U.S. patent application number 10/371429 was filed with the patent office on 2003-08-21 for transdermal administration of oxybutynin using hydroxide-releasing agents as permeation enhancers.
Invention is credited to Hsu, Tsung-Min, Luo, Eric C..
Application Number | 20030157156 10/371429 |
Document ID | / |
Family ID | 27739188 |
Filed Date | 2003-08-21 |
United States Patent
Application |
20030157156 |
Kind Code |
A1 |
Hsu, Tsung-Min ; et
al. |
August 21, 2003 |
Transdermal administration of oxybutynin using hydroxide-releasing
agents as permeation enhancers
Abstract
A method is provided for increasing the permeability of skin or
mucosal tissue to transdermally administered oxybutynin. The method
involves use of a specified amount of a hydroxide-releasing agent,
the amount optimized to increase the flux of the drug through a
body surface while minimizing the likelihood of skin damage,
irritation or sensitization. Formulations, drug delivery systems
and methods of treatment are provided as well.
Inventors: |
Hsu, Tsung-Min; (San Diego,
CA) ; Luo, Eric C.; (Plano, TX) |
Correspondence
Address: |
REED & EBERLE LLP
800 MENLO AVENUE, SUITE 210
MENLO PARK
CA
94025
US
|
Family ID: |
27739188 |
Appl. No.: |
10/371429 |
Filed: |
February 20, 2003 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10371429 |
Feb 20, 2003 |
|
|
|
09737828 |
Dec 14, 2000 |
|
|
|
6562368 |
|
|
|
|
09737828 |
Dec 14, 2000 |
|
|
|
09569889 |
May 11, 2000 |
|
|
|
09569889 |
May 11, 2000 |
|
|
|
09465098 |
Dec 16, 1999 |
|
|
|
Current U.S.
Class: |
424/449 ;
514/540 |
Current CPC
Class: |
Y10S 514/946 20130101;
A61K 9/7023 20130101; A61K 31/137 20130101; Y10S 514/944 20130101;
A61K 9/7053 20130101; A61K 47/02 20130101; A61K 9/0014 20130101;
Y10S 514/947 20130101 |
Class at
Publication: |
424/449 ;
514/540 |
International
Class: |
A61K 009/70; A61K
031/24 |
Claims
We claim:
1. A composition of matter useful for the delivery of oxybutynin
through a body surface, comprising: (a) a therapeutically
acceptable amount of oxybutynin; (b) a hydroxide-releasing agent in
an amount effective to enhance the flux of oxybutynin through the
body surface without causing damage thereto and effective to
provide a pH in the range of approximately 8.0 to 13 at the body
surface during oxybutynin administration; and wherein the amount of
hydroxide-releasing agent in the composition is the total of (a)
the amount required to neutralize any acidic species in the
composition plus (b) an amount equal to approximately 0.5 wt % to
25.0 wt % of the composition; and (c) a pharmaceutically acceptable
carrier suitable for topical or transdermal drug
administration.
2. The composition of claim 1, wherein the pH is within the range
of approximately 8.0 to 11.5.
3. The composition of claim 2, wherein the pH is within the range
of approximately 8.5 to 11.5.
4. The composition of claim 1, wherein the composition is
substantially free of organic solvents.
5. The composition of claim 1, wherein the hydroxide-releasing
agent is selected from the group consisting of inorganic
hydroxides, inorganic oxides, metal salts of weak acids, and
mixtures thereof.
6. The composition of claim 5, wherein the hydroxide-releasing
agent is an inorganic hydroxide.
7. The composition of claim 6, wherein the inorganic hydroxide is
selected from the group consisting of ammonium hydroxide, alkali
metal hydroxides, alkaline earth metal hydroxides, and mixtures
thereof.
8. The composition of claim 7, wherein the inorganic hydroxide is
selected from the group consisting of ammonium hydroxide, sodium
hydroxide, calcium hydroxide, potassium hydroxide, magnesium
hydroxide, and mixtures thereof.
9. The composition of claim 8, wherein the inorganic hydroxide is
sodium hydroxide.
10. The composition of claim 8, wherein the inorganic hydroxide is
potassium hydroxide.
11. The composition of claim 6, wherein the amount of inorganic
hydroxide in the composition is the total of (a) the amount
required to neutralize any acidic species in the composition plus
(b) an amount equal to approximately 0.5 wt % to 4.0 wt % of the
composition.
12. The composition of claim 11, wherein the amount of inorganic
hydroxide in the composition is the total of (a) the amount
required to neutralize any acidic species in the composition plus
(b) an amount equal to approximately 0.5 wt % to 3.0 wt % of the
composition.
13. The composition of claim 12, wherein the amount of inorganic
hydroxide in the composition is the total of (a) the amount
required to neutralize any acidic species in the composition plus
(b) an amount equal to approximately 0.75 wt % to 2.0 wt % of the
composition.
14. The composition of claim 5, wherein the hydroxide-releasing
agent is an inorganic oxide.
15. The composition of claim 14, wherein the inorganic oxide is
selected from the group consisting of magnesium oxide, calcium
oxide and mixtures thereof.
16. The composition of claim 14, which contains up to approximately
20 wt % of the hydroxide-releasing agent.
17. The composition of claim 5, wherein the hydroxide-releasing
agent is a metal salt of a weak acid.
18. The composition of claim 17, wherein the hydroxide-releasing
agent is selected from the group consisting of sodium acetate,
sodium borate, sodium metaborate, sodium carbonate, sodium
bicarbonate, tribasic sodium phosphate, dibasic sodium phosphate,
potassium carbonate, potassium bicarbonate, potassium citrate,
potassium acetate, dibasic potassium phosphate, tribasic potassium
phosphate, dibasic ammonium phosphate, and mixtures thereof.
19. The composition of claim 17, which contains up to approximately
20 wt % of the hydroxide-releasing agent.
20. The composition of claim 1, which is an aqueous
formulation.
21. The composition of claim 20, wherein the formulation is
selected from the group consisting of a cream, a gel, a lotion, and
a paste.
22. The composition of claim 21, wherein the formulation is a
cream.
23. The composition of claim 21, wherein the formulation is a
gel.
24. The composition of claim 1, which is a nonaqueous
formulation.
25. The composition of claim 24, wherein the formulation is an
ointment.
26. The composition of claim 1, wherein the oxybutynin is in the
form of an acid addition salt, and the amount in (a) is the amount
required to neutralize the acid addition salt and other acidic
species in the composition.
27. The composition of claim 1, wherein the oxybutynin is in the
form of the free base.
28. The composition of claim 1, wherein the oxybutynin is in the
form of an acid addition salt.
29. The composition of claim 28, wherein the acid addition salt is
oxybutynin hydrochloride.
30. The composition of claim 1, wherein the oxybutynin is present
as a racemate.
31. The composition of claim 1, wherein the oxybutynin is present
as substantially pure (R)-oxybutynin.
32. The composition of claim 1, wherein the oxybutynin is present
as substantially pure (S)-oxybutynin.
33. A system for the transdermal administration of oxybutynin,
comprising: (a) at least one reservoir containing oxybutynin and a
hydroxide-releasing agent in an amount effective to enhance the
flux of oxybutynin through the body surface of a human patient
without causing damage thereto and effective to provide a pH in the
range of approximately 8.0 to 13 at the body surface during
oxybutynin administration; and wherein the amount of
hydroxide-releasing agent in the reservoir is the total of (a) the
amount required to neutralize any acidic species in the reservoir
plus (b) an amount equal to approximately 0.5 wt % to 25.0 wt % of
the reservoir; (b) a means for maintaining the system in drug and
enhancer transmitting relationship to the body surface; and (c) a
backing layer that serves as the outer surface of the system during
use.
34. The system of claim 33, wherein the pH is within the range of
approximately 8.0 to 11.5.
35. The system of claim 34, wherein the pH is within the range of
approximately 8.5 to 11.5.
36. The system of claim 33, wherein the hydroxide-releasing agent
is selected from the group consisting of inorganic hydroxides,
inorganic oxides, metal salts of weak acids, and mixtures
thereof.
37. The system of claim 36, wherein the hydroxide-releasing agent
is an inorganic hydroxide.
38. The system of claim 37, wherein the inorganic hydroxide is
selected from the group consisting of ammonium hydroxide, alkali
metal hydroxides, alkaline earth metal hydroxides, and mixtures
thereof.
39. The system of claim 38, wherein the inorganic hydroxide is
selected from the group consisting of ammonium hydroxide, sodium
hydroxide, calcium hydroxide, potassium hydroxide, magnesium
hydroxide, and mixtures thereof.
40. The system of claim 39, wherein the inorganic hydroxide is
sodium hydroxide.
41. The system of claim 39, wherein the inorganic hydroxide is
potassium hydroxide.
42. The system of claim 37, wherein the amount of inorganic
hydroxide in the reservoir is the total of (a) the amount required
to neutralize any acidic species in the reservoir plus (b) an
amount equal to approximately 0.5 wt % to 4.0 wt % of the
reservoir.
43. The system of claim 42, wherein the amount of inorganic
hydroxide in the reservoir is the total of (a) the amount required
to neutralize any acidic species in the reservoir plus (b) an
amount equal to approximately 0.5 wt % to 3.0 wt % of the
reservoir.
44. The system of claim 43, wherein the amount of inorganic
hydroxide in the reservoir is the total of (a) the amount required
to neutralize any acidic species in the reservoir plus (b) an
amount equal to approximately 0.75 wt % to 2.0 wt % of the
reservoir.
45. The system of claim 36, wherein the hydroxide-releasing agent
is an inorganic oxide.
46. The system of claim 45, wherein the inorganic oxide is selected
from the group consisting of magnesium oxide, calcium oxide and
mixtures thereof.
47. The system of claim 45, which contains up to approximately 20
wt % of the hydroxide-releasing agent.
48. The system of claim 36, wherein the hydroxide-releasing agent
is a metal salt of a weak acid.
49. The system of claim 48, wherein the hydroxide-releasing agent
is selected from the group consisting of sodium acetate, sodium
borate, sodium metaborate, sodium carbonate, sodium bicarbonate,
tribasic sodium phosphate, dibasic sodium phosphate, potassium
carbonate, potassium bicarbonate, potassium citrate, potassium
acetate, dibasic potassium phosphate, tribasic potassium phosphate,
dibasic ammonium phosphate, and mixtures thereof.
50. The system of claim 48, which contains up to approximately 20
wt % of the hydroxide-releasing agent.
51. The system of claim 33, wherein the backing layer is
occlusive.
52. The system of claim 33, wherein the reservoir is comprised of a
polymeric adhesive.
53. The system of claim 52, wherein the polymeric adhesive serves
as the means for maintaining the system in drug and enhancer
transmitting relationship to the body surface.
54. The system of claim 33, wherein the reservoir is comprised of a
hydrogel.
55. The system of claim 33, wherein the reservoir is comprised of a
sealed pouch containing the drug and hydroxide-releasing agent in a
liquid or semi-solid formulation.
56. The system of claim 33, wherein the oxybutynin is in the form
of an acid addition salt, and the amount in (a) is the amount
required to neutralize the acid addition salt and other acidic
species in the reservoir.
57. The system of claim 33, wherein the oxybutynin is in the form
of the free base.
58. The system of claim 33, wherein the oxybutynin is in the form
of an acid addition salt.
59. The system of claim 58, wherein the acid addition salt is
oxybutynin hydrochloride.
60. The system of claim 33, wherein the oxybutynin is present as a
racemate.
61. The system of claim 33, wherein the oxybutynin is present as
substantially pure (R)-oxybutynin.
62. The system of claim 33, wherein the oxybutynin is present as
substantially pure (S)-oxybutynin.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a divisional of U.S. Ser. No. 09/737,828, filed Dec.
14, 2000; which is a continuation-in-part of U.S. Ser. No.
09/569,889, filed May 11, 2000, now abandoned; which is a
continuation-in part of U.S. Ser. No. 09/465,098, filed Dec. 16,
1999, now abandoned; the disclosures of which are incorporated by
reference.
TECHNICAL FIELD
[0002] This invention relates generally to transdermal
administration of pharmacologically active agents, and more
particularly relates to methods and compositions for transdermally
administering oxybutynin.
BACKGROUND
[0003] The delivery of drugs through the skin provides many
advantages; primarily, such a means of delivery is a comfortable,
convenient and noninvasive way of administering drugs. The variable
rates of absorption and metabolism encountered in oral treatment
are avoided, and other inherent inconveniences, e.g.,
gastrointestinal irritation and the like, are eliminated as well.
Transdermal drug delivery also makes possible a high degree of
control over blood concentrations of any particular drug.
[0004] Skin is a structurally complex, relatively thick membrane.
Molecules moving from the environment into and through intact skin
must first penetrate the stratum corneum and any material on its
surface. They must then penetrate the viable epidermis, the
papillary dermis, and the capillary walls into the blood stream or
lymph channels. To be so absorbed, molecules must overcome a
different resistance to penetration in each type of tissue.
Transport across the skin membrane is thus a complex phenomenon.
However, it is the cells of the stratum corneum which present the
primary barrier to absorption of topical compositions or
transdermally administered drugs. The stratum corneum is a thin
layer of dense, highly keratinized cells approximately 10-15
microns thick over most of the body. It is believed to be the high
degree of keratinization within these cells as well as their dense
packing which creates in most cases a substantially impermeable
barrier to drug penetration. With many drugs, the rate of
permeation through the skin is extremely low.
[0005] In order to increase the rate at which a drug penetrates
through the skin, then, various approaches have been followed, each
of which involves the use of either a chemical penetration enhancer
or a physical penetration enhancer. Physical enhancement of skin
permeation include, for example, electrophoretic techniques such as
iontophoresis. The use of ultrasound (or "phonophoresis") as a
physical penetration enhancer has also been researched. Chemical
enhancers are compounds that are administered along with the drug
(or in some cases the skin may be pretreated with a chemical
enhancer) in order to increase the permeability of the stratum
corneum, and thereby provide for enhanced penetration of the drug
through the skin. Ideally, such chemical penetration enhancers (or
"permeation enhancers," as the compounds are referred to herein)
are compounds that are innocuous and serve merely to facilitate
diffusion of the drug through the stratum corneum.
[0006] Nevertheless, the number of drugs that can be safely and
effectively administered through the skin, without concomitant
problems such as irritation and sensitization, remains limited.
[0007] The present invention is directed to the transdermal
administration of 4-diethylamino-2-butynyl
phenylcyclohexlglycolate, or "oxybutynin." Preparation of the drug
in racemic form is described in U.K. Patent No. 940,540. Oxybutynin
is classified as an anticholinergic antispasmodic drug and is
commonly used in treating individuals suffering from an overactive
bladder, e.g., neurogenic bladder. See, for example, U.S. Pat. No.
5,674,895 to Guittard et al.
[0008] Oxybutynin has the molecular structure (I) 1
[0009] and, as may be seen, contains a chiral center. Thus,
oxybutynin exists as two different isomers, as follows: 2
[0010] Isomer (Ia) represents the enantiomer of oxybutynin having
the S absolute stereochemistry and exhibits dextrorotatory
properties. Isomer (Ib) represents the enantiomer of oxybutynin
having the R absolute stereochemistry and exhibits levorotatory
properties. Commercially available preparations contain racemic
oxybutynin in the form of the hydrochloride salt. The amount of
oxybutynin in these preparations ranges from 5 mg to 30 mg per unit
dose.
[0011] Current formulations of oxybutynin are administered orally,
in tablet or syrup form. Conventional tablets are available that
are generally taken two to three times daily. In addition, extended
release tablets are also commercially available for once daily
dosing. The present invention, however, is directed to the
transdermal administration of oxybutynin. There are a number of
advantages to administering oxybutynin transdermally: continuous
delivery provides for sustained blood levels of the drug, there is
no first-pass effect; side effects typically associated with oral
administration may be avoided; continuous delivery provides for
sustained blood levels; the transdermal patch is easily removable
if any side effects do occur; and the likelihood of both patient
acceptance and patient compliance is significantly improved.
[0012] Transdermal administration of oxybutynin has been proposed.
U.S. Pat. No. 5,614,211 to Gale et al. describes a device for
transdermally administering oxybutynin, the device comprising a
special layer that eliminates blooming and delamination between the
contact adhesive and drug reservoir due to migration of surfactant
into other layers of the device. U.S. Pat. No. 5,500,222 to Lee et
al. also describes transdermal administration of oxybutynin. In the
aforementioned patent, however, a dual permeation enhancer mixture
comprising lauryl acetate and a monoglyceride is required for
sufficient flux of oxybutynin through the skin. U.S. Pat. No.
5,532,278 to Aberg et al. describes methods and compositions for
treating urinary incontinence using optically pure (S)-oxybutynin.
Although transdermal administration of (S)-oxybutynin is discussed,
the patent describes transdermal systems that include only
conventional permeation enhancers. Furthermore, U.S. Pat. No.
6,123,961 Aberg describes transdermal administration of
(R)-oxybutynin. Permeations enhancers, however, are not mentioned.
As will also be appreciated, conversion of the salt forms of
oxybutynin, e.g., oxybutynin hydrochloride, is typically necessary
before incorporation into a transdermal drug delivery system, since
the acid addition salt exhibits even lower skin flux than the free
base. See, for example, U.S. Pat. No. 5,614,211 to Gale et al.
[0013] Accordingly, there is a need in the art for a way to
transdermally administer oxybutynin without being limited by the
drug's low skin flux.
[0014] As indicated above, various compounds for enhancing the
permeability of skin are known in the art and described in the
pertinent texts and literature. Compounds that have been used to
enhance skin permeability include: sulfoxides such as
dimethylsulfoxide (DMSO) and decylmethylsulfoxide (C.sub.10MSO);
ethers such as diethylene glycol monoethyl ether (available
commercially as Transcutol.RTM.) and diethylene glycol monomethyl
ether; surfactants such as sodium laurate, sodium lauryl sulfate,
cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer
(231, 182, 184), Tween (20, 40, 60, 80) and lecithin (U.S. Pat. No.
4,783,450); the 1-substituted azacycloheptan-2-ones, particularly
1-n-dodecylcyclazacycloheptan-2-one (available under the trademark
Azone.RTM. from Nelson Research & Development Co., Irvine,
Calif.; see U.S. Pat. Nos. 3,989,816, 4,316,893, 4,405,616 and
4,557,934); alcohols such as ethanol, propanol, octanol, benzyl
alcohol, and the like; fatty acids such as lauric acid, oleic acid
and valeric acid; fatty acid esters such as isopropyl myristate,
isopropyl palmitate, methylpropionate, and ethyl oleate; polyols
and esters thereof such as propylene glycol, ethylene glycol,
glycerol, butanediol, polyethylene glycol, and polyethylene glycol
monolaurate (PEGML; see, e.g., U.S. Pat. No. 4,568,343); amides and
other nitrogenous compounds such as urea, dimethylacetamide (DMA),
dimethylformamide (DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone,
ethanolamine, diethanolamine and triethanolamine; terpenes;
alkanones; organic acids, particularly salicylic acid and
salicylates, citric acid and succinic acid; and certain peptides,
e.g., peptides having Pro-Leu at the N-terminus and followed by a
protective group (see U.S. Pat. No. 5,534,496). Percutaneous
Penetration Enhancers, eds. Smith et al. (CRC Press, 1995) provides
an excellent overview of the field and further background
information on a number of chemical and physical enhancers.
[0015] Although many chemical permeation enhancers are known, there
is an ongoing need for enhancers that are highly effective in
increasing the rate at which a drug permeates the skin, do not
result in skin damage, irritation, sensitization, or the like, and
also allows neutralization of an acid addition salt such as
oxybutynin hydrochloride during, rather than prior to, patch
manufacture. It has now been discovered that hydroxide-releasing
agents are highly effective permeation enhancers, even when used
without co-enhancers, and provide all of the aforementioned
advantages relative to known permeation enhancers. Furthermore, in
contrast to conventional enhancers, transdermal administration of
drugs such as oxybutynin with hydroxide-releasing agents as
permeation enhancers, employed at the appropriate levels, does not
result in systemic toxicity.
SUMMARY OF THE INVENTION
[0016] It is thus a primary object of the invention to address the
above-described need in the art by providing a method for
transdermally administering oxybutynin in neutral, uncharged
form.
[0017] It is another object of the invention to provide a method
for treating conditions, disorders or diseases that are responsive
to administration of oxybutynin by transdermally administering
oxybutynin to a patient in need of such therapy.
[0018] It is another object of the invention to provide such a
method wherein a hydroxide-releasing agent is employed as a
permeation enhancer to increase the flux of oxybutynin through a
patient's skin or mucosal tissue.
[0019] It is still another object of the invention to provide such
a method wherein the amount of hydroxide-releasing agent employed
is optimized to enhance permeation while minimizing or eliminating
the possibility of skin damage, irritation or sensitization.
[0020] It is an additional object of the invention to provide
formulations and drug delivery systems for carrying out the
aforementioned methods.
[0021] Additional objects, advantages and novel features of the
invention will be set forth in part in the description that
follows, and in part will become apparent to those skilled in the
art upon examination of the following, or may be learned by
practice of the invention.
[0022] In one aspect of the invention, then, a method is provided
for increasing the rate at which oxybutynin permeates through the
body surface of a patient. The method involves administering the
drug to a predetermined area of the patient's body surface in
combination with a hydroxide-releasing agent in a predetermined
amount effective to enhance the flux of the agent through the body
surface without causing damage thereto. The predetermined amount of
the hydroxide-releasing enhancer is preferably an amount effective
to provide a pH at the body surface in the range of about 8.0 to
13, preferably about 8.0 to 11.5, more preferably about 8.5 to
11.5, during drug administration. If a skin patch is used, this is
the preferred pH at the interface between the basal surface of the
patch (i.e., the skin-contacting or mucosal-contacting surface of
the patch) and the body surface. The optimal amount (or
concentration) of any one hydroxide-releasing agent will, however,
depend on the specific hydroxide-releasing agent, i.e., on the
strength or weakness of the base, its molecular weight, and other
factors as will be appreciated by those of ordinary skill in the
art of transdermal drug delivery. This optimal amount may be
determined using routine experimentation to ensure that the pH at
the body surface is within the aforementioned ranges, i.e., in the
range of about 8.0 to 13, preferably about 8.0 to 11.5, more
preferably about 8.5 to 11.5. A conventional transdermal drug
delivery device or "patch" may be used to administer the active
agent, in which case the drug and hydroxide-releasing agent are
generally present in a drug reservoir or reservoirs. However, the
drug and hydroxide-releasing agent may also be administered to the
body surface using a liquid or semisolid formulation.
Alternatively, or in addition, the body surface may be pretreated
with the enhancer, e.g., treated with a dilute solution of the
hydroxide-releasing agent prior to transdermal drug administration.
Such a solution will generally be comprised of a protic solvent
(e.g., water or alcohol) and have a pH in the range of about 8.0 to
13, preferably about 8.0 to 11.5, and more preferably about 8.5 to
11.5.
[0023] The oxybutynin may be present in racemic form or in the form
of an individual isomer. Transdermal administration of oxybutynin
as provided herein is useful in treating patients suffering from
urinary urgency, urinary frequency, urinary leakage, incontinence,
and painful or difficult urination caused by neurogenic
bladder.
[0024] In a related aspect of the invention, a composition of
matter is provided for delivering oxybutynin through a body surface
using a hydroxide-releasing agent as a permeation enhancer.
Generally, the formulation comprises (a) a therapeutically
effective amount of oxybutynin, (b) a hydroxide-releasing agent in
an amount effective to enhance the flux of the oxybutynin through
the body surface without causing damage thereto, and (c) a
pharmaceutically acceptable carrier suitable for transdermal drug
administration. The composition may be in any form suitable for
application to the body surface, and may comprise, for example, a
cream, lotion, solution, gel, ointment, paste or the like, and/or
may be prepared so as to contain liposomes, micelles, and/or
microspheres. The composition may be directly applied to the body
surface or may involve use of a drug delivery device. In either
case, it is preferred although not essential that water be present
in order for the hydroxide-releasing agent to generate hydroxide
ions and thus enhance the flux of the active agent through the
patient's body surface. Thus, a formulation or drug reservoir may
be aqueous, i.e., contain water, or may be nonaqueous and used in
combination with an occlusive overlayer so that moisture
evaporating from the body surface is maintained within the
formulation or transdermal system during drug administration.
[0025] In another aspect of the invention, a drug delivery system
is provided for the transdermal administration of oxybutynin using
a hydroxide-releasing agent as a permeation enhancer. The system
will generally comprise: at least one drug reservoir containing
oxybutynin and the hydroxide-releasing agent in an amount effective
to enhance the flux of the drug through the body surface without
causing damage thereto; a means for maintaining the system in drug
and enhancer transmitting relationship to the body surface; and a
backing layer that serves as the outer surface of the device during
use. The backing layer may be occlusive or nonocclusive, although
it is preferably occlusive. The drug reservoir may be comprised of
a polymeric adhesive, which may serve as the basal surface of the
system during use and thus function as the means for maintaining
the system in drug and enhancer transmitting relationship to the
body surface. The drug reservoir may also be comprised of a
hydrogel, or it may be a sealed pouch within a "patch"-type
structure wherein the drug and hydroxide-releasing agent are
present in the pouch as a liquid or semi-solid formulation. In some
cases, however, e.g., with an occlusive gel, a nonaqueous
formulation may be used with or without an occlusive overlayer.
DETAILED DESCRIPTION OF THE INVENTION
[0026] Definitions and Overview
[0027] Before describing the present invention in detail, it is to
be understood that this invention is not limited to specific drug
delivery systems, device structures, enhancers or carriers, as such
may vary. It is also to be understood that the terminology used
herein is for the purpose of describing particular embodiments
only, and is not intended to be limiting.
[0028] It must be noted that, as used in this specification and the
appended claims, the singular forms "a," "an" and "the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to "a hydroxide-releasing agent"
includes mixtures of two or more hydroxide-releasing agents, and
the like.
[0029] In describing and claiming the present invention, the
following terminology will be used in accordance with the
definitions set out below.
[0030] The terms "drug" or "pharmacologically active agent" or
"active agent" as used herein refer to a compound or composition of
matter which, when administered to an organism (human or animal)
induces a desired pharmacologic and/or physiologic effect by local
and/or systemic action. Also included are derivatives and analogs
of those compounds or classes of compounds specifically mentioned
which also induce the desired effect. The primary active agent
herein is oxybutynin.
[0031] The terms "treating" and "treatment" as used herein refer to
reduction in severity and/or frequency of symptoms, elimination of
symptoms and/or underlying cause, prevention of the occurrence of
symptoms and/or their underlying cause, and improvement or
remediation of damage. The present method of "treating" a patient,
as the term is used herein, thus encompasses both prevention of a
disorder in a predisposed individual and treatment of the disorder
in a clinically symptomatic individual.
[0032] The term "hydroxide-releasing agent" as used herein is
intended to mean an agent that releases free hydroxide ions in an
aqueous environment. The agent may contain hydroxide ions and thus
release the ions directly (e.g., an alkali metal hydroxide), or the
agent may be one that is acted upon chemically in an aqueous
environment to generate hydroxide ions (e.g., a metal
carbonate).
[0033] By "therapeutically effective" amount is meant a nontoxic
but sufficient amount of an active agent to provide the desired
therapeutic effect.
[0034] By "transdermal" drug delivery is meant administration of a
drug to the skin surface of an individual so that the drug passes
through the skin tissue and into the individual's blood stream,
thereby providing a systemic effect. The term "transdermal" is
intended to include "transmucosal" drug administration, i.e.,
administration of a drug to the mucosal (e.g., sublingual, buccal,
vaginal, rectal) surface of an individual so that the drug passes
through the mucosal tissue and into the individual's blood
stream.
[0035] The term "topical administration" is used in its
conventional sense to mean delivery of a topical drug or
pharmacologically active agent to the skin or mucosa, as in, for
example, the treatment of various skin disorders. Topical
administration, in contrast to transdermal administration, provides
a local rather than a systemic effect. Unless otherwise stated or
implied, the terms "topical drug administration" and "transdermal
drug administration" are used interchangeably.
[0036] The term "body surface" is used to refer to skin or mucosal
tissue.
[0037] By "predetermined area" of skin or mucosal tissue, which
refers to the area of skin or mucosal tissue through which a
drug-enhancer formulation is delivered, is intended a defined area
of intact unbroken living skin or mucosal tissue. That area will
usually be in the range of about 5 cm.sup.2 to about 200 cm.sup.2,
more usually in the range of about 5 cm.sup.2 to about 100
cm.sup.2, preferably in the range of about 20 cm.sup.2 to about 60
cm.sup.2. However, it will be appreciated by those skilled in the
art of drug delivery that the area of skin or mucosal tissue
through which drug is administered may vary significantly,
depending on patch configuration, dose, and the like.
[0038] "Penetration enhancement" or "permeation enhancement" as
used herein relates to an increase in the permeability of the skin
or mucosal tissue to the selected pharmacologically active agent,
i.e., so that the rate at which the agent permeates therethrough
(i.e., the "flux" of the agent through the body surface) is
increased relative to the rate that would be obtained in the
absence of permeation enhancement. The enhanced permeation effected
through the use of such enhancers can be observed by measuring the
rate of diffusion of drug through animal or human skin using, for
example a Franz diffusion apparatus as known in the art.
[0039] An "effective" amount of a permeation enhancer is meant a
nontoxic, nondamaging but sufficient amount of the enhancer to
provide the desired increase in skin permeability and,
correspondingly, the desired depth of penetration, rate of
administration, and amount of drug delivered.
[0040] "Carriers" or "vehicles" as used herein refer to carrier
materials suitable for transdermal drug administration. Carriers
and vehicles useful herein include any such materials known in the
art which are nontoxic and does not interact with other components
of the composition in a deleterious manner.
[0041] The term "aqueous" refers to a formulation or drug delivery
system that contains water or that becomes water-containing
following application to the skin or mucosal tissue.
[0042] The term "racemic oxybutynin" as used herein refers to a
mixture of the two isomers of oxybutynin, i.e., d-oxybutynin and
1-oxybutynin. Oxybutynin is generally although not necessarily
administered in uncharged (electronically neutral) form, wherein
the amine group of the molecule exists in free base form, i.e.,
containing an uncharged diethylamino group.
[0043] Accordingly, the invention pertains to a method, composition
and drug delivery system for increasing the rate at which
oxybutynin permeates through the body surface of a patient, wherein
the method involves administering the agent to a predetermined area
of the patient's body surface in combination with a
hydroxide-releasing agent in an amount effective to enhance the
flux of the agent through the body surface without causing damage
thereto.
[0044] The Hydroxide-Releasing Agent
[0045] The "hydroxide-releasing agent" is a chemical compound that
releases free hydroxide ions in the presence of an aqueous fluid.
The aqueous fluid may be natural moisture at the skin surface, or a
patch or composition that is used may contain added water, and/or
be used in connection with an occlusive backing. Similarly, any
liquid or semisolid formulation that is used is preferably aqueous
or used in conjunction with an overlayer of an occlusive
material.
[0046] Any hydroxide-releasing agent may be used provided that the
compound releases free hydroxide ions in the presence of an aqueous
fluid. Examples of suitable hydroxide-releasing agents include, but
are not limited to, inorganic hydroxides, inorganic oxides, and
alkali metal or alkaline earth metal salts of weak acids. Inorganic
hydroxides include, for example, ammonium hydroxide, alkali metal
hydroxide and alkaline earth metal hydroxides, such as sodium
hydroxide, calcium hydroxide, potassium hydroxide, magnesium
hydroxide, and the like. Inorganic oxides include, for example,
magnesium oxide, calcium oxide, and the like. Metal salts of weak
acids include, for example, sodium acetate, sodium borate, sodium
metaborate, sodium carbonate, sodium bicarbonate, sodium phosphate
(tribasic), sodium phosphate (dibasic), potassium carbonate,
potassium bicarbonate, potassium citrate, potassium acetate,
potassium phosphate (dibasic), potassium phosphate (tribasic),
ammonium phosphate (dibasic), and the like. Preferred
hydroxide-releasing agents are metal hydroxides such as sodium
hydroxide and potassium hydroxide.
[0047] It is important that the amount of hydroxide-releasing agent
in any patch or formulation is optimized so as to increase the flux
of oxybutynin through the body surface while minimizing any
possibility of skin damage. In general, this means that the pH at
the body surface in contact with a formulation or drug delivery
system of the invention (i.e., the interface between the body
surface and the formulation or delivery system) should be in the
range of approximately 8.0 to 13, preferably about 8.0 to 11.5,
more preferably about 8.5 to 11.5. This will typically although not
necessarily mean that the pH of the formulation or the drug
composition contained within a delivery system will be in the range
of approximately 8.0 to 13, preferably about 8.0 to 11.5, more
preferably about 8.5 to 11.5.
[0048] For inorganic hydroxides, the amount of hydroxide-releasing
agent will typically represent about 0.5 wt % to 4.0 wt %,
preferably about 0.5 wt % to 3.0 wt %, more preferably about 0.75
wt % to 2.0 wt % and optimally about 1.0 wt %, of a topically
applied formulation or of a drug reservoir of a drug delivery
system, or "patch." The aforementioned amount applies to
formulations and patches in which oxybutynin is (1) in uncharged,
free base form, and where (2) there are no additional species in
the formulation or patch that could react with or be neutralized by
the inorganic hydroxide. For formulations when oxybutynin is
present in the form of an acid addition salt, e.g., oxybutynin
hydrochloride and/or wherein there are additional species in the
formulations or systems that can be neutralized by or react with
the hydroxide-releasing agent (i.e., acidic inactive ingredients),
the amount of the inorganic hydroxide will be the total of (1) the
amount necessary to neutralize or react with the drug and/or other
base-neutralizable species, plus (2) about 0.5 wt % to 4.0 wt %,
preferably about 0.5 wt % to 3.0 wt %, more preferably about 0.75
wt % to 2.0 wt % and optimally about 1.0 wt %, of the formulation
or drug reservoir to enhance the flux of the drug through the skin
or mucosal tissue. For patches, the aforementioned percentages are
given relative to the total dry weight of the formulation
components and the adhesive, gel or liquid reservoir.
[0049] For other hydroxide-releasing agents such as inorganic
oxides and metal salts of weak acids, the amount of
hydroxide-releasing agent in the formulation or drug delivery
system may be substantially higher, as high as about 20 wt %, in
some cases as high as about 25 wt % or higher, but will generally
be in the range of about 2 wt % to about 20 wt %.
[0050] Still greater amounts of hydroxide-releasing agent may be
used by controlling the rate and/or quantity of release of the
hydroxide-releasing agent preferably during the drug delivery
period itself.
[0051] However, for all hydroxide-releasing agents herein, the
optimum amount of any particular agent will depend on the strength
or weakness of the base, the molecular weight of the base, and
other factors such as any other acidic species in the formulation
or patch. One skilled in the art may readily determine the optimum
amount for any particular agent by ensuring that a formulation or
drug delivery system should in all cases be effective to provide a
pH at the skin surface in the range of about 8.0 to 13, preferably
in the range of about 8.0 to 11.5, more preferably in the range of
about 8.5 to 11.5, during application to reach the desired pH at
the body surface. This in turn ensures that the degree of
enhancement is optimized while the possibility of damage to the
body surface is eliminated or at least substantially minimized.
[0052] The Active Agent
[0053] The active agent administered is oxybutynin in the form of a
racemate or a single isomer. Although disagreement exists
concerning which isomer possesses greater pharmacologic activity,
several studies indicate that the activity of the racemate resides
predominantly in the R enantiomer. See Noronha-Blob (1990) J.
Pharmacol. Exp. Ther. 256(2):562-567 and Goldenberg (1999) Clin.
Ther. 21(4):634-642.
[0054] As previously stated, U.K. Patent No. 940,540 describes the
preparation of racemic oxybutynin. Synthesis of (S)-oxybutynin is
also known. For example, the S enantiomer may be obtained by
resolution of the intermediate mandelic acid followed by
esterification. See Kachur et al. (1988) J. Pharmacol. Exp. Ther.
247(3):867-72. The R enantiomer may obtained by first preparing
4-diethylamino-2-butynyl chloride from dichlorobutyne followed by
reacting the single R enantiomer of cyclohexylphenylglycolic acid
with the prepared 4-diethylamino-2-butynyl chloride to yield the R
enantiomer of 4-diethylamino-2-butynyl phenylcyclohexlglycolate,
i.e., (R)-oxybutynin. See U.S. Pat. No. 6,123,961 to Aberg.
Alternatively, the individual isomers may be isolated from a
racemic mixture of oxybutynin using techniques known in the art
such as chromatography-based methods that use a chiral
substrate.
[0055] When an individual enantiomer of oxybutynin is used in
accordance with the invention, the enantiomer is in substantially
pure form, i.e., at least 90%, more preferably 97%, and most
preferably 99% of the total amount (based on weight) of oxybutynin
is present as the enantiomer. Thus, for example, drug delivery
systems containing substantially pure (R)-oxybutynin will have at
least 90%, more preferably 97%, and most preferably 99% of the
total amount of oxybutynin as the R enantiomer.
[0056] If desired, oxybutynin can be co-administered with any of a
number of other active agents. These additional active agents
include the broad classes of compounds normally delivered through
body surfaces and membranes, including skin. In general, this
includes: analgesic agents; anesthetic agents; antiarthritic
agents; respiratory drugs, including antiasthmatic agents;
anticancer agents, including antineoplastic drugs;
anticholinergics; anticonvulsants; antidepressants such as
tricyclic antidepressants; antidiabetic agents; antidiarrheals;
antihelminthics; antihistamines; antihyperlipidemic agents;
antihypertensive agents; anti-infective agents such as antibiotics
and antiviral agents; antiinflammatory agents; antimigraine
preparations; antinauseants; antineoplastic agents;
antiparkinsonism drugs; antipruritics; antipsychotics;
antipyretics; antispasmodics; antitubercular agents; antiulcer
agents; antiviral agents; anxiolytics; appetite suppressants;
attention deficit disorder (ADD) and attention deficit
hyperactivity disorder (ADHD) drugs; cardiovascular preparations
including calcium channel blockers, CNS agents; beta-blockers and
antiarrhythmic agents; central nervous system stimulants; cough and
cold preparations, including decongestants; diuretics; genetic
materials; herbal remedies; hormonolytics; hypnotics; hypoglycemic
agents; immunosuppressive agents; leukotriene inhibitors; mitotic
inhibitors; muscle relaxants; narcotic antagonists; nicotine;
nutritional agents, such as vitamins, essential amino acids and
fatty acids; ophthalmic drugs such as antiglaucoma agents;
parasympatholytics; peptide drugs; psychostimulants; sedatives;
steroids; sympathomimetics; tranquilizers; and vasodilators
including general coronary, peripheral and cerebral.
[0057] Preferred classes of active agents for coadministration with
oxybutynin using the present systems and methods are, like
oxybutynin, drugs commonly used in treating bladder disorders.
Specific examples of preferred active agents for co-administration
with oxybutynin include, but are not limited to, amitriptyline
hydrochloride, atropine, biperiden, dicyclomine hydrochloride,
desmopressin acetate, glycopyrolate, imipramine hydrochloride,
propantheline bromide, and tolterodine tartrate.
[0058] Formulations
[0059] The method of delivery of oxybutynin may vary, but
necessarily involves application of a formulation or drug delivery
system containing oxybutynin and a hydroxide-releasing agent to a
predetermined area of the skin or other tissue for a period of time
sufficient to provide the desired systemic effect. The method may
involve direct application of the composition as an ointment, gel,
cream, or the like, or may involve use of a drug delivery device.
In either case, water must be present in order for the
hydroxide-releasing agent to generate hydroxide ions and thus
enhance the flux of the active agent through the patient's body
surface. Thus, a formulation or drug reservoir may be aqueous,
i.e., contain water, or may be nonaqueous and used in combination
with an occlusive overlayer so that moisture evaporating from the
body surface is maintained within the formulation or transdermal
system during drug administration. In some cases, however, e.g.,
with an occlusive gel, a nonaqueous formulation may be used with or
without an occlusive overlayer.
[0060] Suitable formulations include ointments, creams, gels,
lotions, pastes, and the like. Ointments, as is well known in the
art of pharmaceutical formulation, are semisolid preparations that
are typically based on petrolatum or other petroleum derivatives.
The specific ointment base to be used, as will be appreciated by
those skilled in the art, is one that will provide for optimum drug
delivery, and, preferably, will provide for other desired
characteristics as well, e.g., emolliency or the like. As with
other carriers or vehicles, an ointment base should be inert,
stable, nonirritating and nonsensitizing. As explained in
Remington: The Science and Practice of Pharmacy, 19th Ed. (Easton,
Pa.: Mack Publishing Co., 1995), at pages 1399-1404, ointment bases
may be grouped in four classes: oleaginous bases; emulsifiable
bases; emulsion bases; and water-soluble bases. Oleaginous ointment
bases include, for example, vegetable oils, fats obtained from
animals, and semisolid hydrocarbons obtained from petroleum.
Emulsifiable ointment bases, also known as absorbent ointment
bases, contain little or no water and include, for example,
hydroxystearin sulfate, anhydrous lanolin and hydrophilic
petrolatum. Emulsion ointment bases are either water-in-oil (W/O)
emulsions or oil-in-water (O/W) emulsions, and include, for
example, cetyl alcohol, glyceryl monostearate, lanolin and stearic
acid. Preferred water-soluble ointment bases are prepared from
polyethylene glycols of varying molecular weight; again, see
Remington: The Science and Practice of Pharmacy for further
information.
[0061] Creams, as also well known in the art, are viscous liquids
or semisolid emulsions, either oil-in-water or water-in-oil. Cream
bases are water-washable, and contain an oil phase, an emulsifier
and an aqueous phase. The oil phase, also called the "internal"
phase, is generally comprised of petrolatum and a fatty alcohol
such as cetyl or stearyl alcohol. The aqueous phase usually,
although not necessarily, exceeds the oil phase in volume, and
generally contains a humectant. The emulsifier in a cream
formulation is generally a nonionic, anionic, cationic or
amphoteric surfactant.
[0062] As will be appreciated by those working in the field of
pharmaceutical formulation, gels are semisolid, suspension-type
systems. Single-phase gels contain organic macromolecules
distributed substantially uniformly throughout the carrier liquid,
which is typically aqueous, but also, preferably, contain an
alcohol and, optionally, an oil. Preferred "organic
macromolecules," i.e., gelling agents, are crosslinked acrylic acid
polymers such as the "carbomer" family of polymers, e.g.,
carboxypolyalkylenes that may be obtained commercially under the
Carbopol.RTM. trademark. Also preferred are hydrophilic polymers
such as polyethylene oxides, polyoxyethylene-polyoxypropylene
copolymers and polyvinylalcohol; cellulosic polymers such as
hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl
methylcellulose, hydroxypropyl methylcellulose phthalate, and
methyl cellulose; gums such as tragacanth and xanthan gum; sodium
alginate; and gelatin. In order to prepare a uniform gel,
dispersing agents such as alcohol or glycerin can be added, or the
gelling agent can be dispersed by trituration, mechanical mixing or
stirring, or combinations thereof.
[0063] Lotions, which are preferred for delivery of cosmetic
agents, are preparations to be applied to the skin surface without
friction, and are typically liquid or semiliquid preparations in
which solid particles, including the active agent, are present in a
water or alcohol base. Lotions are usually suspensions of solids,
and preferably, for the present purpose, comprise a liquid oily
emulsion of the oil-in-water type. Lotions are preferred
formulations herein for treating large body areas, because of the
ease of applying a more fluid composition. It is generally
necessary that the insoluble matter in a lotion be finely divided.
Lotions will typically contain suspending agents to produce better
dispersions as well as compounds useful for localizing and holding
the active agent in contact with the skin, e.g., methylcellulose,
sodium carboxymethyl-cellulose, or the like.
[0064] Pastes are semisolid dosage forms in which the active agent
is suspended in a suitable base. Depending on the nature of the
base, pastes are divided between fatty pastes or those made from a
single-phase aqueous gels. The base in a fatty paste is generally
petrolatum or hydrophilic petrolatum or the like. The pastes made
from single-phase aqueous gels generally incorporate
carboxymethylcellulose or the like as a base.
[0065] Formulations may also be prepared with liposomes, micelles,
and microspheres. Liposomes are microscopic vesicles having a lipid
wall comprising a lipid bilayer, and can be used as drug delivery
systems herein as well. Generally, liposome formulations are
preferred for poorly soluble or insoluble pharmaceutical agents.
Liposomal preparations for use in the instant invention include
cationic (positively charged), anionic (negatively charged) and
neutral preparations. Cationic liposomes are readily available. For
example, N[1-2,3-dioleyloxy)propyl]-N,N,N-trie- thylammonium
(DOTMA) liposomes are available under the tradename Lipofectin.RTM.
(GIBCO BRL, Grand Island, N.Y.). Similarly, anionic and neutral
liposomes are readily available as well, e.g., from Avanti Polar
Lipids (Birmingham, Ala.), or can be easily prepared using readily
available materials. Such materials include phosphatidyl choline,
cholesterol, phosphatidyl ethanolamine, dioleoylphosphatidyl
choline (DOPC), dioleoylphosphatidyl glycerol (DOPG),
dioleoylphoshatidyl ethanolamine (DOPE), among others. These
materials can also be mixed with DOTMA in appropriate ratios.
Methods for making liposomes using these materials are well known
in the art.
[0066] Micelles are known in the art as comprised of surfactant
molecules arranged so that their polar headgroups form an outer
spherical shell, while the hydrophobic, hydrocarbon chains are
oriented towards the center of the sphere, forming a core. Micelles
form in an aqueous solution containing surfactant at a high enough
concentration so that micelles naturally result. Surfactants useful
for forming micelles include, but are not limited to, potassium
laurate, sodium octane sulfonate, sodium decane sulfonate, sodium
dodecane sulfonate, sodium lauryl sulfate, docusate sodium,
decyltrimethylammonium bromide, dodecyltrimethylammonium bromide,
tetradecyltrimethylammonium bromide, tetradecyltrimethylammonium
chloride, dodecylammonium chloride, polyoxyl 8 dodecyl ether,
polyoxyl 12 dodecyl ether, nonoxynol 10 and nonoxynol 30. Micelle
formulations can be used in conjunction with the present invention
either by incorporation into the reservoir of a topical or
transdermal delivery system, or into a formulation to be applied to
the body surface.
[0067] Microspheres, similarly, may be incorporated into the
present formulations and drug delivery systems. Like liposomes and
micelles, microspheres essentially encapsulate a drug or
drug-containing formulation. They are generally although not
necessarily formed from lipids, preferably charged lipids such as
phospholipids. Preparation of lipidic microspheres is well known in
the art and described in the pertinent texts and literature.
[0068] Various additives, known to those skilled in the art, may be
included in the topical formulations. For example, solvents,
including relatively small amounts of alcohol, may be used to
solubilize certain drug substances. Other optional additives
include opacifiers, antioxidants, fragrance, colorant, gelling
agents, thickening agents, stabilizers, surfactants and the like.
Other agents may also be added, such as antimicrobial agents, to
prevent spoilage upon storage, i.e., to inhibit growth of microbes
such as yeasts and molds. Suitable antimicrobial agents are
typically selected from the group consisting of the methyl and
propyl esters of p-hydroxybenzoic acid (i.e., methyl and propyl
paraben), sodium benzoate, sorbic acid, imidurea, and combinations
thereof.
[0069] It may be desirable to include a second permeation enhancer
in the formulation in addition to the hydroxide-releasing agent,
although in a preferred embodiment the hydroxide-releasing agent is
administered without any other permeation enhancers. Any other
enhancers should, like the hydroxide-releasing agent itself,
minimize the possibility of skin damage, irritation and systemic
toxicity. Example of suitable secondary enhancers (or co-enhancers)
include, but are not limited to: ethers such as diethylene glycol
monoethyl ether (available commercially as Transcutol.RTM.) and
diethylene glycol monomethyl ether; surfactants such as sodium
laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide,
benzalkonium chloride, Poloxamer (231, 182, 184), Tween (20, 40,
60, 80) and lecithin (U.S. Pat. No. 4,783,450); alcohols such as
ethanol, propanol, octanol, benzyl alcohol, and the like; fatty
acids such as lauric acid, oleic acid and valeric acid; fatty acid
esters such as isopropyl myristate, isopropyl palmitate,
methylpropionate, and ethyl oleate; polyols and esters thereof such
as polyethylene glycol, and polyethylene glycol monolaurate (PEGML;
see, e.g., U.S. Pat. No. 4,568,343); amides and other nitrogenous
compounds such as urea, dimethylacetamide (DMA), dimethylformamide
(DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine,
diethanolamine and triethanolamine; terpenes; alkanones; and
organic acids, particularly citric acid and succinic acid.
Azone.RTM. and sulfoxides such as DMSO and C.sub.10MSO may also be
used, but are less preferred. As noted earlier herein, Percutaneous
Penetration Enhancers, eds. Smith et al. (CRC Press, 1995) provides
an excellent overview of the field and further information
concerning possible secondary enhancers for use in conjunction with
the present invention.
[0070] The formulation may also contain irritation-mitigating
additives to minimize or eliminate the possibility of skin
irritation or skin damage resulting from the drug, the enhancer, or
other components of the formulation. Suitable irritation-mitigating
additives include, for example: a-tocopherol; monoamine oxidase
inhibitors, particularly phenyl alcohols such as
2-phenyl-1-ethanol; glycerin; salicylic acids and salicylates;
ascorbic acids and ascorbates; ionophores such as monensin;
amphiphilic amines; ammonium chloride; N-acetylcysteinei;
cis-urocanic acid; capsaicin; and chloroquine. The
irritant-mitigating additive, if present, may be incorporated into
the present formulations at a concentration effective to mitigate
irritation or skin damage, typically representing not more than
about 20 wt %, more typically not more than about 5 wt %, of the
formulations.
[0071] The concentration of the active agent in the formulation can
vary a great deal, and will depend on a variety of factors,
including the disease or condition to be treated, the nature and
activity of the active agent, the desired effect, possible adverse
reactions, the ability and speed of the active agent to reach its
intended target, and other factors within the particular knowledge
of the patient and physician. Preferred formulations will typically
contain on the order of about 0.5 wt % to 50 wt %, optimally about
1 wt % to 30 wt %, active agents.
[0072] Drug Delivery Systems
[0073] An alternative and preferred method involves the use of a
drug delivery system, e.g., a transdermal "patch," wherein the
active agent is contained within a laminated structure that is to
be affixed to the skin. In such a structure, the drug composition
is contained in a layer, or "reservoir," underlying an upper
backing layer. The laminated structure may contain a single
reservoir, or it may contain multiple reservoirs.
[0074] In one embodiment, the reservoir comprises a polymeric
matrix of a pharmaceutically acceptable adhesive material that
serves to affix the system to the skin during drug delivery;
typically, the adhesive material is a pressure-sensitive adhesive
(PSA) that is suitable for long-term skin contact, and which should
be physically and chemically compatible with the active agent,
hydroxide-releasing agent, and any carriers, vehicles or other
additives that are present. Examples of suitable adhesive materials
include, but are not limited to, the following: polyethylenes;
polysiloxanes; polyisobutylenes; polyacrylates; polyacrylamides;
polyurethanes; plasticized ethylene-vinyl acetate copolymers; and
tacky rubbers such as polyisobutene, polybutadiene,
polystyrene-isoprene copolymers, polystyrene-butadiene copolymers,
and neoprene(polychloroprene). Preferred adhesives are
polyisobutylenes.
[0075] The backing layer functions as the primary structural
element of the transdermal system and provides the device with
flexibility and, preferably, occlusivity. The material used for the
backing layer should be inert and incapable of absorbing drug,
hydroxide-releasing agent or components of the formulation
contained within the device. The backing is preferably comprised of
a flexible elastomeric material that serves as a protective
covering to prevent loss of drug and/or vehicle via transmission
through the upper surface of the patch, and will preferably impart
a degree of occlusivity to the system, such that the area of the
body surface covered by the patch becomes hydrated during use. The
material used for the backing layer should permit the device to
follow the contours of the skin and be worn comfortably on areas of
skin such as at joints or other points of flexure, that are
normally subjected to mechanical strain with little or no
likelihood of the device disengaging from the skin due to
differences in the flexibility or resiliency of the skin and the
device. The materials used as the backing layer are either
occlusive or permeable, as noted above, although occlusive backings
are preferred, and are generally derived from synthetic polymers
(e.g., polyester, polyethylene, polypropylene, polyurethane,
polyvinylidine chloride, and polyether amide), natural polymers
(e.g., cellulosic materials), or macroporous woven and nonwoven
materials.
[0076] During storage and prior to use, the laminated structure
includes a release liner. Immediately prior to use, this layer is
removed from the device so that the system may be affixed to the
skin. The release liner should be made from a drug/vehicle
impermeable material, and is a disposable element which serves only
to protect the device prior to application. Typically, the release
liner is formed from a material impermeable to the
pharmacologically active agent and the hydroxide-releasing agent,
and which is easily stripped from the transdermal patch prior to
use.
[0077] In an alternative embodiment, the drug-containing reservoir
and skin contact adhesive are present as separate and distinct
layers, with the adhesive underlying the reservoir. In such a case,
the reservoir may be a polymeric matrix as described above.
Alternatively, the reservoir may be comprised of a liquid or
semisolid formulation contained in a closed compartment or "pouch,"
or it may be a hydrogel reservoir, or may take some other form.
Hydrogel reservoirs are particularly preferred herein. As will be
appreciated by those skilled in the art, hydrogels are
macromolecular networks that absorb water and thus swell but do not
dissolve in water. That is, hydrogels contain hydrophilic
functional groups that provide for water absorption, but the
hydrogels are comprised of crosslinked polymers that give rise to
aqueous insolubility. Generally, then, hydrogels are comprised of
crosslinked hydrophilic polymers such as a polyurethane, a
polyvinyl alcohol, a polyacrylic acid, a polyoxyethylene, a
polyvinylpyrrolidone, a poly(hydroxyethyl methacrylate)
(poly(HEMA)), or a copolymer or mixture thereof. Particularly
preferred hydrophilic polymers are copolymers of HEMA and
polyvinylpyrrolidone.
[0078] Additional layers, e.g., intermediate fabric layers and/or
rate-controlling membranes, may also be present in any of these
drug delivery systems. Fabric layers may be used to facilitate
fabrication of the device, while a rate-controlling membrane may be
used to control the rate at which a component permeates out of the
device. The component may be a drug, a hydroxide-releasing agent,
an additional enhancer, or some other component contained in the
drug delivery system.
[0079] A rate-controlling membrane, if present, will be included in
the system on the skin side of one or more of the drug reservoirs.
The materials used to form such a membrane are selected to limit
the flux of one or more components contained in the drug
formulation. Representative materials useful for forming
rate-controlling membranes include polyolefins such as polyethylene
and polypropylene, polyamides, polyesters, ethylene-ethacrylate
copolymer, ethylene-vinyl acetate copolymer, ethylene-vinyl
methylacetate copolymer, ethylene-vinyl ethylacetate copolymer,
ethylene-vinyl propylacetate copolymer, polyisoprene,
polyacrylonitrile, ethylene-propylene copolymer, and the like.
[0080] Generally, the underlying surface of the transdermal device,
i.e., the skin contact area, has an area in the range of about 5
cm.sup.2 to 200 cm.sup.2, preferably 5 cm.sup.2 to 100 cm.sup.2,
more preferably 20 cm.sup.2 to 60 cm.sup.2. That area will vary, of
course, with the amount of drug to be delivered and the flux of the
drug through the body surface. Larger patches will necessary to
accommodate larger quantities of drug, while smaller patches can be
used for smaller quantities of drug and/or drugs that exhibit a
relatively high permeation rate.
[0081] Such drug delivery systems may be fabricated using
conventional coating and laminating techniques known in the art.
For example, adhesive matrix systems can be prepared by casting a
fluid admixture of adhesive, drug and vehicle onto the backing
layer, followed by lamination of the release liner. Similarly, the
adhesive mixture may be cast onto the release liner, followed by
lamination of the backing layer. Alternatively, the drug reservoir
may be prepared in the absence of drug or excipient, and then
loaded by "soaking" in a drug/vehicle mixture. In general,
transdermal systems of the invention are fabricated by solvent
evaporation, film casting, melt extrusion, thin film lamination,
die cutting, or the like. The hydroxide-releasing agent will
generally be incorporated into the device during patch manufacture
rather than subsequent to preparation of the device.
[0082] In a preferred delivery system, an adhesive overlayer that
also serves as a backing for the delivery system is used to better
secure the patch to the body surface. This overlayer is sized such
that it extends beyond the drug reservoir so that adhesive on the
overlayer comes into contact with the body surface. The overlayer
is useful because the adhesive/drug reservoir layer may lose its
adhesion a few hours after application due to hydration. By
incorporating such an adhesive overlayer, the delivery system
remains in place for the required period of time.
[0083] Other types and configurations of transdermal drug delivery
systems may also be used in conjunction with the method of the
present invention, i.e., the use of a hydroxide-releasing agent as
a permeation enhancer, as will be appreciated by those skilled in
the art of transdermal drug delivery. See, for example, Ghosh,
Transdermal and Topical Drug Delivery Systems (Interpharm Press,
1997), particularly Chapters 2 and 8.
[0084] As with the topically applied formulations of the invention,
the composition containing drug and hydroxide-releasing agent
within the drug reservoir(s) of these laminated system may contain
a number of components. In some cases, the drug and
hydroxide-releasing agent may be delivered "neat," i.e., in the
absence of additional liquid. In most cases, however, the drug will
be dissolved, dispersed or suspended in a suitable pharmaceutically
acceptable vehicle, typically a solvent or gel. Other components
which may be present include preservatives, stabilizers,
surfactants, and the like.
[0085] Utility
[0086] Transdermal administration of oxybutynin is useful in a
variety of contexts, as will be readily appreciated by those
skilled in the art. For example, the transdermal administration of
oxybutynin is useful in the treatment of urinary urgency, urinary
frequency, urinary leakage, incontinence, and painful or difficult
urination. Generally, although not necessarily, these disorders are
caused by neurogenic bladder. In addition, the present compositions
and drug delivery systems are useful to administer oxybutynin to
treat other conditions and disorders that are responsive to
transdermal administration of oxybutynin. For example, oxybutynin
may be administered transdermally to treat individuals suffering
from detrusor hyperreflexia and detrusor instability.
[0087] The amount of drug present in the compositions and drug
delivery systems of the invention and required to achieve an
effective therapeutic result depends on many factors, such as the
minimum necessary dosage of the drug for the particular indication
being treated; the solubility and permeability of the carrier and
adhesive layer; and the period of time for which the device will be
fixed to the skin or other body surface. The minimum amount of drug
is determined by the requirement that sufficient quantities of drug
must be present in the device to maintain the desired rate of
release over the given period of application. The maximum amount
for safety purposes is determined by the requirement that the
quantity of drug present cannot exceed a rate of release that
reaches toxic levels. Generally, the maximum concentration is
determined by the amount of agent that can be received in the
carrier without producing adverse histological effects such as
irritation, an unacceptably high initial pulse of agent into the
body, or adverse effects on the characteristics of the delivery
device such as the loss of tackiness, viscosity, or deterioration
of other properties.
[0088] The daily dosage administered will, of course, vary from
subject to subject and depend on the particular disorder or
condition, the severity of the symptoms, the subject's age, weight
and general condition, and the judgment of the prescribing
physician. Generally, however, a daily dosage of racemic oxybutynin
using the present formulations and delivery systems will be in the
range of about 1 to 20 mg over a 24-hour period. The daily dose of
an individual enantiomer of oxybutynin, i.e., (S)-oxybutynin or
(R)-oxybutynin, using the present formulations and delivery systems
is preferably lower than the corresponding racemate dose.
Specifically, it is preferred that the enantiomer dose be in the
range of about 0.5 to 15 mg over a 24-hour period.
[0089] The invention accordingly provides a novel and highly
effective means for increasing the flux of oxybutynin through the
body surface (skin or mucosal tissue) of a human or animal. The
hydroxide-releasing agents discussed herein, employed in specific
amounts relative to a formulation or drug reservoir, may be used as
permeation enhancers. Surprisingly, the increase in permeation is
not accompanied by any noticeable tissue damage, irritation, or
sensitization. The invention thus represents an important advance
in the field of drug delivery.
[0090] It is to be understood that while the invention has been
described in conjunction with the preferred specific embodiments
thereof, the foregoing description, as well as the example that
follows, are intended to illustrate and not limit the scope of the
invention. Other aspects, advantages and modifications will be
apparent to those skilled in the art to which the invention
pertains. All patents, patent applications, journal articles and
other references cited herein are incorporated by reference in
their entireties.
[0091] The following example is put forth so as to provide those of
ordinary skill in the art with a complete disclosure and
description of how to make and use the materials of the invention,
and are not intended to limit the scope of what the inventors
regard as their invention. Efforts have been made to ensure
accuracy with respect to numbers (e.g., amounts, temperature, etc.)
but some errors and deviations should be accounted for. Unless
indicated otherwise, parts are part by weight, temperature is in
.degree. C. and pressure is at or near atmospheric.
EXAMPLE 1
[0092] An in-vitro skin permeation study was conducted using three
oxybutynin HCl transdermal systems. The formulations used to
prepare these systems are listed in Table 1, which include weight
and weight percent of each ingredient in the formulations. The
weight of sodium hydroxide (NaOH) was 0.15 g, 0.25 g, and 0.35 g
for formulation #Oxy-P1, -P2, and -P3 respectively. Each
formulation was coated on a release liner and dried in an oven at
55.degree. C. for two hours to remove water and other solvents. The
dried drug-in-adhesive/release liner film was laminated to a
backing film. The backing/drug-in-adhesive/release liner laminate
was then cut into round discs with a diameter of {fraction (11/16)}
inch. The theoretical percent weight for each ingredient after
drying (calculated assuming all the volatile ingredients were
completely removed during drying) is listed in Table 2.
[0093] The in-vitro permeation of oxybutynin HCl through human
cadaver skin from these discs was performed using Franz-type
diffusion cells with a diffusion area of 1 cm.sup.2. The volume of
receiver solution was 8 ml. Human cadaver skin was cut to desired
size and placed on a flat surface with the stratum corneum side
facing up. The release liner was peeled away from the disc
laminate. The backing/drug-in-adhesive film was placed and pressed
on the skin with the adhesive side facing the stratum corneum. The
skin/adhesive/backing laminate was clamped between the donor and
receiver chambers of the diffusion cell with the skin side facing
the receiver solution. Three diffusion cells were used for each
formulation.
[0094] The cells were filled with 10% ethanol/90% water solution.
The receiver solution was completely withdrawn and replaced with
fresh ethanol/water solution at each time point. The samples taken
were analyzed by an HPLC for the concentration of oxybutynin HCl in
the receiver solution. The cumulative amount of oxybutynin HCl
across human cadaver skin was calculated using the measured
oxybutynin HCl concentrations in the receiver solutions, which were
shown in Table 3.
1TABLE 1 Weight and Weight Percent of Each Ingredient Based on
Total Solution Weight for Three Oxybutynin HCl Transdermal Systems
Oxy-P1 Oxy-P2 Oxy-P3 Oxybutynin HCl 0.5 g (6.5%) 0.5 g (6.3%) 0.5 g
(6.2%) DI water 0.65 g (8.4%) 0.75 g (9.5%) 0.85 g (10.5%) NaOH
0.15 g (1.9%) 0.25 g (3.2%) 0.35 g (4.3%) Propylene glycol 0.3 g
(9.9%) 0.3 g (3.8%) 0.3 g (3.7%) Triton X100 0.1 g (1.3%) 0.1 g
(1.3%) 0.1 g (1.2%) PIB adhesive (30% 4 g (51.9%) 4 g (50.6%) 4 g
(49.4%) solid) Methylal 1 g (13.0%) 1 g (12.7%) 1 g (12.3%) Heptane
1 g (13.0%) 1 g (12.7%) 1 g (12.3%)
[0095]
2TABLE 2 Weight and Theoretical Weight Percent of Each Ingredient
in the Dried Film for Three Oxybutynin HCl Transdermal Systems
Oxy-P1 Oxy-P2 Oxy-P3 Oxybutynin HCl 0.5 g (15.4%) 0.5 g (14.9%) 0.5
g (14.5%) NaOH 0.15 g (4.6%) 0.25 g (7.5%) 0.35 g (10.1%) Propylene
glycol 0.3 g (9.2%) 0.3 g (9.0%) 0.3 g (8.7%) Triton X100 0.1 g
(3.1%) 0.1 g (3.0%) 0.1 g (2.9%) PIB adhesive 1.2 g (36.9%) 1.2 g
(35.8%) 1.2 g (34.8%) Methylal 1 g (30.8%) 1 g (29.9%) 1 g
(29.0%)
[0096]
3TABLE 3 Cumulative Amount of Oxybutynin HCl across human cadaver
skin for Oxybutynin HCl Transdermal Systems (g/cm.sup.2) Oxy-P1
Oxy-P2 Oxy-P3 5 hours 691.0 2108.7 1399.5 10.5 hours 1259.4 2615.9
1865.9 24 hours 1747.7 2853.5 2322.8
[0097] The cumulative amount of oxybutynin HCl across human cadaver
skin at 24 hours ranged from 1747.7 .mu.g/cm.sup.2 to 2322.8
.mu.g/cm.sup.2 when the NaOH concentration in the dried patch was
increased from 4.6% to 10.1%.
* * * * *