U.S. patent application number 09/992488 was filed with the patent office on 2003-10-02 for pharmaceutical compositions containing oxybutynin.
Invention is credited to Ricci, Marcelo A., Vergez, Juan A..
Application Number | 20030185882 09/992488 |
Document ID | / |
Family ID | 25538393 |
Filed Date | 2003-10-02 |
United States Patent
Application |
20030185882 |
Kind Code |
A1 |
Vergez, Juan A. ; et
al. |
October 2, 2003 |
Pharmaceutical compositions containing oxybutynin
Abstract
A pharmaceutical composition and dosage form for the treatment
of incontinence with oxybutynin and a second drug is provided. The
second drug can be darifenacin or tolterodine. Depending upon the
route of administration, the dosage form used, and the second drug
used, the dosage form may independently include therapeutic or
sub-therapeutic amounts of the oxybutynin and the second drug.
Particular embodiments include a dosage form that provides a
controlled release of oxybutynin and the second drug to maintain
therapeutically effective levels oxybutynin and/or the second in a
mammal for an extended period of time. An osmotic device containing
a bi-layered core is provided. The osmotic device provides a dual
controlled release of both drugs from the core. A method of
treating urinary (stress or urge) incontinence with the
pharmaceutical composition and dosage form is provided. Together,
oxybutynin and the second drug provide an overall improved
therapeutic benefit over either agent alone when administered at
approximately the same dose.
Inventors: |
Vergez, Juan A.; (Buenos
Aires, AR) ; Ricci, Marcelo A.; (Buenos Aires,
AR) |
Correspondence
Address: |
INNOVAR, LLC
P O BOX 250647
PLANO
TX
75025
US
|
Family ID: |
25538393 |
Appl. No.: |
09/992488 |
Filed: |
November 6, 2001 |
Current U.S.
Class: |
424/465 ;
514/422; 514/540 |
Current CPC
Class: |
A61P 13/00 20180101;
A61K 31/216 20130101; A61K 9/0004 20130101; A61K 2300/00 20130101;
A61K 9/209 20130101; A61K 45/06 20130101; A61K 31/216 20130101 |
Class at
Publication: |
424/465 ;
514/540; 514/422 |
International
Class: |
A61K 009/20; A61K
031/24; A61K 031/4025 |
Claims
We claim:
1) A pharmaceutical composition comprising: a) oxybutynin; b) a
second drug for treating incontinence, wherein the second drug is
selected from the group consisting of darifenacin and tolterodine;
and c) at least one pharmaceutical excipient.
2) The pharmaceutical composition of claim 1, wherein the
pharmaceutical composition is present as a manufactured batch.
3) The pharmaceutical composition of claim 2 comprising: a) a
homogeneous mixture of oxybutynin, the second drug and at least one
pharmaceutical excipient.
4) The pharmaceutical composition of claim 2 comprising: a) a
heterogeneous mixture of oxybutynin, the second drug and at least
one pharmaceutical excipient.
5) The pharmaceutical composition of claim 1, wherein the
pharmaceutical composition is present as a unit dose.
6) The pharmaceutical composition of claim 5, wherein at least one
of the oxybutynin and the second drug is present in a
therapeutically effective amount.
7) The pharmaceutical composition of claim 5, wherein the
oxybutynin and the second drug are each present in a
therapeutically effective amount.
8) The pharmaceutical composition of claim 5, wherein at least one
of the oxybutynin and the second drug is present in a
sub-therapeutically effective amount.
9) The pharmaceutical composition of claim 5, wherein the
oxybutynin and the second drug are present in sub-therapeutically
effective amounts.
10) The pharmaceutical composition of claim 5 comprising: a) a
homogeneous mixture of oxybutynin, the second drug and at least one
pharmaceutical excipient.
11) The pharmaceutical composition of claim 5 comprising: a) a
heterogeneous mixture of oxybutynin, the second drug and at least
one pharmaceutical excipient.
12) The pharmaceutical composition of claim 1, 2 or 5, wherein the
weight ratio of oxybutynin to second drug ranges from 1:0.1 to
1:20.
13) A dosage form comprising: a) oxybutynin; b) a second drug for
treating incontinence, wherein the second drugs is selected from
the group consisting of darifenacin and tolterodine; and c) at
least one pharmaceutical excipient.
14) The dosage form of claim 13 comprising: a) a first composition
comprising oxybutynin and at least one pharmaceutical excipient;
and b) a different second composition comprising the second drug
and at least one pharmaceutical excipient.
15) The dosage form of claim 14, wherein the first and second
compositions are in admixture.
16) The dosage form of claim 14, wherein the first and second
compositions are separate.
17) The dosage form of claim 16, wherein the first and second
compositions are in contact with one another.
18) The dosage form of claim 13, wherein at least one of the
oxybutynin and the second drug is present in a sub-therapeutically
effective amount
19) The dosage form of claim 18, wherein the oxybutynin and second
drug together provide a synergistic therapeutic effect when the
dosage form is administered to a subject.
20) The dosage form of claim 13, wherein the oxybutynin and second
drug are present in therapeutically effective amounts.
21) The dosage form of claim 13, wherein the release profile for
oxybutynin and the second drug is independently selected from a
controlled, delayed, extended, pulsatile, sustained, immediate,
timed, slow, immediate or rapid release when the dosage form is
exposed to an aqueous environment.
22) The dosage form of claim 21, wherein oxybutynin and the second
drug have approximately the same release profile.
23) The dosage form of claim 21, wherein oxybutynin and the second
drug have different release profiles.
24) The dosage form of claim 21, wherein the dosage form provides a
controlled release of oxybutynin and the second drug.
25) The dosage form of claim 24, wherein the dosage form provides
therapeutically effective plasma levels of oxybutynin and the
second drug for a period of at least 12 hours after administration
when administered to a subject.
26) The dosage form of claim 13, wherein the dosage form, when
administered to a subject, provides an improved toxicity profile as
compared to oxybutynin or the second drug when either agent is
administered alone to the same subject.
27) The dosage form of claim 13, 18, 20, 21 or 26, wherein the
dosage form is selected from the group consisting of a tablet,
osmotic device, capsule, tape, suspension, liquid, implant, gel,
pill, cream, ointment, inhaler, paste, troche, lozenge, bead,
granule, granulation, spheroid, particulate solid, reconstitutable
solid, powder, extruded solid, suppository, stick, and
mini-pump.
28) A method of treating incontinence in a subject comprising the
step of administering a pharmaceutical composition according to any
one of claims 1, 5, 6, 8, 10, 11.
29) A method of treating incontinence in a subject comprising the
step of administering a dosage form according to any one of claims
13-16, 18, 20-23 or 26.
30) A coated solid dosage form comprising: a) a core comprising
oxybutynin, a second drug for treating incontinence and at least
one pharmaceutical excipient, wherein the second drug is selected
from the group consisting of darifenacin and tolterodine; and b) a
wall enveloping the core.
31) The dosage form of claim 30, wherein the core comprises: a) a
first composition comprising oxybutynin and at least one
pharmaceutical excipient; and b) a different second composition
comprising the second drug and at lease one pharmaceutical
excipient.
32) The dosage form of claim 31, wherein the first and second
compositions are in admixture.
33) The dosage form of claim 31, wherein the first and second
compositions are separate.
34) The dosage form of claim 33, wherein the first and second
compositions are in contact with one another.
35) The dosage form of claim 34, wherein the first and second
compositions are in stacked arrangement.
36) The dosage form of claim 30 or 31, wherein the release profile
for oxybutynin and the second drug is independently selected from a
controlled, delayed, extended, pulsatile, sustained, timed, or slow
release when the dosage form is exposed to an aqueous
environment.
37) The dosage form of claim 36, wherein the dosage form provides a
controlled release of oxybutynin and the second drug.
38) The dosage form of claim 36, wherein oxybutynin and the second
drug have approximately the same release profile.
39) The dosage form of claim 36, wherein oxybutynin and the second
drug have different release profiles.
40) The dosage form of claim 30 or 31, wherein the dosage form is
selected from the group consisting of a tablet, bead, osmotic
device, granule, suppository, implant, pill, troche, lozenge, and
stick.
41) The dosage form of claim 30, wherein the core comprises a
homogeneous or heterogeneous mixture of oxybutynin, the second drug
and at least one pharmaceutical mixture.
42) The dosage form of claim 41, wherein the wall is microporous,
permeable, semipermeable or impermeable.
43) The dosage form of claim 42, wherein the wall further comprises
one or more preformed passageways to permit release of oxybutynin
and the second drug when the dosage form is exposed to an aqueous
environment.
44) The dosage form of claim 41, wherein the wall is a
multi-layered wall comprising two or more laminas that are
independently selected at each occurrence from inert and
drug-containing.
45) The dosage form of claim 44, wherein the two or more laminas
are independently selected at each occurrence from microporous,
permeable, semipermeable and impermeable.
46) The dosage form of claim 44, wherein the two or more laminas
are independently selected at each occurrence from water soluble
and water erodible.
47) The dosage form of claim 41, wherein the wall is inert or
contains drug.
48) The dosage form of claim 47, wherein the wall is water soluble
or water erodible.
49) An osmotic device comprising: a) a core comprising a first
composition comprising a first drug and at least one pharmaceutical
excipient, and a different second composition comprising a second
drug and at least one pharmaceutical excipient, wherein the first
and second compositions contact one another and are in stacked
arrangement; and b) a membrane enveloping the core and having at
least two passageways to permit a controlled release of the first
and second drugs from the core when the osmotic device is exposed
to an aqueous environment, wherein at least one first passageway is
in communication with the first composition and at least one second
passageway is in communication with the second composition.
50) The osmotic device of claim 49, wherein the membrane is
semipermeable.
51) The osmotic device of claim 49 further comprising at least one
external coat exterior to the membrane.
52) The osmotic device of claim 51, wherein the external coat is
independently selected at each occurrence from water soluble and
water erodible.
53) The osmotic device of claim 51, wherein the external coat is
independently selected at each occurrence from inert and
drug-containing.
54) The osmotic device of claim 51, wherein the external coat is
independently selected at each occurrence from microporous,
permeable, semipermeable and impermeable.
55) The osmotic device of claim 49 further comprising at least one
internal coat interposed the core and the membrane.
56) The osmotic device of claim 55, wherein the internal coat is
independently selected at each occurrence from water soluble and
water erodible.
57) The osmotic device of claim 55, wherein the internal coat is
independently selected at each occurrence from inert and
drug-containing.
58) The osmotic device of claim 55, wherein the internal coat is
independently selected at each occurrence from microporous,
permeable, semipermeable and impermeable.
59) The osmotic device of claim 49, wherein the first drug and the
second drug are released sequentially or in an overlapping manner
when the osmotic device is exposed to an aqueous environment.
60) The osmotic device of claim 49 further comprising an external
coat surrounding the semipermeable membrane, wherein the first
passageway has been formed after application of the external coat
to the semipermeable membrane and the second passageway has been
formed before application of the external coat to the semipermeable
membrane such that the second passageway is plugged by the external
coat and release of the second drug begins after release of the
first drug has started.
61) The osmotic device of claim 49 further comprising an external
coat surrounding the semipermeable membrane, wherein the first and
second passageways have been formed before application of the
external coat to the semipermeable membrane; the first and second
passageways are plugged by the external coat; and release of the
first drug and the second drug is delayed for a period of time
after exposure to an aqueous environment.
62) The osmotic device of claim 50, wherein the first drug and the
second drug are released sequentially or in an overlapping manner
when the osmotic device is exposed to an aqueous environment.
63) The osmotic device of claim 49, 50, 51, 55, 59 or 62, wherein
each drug is independently released according to a timed, targeted,
pseudo-first order, first order, pseudo-zero order, zero-order,
second order and/or delayed release profile.
64) An osmotic device comprising: a) a core comprising a first
composition comprising oxybutynin and at least one pharmaceutical
excipient, and a different second composition comprising a second
drug, selected from the group consisting of darifenacin and
tolterodine, and at least one pharmaceutical excipient; and b) a
semipermeable membrane enveloping the core and having at least two
passageways to permit controlled release of oxybutynin and the
second drug from the core when the osmotic device is exposed to an
aqueous environment, wherein at least one passageway is in
communication with the first composition and at least one
passageway is in communication with the second composition.
65) The osmotic device of claim 64, wherein the first and second
compositions contact one another and are in stacked
arrangement.
66) The osmotic device of claim 64, wherein, when the osmotic
device is exposed to an aqueous environment, oxybutynin is released
approximately as follows:
18 Time Minimum Amount Maximum Amount (hours) Released (%) Released
(%) 1 0 10 3 5 25 7 20 50 11 40 70 15 58 84 19 70 89 24 76 100
67) The osmotic device of claim 66, wherein the osmotic device
provides plasma levels for oxybutynin in the range of about 1-12 ng
per ml of plasma.
68) The osmotic device of claim 64, wherein, the second drug is
darifenacin and is released approximately as follows when the
osmotic device is exposed to an aqueous environment:
19 Time Minimum Amount Maximum Amount (hours) Released (%) Released
(%) 1 0 12 3 10 35 7 25 65 11 45 89 15 90 98 24 89 100
69) The osmotic device of claim 64 or 65, the second drug is
darifenacin and is released approximately as follows when the
osmotic device is exposed to an aqueous environment:
20 Time Minimum Amount Maximum Amount (hours) Released (%) Released
(%) 1 0 5 3 0 15 7 10 45 11 29 74 15 52 84 19 60 89 24 80 100
70) The osmotic device of claim 64 or 65, wherein the second drug
is tolterodine and is released approximately as follows when the
osmotic device is exposed to an aqueous environment:
21 Time Minimum Amount Maximum Amount (hours) Released (%) Released
(%) 1 0 12 3 3 25 5 17 36 7 31 50 9 49 66 11 61 76 15 74 90 24 76
100
71) The osmotic device of claim 64 or 65, wherein the release of
oxybutynin and/or the second drug is delayed.
72) A method of treating incontinence in a subject comprising the
step of administering a dosage from according to claim 36.
73) A method of treating incontinence in a subject comprising the
step of administering a dosage from according to claim 30-33, 41,
42, 44 or 47.
74) A method of treating incontinence in a subject comprising the
step of administering an osmotic device according to claim 64-66 or
68.
75) A dual controlled release osmotic device comprising: a) a core
comprising a first active agent-containing layer and a second
active agent-containing layer; and b) a semipermeable membrane
surrounding the core, wherein the membrane comprises at least one
preformed passageway in communication with at least one of the
first and second active agent-containing layers; whereby the
osmotic device provides a controlled release of the first active
agent through the at least one preformed passageway according to a
first release profile and the second layer provides a controlled
release of the second active through the at least one preformed
passageway according to a second release profile.
76) The osmotic device of claim 75, wherein the layers are in
stacked arrangement and in contact with one another.
77) The osmotic device of claim 75, wherein the second active
agent-containing layer surrounds the first active agent-containing
layer.
78) The osmotic device of claim 76 or 77, wherein the osmotic
device comprises at least one first preformed passageway in
communication with the first active agent-containing layer and at
least one second preformed passageway in communication with the
second active agent-containing layer.
79) The osmotic device of claim 76 or 77, wherein the membrane
comprises at least one preformed passageway in communication with
both the first and second active agent-containing layers.
80) The osmotic device of claim 76 or 77, wherein the membrane
comprises at least two preformed passageways and at least one of
the two preformed passageways is plugged with a water soluble or
water erodible material.
81) The osmotic device of claim 76 or 77, wherein the membrane
comprises at least two preformed passageways both of which are
plugged with a water soluble or water erodible material, wherein
the material plugging the first passageway is the same as the
material plugging the second passageway.
82) The osmotic device of claim 76 or 77, wherein the membrane
comprises at least two preformed passageways both of which are
plugged with a water soluble or water erodible material, wherein
the material plugging the first passageway is different than the
material plugging the second passageway.
83) The osmotic device of claim 76 or 77 further comprising at
least one external coat exterior to the membrane.
84) The osmotic device of claim 83, wherein the external coat is
independently selected at each occurrence from water soluble and
water erodible.
85) The osmotic device of claim 83, wherein the external coat is
independently selected at each occurrence from inert and
drug-containing.
86) The osmotic device of claim 83, wherein the external coat is
independently selected at each occurrence from microporous,
permeable, semipermeable and impermeable.
87) The osmotic device of claim 76 or 77 further comprising at
least one internal coat interposed the core and the membrane.
88) The osmotic device of claim 87, wherein the internal coat is
independently selected at each occurrence from water soluble and
water erodible.
89) The osmotic device of claim 87, wherein the internal coat is
independently selected at each occurrence from inert and
drug-containing.
90) The osmotic device of claim 87, wherein the internal coat is
independently selected at each occurrence from microporous,
permeable, semipermeable and impermeable.
91) The osmotic device of claim 76 or 77, wherein the first drug
and the second drug are released sequentially or in an overlapping
manner when the osmotic device is exposed to an aqueous
environment.
92) The osmotic device of claim 75 further comprising an external
coat surrounding the membrane, and the membrane comprises at least
a first preformed passageway and at least a second preformed
passageway, wherein the first passageway has been formed after
application of the external coat to the membrane, and the second
passageway has been formed before application of the external coat
to the membrane such that the second passageway is plugged by the
external coat, and release of the second drug begins after release
of the first drug has started.
93) The osmotic device of claim 75 further comprising an external
coat surrounding the membrane, and the membrane comprises at least
a first preformed passageway and at least a second preformed
passageway, wherein the first and second passageways have been
formed before application of the external coat to the membrane; and
the first and second passageways are plugged by the external
coat.
94) The osmotic device of claim 93, wherein release of the first
drug and the second drug is delayed for a period of time after
exposure to an aqueous environment.
95) The osmotic device of claims any one of claims 75, 76 or 77,
wherein each drug is independently released according to a timed,
targeted, pseudo-first order, first order, pseudo-zero order,
zero-order, second order and/or delayed release profile.
96) The osmotic device of claim 78, wherein each drug is
independently released according to a timed, targeted, pseudo-first
order, first order, pseudo-zero order, zero-order, second order
and/or delayed release profile.
97) The osmotic device of claim 79, wherein each drug is
independently released according to a timed, targeted, pseudo-first
order, first order, pseudo-zero order, zero-order, second order
and/or delayed release profile.
98) The osmotic device of claim 80, wherein each drug is
independently released according to a timed, targeted, pseudo-first
order, first order, pseudo-zero order, zero-order, second order
and/or delayed release profile.
99) The osmotic device of claim 81, wherein each drug is
independently released according to a timed, targeted, pseudo-first
order, first order, pseudo-zero order, zero-order, second order
and/or delayed release profile.
100) The osmotic device of claim 82, wherein each drug is
independently released according to a timed, targeted, pseudo-first
order, first order, pseudo-zero order, zero-order, second order
and/or delayed release profile.
101) The osmotic device of claim 83, wherein each drug is
independently released according to a timed, targeted, pseudo-first
order, first order, pseudo-zero order, zero-order, second order
and/or delayed release profile.
102) The osmotic device of claim 87, wherein each drug is
independently released according to a timed, targeted, pseudo-first
order, first order, pseudo-zero order, zero-order, second order
and/or delayed release profile.
103) The osmotic device of claim 91, wherein each drug is
independently released according to a timed, targeted, pseudo-first
order, first order, pseudo-zero order, zero-order, second order
and/or delayed release profile.
104) The osmotic device of claim 92 or 93, wherein each drug is
independently released according to a timed, targeted, pseudo-first
order, first order, pseudo-zero order, zero-order, second order
and/or delayed release profile.
105) The dosage form of claim 16, wherein the first and second
compositions are not in contact with one another.
106) The dosage form of claim 14, wherein at least one of the
oxybutynin and the second drug is present in a sub-therapeutically
effective amount
107) The dosage form of claim 14, wherein the oxybutynin and second
drug are present in therapeutically effective amounts.
108) The dosage form of claim 13 comprising: a) a homogeneous or
homogeneous mixture of oxybutynin, the second drug and at least one
pharmaceutical excipient.
109) A method of treating incontinence in a subject comprising the
step of administering an osmotic device according to claim 69.
110) A method of treating incontinence in a subject comprising the
step of administering an osmotic device according to claim 70.
111) A method of treating incontinence in a subject comprising the
step of administering an osmotic device according to claim 71.
112) An osmotic device comprising: a) a core comprising a first
composition comprising oxybutynin and at least one pharmaceutical
excipient, and a different second composition comprising a second
drug, selected from the group consisting of darifenacin and
tolterodine, and at least one pharmaceutical excipient, wherein the
first and second compositions contact one another and are in
stacked arrangement; and b) a semipermeable membrane enveloping the
core and having at least two passageways to permit controlled
release of oxybutynin and the second drug from the core when the
osmotic device is exposed to an aqueous environment, wherein at
least one passageway is in communication with the first composition
and at least one passageway is in communication with the second
composition; wherein, when the osmotic device is exposed to an
aqueous environment, oxybutynin is released approximately as
follows:
22 Amount Released (%) Time (hs) Min Max 1 0 10 3 5 25 5 17 36 7 20
50 11 40 70 15 58 85 19 70 90 24 76 100
113) The osmotic device of claim 112, wherein, when the osmotic
device is exposed to an aqueous environment, the second drug is
released approximately as follows:
23 Amount Range (%) Time (hs) Min Max 1 0 12 3 3 25 5 17 36 7 31 50
9 49 66 11 61 76 15 74 90 24 76 100
114) The osmotic device of claim 112 or 113, wherein the second
drug is darifenacin, and the osmotic device provides a single dose
plasma level for darifenacin that is sufficient to provide the
desired therapeutic response.
115) The osmotic device of claim 112 or 113, wherein the second
drug is tolterodine, and the osmotic device provides a single dose
plasma level for tolterodine in the range of about 0.5 to 25 ng per
ml of plasma.
116) The osmotic device of claim 112 further comprising at least
one external coat exterior to the membrane.
117) The osmotic device of claim 116, wherein the external coat is
independently selected at each occurrence from water soluble and
water erodible.
118) The osmotic device of claim 116, wherein the external coat is
independently selected at each occurrence from inert and
drug-containing.
119) The osmotic device of claim 116, wherein the external coat is
independently selected at each occurrence from microporous,
permeable, semipermeable and impermeable.
120) A method of treating incontinence in a subject comprising the
step of administering an osmotic device according to claim 112,
113, 116-118 or 119.
121) A method of treating incontinence in a subject comprising the
step of administering an osmotic device according to claim 114.
122) A method of treating incontinence in a subject comprising the
step of administering an osmotic device according to claim 115.
123) A method of treating incontinence comprising the step of
administering to a subject in need thereof oxybutynin and
darifenacin.
124) The method of claim 123 wherein the oxybutynin and darifenacin
are in the same dosage form.
125) The method of claim 124 wherein the oxybutynin and darifenacin
are released from the dosage form in a controlled manner over an
extended period of time.
126) The method of claim 123 wherein the oxybutynin and darifenacin
are in separate dosage forms.
127) The method of claim 126 wherein the oxybutynin and darifenacin
are released from their respective dosage forms in a controlled
manner over an extended period of time.
128) A method of treating incontinence comprising the step of
administering to a subject in need thereof oxybutynin and
tolterodine.
129) The method of claim 128 wherein the oxybutynin and tolterodine
are in the same dosage form.
130) The method of claim 129 wherein the oxybutynin and tolterodine
are released from the dosage form in a controlled manner over an
extended period of time.
131) The method of claim 128 wherein the oxybutynin and tolterodine
are in separate dosage forms.
132) The method of claim 131 wherein the oxybutynin and tolterodine
are released from their respective dosage forms in a controlled
manner over an extended period of time.
Description
FIELD OF THE INVENTION
[0001] This invention pertains to pharmaceutical compositions
containing oxybutynin and at least one other drug for the treatment
of incontinence. More particularly, it pertains to pharmaceutical
compositions and dosage forms containing oxybutynin and darifenacin
or oxybutynin and tolterodine and methods of using the same.
BACKGROUND OF THE INVENTION
[0002] Oxybutynin is useful for treating stress and urge urinary
incontinence (over active bladder). DITROPAN.TM. tablets are
commercially available tablets that provide a rapid release of
oxybutynin in the stomach and upper intestinal tract. Rapid release
tablets are typically administered at a rate of about 3-4 tablets
per day to treat urinary incontinence. Rapid release tablets,
however, typically have undesirable side effects associated with
them due to the high plasma oxybutynin concentrations they provide.
These tablets also have a short duration of action due to the short
half-life (t.sub.1/2.apprxeq.2 hr) of oxybutynin in plasma.
[0003] In order to overcome these disadvantages, controlled release
tablets of oxybutynin have been developed. In general, known
controlled release tablets provide a sustained delivery of
oxybutynin for a period of up to 8-30 hours after administration
depending upon the formulation used. Sequential administration (2-3
times per day) of oxybutynin tablets having the same release
profile is known.
[0004] A number of publications disclose controlled release
formulations containing oxybutynin: a) U.S. Pat. No. 5,788,987 to
Busetti et al.; b) International Publication No. WO 00/19997 to
Alza Corp.; c) International Publication No. WO 96/12477 to Leiras
OY; and d) Japanese Patents No. 2,646,170 and No. 2,665,858 to
Nippon Hoechst Marion Roussel Ltd. A number of scientific
publications disclose extended and controlled release formulations
containing oxybutynin. In addition, Alza Corporation currently
markets DITROPAN XL.TM., which is a controlled release tablet
formulation containing oxybutynin. None of these publications
disclose a combination formulation or pharmaceutical composition
containing oxybutynin and another drug.
[0005] U.S. Pat. No. 5,399,359 to Baichwal, the entire disclose of
which is hereby incorporated by reference, discloses many different
controlled release tablet formulations that provide a controlled
release of oxybutynin for periods of up to 8, 12, 16, 18, 24 or 30
hours. This patent does not disclose the combined administration of
oxybutynin and another drug used to treat incontinence.
[0006] U.S. Pat. No. 5,912,268, No. 5,840,754 and No. 5,674,895 to
Guittard, the entire disclosures of which are hereby incorporated
by reference, disclose osmotic device formulations that deliver
oxybutynin at a controlled rate for a period of about 24 hours.
This patent does not disclose the combined administration of
oxybutynin and another drug used to treat incontinence.
[0007] Appell et al. ("Clinical Evaluation of a Sustained Release
Form of Oxybutynin, Urodynamics Society Symposium Abstracts (1990),
pg. 228), the entire disclosure of which is hereby incorporated by
reference, discloses a controlled release tablet DITROPAN.TM. SR
that provides a controlled delivery of oxybutynin for about 8-12
hours. This publication does not disclose the combined
administration of oxybutynin and another drug used to treat
incontinence.
[0008] Sirki et al. ("Use of hydrophilic polymers to control drug
release from press-coated oxybutynin hydrochloride tablets", S.T.P.
Pharmacia Sci. (1993), 3(6), pg. 453-458), the entire disclosure of
which is hereby incorporated by reference, discloses a controlled
release tablet formulation that provides a controlled delivery of
oxybutynin for about 8-12 hours. This publication does not disclose
the combined administration of oxybutynin and another drug used to
treat incontinence.
[0009] Japanese Patent Applications Serial No. 9,388 and No.
163,901 to Enomoto et al., the entire disclosures of which are
hereby incorporated by reference, disclose controlled release
tablet formulations that deliver oxybutynin at a controlled rate
for a period of about 12 hours for once or twice-a-day
administration. These patents do not disclose the combined
administration of oxybutynin and another drug used to treat
incontinence.
[0010] A number of scientific publications disclose the results of
tests on the therapeutic, pharmacological and/or pharmacodynamic
properties of formulations containing darifenacin
((S)-2-[1-[2-(2,3-dihydrobenzofuran-5-
-yl)ethyl]-3-pyrrolidinyl]-2,2-diphenyl-acetamide). The darifenacin
formulations described in these publication include only i.v.,
i.p., and immediate release formulations. None of these references,
however, disclose the combined administration of darifenacin and
oxybutynin.
[0011] International Publication No. WO 97/09980 and U.S. Pat. No.
6,106,864 to Dolan et al. of Pfizer, Inc. discloses a controlled
release formulation comprising darifenacin, wherein at least 10% of
the darifenacin is delivered to the lower gastrointestinal tract.
Dolan et al. disclose that the controlled release formulation can
be any of a number of different formulations, including osmotic
devices, as long as it provides the specified release profile.
Dolan et al., however, do not disclose or suggest the
coadministration of oxybutynin with darifenacin.
[0012] Dmochowski et al. (Urology (2000), 56(6), Suppl. A, pp.
41-49) disclose a number of different therapeutic agents for the
treatment of incontinence. Dmochowski et al., however, do not
disclose or suggest the coadministration of oxybutynin with
darifenacin.
[0013] International Publication No. WO 97/18814 to Pfizer Research
and Development Company discloses a number of controlled release
formulations. One example in the disclosure includes a controlled
release tablet comprising darifenacin. This publication also does
not disclose or suggest the coadministration of oxybutynin with
darifenacin.
[0014] A number of scientific publications disclose the results of
clinical tests comparing the therapeutic, pharmacological, and/or
pharmacodynamic properties of formulations containing tolterodine
((R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine).
The formulations include controlled, immediate or rapid release
formulations. None of these references, however, disclose the
combined administration of tolterodine and oxybutynin.
[0015] International Publication No. WO 00/12069 to Pharmacia
Upjohn AB discloses controlled release formulations containing
tolterodine. This publication, however, does not disclose a
combination formulation containing tolterodine and oxybutynin. In
addition, Pharmacia Upjohn currently markets DETROL LA.TM., which
is an extended release capsule formulation containing
tolterodine.
[0016] Side effects in drug therapies for the treatment of
incontinence continue to be a problem. Practitioners are in search
of therapies having an improved toxicity profile, enhanced
therapeutic efficacy or reduced total drug dose requirement.
[0017] Osmotic devices and other tablet formulations are known for
their ability to provide a controlled release of a wide range of
drugs. Such osmotic devices and other tablet formulations are
disclosed in U.S. Pat. No. 4,014,334 to Theeuwes et al., U.S. Pat.
No. 4,576,604 to Guittard et al., Argentina Patent No. 234,493,
U.S. Pat. No. 4,673,405 to Guittard et al., U.S. Pat. No. 5,558,879
to Chen et al., U.S. Pat. No. 4,810,502 to Ayer et al., U.S. Pat.
No. 4,801,461 to Hamel et al., U.S. Pat. No. 5,681,584 to Savastano
et al., U.S. Pat. No. 3,845,770 and Argentina Patent No. 199,301,
the entire disclosures of which are hereby incorporated by
reference.
[0018] Osmotic devices have demonstrated utility in delivering
beneficial active agents, such as medicines, nutrients, food,
pesticides, herbicides, germicides, algaecides, chemical reagents,
and others, to an environment of use in a controlled manner over
prolonged periods of time. Known devices include tablets, pills,
and capsules.
[0019] Advancements in the art have focused on developing osmotic
devices with improved semipermeable or porous membranes, various
coatings surrounding the core and/or the semipermeable membrane,
layered osmotically effective agents in the core of the device,
specific release profiles for specific active substances, and
specific membrane or core compositions.
[0020] U.S. Pat. No. 4,931,285, No. 5,006,346 and No. 5,160,743 to
Edgren et al., No. 5,160,744, No. 5,190,765 and No. 5,252,338 to
Jao et al., No. 4,612,008, No. 4,765,989 and No. 5,082,668 to Wong
et al., No. 4,327,725 to Cortese et al., No. 5,208,037 to Wright et
al., No. 4,904,474 to Theeuwes et al. and No. 4,627,971 to Ayer
disclose osmotic devices comprising a bi-layered core surrounded by
a semipermeable membrane having at least one hole (or passageway).
The bi-layered core, however, comprises a first push-layer
containing no drug and a second layer containing drug. The hole(s)
can be placed anywhere along the semipermeable membrane. These
patents do not disclose a core having two different drug-containing
layers, each providing a controlled release of drug through a
respective hole in the semipermeable membrane.
[0021] U.S. Pat. No. 5,543,155 to Fekete et al. discloses an
osmotic device comprising a bi-layered core surrounded by a
semipermeable membrane having two holes (or passageways). The
bi-layered core, however, comprises a first push-layer containing
no drug and a second layer containing drug. The hole(s) can be
placed anywhere along the semipermeable membrane. This patent does
not disclose a core having two different drug-containing layers,
each providing a controlled release of drug through a respective
hole in the semipermeable membrane.
[0022] U.S. Pat. No. 4,662,880 to Hamel et al., No. 4,723,957, No.
4,867,969 and No. 4,971,790 to Magruder et al. disclose osmotic
devices comprising a single-layered core surrounded by a
semipermeable membrane having two oppositely placed holes. A
drug-containing coat further surrounds the semipermeable membrane.
These patents do not disclose a core having two different
drug-containing layers, each providing a controlled release of drug
through a respective hole in the semipermeable membrane.
[0023] U.S. Pat. No. 4,624,847 to Ayer et al. discloses an osmotic
device comprising a semipermeable membrane surrounding a
compartment that houses a drug-containing polymer that increases in
size and releases drug. The semipermeable membrane has two
oppositely placed holes for releasing drug. These patents do not
disclose a core having two different drug-containing layers, each
providing a controlled release of drug through a respective hole in
the semipermeable membrane.
[0024] U.S. Pat. No. 4,915,954 to Ayer et al. and No. 4,814,181 to
Jordan et al. disclose an osmotic device having a bi-layered core
surrounded by a semipermeable membrane. The first layer comprises a
first drug that is released from the core rapidly over a period of
2 min to 2 hr. The second layer comprises a second drug that is
released from the core at a controlled rate over a long period of
time. The layers of the core are in intimate contact and are not
separated by another layer, lamina or membrane. The semipermeable
membrane can have two holes, one hole adjacent each of the two
layers of the core such that each layer releases drug through its
own respective hole. The Ayer et al. and Jordan et al. patents do
not disclose an osmotic device having a bi-layered core, wherein
the layers are in contact with each other and in laminar
arrangement with respect to one another and wherein each layer
provides a prolonged and controlled release of an active agent.
[0025] U.S. Pat. No. 4,455,143 to Theeuwes et al. discloses an
osmotic device having two compartments defined by a surrounding
semipermeable membrane and a partition between the compartments.
The semipermeable membrane has two oppositely placed holes, one for
each compartment. Each compartment contains a drug that is
delivered at a controlled rate through a respective hole in the
surrounding membrane. The partition is require and retains its
integrity during operation of the osmotic device.
[0026] U.S. Pat. No. 5,866,164 to Kuczynski et al. of Alza
Corporation discloses an osmotic device having a bi-layered core
surrounded by a semipermeable membrane. There is no partition
between the layers. The core includes a drug-containing layer and a
push-layer; and passageways in the surrounding semipermeable
membrane only communicate the drug-containing layer, and not the
push-layer, to the exterior of the device. This osmotic device was
specifically designed to release only the drug in the
drug-containing layer and retain the drug in the push-layer.
[0027] While the prior art discloses a wide variety of osmotic
devices, none of the prior art discloses an osmotic device that
provides a controlled delivery of at least two different active
agents, wherein: a) the core of the osmotic device is bi-layered
and comprises a first pharmaceutical composition in laminar
arrangement with a second pharmaceutical composition; b) the
pharmaceutical compositions are in contact with one another; and c)
drug is released from each layer through a passageway in a
surrounding membrane (coat).
[0028] None of the prior art discloses a method of treating
incontinence by coadministering oxybutynin with another drug, such
as darifenacin or tolterodine. Likewise, none of the references
disclose a pharmaceutical composition, or dosage form, comprising a
combination of darifenacin and oxybutynin or of tolterodine and
oxybutynin.
[0029] None of the prior art discloses an osmotic device comprising
a dual layered core, wherein each layer of the core provides a
controlled release of its respective drug and wherein the layers
are in intimate contact, i.e., the layers are not separated by a
partition, and wherein neither layer is required to be a
push-layer, per se.
SUMMARY OF THE INVENTION
[0030] The present invention provides a pharmaceutical composition
for the treatment of incontinence. The pharmaceutical composition
can be administered to a subject by any conventional means. The
pharmaceutical composition comprises:
[0031] oxybutynin present in a sub-therapeutic or therapeutic
amount; and
[0032] a second drug for treating incontinence present in a
sub-therapeutic or therapeutic amount; wherein the oxybutynin and
second drug together provide a therapeutic benefit in the treatment
of incontinence.
[0033] The pharmaceutical composition of the invention can also
comprise oxybutynin, a second drug for treating incontinence, and
at least one pharmaceutical excipient.
[0034] Specific embodiments of the invention include those wherein:
a) the second drug is darifenacin or tolterodine; 2) at least one
of the oxybutynin and the second drug is present in a therapeutic
amount; 3) the oxybutynin and the second drug are each present in a
therapeutically effective amount; 4) at least one of the oxybutynin
and the second drug is present in a sub-therapeutically effective
amount; 5) the pharmaceutical composition is included in a dosage
form; 6) the oxybutynin and second drug together provide a
synergistic therapeutic effect; 7) the oxybutynin and second drug
together provide an additive therapeutic effect; 8) the
pharmaceutical composition, when administered to a subject, has an
improved toxicity (side effect) profile over oxybutynin or the
second drug when either agent is administered alone in a
therapeutic amount to the same subject; 9) the pharmaceutical
composition is a manufactured batch; 10) the pharmaceutical
composition is a homogeneous or heterogeneous mixture; and/or 11)
the weight ratio of oxybutynin to second drug is in the range of
about 1:0.1 to 1:10.6 or 1:0.1 to 1:20.
[0035] Other specific embodiments of the invention include those
wherein: 1) oxybutynin and the second drug are present in different
compositions; 2) the pharmaceutical composition is adapted for
oral, buccal, ocular, otic, dermal, rectal, vaginal, parenteral,
sublingual, nasal, or pulmonary delivery; 3) the molar ratio of
oxybutynin to second drug is in the range of about 1:0.08 to 1:8.2
or 1:0.05 to 1:15; 4) the pharmaceutical composition is a solid
dosage form that independently provides a controlled, delayed,
sustained, immediate, timed, slow, extended, targeted, pulsatile or
rapid release of each of oxybutynin and the second drug; 5) the
pharmaceutical composition provides therapeutically effective
plasma levels of oxybutynin and the second drug for a period of at
least 12 hours after administration; 6) the pharmaceutical
composition comprises two different drug-containing compositions
that are in admixture, separate, or in contact with one another; 7)
the pharmaceutical composition comprises two different
drug-containing compositions that are stacked or wherein one
composition surrounds the other; 8) oxybutynin and the second drug
have the same release profile; and/or 9) oxybutynin and the second
drug have different release profiles.
[0036] Yet another aspect of the invention provides a rapid release
dosage form comprising oxybutynin and a second drug for treating
incontinence, wherein each drug is released rapidly and the dosage
form provides therapeutically effective levels of each drug for a
period of at least 3-8 hours. The plasma levels of drug are either
independent of or dependent upon one another.
[0037] The pharmaceutical composition of the invention can be
included in any dosage form suitable for the administration of
drugs to a subject for the treatment of incontinence. Suitable
dosage forms for administration of the drug combination to a
subject are selected from the group consisting of a tablet, osmotic
device, capsule, tape, suspension, liquid, implant, gel, inhaler,
paste, pill, cream, ointment, troche, lozenge, granulation,
particulate solid, powder, extruded solid, suppository, stick,
mini-pump (such as the ALZET.TM. osmotic pump which is a miniature
implantable pump). The dosage form can be coated or uncoated. The
dosage form can be tailored for oral, ocular, nasal, vaginal,
glandular, gastrointestinal tract, rectal, cervical, intrauterine,
arterial, venous, otic, ophthalmic, sublingual, dermal, epidermal,
subdermal, implant, buccal, bioadhesive, or mucosal
administration.
[0038] The dosage form containing the drug combination can provide
a release of each drug that is independently rapid, immediate,
delayed, timed, targeted, sustained, controlled, slow, pulsatile or
extended. In other words, the release profile for the oxybutynin
can be independent of or dependent upon the release profile for the
second drug. For example, the oxybutynin may be released in a
controlled manner and the second drug may be released in a delayed
and rapid manner. Specific embodiments of the invention include
those wherein the dosage form provides a controlled release of both
oxybutynin and the second drug.
[0039] Oxybutynin and the second drug can be included in a dosage
form and pharmaceutical composition as: 1) a homogeneous mixture;
or 2) a heterogeneous mixture. For example, the oxybutynin can be
included in a first granulated composition and the second drug can
be included in a second granulated composition and a heterogeneous
mixture of both compositions can be used to fill capsules. The
drugs can also be separate in the dosage form, for example as
separate parts of the same dosage form. Accordingly, oxybutynin and
the second drug can be located in the same composition or in
different compositions in the same dosage form. In Examples 1, 2,
7, 8 and 12, the oxybutynin and the second drug are located in
different compositions in the same dosage form. In examples 3, 4,
5, 6, 9, 10 and 11, the oxybutynin and the second drug are located
in the same composition.
[0040] The invention also provides a method of treating
incontinence by administering to a subject oxybutynin and a second
drug used in the treatment of incontinence. The oxybutynin and the
second drug can be administered concurrently, sequentially, in an
overlapping manner or in a spaced apart manner.
[0041] Specific embodiments of the invention include those wherein:
1) the oxybutynin and the second drug are administered in the same
dosage form; and/or 2) the oxybutynin and the second drug are
administered in separate dosage forms.
[0042] When the oxybutynin and the second drug for treating
incontinence are provided in separate dosage forms, the invention
provides a kit comprising at least one first dosage form comprising
oxybutynin and at least one second dosage form comprising the
second drug.
[0043] In one embodiment, the invention provides a dosage form
comprising:
[0044] oxybutynin present in a sub-therapeutic or therapeutic
amount; and
[0045] a second drug for treating incontinence present in a
sub-therapeutic or therapeutic amount; wherein the oxybutynin and
second drug together provide a therapeutic benefit in the treatment
of incontinence.
[0046] Specific embodiments of the invention include those wherein:
1) the dosage form provides a sustained delivery of oxybutynin and
of the second drug for about one day or a period of about 18-26
hours, and preferably about 24 hours; 2) the dosage form begins to
release oxybutynin and then begins to release the second drug; 3)
the dosage form begins to release the second drug and then begins
to release the oxybutynin; 4) the dosage form provides a
therapeutic benefit sufficient for once-daily administration;
and/or 5) the dosage form is an oral dosage form that delivers drug
to the various regions of the intestinal tract including the buccal
cavity, esophagus, stomach, duodenum, jejunum, small intestine,
large intestine and/or rectum.
[0047] Target therapeutic levels of oxybutynin are in the range of
about 1-12 ng, preferably 3-8 ng and more preferably 4-7 ng, of
oxybutynin per ml of plasma. Target therapeutic levels for
darifenacin are those levels that are sufficient to provide the
desired therapeutic response in a subject. Target therapeutic
levels for tolterodine are in the range of about 0.5 to 25 ng per
ml of plasma.
[0048] The present invention also provides an osmotic device that
provides a controlled release device of two or more different
active agents. The core of the osmotic device is bi-layered such
that the two layers are in intimate contact with each other. Each
layer comprises a respective pharmaceutical composition that
provides a controlled release of a respective active agent. The
core is surrounded by a membrane having at least one or two
preformed holes. At least one hole in the membrane contacts the
first layer of the core, and at least one hole in the membrane
contacts the second layer of the core. The first pharmaceutical
composition provides a controlled release of a first active agent
through its respective first preformed passageway(s) in the
semipermeable membrane. The second pharmaceutical composition
provides a controlled release of a second active agent through a
respective second passageway(s) in the semipermeable membrane. Both
layers deliver their respective active agent through osmotic
pumping. The first and second passageways can be located anywhere
on their respective portions of the semipermeable membrane;
however, the first and second passageways can oppose one
another.
[0049] One aspect of the invention provides a dual controlled
release osmotic device comprising:
[0050] a core comprising a first layer and a second layer, wherein
the layers are in laminar arrangement and in intimate contact with
one another; and
[0051] a semipermeable membrane surrounding the core, wherein the
membrane comprises at least two preformed passageways, wherein at
least one first passageway is in communication with the first layer
and at least one second passageway is in communication with the
second layer;
[0052] whereby the first layer provides a controlled release of a
first active agent through the first passageway according to a
first release profile and the second layer provides a controlled
release of a different second active through the second passageway
according to a second release profile.
[0053] Specific embodiments of the invention include those wherein:
a) the release profile for the first active agent approximates the
release profile of the second active agent; b) the release profile
of the first active agent is different than the release profile of
the second active agent; c) the first active agent is delivered to
the upper to middle GI tract and the second active agent is
delivered to the upper to lower GI tract of a mammal to which the
dual osmotic device is delivered; d) the first and second active
agents are delivered in a concurrent, sequential or overlapping
manner; e) the first active agent is oxybutynin and the second
active agent is a different drug used for the treatment of
incontinence; f) the first active agent is delivered to the upper
to middle GI tract and the second active agent is delivered to the
middle to lower GI tract of a mammal to which the osmotic device is
delivered; and/or g) neither of the first or second layers is a
"push-layer".
[0054] Another aspect of the invention provides a dual controlled
release osmotic device comprising:
[0055] a core comprising a first active agent-containing layer and
a second active agent-containing layer; and
[0056] a semipermeable membrane surrounding the core, wherein the
membrane comprises at least one preformed passageway in
communication with at least one of the first and second active
agent-containing layers;
[0057] whereby the osmotic device provides a controlled release of
the first active agent through the at least one preformed
passageway according to a first release profile and the second
layer provides a controlled release of the second active through
the at least one preformed passageway according to a second release
profile.
[0058] Specific embodiments of the invention include those wherein:
1) the layers are in stacked arrangement and in contact with one
another; 2) the second active-agent containing layer surrounds the
first active agent containing layer; 3) the osmotic device
comprises at least one first preformed passageway in communication
with the first active agent-containing layer and at least one
second preformed passageway in communication with the second active
agent-containing layer; 4) the membrane comprises at least one
preformed passageway in communication with both the first and
second active agent-containing layers; 5) the membrane comprises at
least two preformed passageways and at least one of the two
preformed passageways is plugged with a water soluble or water
erodible material; 6) the membrane comprises at least two preformed
passageways both of which are plugged with a water soluble or water
erodible material, wherein the material plugging the first
passageway may be the same as or different than the material
plugging the second passageway; 7) the passageway(s) are plugged by
the material comprising an external finish coat; 8) the osmotic
device further comprises one or more coats interposed the
semipermeable membrane and the core; 9) the osmotic device further
comprises one or more coats external to the semipermeable membrane;
10) the osmotic device further comprises an external coat
surrounding the membrane, and the membrane comprises at least a
first preformed passageway and at least a second preformed
passageway, wherein the first passageway has been formed after
application of the external coat to the membrane, and the second
passageway has been formed before application of the external coat
to the membrane such that the second passageway is plugged by the
external coat, and release of the second drug begins after release
of the first drug has started 11) the osmotic device further
comprises an external coat surrounding the membrane, and the
membrane comprises at least a first preformed passageway and at
least a second preformed passageway, wherein the first and second
passageways have been formed before application of the external
coat to the membrane; and the first and second passageways are
plugged by the external coat; 12) the first and second active
agents are the same; 13) the first and second active agents are
different; and/or 14) the external coat comprises one or more
active agents that are the same as or different than the first and
second active agents.
[0059] Yet another aspect of the invention provides an osmotic
device comprising:
[0060] a core comprising a first composition comprising a first
drug and at least one pharmaceutical excipient, and a different
second composition comprising a second drug and at least one
pharmaceutical excipient, wherein the first and second compositions
contact one another and are in stacked arrangement; and
[0061] a membrane enveloping the core and having at least two
passageways to permit release of the first and second drugs from
the core when the osmotic device is exposed to an aqueous
environment, wherein at least one first passageway is in
communication with the first composition and at least one second
passageway is in communication with the second composition.
[0062] Still another aspect of the invention provides an osmotic
device comprising:
[0063] a core comprising a first composition comprising oxybutynin
and at least one pharmaceutical excipient, and a different second
composition comprising a second drug, selected from the group
consisting of darifenacin and tolterodine, and at least one
pharmaceutical excipient; and
[0064] a semipermeable membrane enveloping the core and having at
least two passageways to permit controlled release of oxybutynin
and the second drug from the core when the osmotic device is
exposed to an aqueous environment, wherein at least one passageway
is in communication with the first composition and at least one
passageway is in communication with the second composition.
[0065] Specific embodiments of the invention includes those
wherein: 1) the osmotic device provides an oxybutynin release
profile as described herein; 2) the osmotic device provides a
second drug release profile as described herein; 3) the osmotic
device provides an oxybutynin plasma concentration profile as
described herein; and/or 4) the osmotic device provides a second
drug plasma concentration profile as described herein.
[0066] Another aspect of the invention provides a coated dosage
form comprising:
[0067] a core comprising oxybutynin, a second drug for treating
incontinence and at least one pharmaceutical excipient, wherein the
second drug is selected from the group consisting of darifenacin
and tolterodine; and
[0068] a wall enveloping the core.
[0069] Specific embodiments of the invention include those wherein:
1) the wall is microporous, permeable, semipermeable or
impermeable; 2) the wall further comprises one or more preformed
passageways to permit release of oxybutynin and the second drug
when the dosage form is exposed to an aqueous environment; 3) the
wall is a multi-layered wall comprising two or more laminas that
are independently selected at each occurrence from inert and
drug-containing; 4) the two or more laminas are independently
selected at each occurrence from microporous, permeable,
semipermeable and impermeable; and/or 5) the two or more laminas
are independently selected at each occurrence from water soluble
and water erodible.
[0070] A more specific aspect of the invention provides an osmotic
device comprising:
[0071] a core comprising a first composition comprising oxybutynin
and at least one pharmaceutical excipient, and a different second
composition comprising a second drug, selected from the group
consisting of darifenacin and tolterodine, and at least one
pharmaceutical excipient, wherein the first and second compositions
contact one another and are in stacked arrangement; and
[0072] a semipermeable membrane enveloping the core and having at
least two passageways to permit controlled release of oxybutynin
and the second drug from the core when the osmotic device is
exposed to an aqueous environment, wherein at least one passageway
is in communication with the first composition and at least one
passageway is in communication with the second composition;
[0073] wherein, when the osmotic device is exposed to an aqueous
environment, oxybutynin is released according to a release profile
as described herein.
[0074] Other specific embodiments of the invention include those
wherein: 1) the osmotic device provides a single dose plasma level
for darifenacin is sufficient to provide a desired therapeutic
response in a subject; 2) the osmotic device provides a single dose
plasma level for oxybutynin in the range of about 4-7 or 1-10 ng
per ml of plasma; 3) the osmotic device provides a single dose
plasma level for tolterodine in the range of about 0.5-25 ng per ml
of plasma; or 4) the osmotic device comprises a finish coat
exterior to the semipermeable membrane.
[0075] The invention also provides a therapeutic device for the
delivery of pharmaceutically active agents, ranging in solubility
from slightly soluble to very soluble drugs, in a controlled,
continuous and approximately steady, preferably zero order, rate
over a prolonged period of time. Depending upon the excipients
used, among other things, the osmotic device can also deliver drugs
according to first order, pseudo-first order, second order or
pseudo-second order release profiles. In addition, the osmotic
device may provide targeted delivery of a drug.
[0076] The device of the present invention is optionally provided
with an external coating disposed on the outside of the osmotic
device and comprising one or more active agents for immediate
delivery to the environment of use. The external coating can
contain a loading dose of an active agent in the core of the
device.
[0077] Active agents useful in the delivery device include, for
example, compounds such as biologically or pharmacologically active
agents, medicines, nutrients, food products, insecticides,
pesticides, herbicides, germicides, algaecides, fungicides,
chemical reagents, growth regulating substances, parasiticides, sex
sterilants, fertility promoters, biocides, rodenticides,
disinfectants, anti-oxidants, plant growth promoters,
preservatives, fermentation agents, fertility inhibitors,
deodorants, micro-organism attenuators, catalysts, food
supplements, cosmetics, vitamins, and other agents that benefit the
environment of use.
[0078] The osmotic device of the invention may be used in
biological environments, aquariums, industrial warehouses,
laboratory facilities, hospitals, chemical reactions and other
facilities.
[0079] Other features, advantages and embodiments of the invention
will become apparent to those of ordinary skill in the art by the
following description, accompanying examples and appended
claims.
BRIEF DESCRIPTION OF THE FIGURES
[0080] The following drawings are part of the present specification
and are included to further demonstrate certain aspects of the
invention. The invention may be better understood by reference to
one or more of these drawings in combination with the detailed
description of the specific embodiments presented herein.
[0081] FIG. 1 depicts a sectional side view of a delivery device
according to the present invention.
[0082] FIG. 2 depicts a sectional side view of an alternate
delivery device according to the present invention.
[0083] FIG. 3 depicts a sectional side view of a second alternate
delivery device.
[0084] FIG. 4 depicts a sectional side view of a third alternate
delivery device.
[0085] FIG. 5 depicts a sectional side view of a fourth alternate
delivery device.
[0086] FIG. 6 depicts an in vitro release profile for oxybutynin
and tolterodine as they are released from the osmotic device of
Example 1.
[0087] FIG. 7 depicts an in vitro release profile for oxybutynin
and darifenacin as they are released from the osmotic device of
Example 2.
[0088] FIG. 8 depicts an in vitro release profile for oxybutynin
and darifenacin as they are released from the osmotic device of
Example 12.
DETAILED DESCRIPTION OF THE INVENTION
[0089] The present invention provides a pharmaceutical composition
for treating incontinence. The pharmaceutical composition can be
included in any dosage form. The pharmaceutical composition
contains oxybutynin and another drug that is known to be useful in
treating incontinence. Together, the oxybutynin and second drug
provide an overall therapeutic benefit that is better than the
overall therapeutic benefit provided by either agent when it is
administered alone. The therapeutic benefit can include improved
safety, reduced toxicity, improved efficacy, reduced number of
overall side-effects, and/or reduced severity of one or more
side-effects.
[0090] In one embodiment, oxybutynin and the second drug are
released concurrently from a dosage form when the two drugs are
included together in, for example, a tablet core, powder, capsule,
bead, granule, liquid, paste, gel, cream, ointment, patch, implant
or other similar dosage form capable of simultaneously delivering
two or more drugs.
[0091] In another embodiment, oxybutynin and the second drug are
released sequentially from a dosage form when the first drug is
included in one part of a dosage form and the second drug is
included in another part of the same dosage form, and release of
the second drug begins shortly after, during or nearly at the end
of completion of release of the first drug. Such dosage form would
include, for example, those wherein the first drug is included in a
core and the second drug is included in a coat surrounding the
core, a bi-layered tablet with each drug being in a different part
of the core, a dosage form providing a rapid release of the first
drug and a controlled release of the second drug. Suitable dosage
forms for this embodiment include, for example, a layered patch,
layered or coated tablet or bead, layered or coated osmotic device,
capsule containing a mixture of beads that provide different
release profiles for the drugs, layered or coated implant, or an
admixture of two compositions each containing a drug.
[0092] In yet another embodiment, oxybutynin and the second drug
are released in spaced apart periods of time from a dosage form
such that the first drug is released during a first period of time
and the second drug is released during a later second period of
time. Dosage forms suitable for this type of release are generally
considered targeted, enteric or timed-release dosage forms.
Suitable dosage forms for this embodiment include, for example, a
layered patch, layered or coated tablet, layered or coated osmotic
device, capsule containing a mixture of beads that provide
different release profiles for the drugs, and layered or coated
implant.
[0093] Each drug will be released independently from a solid dosage
form according to a rapid, immediate, controlled, sustained, slow,
timed, targeted, pseudo-first order, first order, pseudo-zero
order, zero-order, second order and/or delayed release profile. The
particular release profiles for oxybutynin and the second drug in a
particular dosage form will depend upon the specific combination of
oxybutynin and second drug present and the excipients used to make
the dosage form. For example, a dosage form might provide: 1) a
controlled release of the first drug and a controlled release of
the second drug; 2) a controlled release of the second drug and a
rapid release of the first drug; 3) a controlled release of the
first drug and a rapid release of the second drug; 4) a rapid
release of the first drug and the second drug; 5) a rapid release
of the first drug and a delayed but rapid release of the second
drug; 6) a rapid release of the first drug and a timed but
controlled release of the second drug; 7) a rapid release of the
second drug and a delayed but rapid release of the first drug; 8) a
rapid release of the second drug and timed but controlled release
of the first drug; or 9) a controlled and delayed release of the
first drug and a controlled but not substantially delayed release
of the second drug.
[0094] Controlled release formulations containing the
pharmaceutical composition of the invention can be made according
to Biorelated Polymers and Gels: Controlled Release and
Applications in Biomedical Engineering (ed. Teruo Okano; 1998);
Encyclopedia of Controlled Drug Delivery (ed. Edith Mathiowitz;
1999); Future Strategies for Drug Delivery with Particulate Systems
(ed. J. E. Diederichs; 1998); Controlled Release Series (ed. J. M.
Anderson; 1987); Controlled Drug Delivery Series (Ed. S. D. Bruck;
1983); Controlled Release of Drugs Series (ed. M. Rosoff; 1989);
Controlled Release Technology: Pharmaceutical Applications (ACS
Symposium Series No. 348) (eds. P. I. Lee and W. R. Good; 1987);
Extended Release Dosage Forms (ed. L. Krowczynski; 1987); Handbook
of Pharmaceutical Controlled Release Technology (ed. D. L. Wise;
2000); Intelligent Materials for Controlled Release (ed. S. M.
Dinh; 1999); Multicomponent Transport in Polymer Systems for
Controlled Release (Polymer Science and Engineering Monograph
Series) (ed. A. Polishchuk; 1997); Pharmaceutical Technology:
Controlled Drug Release (ed. M. Rubenstein; 1987); Polymers for
Controlled Drug Delivery (ed. P. J. Tarcha; 1991); Tailored
Polymeric Materials for Controlled Delivery Systems (ACS Symposium
Series No. 709) (ed. I. McCulloch; 1998); Oral Colon-Specific Drug
Delivery (ed. D. R. Friend, 1992); and other publications known to
those of ordinary skill in the art, the entire disclosures of which
are hereby incorporated by reference. The dosage forms thereof can
be amended as described herein to include oxybutynin and a second
drug to treat incontinence.
[0095] Topical formulations for administering the pharmaceutical
composition of the invention can be prepared as disclosed in
Electrically Assisted Transdermal and Topical Drug Delivery (ed. A.
K. Banga; 1998); Topical Drug Bioavailability Bioequivalence and
Penetration (ed. V. P. Shah; 1993); Topical Drug Delivery
Formulations (ed. D. W. Osborne); Transdermal and Topical Drug
Delivery Systems (ed. T. K. Ghosh; 1997); and other publications
known to those of ordinary skill in the art, the entire disclosures
of which are hereby incorporated by reference. The dosage forms
thereof can be amended as described herein to include oxybutynin
and a second drug to treat incontinence.
[0096] The pharmaceutical composition of the invention can also be
administered in other dosage forms such as those disclosed in
Handbook on Injectible Drugs 3rd Ed. (Trissel, 1983); Wang, et al.,
"Review of Excipients and pH's for Parenteral Products Used in the
United States", Journal of the Parenteral Drug Association
14(6):452 (1980) and Hard Capsules Development and Technology (The
Pharmaceutical Press, 1987), the disclosures of which are hereby
incorporated by reference. The dosage forms thereof can be amended
as described herein to include oxybutynin and a second drug to
treat incontinence.
[0097] Oxybutynin is commercially available as the free base or in
its hydrochloride salt form from Abbott Laboratories Pharmaceutical
Division (United States of America), Seloc AG (France), Sifa Ltd,
(Ireland), Orgamol SA, Synkem Div. Plasto SA, Cedex (France),
Gruppo Lepetit SA, Garessio (Italy) and Juzen Chemical Co. Ltd. The
invention provides for the administration of oxybutynin in its free
base, racemic, optically enriched, optically pure (R)- or (S)-,
and/or pharmaceutically acceptable salt forms. The optically pure
and optically enriched forms of oxybutynin are available from
Sepracor (United States of America). The oxybutynin can also be
included in a prodrug form or metabolite form (desethyloxybutynin).
Unless otherwise specified, the term oxybutynin refers to all of
the above-described forms of oxybutynin.
[0098] Oxybutynin is available in a rapid release tablet dosage
form from Alza (Palo Alto, Calif.), Rosemont (Denver, Colo.),
Sidmark Laboratories (NJ), Vintage Pharmaceuticals (Huntsville,
Ala.), Laboratorios Phoenix (Argentina), and Leiras OY (Finland).
Oxybutynin is typically completely released from these tablet
dosage forms within about 0.1-3.0 hours after administration. These
dosage forms can be modified according to the present invention to
include a second drug for treating incontinence.
[0099] Oxybutynin is available in controlled release osmotic device
tablet dosage forms called DITROPAN.TM. XL from Alza Corporation
(Palo Alto, Calif.) and called DITROPAN.TM. UD from Osmodex (Buenos
Aires, Argentina) and as a non-osmotic device tablet dosage form
called CYSTRIN.TM. CR from Leiras OY (Finland). Oxybutynin is
released from these tablet dosage forms at a controlled rate over a
period of about 24 hours. Controlled release dosage forms of
oxybutynin can also be manufactured according to the U.S. and
foreign patents and patent applications incorporated herein by
reference, and in particular according to U.S. Pat. No. 5,399,359,
No. 5,912,268, No. 5,840,754, and No. 5,674,895, Japanese Patent
Applications Serial No. 9,388 and No. 163,901. Controlled release
dosage forms containing oxybutynin can also be prepared according
to Nilsson et al. (Neurourol. Urodyn. (1997), 16(6), pg. 533-42),
International Publications No. WO 95/23,593, and No. WO 96/12,477
and U.S. Pat. No. 5,368,861, the entire disclosures of which are
hereby incorporated by reference. These dosage forms can be
modified according to the present invention to include a second
drug for treating incontinence. Controlled release dosage forms can
also be manufactured according to the examples herein.
[0100] Useful drugs suitable for the treatment of incontinence
include darifenacin, tolterodine, amitryptyline, atropine,
propantheline, imipramine, terodiline, dicyclomine, flurbiprofen,
nitroflurbiprofen (HCT-1026), hyoscyamine, trospium, duloxetine,
resiniferatoxin, desmopressin, propiverine, midodrine,
glycopyrrolate, KRP-197, and others known to those of ordinary
skill in the art. Other drugs suitable for the treatment of
incontinence also include the histamine and serotonin compounds as
disclosed in U.S. Pat. No. 5,877,198; the 1,2-diamino derivatives
of cyclobutene 3-4 diones of U.S. Pat. No. 5,506,252, eg.,
(R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-3--
ethyl-benzonitrile; the pyrrole derivatives of U.S. Pat. No.
6,172,102; the 4,5-diamino derivatives of (1H)-pyrazoles of U.S.
Pat. No. 6,172,222; the selective vasopressin V2 agonists of U.S.
Pat. No. 6,194,407;the (+)-venlafaxine derivatives of U.S. Pat. No.
6,197,828; the enantiomerically enriched (R,R)-glycopyrrolate as
disclosed in U.S. Pat. No. 6,204,285; the enantiomerically enriched
(R)-trihexyphenidyl as disclosed in U.S. Pat. No. 6,207,681; the
substituted esters, amides and ketones having smooth muscle
relaxing properties of U.S. Pat. No. 6,207,852; the tropone
derivatives of U.S. Patent No, 6,221,868; the
.alpha..sub.1L-adrenoceptor agonist compounds disclosed in U.S.
Pat. No. 6,268,389, e.g.,
2-(3-dimethylamino-2-methylphenylimino)-imidazolidine;
2-(6-bromo-3-dimethylamino-2-methylphenylimino)imidazolidine;
2-(5-amino-2-chloro-4-dimethylamino-2-methylphenylimino)imidazolidine;
2-(2-chloro-5-trifluoromethylphenylamino)imidazolidine,
2-(3-amino-2-methylphenylimino)-imidazolidine,
2-(6-chloro-3-dimethylamin- o-2-methylphenylimino)imidazolidine and
tiamenidine; the tricyclic pyridine N-oxides of U.S. Pat. No.
6,235,900; the compounds
4-[(2-tert-butylamino-3,4-dioxo-cyclobut-1-enylamino)-methyl]-3-chloro-be-
nzonitrile and
3-(2,3dichloro-6-methyl-benzylamino)-4-(1,1-dimethyl-propyl-
amino)-cyclobut-3-ene-1,2-dione disclosed in PCT International
Publication No. WO 98/11888; the analogs of glutamic acid and
gamma-aminobutyric acid disclosed in PCT International Publication
No. WO 00/61135; the 1-amino ethylindole derivatives disclosed in
PCT International Publication No. WO 00/61554; the
quinolinomorphinan derivatives disclosed in PCT International
Publication No. WO 01/05795; the compounds
5-(2-ethyl-2Htetrazol-5-yl)-1,2,3,6-tetrahydropyridine,
5-(2-ethyl-2H-tetrazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine as
disclosed in PCT International Publication No. WO 01/13918; the
compounds (+)-tramadol, O-demethyl-tramadol,
(+)-O-demethyltramadol, O-desmethyl-N-mono-desmethyl-tramadol,
(+)-O-desmethyl-N-mono-desmethyl-t- ramadol as disclosed in PCT
International Publication No. WO 01/24783, and the
quinolinoisoquinoline derivatives disclosed in PCT International
Publication No. WO 01/40225. Still other suitable drugs for the
treatment of incontinence are disclosed in PCT International
Publications No. WO 98/09948, No. WO 99/52856, No. WO 00/02846, No.
WO 01/02406, No. WO 01/27104, No. WO 01/36375, No. WO 01/36418, No.
WO 01/47503, No. WO 01/600352. Additional suitable drugs for the
treatment of incontinence are disclosed in U.S. Pat. No. 6,159,998,
No. 6,172,041, No. 6,194,447, No. 6,218,404, and No. 6,248,549, the
entire disclosures of which are hereby incorporated by reference.
These drugs may be included as the second drug in the present
pharmaceutical composition. Preferred second drugs include
darifenacin and tolterodine.
[0101] Darifenacin can be used for treating irritable bowel
syndrome and urinary incontinence. Darifenacin can be made
according to the procedure described by Pfizer (European Patent No.
388,054 (1990) or Graul et al (J Drugs Future (1996), 21(11),
1105-1108). Darifenacin is available in the (R)-, (S)-, optically
enriched and racemic form as well as the free-base or salt form.
The darifenacin can also be included in a prodrug form or
metabolite form. Unless otherwise specified, the term darifenacin
refers to all of the above-described forms of darifenacin.
[0102] A targeted or enteric release dosage form containing
darifenacin can be prepared according to Dolan et al. (U.S. Pat.
No. 6,106,864). The dosage form of Dolan et al. can be modified
according to the present invention to include oxybutynin.
[0103] Darifenacin is generally administered at a dose of 5-75 mg
daily.
[0104] Tolterodine can be made according to the procedure described
by KabiVitrum (European Patent No. 325,571 (1989)) or Andersson et
al. (J. O. C. (1998), 63, 8067-8070). Tolterodine is available in
the (R)-, (S)-, optically enriched and racemic form as well as the
free-base or salt form. The tolterodine can also be included in a
prodrug form or metabolite form (such as PNU-200577;
(R)-N,N-diisopropyl-3-(2-hydroxy-5-h-
ydroxymethylphenyl)-3-phenylpropylamine). Unless otherwise
specified, the term tolterodine refers to all of the
above-described forms of tolterodine.
[0105] Tolterodine is generally administered at a dose of 2 to 4 or
0.5 to 5 mg daily.
[0106] The pharmaceutical composition and dosage forms of the
invention are used to treat urinary (stress or urge) incontinence,
also referred to as over active bladder (OAB). Since some of the
drugs herein possess bimodal activities, the pharmaceutical
composition and dosage form of the invention can be used treat
inflammatory bowel syndrome.
[0107] The oxybutynin and second drug can be formulated as its
pharmaceutically acceptable salts. As used herein,
"pharmaceutically acceptable salts" refer to derivatives of the
disclosed compounds, wherein the therapeutic compound is modified
by making acid or base salts thereof. Examples of pharmaceutically
acceptable salts include, but are not limited to, mineral or
organic acid salts of oxybutynin. The pharmaceutically acceptable
salts include the conventional non-toxic salts, for example, from
non-toxic inorganic or organic acids. For example, such
conventional non-toxic salts include those derived from inorganic
acids such as hydrochloric, hydrobromic, sulfuric, sulfonic,
sulfamic, phosphoric, nitric and the like; and the salts prepared
from organic acids such as amino acids, acetic, propionic,
succinic, glycolic, stearic, lactic, malic, tartaric, citric,
ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,
benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,
toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic,
isethionic, and others known to those of ordinary skill in the art.
For acidic compounds, the salt may include an amine-based (primary,
secondary, tertiary or quaternary amine) counter ion, an alkali
metal cation, or a metal cation. Lists of suitable salts are found
in texts such as Remington's Pharmaceutical Sciences, 18.sup.th Ed.
(Alfonso R. Gennaro, ed.; Mack Publishing Company, Easton, Pa.,
1990); Remington: the Science and Practice of Pharmacy 19.sup.th
Ed.(Lippincott, Williams & Wilkins, 1995); Handbook of
Pharmaceutical Excipients, 3.sup.rd Ed. (Arthur H. Kibbe, ed.;
Amer. Pharmaceutical Assoc., 1999); the Pharmaceutical Codex:
Principles and Practice of Pharmaceutics 12.sup.th Ed. (Walter Lund
ed.; Pharmaceutical Press, London, 1994); The United States
Pharmacopeia: The National Formulary (United States Pharmacopeial
Convention); and Goodman and Gilman's: the Pharmacological Basis of
Therapeutics (Louis S. Goodman and Lee E. Limbird, eds.; McGraw
Hill, 1992), the disclosures of which are hereby incorporated by
reference.
[0108] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[0109] The tablet dosage forms useful in the present invention
include, by way of example and without limitation, pressed tablets,
layered tablets, osmotic device tablets, coated tablets, uncoated
tablets, enteric coated tablets, multiple compressed tablets,
centered tablets (tablets containing another tablet inside),
prolonged release tablets, slow release tablets, buccal and
sublingual tablets, and molded tablets.
[0110] FIG. 1 depicts a controlled release dosage form (1)
including a bi-layered core, wherein the first drug-containing
layer (4) is in laminar (stacked) arrangement with respect to the
second drug-containing layer (6). The core is enveloped by a wall
(3) having at least two preformed passageways (5, 7). The
passageway (5) is in communication with the first drug-containing
layer (4), and the passageway (7) is in communication with the
second drug-containing layer (6). The dosage form also includes an
optional external coat (2). As depicted, the passageways (5,7) is
made after the external coat (2) is placed onto the wall (3).
[0111] The wall (3) can be microporous, permeable, impermeable or
semipermeable. By "microporous" is meant a membrane that permits
release of the active agent in the core by diffusion through
micropores or pores in a surrounding membrane. By "permeable" is
meant that the wall permits passage of fluid and of ingredient(s).
By "impermeable" is meant that the wall does not permit passage of
any fluid or ingredient(s). By semipermeable membrane is meant a
membrane that permits the influx of a liquid from the exterior of
the delivery device to the interior of the delivery device, while
at the same allowing release of the active agent in the core by
osmotic pumping through the preformed passageway in the
semipermeable membrane. The wall can maintain or lose its physical
integrity during use. The permeability and physical stability of
the wall depend upon the materials used to make the wall.
[0112] The external coat (2) is optional and can be inert, i.e.,
excluding any active agent, or can contain one or more active
agents, e.g., a drug-containing coat. The external coat can
maintain or lose its physical integrity during use, i.e., the coat
can be water soluble or water erodible. The physical stability of
the wall depends upon the materials used to make the wall. If the
external coat contains an active agent, the release rate of the
active agent can be rapid, immediate, controlled, delayed, slow,
sustained, timed, or targeted. The external coat can also include a
loading dose of oxybutynin and the second drug in the core of the
dosage form.
[0113] The core releases oxybutynin and the second drug; however,
the rate of release of each is determined by the composition of the
layer in which each is found, the composition of the wall (3) and
the composition of the optional external coat (2). For example,
when the wall (3) is a semipermeable or impermeable wall, the
dosage form will provide a controlled release of both oxybutynin
and the second drug. When the wall (3) is permeable or microporous,
the dosage form will provide a more rapid and less controlled
release of both oxybutynin and the second drug. Generally, the
release rate of oxybutynin and the second drug from the core
increases as the permeability of the wall (3) increases.
[0114] Unlike other known osmotic devices, the layers of the core
in the osmotic device (1) can be adjacent and in intimate contact
with one another. Each layer (4,6) releases its drug at a
controlled rate. Surprisingly, the osmotic device does not require
a push-layer, i.e., a layer that absorbs water and expands, in
order to release drug from each layer or from the opposing surfaces
of the osmotic device. Also, the osmotic device unexpectedly does
not require a partition between the layers (4,6) of the core in
order to release drug from each layer or from the opposing surfaces
of the osmotic device.
[0115] Exemplary formulations for the dosage form (1) are detailed
in Examples 1 and 2, wherein the dosage form is an osmotic device
and includes an inert water soluble or erodible external coat (2)
that does not contain drug. The osmotic device of Example 1
includes two different compositions in the core, which is
surrounded by a semipermeable membrane. The first composition
comprises oxybutynin, whereas the second composition comprises
tolterodine. When this osmotic device is placed in an aqueous
environment, it provides a controlled release of oxybutynin and
tolterodine.
[0116] The dosage form (1) can also include: a) the external coat
(2) as a drug-containing coat that contains oxybutynin and a second
drug in rapid or immediate release form; b) the wall (3) as a water
soluble or erodible coat; and c) a core as a controlled, slow,
sustained, or rapid release core that contains oxybutynin and a
second drug. Although the core is depicted in each figure as a
bi-layered core, the invention includes embodiments wherein the
core is a homogeneous or heterogeneous mixture of the drugs and
pharmaceutical excipients.
[0117] The passageway of the device (1) can be in communication
with both layers of the core. The passageway (8) extends through
the external coat (2) and the wall (3) and communicates the
exterior of the device to both compositions (4, 6) in the core. By
using this type of construction, the device can deliver both drugs
simultaneously through a single passageway.
[0118] The relative amounts of oxybutynin and second drug released
at a given time can be controlled by changing the location of the
passageway(s) in the wall (3). For example, if the first (4) and
second (6) compositions have the same release properties and the
device includes the sole passageway (5) centered on the composition
(4), the device (1) will release a major portion of the first
composition (4) before it releases any of the composition (6). If
the first (4) and second (6) compositions have the same release
properties and the device includes the sole passageway (5) in
communication with the composition (4) and proximal but not in
direct communication with the composition (6), the device (1) will
release only a minor portion of the first composition (4) by the
time it begins to release the second composition (6).
[0119] The relative amounts of oxybutynin and second drug released
at a given time can be controlled by using compositions possessing
predetermined release profiles. For example, if each composition
(4, 6) has its own passageway (5, 7, respectively) located as
depicted in FIG. 1, the device will provide a faster release of the
drug in composition (4) if the composition (4) possesses a
twelve-hour controlled release profile and the composition (6)
possesses a twenty four-hour controlled release profile.
[0120] Where the coat (2) includes one or more drugs, those drugs
can be the same as or different than the drugs in the core of the
device. Therefore, the device can be used to deliver two or more
different drugs.
[0121] Where the composition (4) includes an enteric release
polymer and the composition (6) does not, the device (1) can
provide a delayed and controlled release of the drug in the
composition (4) and a controlled but not substantially delayed
release of the drug in the composition (6).
[0122] FIG. 2 depicts an alternate embodiment of a controlled
release dosage form according to the invention. The dosage form
(10) includes a core comprising a first composition (13) in stacked
arrangement with a second composition (15), wherein the core is
enveloped by an internal coat (12) and then by a wall (11). The
first composition (13) comprises oxybutynin and the second
composition (15) comprises a second drug. The internal coat (12)
can be an inert, release rate controlling, enteric, microporous,
permeable, semipermeable, delayed release, water soluble, or water
erodible coat. The wall (11) can be a microporous, impermeable,
semipermeable or impermeable wall. The internal coat (12) and wall
(11) have different compositions. The wall (11) includes plural
passageways (14, 16). The passageways (14) permit release of
oxybutynin from the core. The passageways (16) permit release of
the second drug from the core. In one embodiment, the wall is a
semipermeable wall, the internal coat is an inert water soluble or
water erodible coat, and the dosage form provides a concurrent
controlled release of oxybutynin and the second drug. Although not
depicted in FIG. 2, the passageways (14, 16) can extend through the
wall (11) and the internal coat (12).
[0123] When the internal coat (12) is a release rate-controlling
coat, it will control the rate of release of the oxybutynin and the
second drug. When the internal coat (12) is an enteric release
coat, it will delay release of the oxybutynin and the second drug
until the dosage form has reached the portion of the
gastrointestinal tract downstream of the stomach, e.g, the ileum,
duodenum, jejunum, intestines, colon and/or rectum. When the
internal coat (12) is a microporous coat it will control release of
the drugs from the core in a manner dependent upon the porosity of
the coat, such that the rate of drug release increases as the
porosity of the microporous coat increases.
[0124] As depicted, the passageways (14, 16) are not blocked by a
water soluble or water erodible material, since no additional
material is coated onto the wall (11) after the passageways are
drilled.
[0125] FIG. 3 depicts a controlled release dosage form (20) that
includes a bi-layered core having first (27) and second (25)
drug-containing layers. The core is surrounded by a wall (23),
which is then surrounded by an internal coat (22) that does not
contain drug. The external drug-containing or inert coat (21)
surrounds the internal coat. The internal coat (22) is similar to
and can include the same features of the internal coat (12) of the
dosage form (10). The external coat (21) is similar to and can
include the same features of the external coat (2) of the dosage
form (1). The dosage form (20) provides a controlled release of
oxybutynin through the passageway(s) (26) and a controlled release
of the second drug through the passageway(s) (24).
[0126] The passageways (24,26) are plugged by the same material
used to form the internal coat (22), since the internal coat is
applied to the wall (23) after the passageways are drilled through
the wall (23).
[0127] When the external coat (21) contains one or more drugs and
the coat (22) is inert and water soluble or water erodible, the
dosage form will provide a delayed release of both drugs from the
core. The length of the delay may be as short as one minute or as
long as several to many hours. For example, the delay may be
0.5-5.0 hours or 1.0-3.0 hours.
[0128] FIG. 4 depicts a bi-layered tablet (30) comprising a first
composition (31) and a different second composition (32), wherein
the tablet includes an optional coat (33). The coat (33) can be
similar to and can include the same features of the external coat
(2) or (21), the internal coat (12) or (22) or the wall (3), (11)
or (23). Accordingly, the dosage form (30) can provide controlled,
sustained, slow or extended release of oxybutynin and a second
drug, optionally in a delayed or enteric release form.
[0129] The wall (33) can be a multi-layered wall comprising two or
more lamina. At each occurrence, a lamina can be water soluble or
water erodible and/or permeable, semipermeable, impermeable or
microporous and/or inert or drug-containing. The wall can comprise
one to six laminas.
[0130] FIG. 5 depicts an osmotic device (40) comprising a
bi-layered core surrounded by a semipermeable membrane (42), which
is then surrounded by a drug-containing external coat (41). The
osmotic device has two different types of preformed passageways.
The passageway(s) (44), which communicates the drug-containing
layer (43) of the core to the exterior of the device, is formed
after the external coat is applied to the semipermeable membrane.
The passageway(s) (46) is formed before the external coat is
applied to the semipermeable membrane. Accordingly, the
passageway(s) (46) is (are) plugged by the same material used to
form the external coat (41). By virtue of its construction, this
device will begin to release drug from the layer (43) before it
begins to release drug from the layer (45). The delay period in the
release of drug from the layer (45) is related to the amount of
time it takes for the external coat (41) to dissolve or erode: the
longer it takes to dissolve or erode, the longer the delay period
for release of drug from the layer (45) through the passageway
(46). The osmotic device (40), therefore, provides a controlled
release of drug from the layer (43), wherein release begins shortly
after exposure of the device to an environment of use, and a
delayed and controlled release of drug from the layer (45), wherein
release begins after release from the layer (43) has already
begun.
[0131] FIG. 6 includes a dissolution profile for oxybutynin and
tolterodine as they are released from the osmotic device of Example
1. The dissolution data is obtained in a paddle apparatus (USP type
2) operated at 100 rpm using distilled water at 37.degree. C. as
dissolution medium. The oxybutynin and tolterodine release profiles
of the formulation of Example 1 are generally described as
follows:
1 Oxybutynin Released Tolterodine Released Range (%) Range (%) Time
(hs) Average (%) Min Max Average (%) Min Max 1 2 0 10 3 0 12 3 12 5
25 17 3 25 5 22 17 36 29 17 36 7 33 20 50 43 31 50 9 -- -- -- 57 49
66 11 56 40 70 69 61 76 15 73 58 84 82 74 90 19 81 70 89 -- -- --
24 85 76 100 89 76 100
[0132] The dissolution profiles for oxybutynin and tolterodine
approximate one another; however, the tolterodine has slightly
faster rate of release. Although not shown in FIG. 6, the
tolterodine can be made to achieve approximately complete
dissolution at about 16 hours, and the oxybutynin can be made to
achieve approximately complete dissolution at about 20 hours.
[0133] FIG. 7 includes a dissolution profile for oxybutynin and
darifenacin as they are released from the osmotic device of Example
2. The dissolution data is obtained in a paddle apparatus (USP type
2) operated as indicated above. The oxybutynin and darifenacin
release profiles of the formulation of Example 2 are generally
described as follows:
2 Oxybutynin Released Darifenacin Released Average Range (%)
Average Range (%) Time (hrs) (%) Min Max (%) Min Max 1 2 0 10 5 0
12 3 12 5 25 25 10 35 7 33 20 50 55 25 65 11 56 40 70 75 45 89 15
73 58 84 90 74 98 19 81 70 89 -- -- -- 24 85 76 100 95 89 100
[0134] The darifenacin has a slightly faster rate of release.
Although not shown in FIG. 7, the darifenacin can be made to
achieve approximately complete dissolution at about 18 hours, and
the oxybutynin can be made to achieve approximately complete
dissolution at about 22 hours.
[0135] FIG. 8 includes a dissolution profile for oxybutynin and
darifenacin as they are released from the osmotic device of Example
12. The dissolution data is obtained in a paddle apparatus (USP
type 2) operated as indicated above. The oxybutynin and darifenacin
release profiles of the formulation of Example 12 are generally
described as follows:
3 Oxybutynin Released Darifenacin Released Average Range (%)
Average Range (%) Time (hrs) (%) Min Max (%) Min Max 1 2 0 10 1 0 5
3 12 5 25 5 0 15 7 33 20 50 25 10 45 11 56 40 70 51 29 74 15 73 58
84 68 52 84 19 81 70 89 79 60 89 24 85 76 100 93 80 100
[0136] The darifenacin and oxybutynin have approximately the same
dissolution profile, but the oxybutynin has a slightly faster rate
of release and slightly lower total amount released at 24 hours.
Although not shown in FIG. 8, the darifenacin can be made to
achieve approximately complete dissolution at about 24 hours, and
the oxybutynin can be made to achieve approximately complete
dissolution at about 20 hours.
[0137] A rapid release dosage form will contain about 0.01-5 mg,
about 1-2.5 mg, or about 1-5 mg of oxybutynin, and about 2.5-50 mg
of darifenacin, or about 0.5-4 mg or 2-4 mg of tolterodine. The
rapid release dosage form will generally provide therapeutic levels
of oxybutynin for a period of about 3-6 or about 2-8 hours after
administration. It will also generally provide therapeutic levels
of darifenacin for a period of several hours, or of tolterodine for
a period of about 4 or about 2-6 hours after administration.
[0138] The rapid release tablets and short acting controlled
release tablets, which are used as the first tablets of the
invention, will provide therapeutically effective levels of
oxybutynin generally for a period of less than 8 hours, preferably
less than 6 hours. The short acting controlled release tablets,
which are used as the second tablets of the invention, will provide
therapeutically effective levels of oxybutynin generally for a
period of not less than 16 hours and not more than 23 hours,
preferably not less than 18 hours and not more than 22 hours.
[0139] When the dosage form is a controlled release dosage form, it
will contain about 2.5-12.5 mg, about 5-12.5 mg, or about 5-10 mg
of oxybutynin, and about 5-50 mg of darifenacin, or about 1-3 mg of
tolterodine. The dosage form will provide therapeutic plasma
concentration levels of oxybutynin for the period between about
0.5-24 hours or 1.5-24 hours after administration. The dosage form
will generally provide therapeutic levels of darifenacin for a
period of about 12-24 hours or 18-24. The dosage form will
generally provide therapeutic levels of tolterodine for a period of
about 12-24 hours or 18-24.
[0140] A specific embodiment of the dosage form includes a
controlled release tablet that completely releases its oxybutynin
charge within about 8 hours, or about 6 hours, after
administration. Another embodiment of the tablet completes
releasing its oxybutynin charge within about 23-24 hours after
administration. A specific embodiment of the dosage form includes a
controlled release tablet that completely releases its oxybutynin
charge within about 8 hours, or about 6 hours, after
administration, and releases its darifenacin charge in the
colon.
[0141] A controlled release dosage form will provide effective
amounts of oxybutynin for a period of not less than 18 hours and
not more than 30 hours, or not less than 20 hours and not more than
28 hours, or not less than 22 hours and not more than 24 hours. The
artisan of ordinary skill will understand that administration of a
single unit dose period of time may be insufficient to maintain
therapeutic plasma levels of oxybutynin for up to 24-30 hours and
that multiple unit doses administered over an equal number of days
may be required to maintain therapeutic plasma levels of oxybutynin
for up to 24-30 hours.
[0142] Depending upon the particular combination of excipients
used, a controlled release dosage form will independently provide
an expected overall oxybutynin, darifenacin or tolterodine release
profile that is pH-dependent or pH-independent; diffusion or
dissolution controlled; pseudo-zero order, zero-order, pseudo-first
order, first-order or second-order; or slow, delayed, timed or
sustained release or otherwise controlled.
[0143] All of the formulations of the invention will provide
sufficient levels of oxybutynin and darifenacin or tolterodine for
at least a predetermined period of time to provide a desired
therapeutic response.
[0144] The external coat can be applied to the surface of a tablet
according to methods known to those of ordinary skill in the art.
Such methods include, for example, applying solids in solution or
suspension through the use of a sprayer that spreads them uniformly
over the core or by employing compression or other suitable methods
known to those of ordinary skill in the art. The external coat can
comprise poly(vinyl pyrrolidone) (PVP) and poly(ethylene glycol)
(PEG) and can further comprise materials such as, by way of example
and without limitation, hydroxypropyl methylcellulose (HPMC),
ethylcellulose (EC), hydroxyethylcellulose (HEC), sodium
carboxymethylcellulose (CMC), dimethylaminoethyl
methacrylate-methacrylic acid ester copolymer, ethyl
acrylate-methyl methacrylate copolymer (GA-MMA), C-5 or 60 SH-50
(Shin-Etsu Chemical Corp.) and combinations thereof. The external
coat can also comprise dissolution aids, stability modifiers, and
bioabsorption enhancers.
[0145] When the external coat comprises a combination of materials,
the relative amounts and ratios of those materials can be varied as
desired. For example, when the external coat comprises PVP and PEG,
the ratio of PVP:PEG will generally range from about 1-65% by
weight of PVP: about 0.1-30% by weight of PEG based upon the weight
of the external coat.
[0146] When oxybutynin and/or the second drug is present in the
external coat, it is present in an amount ranging from about 0.1 to
99% by weight of the coat. This wide range provides great latitude
in the design and application of the first tablet. Those of
ordinary skill in the art will appreciate that the particular
amount of drug employed will vary according to, among other things,
the desired pharmacokinetic behavior in a mammal. For example, if
the initial burst of drug release is intended to be small, then the
external coat would include about 0.01 mg to about 0.5 mg of drug.
If the initial burst of drug release is intended to be moderate,
the external coat would include about 0.5 mg to about 5 mg of
drug.
[0147] When a rapidly dissolving or eroding coat is used in the
tablet formulations of the invention, the coat will generally
comprise an inert and non-toxic material which is at least
partially, and preferably substantially completely, soluble or
erodible in an environment of use. The rapidly dissolving coat will
be soluble in aqueous environments such as, for example, the buccal
cavity and/or upper GI tract, e.g., the stomach, duodenum, jejunum
or upper small intestines. Exemplary materials are disclosed in
U.S. Pat. Nos. 4,576,604 and 4,673,405, and the text Pharmaceutical
Dosage Forms: Tablets Volume I, Second Edition. (A. Lieberman. ed.
1989, Marcel Dekker, Inc.), the relevant disclosures of which are
hereby incorporated by reference. In preferred embodiments, the
rapidly dissolving coat will be soluble in saliva, gastric juices,
or acidic fluids.
[0148] The long acting controlled release tablet formulations that
provide a delayed and sustained release of oxybutynin and the
second drug may include an enteric coat which is soluble or
erodible in intestinal juices, substantially pH neutral or basic
fluids but for the most part insoluble in gastric juices or acidic
fluids. A wide variety of other polymeric materials are known to
possess these various solubility properties. Such other polymeric
materials include, by way of example and without limitation,
cellulose acetate phthalate (CAP), cellulose acetate trimelletate
(CAT), poly(vinyl acetate) phthalate (PVAP), hydroxypropyl
methylcellulose phthalate (HP), poly(methacrylate ethyl acrylate)
(1:1) copolymer (MA-EA), poly(methacrylate methyl methacrylate)
(1:1) copolymer (MA-MMA), poly(methacrylate methyl methacrylate)
(1:2) copolymer, Eudragit L-30-D.TM. (MA-EA, 1:1), Eudragit.TM.
L-100-55.TM. (MA-EA, 1:1), hydroxypropyl methylcellulose acetate
succinate (HPMCAS), Coateric.TM. (PVAP), Aquateric.TM. (CAP),
AQUACOA.TM. (HPMCAS) and combinations thereof The enteric coat can
also comprise dissolution aids, stability modifiers, and
bioabsorption enhancers.
[0149] When the enteric coat is intended to be dissolved, eroded or
become detached from the core in the colon materials such as
hydroxypropylcellulose, microcrystalline cellulose (MCC, Avicel.TM.
from FMC Corp.), poly (ethylene-vinyl acetate) (60:40) copolymer
(EVAC from Aldrich Chemical Co.), 2-hydroxyethylmethacrylate
(HEMA), MMA, terpolymers of HEMA: MMA:MA synthesized in the
presence of
N,N'-bis(methacryloyloxyethyloxycarbonylamino)-azobenzene,
azopolymers, enteric coated timed release system (Time Clock.RTM.
from Pharmaceutical Profiles, Ltd., UK) and calcium pectinate can
be used.
[0150] A polymeric material for use in the enteric coat involves
materials that resist the action of gastric fluid avoiding
permeation through the semipermeable wall while one or more of the
materials in the core of the tablet are solubilized in the
intestinal tract thereby allowing delivery of the drug in the core
by osmotic pumping in an osmotic device to begin. A material that
easily adapts to this kind of requirement is a
poly(vinylpyrrolidone)-vinyl acetate copolymer, such as the
material supplied by BASF under its Kollidon VA64 trademark, mixed
with magnesium stearate and other similar excipients. The enteric
coat can also comprise povidone, which is supplied by BASF under
its Kollidon K 30 trademark, and hydroxypropyl methylcellulose,
which is supplied by Dow under its Methocel E-15 trademark. The
materials can be prepared in solutions of having different
concentrations of polymer according to the desired solution
viscosity. For example, a 10% P/V aqueous solution of Kollidon K 30
has a viscosity of about 5.5-8.5 cps at 20.degree. C., and a 2% P/V
aqueous solution of Methocel E-15 has a viscosity of about 13-18
cps at 20.degree. C.
[0151] The enteric coat can comprise one or more materials that do
not dissolve, disintegrate, or change their structural integrity in
the stomach and during the period of time that the tablet resides
in the stomach. Representative materials that keep their integrity
in the stomach can comprise a member selected from the group
consisting of (a) keratin, keratin sandarac-tolu, salol (phenyl
salicylate), salol beta-naphthylbenzoate and acetotannin, salol
with balsam of Peru, salol with tolu, salol with gum mastic, salol
and stearic acid, and salol and shellac; (b) a member selected from
the group consisting of formalized protein, formalized gelatin, and
formalized cross-linked gelatin and exchange resins; (c) a member
selected from the group consisting of myristic acid-hydrogenated
castor oil-cholesterol, stearic acid-mutton tallow, stearic
acid-balsam of tolu, and stearic acid-castor oil; (d) a member
selected from the group consisting of shellac, ammoniated shellac,
ammoniated shellac-salol, shellac-wool fat, shellac-acetyl alcohol,
shellac-stearic acid-balsam of tolu, and shellac n-butyl stearate;
(e) a member selected from the group consisting of abietic acid,
methyl abictate, benzoin, balsam of tolu, sandarac, mastic with
tolu, and mastic with tolu, and mastic with acetyl alcohol; (f)
acrylic resins represented by anionic polymers synthesized from
methacrylate acid and methacrylic acid methyl ester, copolymeric
acrylic resins of methacrylic and methacrylic acid and methacrylic
acid alkyl esters, copolymers of alkacrylic acid and alkacrylic
acid alkyl esters, acrylic resins such as
dimethylaminoethylmethacrylate-butylmethacrylate-methylmethacrylate
copolymer of 150,000 molecular weight, methacrylic acid-methyl
methacrylate 50:50 coploymer of 135,000 molecular weight,
methacrylic acid-methylmethacrylate-30:70-copolymer of 135,000 mol.
wt., methacrylic acid-dimethylaminoethyl-methacrylate-ethyl
acrylate of 750,000 mol. wt., methacrylic acid-methyl
methacrylate-ethyl acrylate of 1,000,000 mol. wt., and ethyl
acrylate-methyl methacrylate-ethyl acrylate of 550,000 mol. wt;
and, (g) an enteric composition comprising a member selected from
the group consisting of cellulose acetyl phthalate, cellulose
diacetyl phthalate, cellulose triacetyl phthalate, cellulose
acetate phthalate, hydroxypropyl methylcellulose phthalate, sodium
cellulose acetate phthalate, cellulose ester phthalate, cellulose
ether phthalate, methylcellulose phthalate, cellulose ester-ether
phthalate, hydroxypropyl cellulose phthalate, alkali salts of
cellulose acetate phthalate, alkaline earth salts of cellulose
acetate phthalate, calcium salt of cellulose acetate phthalate,
ammonium salt of hydroxypropyl methylcellulose phthalate, cellulose
acetate hexahydrophthalate, hydroxypropyl methylcellulose
hexahydrophthalate, polyvinyl acetate phthalate diethyl phthalate,
dibutyl phthalate, dialkyl phthalate wherein the alkyl comprises
from 1 to 7 straight and branched alkyl groups, aryl phthalates,
and other materials known to one or ordinary skill in the art.
[0152] When the controlled release tablet is an osmotic device, the
semipermeable membrane of the osmotic device is formed of a
material that is substantially permeable to the passage of fluid
from the environment of use to the core and substantially
impermeable to the passage of active agent from the core. Many
common materials known by those of ordinary skill in the art are
suitable for this purpose. Exemplary materials are cellulose
esters, cellulose ethers and cellulose esters-ethers. However, it
has been found that a semipermeable membrane consisting essentially
of cellulose acetate (CA) and poly(ethylene glycol) (PEG), in
particular PEG 400, are preferred when used in combination with the
other materials required in the present osmotic device. This
particular combination of CA and PEG provides a semipermeable
membrane that gives the osmotic device a well controlled release
profile for the active agent in the core and that retains its
chemical and physical integrity in the environment of use. The
ratio of CA:PEG generally ranges from about 50-99% by weight of CA:
about 50-1% by weight of PEG, and preferably about 95% by weight of
CA: about 5% by weight of PEG. The ratio can be varied to alter
permeability and ultimately the release profile of the osmotic
device. Other preferred materials can include a selected member of
the group of cellulose acylates such as cellulose acetate,
cellulose diacetate, cellulose triacetate and combinations thereof.
Many suitable polymers, include those disclosed in Argentine Patent
No. 199,301 and other references cited herein, the disclosures of
which are hereby incorporated by reference.
[0153] The osmotic device of the invention comprises at least one
preformed passageway (pore, hole, or aperture) that communicates
the exterior of the semipermeable wall with the core of the device.
The preformed passageway can be formed according to any of the
known methods of forming passageways in a membrane. Such methods
include, for example, 1) drilling a hole through the semipermeable
membrane with a bit or laser; 2) including a water soluble material
within the composition that forms the semipermeable membrane such
that a pore forms when the osmotic device is in an aqueous
environment of use; 3) punching a hole through the semipermeable
membrane; or 4) employing a tablet punch having a pin to punch a
hole through the semipermeable lamina. The preformed passageway can
pass through the semipermeable wall and one or more of any other
lamina coated onto the semipermeable membrane or between the
semipermeable membrane and the core. The passageway(s) can be
shaped as desired. In some embodiments, the passageway is laser
drilled and is shaped as an oval, ellipse, slot, slit, cross or
circle. Micropores in a microporous membrane are distinguished from
preformed passageways.
[0154] The depth of penetration of a preformed passageway can be
tailored to provide specific drug release profiles, to control the
extent to which release of a drug is delayed, and/or to control the
order in which drugs are released. The order in which the process
steps of forming a preformed passageway and applying a coating
composition are conducted can be performed to provide specific drug
release profiles, to control the extent to which release of a drug
is delayed, and/or to control the order in which drugs are
released.
[0155] Methods of forming passageways in membranes of osmotic
devices are disclosed in U.S. Pat. No. 4,088,864 to Theeuwes et
al., No. 4,016,880 to Theeuwes et al., No. 3,916,899 to Theeuwes et
al., No. 4,285,987 to Ayer et al., No. 4,783,337 to Wong et al.,
No. 5,558,879 to Chen et al., No. 4,801,461 to Hamel et al., and
No. 3,845,770 to Theeuwes et al., the disclosures of which are
hereby incorporated by reference.
[0156] When the controlled release tablet is an osmotic device,
osmotically effective solutes, osmotic agents or osmagents are
added. These osmagents will aid in either the suspension or
dissolution of oxybutynin and the second drug in the core.
Exemplary osmagents include organic and inorganic compounds such as
salts, acids, bases, chelating agents, sodium chloride, lithium
chloride, magnesium chloride, magnesium sulfate, lithium sulfate,
potassium chloride, sodium sulfite, calcium bicarbonate, sodium
sulfate, calcium sulfate, calcium lactate, d-mannitol, urea,
tartaric acid, raffinose, sucrose, alpha-d-lactose monohydrate,
glucose, combinations thereof and other similar or equivalent
materials which are widely known in the art. Osmagents can also be
incorporated to the core of the osmotic device to control the
release of oxybutynin therefrom.
[0157] The tablets of the invention can also comprise adsorbents,
antioxidants, buffering agents, colorants, flavorants, sweetening
agents, tablet antiadherents, tablet binders, tablet and capsule
diluents, tablet direct compression excipients, tablet
disintegrants, tablet glidants, tablet lubricants, tablet or
capsule opaquants and/or tablet polishing agents.
[0158] As used herein, the term "adsorbent" is intended to mean an
agent capable of holding other molecules onto its surface by
physical or chemical (chemisorption) means. Such compounds include,
by way of example and without limitation, powdered and activated
charcoal and other materials known to one of ordinary skill in the
art.
[0159] As used herein, the term "antioxidant" is intended to mean
an agent which inhibits oxidation and thus is used to prevent the
deterioration of preparations by the oxidative process. Such
compounds include, by way of example and without limitation,
ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole,
butylated hydroxytoluene, hypophosphorous acid, monothioglycerol,
propyl gallate, sodium ascorbate, sodium bisulfite, sodium
formaldehyde sulfoxylate and sodium metabisulfite and other
materials known to one of ordinary skill in the art.
[0160] As used herein, the term "buffering agent" is intended to
mean a compound used to resist change in pH upon dilution or
addition of acid or alkali. Such compounds include, by way of
example and without limitation, potassium metaphosphate, potassium
phosphate, monobasic sodium acetate and sodium citrate anhydrous
and dehydrate and other materials known to one of ordinary skill in
the art.
[0161] As used herein, the term "sweetening agent" is intended to
mean a compound used to impart sweetness to a preparation. Such
compounds include, by way of example and without limitation,
aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol
and sucrose and other materials known to one of ordinary skill in
the art.
[0162] As used herein, the term "tablet antiadherents" is intended
to mean agents which prevent the sticking of tablet formulation
ingredients to punches and dies in a tableting machine during
production. Such compounds include, by way of example and without
limitation, magnesium stearate, talc, calcium stearate, glyceryl
behenate, PEG, hydrogenated vegetable oil, mineral oil, stearic
acid and other materials known to one of ordinary skill in the
art.
[0163] As used herein, the term "tablet binders" is intended to
mean substances used to cause adhesion of powder particles in table
granulations. Such compounds include, by way of example and without
limitation, acacia, alginic acid, carboxymethylcellulose sodium,
poly(vinylpyrrolidone), compressible sugar (e.g., NuTab),
ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone
and pregelatinized starch and other materials known to one of
ordinary skill in the art.
[0164] When needed, binders may also be included in the tablets.
Exemplary binders include acacia, tragacanth, gelatin, starch,
cellulose materials such as methyl cellulose and sodium carboxy
methyl cellulose, alginic acids and salts thereof, polyethylene
glycol, guar gum, polysaccharide, bentonites, sugars, invert
sugars, poloxamers (PLURONIC F68, PLURONIC F127), collagen,
albumin, gelatin, cellulosics in nonaqueous solvents, combinations
thereof and the like. Other binders include, for example,
polypropylene glycol, polyoxyethylene-polypropylene copolymer,
polyethylene ester, polyethylene sorbitan ester, polyethylene
oxide, combinations thereof and other materials known to one of
ordinary skill in the art.
[0165] As used herein, the term "tablet and capsule diluent" or
"fillers" is intended to mean inert substances used as fillers to
create the desired bulk, flow properties, and compression
characteristics in the preparation of tablets and capsules. Such
compounds include, by way of example and without limitation,
dibasic calcium phosphate, kaolin, lactose, sucrose, mannitol,
microcrystalline cellulose, powdered cellulose, precipitated
calcium carbonate, sorbitol, and starch and other materials known
to one of ordinary skill in the art.
[0166] As used herein, the term "tablet direct compression
excipient" is intended to mean a compound used in direct
compression tablet formulations. Such compounds include, by way of
example and without limitation, dibasic calcium phosphate (e.g.,
Ditab) and other materials known to one of ordinary skill in the
art.
[0167] As used herein, the term "tablet glidant" is intended to
mean agents used in tablet and capsule formulations to promote
flowability of the granulation. Such compounds include, by way of
example and without limitation, colloidal silica, cornstarch, talc,
calcium silicate, magnesium silicate, colloidal silicon, silicon
hydrogel and other materials known to one of ordinary skill in the
art.
[0168] As used herein, the term "tablet lubricant" is intended to
mean substances used in tablet formulations to reduce friction
during tablet compression. Such compounds include, by way of
example and without limitation, calcium stearate, magnesium
stearate, mineral oil, stearic acid, and zinc stearate and other
materials known to one of ordinary skill in the art.
[0169] As used herein, the term "tablet/capsule opaquant" is
intended to mean a compound used to render a capsule or a tablet
coating opaque. May be used alone or in combination with a
colorant. Such compounds include, by way of example and without
limitation, titanium dioxide and other materials known to one of
ordinary skill in the art.
[0170] As used herein, the term "tablet polishing agent" is
intended to mean a compound used to impart an attractive sheen to
coated tablets. Such compounds include, by way of example and
without limitation, carnauba wax, and white wax and other materials
known to one of ordinary skill in the art.
[0171] As used herein, the term "tablet disintegrant" is intended
to mean a compound used in solid dosage forms to promote the
disruption of the solid mass into smaller particles which are more
readily dispersed or dissolved. Exemplary disintegrants include, by
way of example and without limitation, starches such as corn
starch, potato starch, pre-gelatinized and modified starches
thereof, sweeteners, clays, such as bentonite, microcrystalline
cellulose (e.g., Avicel), carboxymethylcellulose calcium, cellulose
polyacrilin potassium (e.g., Amberlite), alginates, sodium starch
glycolate, gums such as agar, guar, locust bean, karaya, pectin,
tragacanth and other materials known to one of ordinary skill in
the art.
[0172] As used herein, the term "colorant" is intended to mean a
compound used to impart color to solid (e.g., tablets)
pharmaceutical preparations. Such compounds include, by way of
example and without limitation, FD&C Red No. 3, FD&C Red
No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green
No. 5, D&C Orange No. 5, D&C Red No. 8, caramel, and ferric
oxide, red, other F.D. & C. dyes and natural coloring agents
such as grape skin extract, beet red powder, beta-carotene, annato,
carminic acid, turmeric, paprika, and other materials known to one
of ordinary skill in the art. The amount of coloring agent used
will vary as desired.
[0173] As used herein, the term "flavorant" is intended to mean a
compound used to impart a pleasant flavor and often odor to a
pharmaceutical preparation. Exemplary flavoring agents or
flavorants include synthetic flavor oils and flavoring aromatics
and/or natural oils, extracts from plants, leaves, flowers, fruits
and so forth and combinations thereof. These may also include
cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay
oil, anise oil, eucalyptus, thyme oil, cedar leave oil, oil of
nutmeg, oil of sage, oil of bitter almonds and cassia oil. Other
useful flavors include vanilla, citrus oil, including lemon,
orange, grape, lime and grapefruit, and fruit essences, including
apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple,
apricot and so forth. Flavors that have been found to be
particularly useful include commercially available orange, grape,
cherry and bubble gum flavors and mixtures thereof. The amount of
flavoring may depend on a number of factors, including the
organoleptic effect desired. Flavors will be present in any amount
as desired by those of ordinary skill in the art. Particularly
preferred flavors are the grape and cherry flavors and citrus
flavors such as orange.
[0174] The present formulations can also employ one or more
commonly known surface active agents or cosolvents that improve
wetting or disintegration of the tablet core or layers.
[0175] Plasticizers can also be included in the formulations to
modify the properties and characteristics of the polymers used in
the coats or core of the tablets. As used herein, the term
"plasticizer" includes all compounds capable of plasticizing or
softening a polymer or binder used in invention. The plasticizer
should be able to lower the melting temperature or glass transition
temperature (softening point temperature) of the polymer or binder.
Plasticizers, such as low molecular weight PEG, generally broaden
the average molecular weight of a polymer in which they are
included thereby lowering its glass transition temperature or
softening point. Plasticizers also generally reduce the viscosity
of a polymer. It is possible the plasticizer will impart some
particularly advantageous physical properties to the osmotic device
of the invention.
[0176] Plasticizers useful in the invention can include, by way of
example and without limitation, low molecular weight polymers,
oligomers, copolymers, oils, small organic molecules, low molecular
weight polyols having aliphatic hydroxyls, ester-type plasticizers,
glycol ethers, poly(propylene glycol), multi-block polymers, single
block polymers, low molecular weight poly(ethylene glycol), citrate
ester-type plasticizers, triacetin, propylene glycol and glycerin.
Such plasticizers can also include ethylene glycol, 1,2-butylene
glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol,
triethylene glycol, tetraethylene glycol and other poly(ethylene
glycol) compounds, monopropylene glycol monoisopropyl ether,
propylene glycol monoethyl ether, ethylene glycol monoethyl ether,
diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate,
butyl lactate, ethyl glycolate, dibutylsebacate,
acetyltributylcitrate, triethyl citrate, acetyl triethyl citrate,
tributyl citrate and allyl glycolate. All such plasticizers are
commercially available from sources such as Aldrich or Sigma
Chemical Co. It is also contemplated and within the scope of the
invention, that a combination of plasticizers may be used in the
present formulation. The PEG based plasticizers are available
commercially or can be made by a variety of methods, such as
disclosed in Poly(ethylene glycol) Chemistry: Biotechnical and
Biomedical Applications (J. M. Harris, Ed.; Plenum Press, New York)
the disclosure of which is hereby incorporated by reference.
[0177] The formulations of the invention can also include oils, for
example, fixed oils, such as peanut oil, sesame oil, cottonseed
oil, corn oil and olive oil; fatty acids, such as oleic acid,
stearic acid and isotearic acid; and fatty acid esters, such as
ethyl oleate, isopropyl myristate, fatty acid glycerides and
acetylated fatty acid glycerides. It can also be mixed with
alcohols, such as ethanol, isopropanol, hexadecyl alcohol, glycerol
and propylene glycol; with glycerol ketals, such as
2,2-dimethyl-1,3-dioxolane-4-methanol; with ethers, such as
poly(ethyleneglycol) 450, with petroleum hydrocarbons, such as
mineral oil and petrolatum; with water, or with mixtures thereof;
with or without the addition of a pharmaceutically suitable
surfactant, suspending agent or emulsifying agent.
[0178] Soaps and synthetic detergents may be employed as
surfactants and as vehicles for detergent compositions. Suitable
soaps include fatty acid alkali metal, ammonium, and
triethanolamine salts. Suitable detergents include cationic
detergents, for example, dimethyl dialkyl ammonium halides, alkyl
pyridinium halides, and alkylamine acetates; anionic detergents,
for example, alkyl, aryl and olefin sulfonates, alkyl, olefin,
ether and monoglyceride sulfates, and sulfosuccinates; nonionic
detergents, for example, fatty amine oxides, fatty acid
alkanolamides, and poly(oxyethylene)-block-poly(oxypropylene)
copolymers; and amphoteric detergents, for example, alkyl
.beta.-aminopropionates and 2-alkylimidazoline quaternary ammonium
salts; and mixtures thereof.
[0179] Various other components, not otherwise listed above, can be
added to the present formulation for optimization of a desired
active agent release profile including, by way of example and
without limitation, glycerylmonostearate, nylon, cellulose acetate
butyrate, d, 1-poly(lactic acid), 1,6-hexanediamine,
diethylenetriamine, starches, derivatized starches, acetylated
monoglycerides, gelatin coacervates, poly (styrene-maleic acid)
copolymer, glycowax, castor wax, stearyl alcohol, glycerol
palmitostearate, poly(ethylene), poly(vinyl acetate), poly(vinyl
chloride), 1,3-butylene-glycoldimethacrylate,
ethyleneglycol-dimethacryla- te and methacrylate hydrogels.
[0180] It should be understood, that compounds used in the art of
pharmaceutical formulation generally serve a variety of functions
or purposes. Thus, if a compound named herein is mentioned only
once or is used to define more than one term herein, its purpose or
function should not be construed as being limited solely to that
named purpose(s) or function(s).
[0181] The term "unit dose" is used herein to mean an amount of the
pharmaceutical composition that is included in one or more dosage
forms that together provide a therapeutically effective amount of
oxybutynin and the second drug. Depending upon the specific
combination and amounts of oxybutynin and second drug included
within the dosage form, an improved, additive or synergistic
therapeutic effect will be observed. Accordingly, a unit dose may
include therapeutic or sub-therapeutic amounts of oxybutynin and
the drug. An improved therapeutic effect is one wherein the second
drug enhances the therapeutic benefit provided by oxybutynin alone.
An additive therapeutic effect is one wherein each of oxybutynin
and second drug possesses therapeutic properties, and the
combination of the two drugs provides an overall therapeutic effect
that approximates the sum of their individual therapeutic effects.
A synergistic therapeutic effect is one wherein each of oxybutynin
and second drug possesses therapeutic properties, and the
combination of the two drugs provides an overall therapeutic effect
that is greater than the sum of their individual therapeutic
effects. In each embodiment of the invention, a particular
combination of drugs will provide at least an improved therapeutic
effect as compared to the individual drugs.
[0182] By the term "effective amount", it is understood that, with
respect to, for example, pharmaceuticals, a therapeutically or
sub-therapeutically effective amount is contemplated. A
therapeutically effective amount is the amount or quantity of drug
that is sufficient to elicit the required or desired therapeutic
response, or in other words, the amount that is sufficient to
elicit an appreciable biological response when administered to a
patient. A sub-therapeutically effective amount is an amount that
is less than the therapeutically effective amount when the dosage
form of the invention is administered to a subject. The
pharmaceutical composition and dosage form of the invention can
contain therapeutically effective or sub-therapeutically effective
amounts of oxybutynin and the second drug.
[0183] For nasal administration, the pharmaceutical composition may
be included in a paste, cream, spray, powder, nebulizer, aerosol or
ointment containing the appropriate solvents (such as water,
aqueous, nonaqueous, polar, apolar, hydrophobic, hydrophilic and/or
combinations thereof) and optionally other compounds (stabilizers,
perfumes, antimicrobial agents, antioxidants, pH modifiers,
surfactants and/or bioavailability modifiers). It is contemplated
that bioavailability enhancers such as alcohols or other compounds
that enhance the penetration of the therapeutic compound from the
pharmaceutical formulation into the nasal mucosa may be needed to
prepare suitable formulations for nasal administration.
[0184] For oral, buccal, and sublingual administration, the
pharmaceutical composition may be in the form of a caplet, tablet,
chewable tablet, suspension, agglomerate, granulate, lozenge,
troche, or powder.
[0185] For rectal administration, the pharmaceutical composition
can be included in a suppository, ointment, enema, tablet or cream
for release of a therapeutic compound into the intestines, sigmoid
flexure and/or rectum.
[0186] Tablets can differ in size, shape, color and amount of
oxybutynin and the second drug. The tablets of the invention can
assume any shape or form known in the art of pharmaceutical
sciences. The device of the invention can be a pill, sphere,
tablet, bar, plate, granule, agglomerate, paraboloid of revolution,
ellipsoid of revolution or other shape known to those of ordinary
skill in the art. The tablets can also include surface markings,
cuttings, grooves, letters and/or numerals for the purposes of
decoration, identification and/or other purposes.
[0187] The tablets of the invention can be prepared according to
the methods disclosed herein or those well known in the art, more
specifically according to the methods disclosed in the disclosure
incorporated herein by reference. For example, according to one
manufacturing technique, oxybutynin, the second drug and excipients
that comprise the core are mixed in solid, semisolid or gelatinous
form, then moistened and sieved through a specified screen to
obtain uncoated cores. The uncoated cores are then dried in a dryer
and compressed, for example, by punching.
[0188] If coated tablets are desired, the compressed and uncoated
cores are then covered with a solution of suitable materials to
provide the desired drug release profile. For example, if the
tablet is to be an osmotic device, then the tablet core may be
coated with a semipermeable membrane. Subsequently, the
semipermeable membrane surrounding the core should be perforated
with, for example, laser equipment.
[0189] The tablets of the invention can be coated with a finish
coat as is commonly done in the art to provide the desired shine,
color, taste or other aesthetic characteristics. Materials suitable
for preparing the finish coat are well known in the art and found
in the disclosures of many of the references cited and incorporated
by reference herein. A finish coat is generally water soluble or
water erodible. The finish coat will plug a preformed passageway
that has been formed just prior to application of the finish
coat.
[0190] The pharmaceutical composition of the invention can be
present as a manufactured batch or unit dose. The term
"manufactured batch" is taken to mean any size batch of a
composition containing the elements set forth herein but not yet
included in a dosage form.
[0191] The pharmaceutical composition can be a homogeneous or
heterogeneous mixture of the components therein. The pharmaceutical
composition can comprise two different compositions, such as a
first composition comprising oxybutynin and a second composition
comprising the second drug. The first and second compositions can
be stacked in the core of a solid dosage form or be in admixture or
one of the first and second compositions can surround the other
composition.
[0192] The method of the invention comprises the step of
administering to a subject suffering from incontinence a dosage
form or pharmaceutical composition comprising oxybutynin and a
second drug. Alternatively, the method of the invention comprises
the step of administering to a subject suffering from incontinence
a dosage form or pharmaceutical composition comprising oxybutynin
and another dosage form or pharmaceutical composition comprising a
second drug.
[0193] The steps of the invention can comprise the steps of
determining the pharmacokinetic, pharmacodynamic, pharmacological,
therapeutic, behavioral and/or toxicological response of the
subject to the system. These responses can be determined easily by
those of ordinary skill in the art by monitoring the occurrence of
side effects associated with the therapy, monitoring blood levels
of drug, correlating blood levels of drug to particular
formulations or patient profile, and/or observing improvement of
urinary incontinence associated symptoms. When oxybutynin and the
second drug are found in separate dosage forms, the dosage forms
can be included in a kit.
[0194] The method of the invention can be adapted as follows. For
frail elderly patients, lower dosages of drug will be required. For
patients that respond poorly, i.e., receive a minimal therapeutic
benefit from therapy, higher dosages will be required. For patients
who exhibit side effects caused by drug, lower dosage will be
required. For patients whose eating habits interfere with drug
therapy, dosages can be adjusted according to observed plasma drug
concentrations to provide the desired concentrations, i.e.,
undesirably low plasma drug concentrations are overcome by
administering higher dosages of drug. If one particular embodiment
of the invention is practiced on a mammal and unwanted side effects
due to high plasma drug concentrations are observed, the system can
be modified by changing the formulation(s) used such that the
plasma level concentrations of the drugs are lower.
[0195] The kit is provided such that physicians and patients can
easily determine the proper combination of first and second dosage
forms that should be administered according to the above guiding
principles. A start-up kit of the system is generally used as
follows. An exemplary start-up kit comprises at least two first
different tablets containing oxybutynin and at least two different
tablets containing second drug. The physician administers and/or
prescribes one formulation from each of the first and second
tablets. After a period of time, usually one to fourteen days, the
patient's response is determined. Depending upon the response, the
physician may administer and/or prescribe different formulations
for the first and/or second tablets. Where the patient exhibits
accumulation of oxybutynin or the second drug, the physician may
recommend lower dose first and/or second tablets, or use first or
second tablets having a different release profile. Where the
patient exhibits unwanted side effects during the initial part of
each 24 hour period that the kit is administered, the physician may
recommend lower dose controlled release tablets that provide lower
initial plasma levels of the drugs. Where the patient exhibits a
loss of therapeutic benefit during the latter part of each 24-hour
period that the kit is administered, the physician may recommend
tablets that release oxybutynin and/or the second drug over a
longer period of time or that contain a higher dose of oxybutynin
and/or second drug. When the first and second tablets are
administered concurrently, they may be administered encased in a
capsule, such as a hard or soft gelatin capsule. Alternatively, the
first tablet can be a rapidly dissolving tablet that dissolves in
the buccal cavity or a chewable tablet, while the second tablet is
one that would be swallowed whole. Still, the first tablet could be
a short acting controlled release tablet that begins to release
oxybutynin shortly after administration while the second tablet is
a conventional long acting delayed and controlled release tablet
that begins to release the second drug at least three hours after
administration.
[0196] The advantages of the present kit over known systems for
treating oxybutynin include improved therapeutic benefit and/or
reduced severity or occurrence of side effects.
[0197] The following examples should not be considered exhaustive,
but merely illustrative of only a few of the many embodiments
contemplated by the present invention. The methods described herein
can be followed to prepare osmotic devices according to the
invention.
EXAMPLE 1
[0198] The following procedure is used to prepare osmotic device
formulations containing oxybutynin (2.5, 5 and 10 mg strength) and
tolterodine (1 and 2 mg strength). The oxybutynin and the
tolterodine are located in separate stacked layers in the core of
the osmotic device. The osmotic device formulations contain the
following ingredients in the amounts indicated:
4 AMOUNT AMOUNT AMOUNT AMOUNT INGREDIENT (mg) (mg) (mg) (mg)
Oxybutynin Strength 5 5 10 2.5 Tolterodine Strength 1 2 2 2 CORE
LAYER A Oxybutynin 5.15 5.15 10.30 2.57 Hydrochloride Mannitol
69.00 69.00 138.00 50.00 Anhydrous Dextrose 30.00 30.00 60.00 22.00
Povidone 6.35 6.35 12.70 15.30 Polyethylene Glycol 400 1.15 1.15
2.30 1.23 Polyethylene Glycol 4.00 4.00 8.00 4.00 6000 Tartaric
Acid 2.00 2.00 4.00 2.20 Magnesium Stearate 1.35 1.35 2.70 1.70
Colloidal Silicon Dioxide 1.00 1.00 2.00 1.00 LAYER B Tolterodine
L-Tartrate 1.46 2.92 2.92 2.92 Sodium Chloride 50.00 50.00 50.00
50.00 Microcrystalline 78.54 77.08 77.08 77.08 cellulose Povidone
9.00 9.00 9.00 9.00 Polyethylene Glycol 5.00 5.00 5.00 5.00 6000
Polyethylene Glycol 400 2.00 2.00 2.00 2.00 Red Ferric Oxide 1.00
1.00 1.00 1.00 Colloidal Silicon Dioxide 1.00 1.00 1.00 1.00
Magnesium Stearate 2.00 2.00 2.00 2.00 COATING A Cellulose Acetate
19.05 19.05 23.75 23.75 Polyethylene Glycol 400 0.95 0.95 1.25 1.25
COATING B Hydroxypropyl 3.70 3.70 5.55 5.55 methylcellulose 2910
Copolyvidone 3.00 3.00 1.58 1.58 Polyethylene Glycol 1.05 1.05 4.50
4.50 6000 Titanium Dioxide 2.25 2.25 3.37 3.37
[0199] The oxybutynin composition is prepared by mixing oxybutynin
HCl, povidone, mannitol, and anhydrous dextrose. The mixture is wet
with a blend of polyethylene glycol 6000 and polyethylene glycol
400 in alcohol 96.degree.. The blend is granulated and dried at
40-50.degree. C. for 4 hours; then, it is screened and mixed with
colloidal silicon dioxide and tartaric acid. The blend is mixed to
homogeneity and magnesium stearate is added.
[0200] The tolterodine composition is prepared by mixing
tolterodine L-tartrate sodium chloride, povidone, microcrystalline
cellulose and red ferric oxide. The mixture is wet with a blend of
polyethylene glycol 6000, and polyethylene glycol 400 in alcohol
96.degree.. The blend is granulated and dried at 40-50.degree. C.
for 4 hours; then, it is screened and mixed with colloidal silicon
dioxide. The blend is mixed to homogeneity and magnesium stearate
is added.
[0201] The stacked core is prepared as follows. First, the
oxybutynin composition is added to a punch die set, and tamped.
Next, the tolterodine composition is added on top of the tamped
oxybutynin and the two layers compressed using 8.50 mm diameter
punches to form bi-layered cores.
[0202] A first composition to cover the core is prepared as
follows: a mixture of cellulose acetate and polyethylene glycol 400
is added to a blend of acetone and methanol. This polymer mixture
is sprayed onto the tablets in a conventional pan coater to obtain
film-coated tablets.
[0203] The second coating is prepared by mixing hydroxypropyl
methylcellulose 2910, polyethylene glycol 6000, copolyvidone, and
titanium dioxide in a mixture of methylene chloride-alcohol
96.degree. 70:30 (volume/volume). This polymer mixture is sprayed
onto the final tablets in a conventional pan coater to obtain
film-coated tablets. A 0.50 mm hole is drilled through the coating
in each face of the tablet.
EXAMPLE 2
[0204] The procedure of Example 1 is used to prepare osmotic device
formulations containing oxybutynin (5 and 10 mg strength) and
darifenacin (5 and 10 mg strength) except that the formulations
contain the following ingredients in the amounts indicated.
5 AMOUNT AMOUNT INGREDIENT (mg) (mg) Oxybutynin Strength 5 10
Darifenacin Strength 10 5 CORE LAYER A Oxybutynin Hydrochloride
5.15 10.30 Mannitol 69.00 138.00 Anhydrous Dextrose 30.00 60.00
Povidone 6.35 12.70 Polyethylene Glycol 400 1.15 2.30 Polyethylene
Glycol 6000 4.00 8.00 Tartaric Acid 2.00 4.00 Magnesium Stearate
1.35 2.70 Colloidal Silicon Dioxide 1.00 2.00 LAYER B Darifenacin
Hydrobromide 11.90 5.95 Sodium Chloride 52.00 98.05
Microcrystalline cellulose 76.10 68.00 Povidone 9.00 16.00
Polyethylene Glycol 6000 5.00 5.50 Polyethylene Glycol 400 2.00
4.00 Red Ferric Oxide 1.00 0.50 Colloidal Silicon Dioxide 1.00 1.00
Magnesium Stearate 2.00 1.00 COATING A Cellulose Acetate 18.50
33.75 Polyethylene Glycol 400 1.50 1.25 COATING B Hydroxypropyl
methylcellulose 2910 3.70 5.55 Copolyvidone 3.00 1.58 Polyethylene
Glycol 6000 1.05 4.50 Oxybutynin Strength 5 10 Darifenacin Strength
10 5 Titanium Dioxide 2.25 3.37
EXAMPLE 3
[0205] The following procedure is used to prepare osmotic devices
comprising oxybutynin (5 or 10 mg strength) and darifenacin (5 or
10 mg strength) in the same composition. The oxybutynin and
darifenacin composition is located in the core. The osmotic device
formulation contain the following ingredients in the amounts
indicated:
6 AMOUNT AMOUNT INGREDIENT (mg) (mg) Oxybutynin Strength 5 10
Darifenacin Strength 10 5 CORE Oxybutynin Hydrochloride 5.15 10.30
Darifenacin Hydrobromide 11.90 5.95 Mannitol 119.35 240.55
Anhydrous Dextrose 91.50 183.00 Povidone 8.50 17.00 Polyethylene
Glycol 400 2.00 4.00 Polyethylene Glycol 6000 4.00 8.00 Tartaric
Acid 2.60 5.20 Colloidal Silicon Dioxide 2.00 4.00 Magnesium
Stearate 3.00 6.00 COATING A Cellulose Acetate 23.35 28.85
Polyethylene Glycol 400 1.65 1.15 COATING B Opadry 1 10.00 15.00
Purified water 73.00 110.00
[0206] The core composition is prepared by mixing: oxybutynin HCl,
darifenacin HBr, povidone, mannitol, and anhydrous dextrose. The
mixture is wet with a blend of polyethylene glycol 6000 and
polyethylene glycol 400 in alcohol 96.degree.. The blend is
granulated and dried at 40-50.degree. C. for 4 hours; then, it is
screened and mixed with colloidal silicon dioxide and tartaric
acid. The blend is mixed to homogeneity magnesium stearate is
added. This final blend is tabletted using biconcave 8.0 mm
diameter punches.
[0207] A first composition to cover the cores is prepared as
follows: cellulose acetate and polyethylene glycol 400 are added to
a blend of acetone and methanol. This polymer mixture is sprayed
onto the tablets in a conventional pan coater to obtain film-coated
tablets. A 0.50 mm hole is drilled through the coating of the
tablet.
[0208] The second coating is prepared by mixing Opadry in purified
water. This polymer mixture is sprayed onto the final tablets in a
conventional pan coater to obtain film-coated tablets.
EXAMPLE 4
[0209] The procedure of Example 3 is used to prepare osmotic device
formulations containing oxybutynin (2.5, 5 and 10 mg strength) and
tolterodine L-tartrate (1 or 2 mg strength) except that the
formulations contain the following ingredients in the amounts
indicated.
7 AMOUNT AMOUNT AMOUNT AMOUNT INGREDIENT (mg) (mg) (mg) (mg)
Oxybutynin Strength 5 5 10 2.5 Tolterodine Strength 1 2 2 2 CORE
Oxybutynin 5.15 5.15 10.30 2.57 Hydrochloride Tolterodine
L-tartrate 1.46 2.92 2.92 2.92 Mannitol 85.00 85.00 170.00 169.73
Anhydrous Dextrose 178.54 177.08 355.08 355.08 Povidone 9.00 9.00
18.00 18.00 Polyethylene Glycol 5.00 5.00 10.00 10.00 4000
Polyethylene Glycol 400 2.00 2.00 4.00 4.00 Colloidal Silicon
Dioxide 1.00 1.00 2.00 2.00 Magnesium Stearate 2.85 2.85 5.70 5.70
COATING A Cellulose Acetate 23.05 23.05 30.25 21.25 Polyethylene
Glycol 400 1.95 1.95 1.75 0.75 COATING B Opadry 1 10.00 10.00 15.00
15.00 Purified water 73.00 73.00 110.00 110.00
EXAMPLE 5
[0210] The following procedure is used to prepare controlled
release matrix tablets formulations containing oxybutynin (2.5, 5
or 10 mg strength) and tolterodine L-tartrate (1 or 2 mg strength)
in the same composition.
8 AMOUNT AMOUNT AMOUNT AMOUNT INGREDIENT (mg) (mg) (mg) (mg)
Oxybutynin Strength 5 5 10 2.5 Tolterodine Strength 1 2 2 2 CORE
Oxybutynin 5.15 5.15 10.30 2.57 Hydrochloride Tolterodine
1-tartrate 1.46 2.92 2.92 2.92 Lactose DT 71.24 70.78 142.48 142.21
HPMC 2208 (4,000 cps) 106.30 106.30 212.60 212.60 Tartaric Acid
2.00 2.00 4.00 4.00 Colloidal Silicon Dioxide 1.90 1.90 3.80 3.80
Magnesium Stearate 0.95 0.95 1.90 1.90 COATING A Opadry 1 10.00
10.00 10.00 10.00 Purified water 73.00 73.00 73.00 73.00
[0211] The core composition is prepared by mixing oxybutynin HCl,
tolterodine L-tartrate, lactose DT, and HPMC 2208 for 10 minutes.
Then, the mixture is screened and mixed with colloidal silicon
dioxide and tartaric acid. The blend is mixed to homogeneity and
magnesium stearate is added. The final blend is tabletted using
biconcave 8.0 mm diameter punches.
[0212] The coating is prepared by mixing Opadry 1 in purified
water. The polymer mixture is sprayed onto the final tablets in a
conventional pan coater to obtain film-coated tablets.
EXAMPLE 6
[0213] The procedure of Example 5 is used to prepare controlled
release matrix tables formulations containing oxybutynin (5 or 10
mg strength) and darifenacin (5 or 10 mg strength) in the same
composition except that the formulations contain the following
ingredients in the amounts indicated.
9 AMOUNT AMOUNT INGREDIENT (mg) (mg) Oxybutynin Strength 5 10
Darifenacin Strength 10 5 CORE Oxybutynin Hydrochloride 5.15 10.30
Darifenacin Hydrobromide 11.90 5.95 Cellactose 84.10 170.05 HPMC
2208 (4,000) 142.50 285.00 Tartaric Acid 2.60 5.20 Colloidal
Silicon Dioxide 2.50 5.00 Magnesium Stearate 1.25 2.50 COATING A
Opadry 1 10.00 15.00 Purified water 73.00 110.00
EXAMPLE 7
Bi-Layered Controlled Release Tablet
[0214] These tablets provide a sustained delivery of oxybutynin for
at least a period of about 8 hours and a rapid delivery of
darifenacin in the colon.
10 AMOUNT AMOUNT INGREDIENT (mg) (mg) Oxybutynin Strength 5 10
Darifenacin Strength 10 5 LAYER A Oxybutynin Hydrochloride 5.15
10.30 Myvacet 5-07 10.80 10.80 Povidone K25 5.40 5.40
Microcrystalline Cellulose Spheres 68.68 63.53 Cellulose
Acetophtalate 4.10 4.10 Colloidal Silicon Dioxide 0.60 0.60
Croscarmellose Sodium 1.80 1.80 Magnesium Stearate 10.80 10.80
LAYER B Darifenacin Hydrobromide 11.90 5.95 Guar Gum 52.07 52.07
Red Iron Oxide 0.15 0.15 Microcrystalline Cellulose Spheres 68.68
74.63 Oxybutynin Strength 5 10 Darifenacin Strength 10 5 Eudragit
4.59 4.59 Colloidal Silicon Dioxide 0.60 0.60 Croscarmellose Sodium
1.80 1.80 Magnesium Stearate 10.80 10.80
[0215] The oxybutynin composition is prepared as follows. Myvacet
5-07 is dissolved along with oxybutynin HCl and PVP K 25. This
mixture is then applied onto microcrystalline cellulose spheres.
These microgranules are coated with a coat comprising cellulose
acetophtalate.
[0216] The darifenacin composition is prepared as follows. Guar gum
is dissolved in an appropriate reactor along with red iron oxide.
Darifenacin HBr is added and thoroughly mixed. This mixture is then
applied on microcrystalline cellulose spheres. Next, these
microgranules are coated with a coat comprising Eudragit L.
[0217] Both compositions are thoroughly mixed with colloidal
silicon dioxide, croscarmellose and magnesium stearate and
compressed in a suitable rotary tablet machine to make bilayer
tablets.
EXAMPLE 8
Bi-Layered Controlled Release Tablet
[0218] These tablets provide a sustained delivery of oxybutynin and
tolterodine for a period of at least about 7 hours.
11 AMOUNT AMOUNT INGREDIENT (mg) (mg) Oxybutynin Strength 5 10
Darifenacin Strength 10 5 LAYER A Oxybutynin Hydrochloride 5.15
10.30 Myvacet 5-07 10.80 10.80 Povidone K25 5.40 5.40
Microcrystalline Cellulose Spheres 68.68 63.53 Cellulose
Acetophtalate 4.10 4.10 Colloidal Silicon Dioxide 0.60 0.60
Croscarmellose Sodium 1.80 1.80 Magnesium Stearate 10.80 10.80
LAYER B Tolterodine L-tartrate 2.92 2.92 Myvaplex 600P NF 82.07
82.07 Red Iron Oxide 0.15 0.15 Microcrystalline Cellulose Spheres
67.76 67.76 Cellulose Acetophtalate 4.10 4.10 Colloidal Silicon
Dioxide 0.60 0.60 Croscarmellose Sodium 1.80 1.80 Magnesium
Stearate 0.75 0.75
[0219] The oxybutynin composition is prepared as follows. Myvacet
5-07 is dissolved along with oxybutynin HCl and PVP K 25. This
mixture is then applied onto microcrystalline cellulose spheres.
These microgranules are coated with a coat comprising cellulose
acetophtalate.
[0220] The tolterodine composition is prepared as follows. Myvaplex
600P NF is hot melted in an appropriate reactor supplied with a
heating chamber along with red iron oxide. Tolterodine L-tartrate
is added and thoroughly mixed. This mixture is then applied on
microcrystalline cellulose spheres. Next, these microgranules are
coated with a coat comprising cellulose acetophthalate.
[0221] Both compositions are thoroughly mixed with colloidal
silicon dioxide, croscarmellose and magnesium stearate and
compressed in a suitable rotary tablet machine to make bi-layered
tablets.
EXAMPLE 9
Rapid Release Tablets
[0222] These tablets release about 80% of their oxybutynin and
tolterodine charge rapidly within about 0.5 hours after
administration. These tablets maintain therapeutically effective
levels of oxybutynin and tolterodine in a mammal for a period of up
to about 3 hours after administration. This exemplary tablet
releases oxybutynin and tolterodine for a period of up to about
0.5-3.0 hours after administration.
12 AMOUNT AMOUNT INGREDIENT (mg) (mg) Oxybutynin Strength 5 10
Tolterodine Strength 2 2 Oxybutynin Hydrochloride 5.15 10.30
Tolterodine L-tartrate 2.92 2.92 Monohydrate Lactose 116.23 111.23
Microcrystalline cellulose 36.50 36.35 Povidone 5.40 5.40 Colloidal
Silicon Dioxide 1.20 1.20 Aluminum Lake Brilliant Blue 0.15 0.15
Croscarmellose Sodium 3.60 3.60 Magnesium Stearate 1.50 1.50 Sodium
Lauryl Sulfate 3.50 3.50
[0223] The tablet composition is prepared by mixing oxybutynin,
tolterodine L-tartrate, lactose, and microcrystalline cellulose.
Aluminum lake brilliant blue previously screened through a 200 mesh
is added to the mixture. Then, the blend is granulated with PVP in
960 ethanol and the final granulate is dried in a fluid bed dryer.
The granulated composition is passed through a 50 mesh and blended
with croscarmellose sodium, magnesium stearate and sodium lauryl
sulfate. The final blend is then subjected to compression on a
tabletting machine.
EXAMPLE 10
Immediate Release Tablets
[0224] The tablets of this example are made as follows. The tablets
include exemplary formulations for the different individual types
of tablets.
13 (a) Effervescent Tablets AMOUNT AMOUNT INGREDIENT (mg) (mg)
Oxybutynin Strength 5 10 Tolterodine Strength 2 2 Oxybutynin
Hydrochloride 5.15 10.30 Tolterodine L-tartrate 2.92 2.92 Sorbitol
415.00 409.85 Citric Acid 240.00 240.00 Sodium Bicarbonate 115.00
115.00 Polyethylene Glycol 6000 18.00 18.00 Orange flavor 3.48 3.48
Saccharin Sodium 0.44 0.44
[0225] Effervescent tablets containing oxybutynin and tolterodine
are prepared as follows. Oxybutynin HCl, tolterodine L-tartrate,
sorbitol, citric acid, sodium bicarbonate (dried during 2 hours at
105.degree. C.), polyethylene glycol 6000, orange flavor and
saccharin sodium are mixed. This mixture is screened and then
tabletted at a maximum 25% relative atmospheric humidity, using
biplanar 14.0-mm diameter punches.
14 (b) Chewable Tablets AMOUNT AMOUNT INGREDIENT (mg) (mg)
Oxybutynin Strength 5 10 Tolterodine Strength 2 2 Oxybutynin
Hydrochloride 5.15 10.30 Tolterodine L-tartrate 2.92 2.92
Microcrystalline Cellulose 273.39 268.24 Sorbitol 140.00 140.00
Dextrose 54.50 54.50 Poly(ethylene glycol) 6000 12.00 12.00
Colloidal Silicon Dioxide 1.50 1.50 Magnesium Stearate 4.20 4.20
Strawberry flavor 5.80 5.80 Saccharin Sodium 0.54 0.54
[0226] Chewable tablets containing oxybutynin and tolterodine are
prepared as follows. Oxybutynin HCl, tolterodine L-tartrate,
sorbitol, microcrystalline cellulose, dextrose, polyethylene glycol
6000, strawberry flavor and saccharin sodium are mixed. This
mixture is screened, and then blended with colloidal silicon
dioxide and magnesium stearate. The blend is tabletted using
biplanar 10.0-mm diameter punches.
15 (c) Very Rapidly Dissolving Tablets AMOUNT AMOUNT INGREDIENT
(mg) (mg) Oxybutynin Strength 5 10 Tolterodine Strength 2.2 2
Oxybutynin Hydrochloride 5.15 10.30 Tolterodine L-tartrate 2.92
2.92 Microcrystalline Cellulose 12.08 6.93 Sorbitol 15.40 15.40
Crospovidone 13.55 13.55 Magnesium Stearate 0.25 0.25 Orange flavor
0.60 0.60 Saccharin Sodium 0.05 0.05
[0227] Very rapidly dissolving tablets containing oxybutynin and
tolterodine are prepared as follows. Oxybutynin HCl, sorbitol,
microcrystalline cellulose, crospovidone, orange flavor and
saccharin sodium are mixed. Next, the mixture is screened and then
mixed with magnesium stearate. Finally the blend is tabletted using
biconcave 5.0-mm diameter punches.
EXAMPLE 11
Oxybutynin-Darifenacin Vaginal Cream
[0228]
16 Amount per 5 g dose Ingredient Amount Oxybutynin Hydrochloride
0.05 Darifenacin hydrobromide 0.02 Polyethylene Glycol 1000 0.09
Monocetyl Ether Cetostearyl Alcohol 0.30 Mineral Oil 0.30 White
Petrolatum 0.72 Propyl paraben 0.004 Methyl paraben 0.0075 Benzyl
Alcohol 0.075 Purified Water 3.4085
[0229] Oxybutynin HCl, darifenacin HBr, methyl and propyl paraben
and benzyl alcohol are dissolved in warm water. The polyethylene
glycol 1000, monocetyl ether cetostearyl alcohol, mineral oil and
white petrolatum are melted together on a hot water bath. The
aqueous solution is added to the molten oils and stirred until
cold.
EXAMPLE 12
Oxybutynin-Darifenacin Osmotic Device
[0230] The procedure of Example 1 is used to prepare osmotic device
formulations containing oxybutynin (5 and 10 mg strength) and
darifenacin (5 and 10 mg strength) except that the formulations
contain the following ingredients in the amounts indicated.
17 AMOUNT AMOUNT INGREDIENT (mg) (mg) Oxybutynin Strength 5 10
Darifenacin Strength 10 5 CORE LAYER A Oxybutynin Hydrochloride
5.15 10.30 Mannitol 69.00 138.00 Anhydrous Dextrose 30.00 60.00
Povidone 6.35 12.70 Polyethylene Glycol 400 1.15 2.30 Polyethylene
Glycol 6000 4.00 8.00 Tartaric Acid 2.00 4.00 Magnesium Stearate
1.35 2.70 Colloidal Silicon Dioxide 1.00 2.00 LAYER B Darifenacin
Hydrobromide 11.90 5.95 Hydroxypropylmethylcellulose 2208 (4,000)
91.20 173.28 Cellactose 53.15 117.27 Magnesium Stearate 2.50 5.00
Colloidal Silicon Dioxide 1.25 2.50 Oxybutynin Strength 5 10
Darifenacin Strength 10 5 COATING A Cellulose Acetate 18.50 33.75
Polyethylene Glycol 400 1.50 1.25 COATING B
Hydroxypropylmethylcellulose 2910 3.70 5.55 Copolyvidone 3.00 1.58
Polyethylene Glycol 6000 1.05 4.50 Titanium Dioxide 2.25 3.37
[0231] Those of skill in the art should, in light of the present
disclosure, appreciate that many changes can be made in the
specific embodiments that are disclosed herein and still obtain a
like or similar result without departing from the spirit and scope
of the invention. All of the compositions and methods disclosed and
claimed herein can be made and executed without undue
experimentation in light of the present disclosure.
* * * * *