
intensity of side effects, which can be directly related to the
high plasma levels obtained immediately after taking the oral
medication.
Methods
[0163] 12 rabbits were separated into 4 groups of 3 rabbits each.
Under pentobarbital anesthesia (25 mg/kg, iv) A cylinder-shaped,
curved silastic insert was placed in the vagina of each rabbit.
This was accomplished by the following: a midline laparotomy was
performed and after transvaginal insertion the implant was anchored
with a single 2.0 silk suture through the outer vaginal wall and
knotted to a 1 cm section of a medical-grade tubing to avoid damage
to the vaginal wall. The inserts in group one contained vehicle,
the inserts in groups 2-4 were calculated to release oxybutynin at
rates of 0.5 mg/day; 1 mg/day; and 5 mg/day respectively. The
inserts remained in place for 7 days. Samples of blood (2 ml) were
collected at 12:00 noon on days 1, 3, 5 and 7. After the last blood
sample was obtained, each rabbit was sedated and cystometries were
performed. Immediately after the cystometry, the rabbit was
euthanized, the lower urinary tract including the vagina was
removed and evaluated for irritation. In addition, the bladder was
excised and weighed.
[0164] The samples of blood were frozen and subsequently analyzed.
The oxybutynin and desethyloxybutynin concentrations were
quantified.
Results
[0165] The vaginal insert had no effect on rabbit or bladder weight
(FIG. 11). The analysis of the cystometries showed the typical
effect of oxybutynin on the urinary bladder. There was a
dose-dependent decrease in the cystometric pressures for the three
oxybutynin groups (FIG. 12). The placebo cystometry is shown in
FIG. 13. Simultaneously a dose-dependent decrease in micturition
pressure for the oxybutynin groups was shown (FIG. 14). The
micturition pressure for the 0.5 mg/day group was similar to the
placebo group, whereas there was a significant decrease in the 1
and 5 mg/day oxybutynin groups.
[0166] The plasma levels of oxybutynin for the three groups are
shown in FIGS. 15-17. For the 0.5 and 1.0 mg/day groups, the plasma
concentrations for desethyloxybutynin were below the level of
detection. For the 0.5 mg/day and 1.0 mg/day group, there was an
increase in the plasma concentrations between day 1 and 3, and a
stable concentration between days 3 and 7. For the 5.0 mg/day group
there were stable plasma values for both oxybutynin and
desethyloxybutynin at all time periods (day 1-7). FIG. 18 shows the
stable plasma concentrations for the three groups. The plasma
concentration for the 1.0 mg/day group was significantly
(approximately twice) that of the 0.5 mg/day group, the plasma
concentration for the 5.0 mg/day group was significantly greater
than the two other groups, and approximately 4 fold greater than
the 1.0 mg/day group.
[0167] During the postmortem evaluation of the insert-contacted
vaginal wall no irritation was observed in the area around the
implants. There was however significant irritation (hematoma) in
the area of the vagina where the speculum was placed to allow
access to the upper vagina. Performing the insertion of the implant
without use of a speculum avoided the irritation in control
surgery.
Discussion
[0168] Oxybutynin is one of the most widely prescribed oral
medications for the treatment of bladder instability. However, one
of the major disadvantages to oral oxybutynin is the relative short
half life, and the anticholinergic side effects. In many cases, the
dosing schedule and side effects of this preparation significantly
affect compliance. In order to improve compliance, several
alternative dosing methods have been tried.
[0169] Intravesical instillation of oxybutynin can avoid the first
pass metabolism and reduce systemic side effects [4,5], but is less
convenient, and does not provide a method for continuous medication
over a prolonged time period. Recently a controlled
oxybutynin-release system for oral application was introduced.
These studies have shown that a stable blood level under a
controlled drug release system does not decrease the therapeutic
effect, and allows a lower drug level. Also the appearance of side
effects could be reduced [6-9].
[0170] In the current study, the placement of the vaginal inserts
had no effect on rabbit or bladder weight, nor did the presence of
the insert affect rabbit behavior (eating, sleeping, or drinking).
The results of the cystometries performed one week after vaginal
application of the inserts show the typical effect of oxybutynin on
the urinary bladder. The dose related increased compliance, and
decreased micturation pressure demonstrate that there was
significant, dose-dependent and consistent absorption resulting in
stable plasma oxybutynin levels.
[0171] Vaginal application of a drug release system allows a
prolonged replacement interval. These attributes of this drug
release system can improve the patient's convenience and compliance
towards an oxybutynin based therapy of incontinence. Additionally
it allows the possibility of a combined pessary-based therapy of a
moderate stress- and drug-based therapy of motoric urge
incontinence.
[0172] During the examination of the vaginal wall after a 1-week
duration of direct contact to the insert no irritation could be
shown.
Conclusion
[0173] The present study demonstrates a new method of an
oxybutynin-release system, which creates a stable blood level and
allows much longer application-free intervals. Thus, a device of
the invention provides a new and useful alternative to traditional
oral and intravesical application of oxybutynin. In particular,
this study clearly demonstrates that a device of the invention
releases a controlled, and consistent level oxybutynin, and that
the stable plasma levels had significant effects on bladder
compliance. There was no irritating effect by the insert on the
vaginal wall after a one-week duration of placement. These results
indicate that vaginal implants of oxybutynin are an excellent
method for the chronic, dose dependent, delivery of the
urologically effective agent.
[0174] Many other variations and modifications of the instant
invention will be apparent to those skilled in the art without
departing from the spirit and scope of the instant invention. The
above-described embodiments are therefore, intended to be merely
exemplary, and all such variations and modifications are intended
to be included within the scope of the instant invention as defined
in the appended claims.
[0175] Various publications are cited herein, the disclosures of
which are incorporated by reference in their entireties:
[0176] A. Steers, W. D, Physiology of the urinary bladder. In
Cambells Urology, (eds. Walsh, P. C., Retik, A. B., Starney, T. A.,
and Vaughan, E. D. Jr.) Saunders, Phila., 1992, pp142-176.
[0177] B. Zderic, S. A., Levin, R. M., and Wein, A. J,: Voiding
Function and Dysfunction: A-Relevant Anatomy, Physiology, and
Pharmacology, and molecular biology. In: Adult and Pediatric
Urology. Edited by J. Y. Gillenwater, J. T. Grayhack, S. S. Howards
and J. D. Duckett, Chicago: Mosby Year Book Medical Publishers,
Third Edition, pp. 1159-1219, 1996.
[0178] C. Uvin, R. M., Levin, S. S. and Wein, A. J.: Etiology of
Incontinence: A review and hypothesis. Scandanavian J, Urol.,
Nephrol. 30 (Supp): 15-25, 1996.
[0179] D. Hampel, C., Wienhold, D., Benken, N., Eggersmann, C., and
Thuroff, J. W. Definition of overactive bladder and epidemiology of
urinary incontinence, Urology, 5 0:4-14, 1997.
[0180] E. Levin, R. M., Shofer, F. and Wein, A. J.: Cholinergic,
adrenergic, and purinergic response of sequential strips of rabbit
urinary bladder. J. Pharmacol. Exp., Ther. 212:536-540, 1980.
[0181] 1. Thueroff, J. W., Bunke, B., Ebner, A., Faber, P., de
Geeter, P., Hannapel, J., Heidler, H., Melchior, H., Schaefer, W.,
Schweazer, T., Stoeckle, M.: Randomized double-blind, multicenter
trial on treatment of frequency, urgency and incontinence related
to detrusor hyperactivity: oxybutynin versus propantheline versus
placebo. J. Urol, 145:913, 1991.
[0182] 2. Levin, R. M., Wein, A. J.: Direct measurement of the
anticholinergic activity of a series of pharmacological compounds
on the canine and rabbit urinary bladder. S. Urol.;128:396-398,
1982.
[0183] 3. Wein, A. J,: Pharmacologic options for the overactive
bladder. Urology 51 (2A Suppl):43-7, 1998.
[0184] 4. Buyse, G., Waldeck, K., Verpoorten, C., Bjoerk, H.,
Casaer, P., Andersson, K. E.: Intravesical oxybutynin for
neurogenic bladder dysfunction: Less systemic side effects due to
reduced first pass metabolism. J. Urol 160 (3Ptl):892-6, 1998.
[0185] 5. Masad, C. A., Kogan, B. A., Trigo-Rocha, F. E.: The
pharmacokinetics of intravesical and oral oxybutynin chloride. J.
Urol., 148:595-597, 1992.
[0186] 6. Goldenberg, M. M.: An extended-release formulation of
oxybutynin chloride for the treatment of overactive urinary
bladder. Clin Ther 21 (4),634-42, 1999.
[0187] 7. Anderson, R. U., Mobley, D., Blank, B., Saltzstein, D.,
Susset, J. and Brown, J. S.: Once daily controlled versus immediate
release oxybutynin Chloride for urinary incontinence. OROS
Oxybutynin Study Group. J.Urol 161(6):1809-12, 1999.
[0188] 8. Gupta, S. K., Sathyan, G.: Pharmacokinetics of an oral
once-a-day controlled-release oxybutynin formulation compared with
immediate-release oxybutynin. J. Clin.Pharmacol. 39 (3):289-96,
1999.
[0189] 9. Gupta, S. K., Sathyan, G., Lindemulder, E. A., Ho, P. L.,
Sheiner, L. B., Aarons, L.: Quantitative characterization of
therapeutic index: Application of mixed-effects modeling to
evaluate, oxybutynin dose-efficacy and dose-side effect
relationships. Clin. Pharmacol, Ther. 65(6); 672-84.
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