U.S. patent application number 11/978556 was filed with the patent office on 2008-06-05 for dermal penetration enhancers and drug delivery systems involving same.
This patent application is currently assigned to Acrux DDS Pty Ltd.. Invention is credited to Barrie Charles Finnin, Timothy Matthias Morgan, Barry Lenard Reed.
Application Number | 20080131494 11/978556 |
Document ID | / |
Family ID | 3792458 |
Filed Date | 2008-06-05 |
United States Patent
Application |
20080131494 |
Kind Code |
A1 |
Reed; Barry Lenard ; et
al. |
June 5, 2008 |
Dermal Penetration enhancers and drug delivery systems involving
same
Abstract
The invention relates to a method for treatment or prophylaxis
of a disease or condition in an animal comprising administering to
a mucosal membrane of said animal in need of such treatment a
therapeutically effective amount of a drug delivery system
comprising at least one physiologically active agent or prodrug
thereof and at least one penetration enhancer selected from safe
ester sunscreens.
Inventors: |
Reed; Barry Lenard;
(Strathmore, AU) ; Morgan; Timothy Matthias;
(Carlton North, AU) ; Finnin; Barrie Charles;
(Glen Iris, AU) |
Correspondence
Address: |
FOLEY AND LARDNER LLP;SUITE 500
3000 K STREET NW
WASHINGTON
DC
20007
US
|
Assignee: |
Acrux DDS Pty Ltd.
|
Family ID: |
3792458 |
Appl. No.: |
11/978556 |
Filed: |
October 30, 2007 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10759303 |
Jan 20, 2004 |
|
|
|
11978556 |
|
|
|
|
09910780 |
Jul 24, 2001 |
6818226 |
|
|
10759303 |
|
|
|
|
09125436 |
Dec 18, 1998 |
6299900 |
|
|
PCT/AU1997/000091 |
Feb 19, 1997 |
|
|
|
09910780 |
|
|
|
|
Current U.S.
Class: |
424/449 ;
424/45 |
Current CPC
Class: |
A61P 13/08 20180101;
Y02A 50/411 20180101; A61K 9/122 20130101; A61P 5/24 20180101; A61P
31/22 20180101; A61P 1/08 20180101; A61P 25/06 20180101; A61K
9/0014 20130101; A61K 8/37 20130101; A61P 15/16 20180101; Y10S
514/974 20130101; A61P 17/14 20180101; A61P 25/04 20180101; Y02A
50/30 20180101; A61P 7/02 20180101; A61P 9/12 20180101; A61K 8/046
20130101; A61K 8/445 20130101; A61P 25/22 20180101; A61P 29/00
20180101; A61K 9/12 20130101; A61P 15/10 20180101; A61P 35/00
20180101; A61P 5/30 20180101; Y10S 514/947 20130101; A61K 47/14
20130101; A61P 11/06 20180101; A61P 11/00 20180101; A61M 35/003
20130101; A61P 25/20 20180101; A61P 39/00 20180101; A61P 15/18
20180101; A61Q 17/04 20130101; A61P 5/26 20180101; A61P 17/10
20180101; A61P 33/06 20180101 |
Class at
Publication: |
424/449 ;
424/45 |
International
Class: |
A61K 9/12 20060101
A61K009/12; A61K 9/70 20060101 A61K009/70; A61P 5/30 20060101
A61P005/30; A61P 15/18 20060101 A61P015/18 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 19, 2006 |
AU |
PN8144/96 |
Claims
1-35. (canceled)
36. An apparatus for applying a metered dose of a non-occlusive
percutaneous or a non-occlusive transdermal hormone composition to
the dermal surface of a person comprising: (a) a container, (b) a
metered dose applicator selected from the group consisting of a
metered dose aerosol, a stored energy metered dose pump, and a
metered dose pump, wherein said container contains: (c) a
non-occlusive percutaneous or non-occlusive transdermal hormone
composition comprising: (i) at least one hormone selected from the
group consisting of oestrogen, progesterone and progestagens other
than progesterone (ii) at least one dermal penetration enhancer,
and (iii) at least one volatile liquid present in an amount to act
as a vehicle for the hormone and penetration enhancer, wherein the
dermal penetration enhancer is (1) adapted to transport the at
least one hormone across a dermal surface of an animal, when the
volatile liquid evaporates, to form a reservoir or depot of the at
least one hormone within said surface and (2) is of low toxicity to
and is tolerated by the dermal surface of the animal.
37. The apparatus of claim 36, wherein said non-occlusive
percutaneous or non-occlusive transdermal hormone composition
consists of: (i) at least one hormone selected from the group
consisting of oestrogen, progesterone and progestagens other than
progesterone, (ii) at least one dermal penetration enhancer, (iii)
at least one volatile liquid present in an amount to act as a
vehicle for the hormone and penetration enhancer, and (iv)
optionally, a propellant.
38. The apparatus of claim 36, wherein after application of the
non-occlusive percutaneous or non-occlusive transdermal hormone
composition to an area of the dermal surface, the area becomes
touch-dry within three minutes of application.
39. The apparatus of claim 37, wherein the dermal penetration
enhancer is a C.sub.6-C.sub.18 alkyl para-aminobenzoate,
C.sub.6-C.sub.18 alkyl dimethyl-para-aminobenzoate,
C.sub.6-C.sub.18 alkyl cinnamate, C.sub.6-C.sub.18 alkyl
methoxycinnamate or C.sub.6-C.sub.18 alkyl salicylate.
40. The apparatus of claim 39, wherein the dermal penetration
enhancer is octyl salicylate.
41. The apparatus of claim 37, wherein the volatile liquid is
ethanol or isopropanol.
42. The apparatus of claim 36, wherein the apparatus provides one
or more fixed metered doses of the non-occlusive percutaneous or
non-occlusive transdermal hormone composition.
43. The apparatus of claim 36, wherein said non-occlusive
percutaneous or non-occlusive transdermal oestrogen composition
comprises: (i) oestrogen, (ii) at least one dermal penetration
enhancer, and (iii) at least one volatile liquid present in an
amount to act as a vehicle for the oestrogen and penetration
enhancer, wherein the dermal penetration enhancer is (1) adapted to
transport the oestrogen across a dermal surface of an animal, when
the volatile liquid evaporates, to form a reservoir or depot of
oestrogen within said surface and (2) is of low toxicity to and is
tolerated by the dermal surface of the animal.
44. The apparatus of claim 37, wherein said non-occlusive
percutaneous or non-occlusive transdermal oestrogen composition
consists of: (i) oestrogen, (ii) at least one dermal penetration
enhancer, (iii) at least one volatile liquid present in an amount
to act as a vehicle for the oestrogen and penetration enhancer, and
(iv) optionally, a propellant.
45. The apparatus of claim 43, wherein the oestrogen comprises
oestradiol in an amount of about 2% (w/v) of the non-occlusive
percutaneous or non-occlusive transdermal oestrogen
composition.
46. The apparatus of claim 43, wherein after application of the
non-occlusive percutaneous or non-occlusive transdermal oestrogen
composition to an area of the dermal surface, the area becomes
touch-dry within three minutes of application.
47. The apparatus of claim 44, wherein the dermal penetration
enhancer is a C.sub.6-C.sub.18 alkyl para-aminobenzoate,
C.sub.6-C.sub.18 alkyl dimethyl-para-aminobenzoate,
C.sub.6-C.sub.18 alkyl cinnamate, C.sub.6-C.sub.18 alkyl
methoxycinnamate or C.sub.6-C.sub.18 alkyl salicylate.
48. The apparatus of claim 47, wherein the dermal penetration
enhancer is octyl salicylate.
49. The apparatus of claim 43, wherein the non-occlusive
percutaneous or non-occlusive transdermal oestrogen composition
comprises: about 2% (w/v) oestradiol, about 8% (v/v) penetration
enhancer, and about 90% (v/v) of one or more volatile liquid.
50. The apparatus of claim 44, wherein the non-occlusive
percutaneous or non-occlusive transdermal oestrogen composition
consists of: about 2% (w/v) oestradiol, about 8% (v/v) penetration
enhancer, and about 90% (v/v) of one or more volatile liquid.
51. The apparatus of claim 44, wherein the volatile liquid is
ethanol or isopropanol.
52. The apparatus of claim 43, wherein the apparatus provides one
or more fixed metered doses of the non-occlusive percutaneous or
non-occlusive transdermal oestrogen composition.
53. The apparatus of claim 43, wherein the metered dose applicator
further comprises a shroud adapted to keep the nozzle of the
apparatus at a pre-determined height above the site of
application.
54. A method of contraception in a woman comprising applying to the
skin of a woman in need thereof an effective amount of a
non-occlusive percutaneous or non-occlusive transdermal hormone
composition comprising: (a) at least one hormone selected from the
group consisting of oestrogen, progesterone and progestagens other
than progesterone (b) at least one dermal penetration enhancer, and
(c) at least one volatile liquid present in an amount to act as a
vehicle for the hormone and penetration enhancer, wherein the
dermal penetration enhancer is (i) adapted to transport the at
least one hormone across a dermal surface of an animal, when the
volatile liquid evaporates, to form a reservoir or depot of the at
least one hormone within said surface and (ii) is of low toxicity
to and is tolerated by the dermal surface of the animal; wherein
said composition is applied dermally using an apparatus comprising:
a container that contains said non-occlusive percutaneous or
non-occlusive transdermal hormone composition, and a metered dose
applicator selected from the group consisting of a metered dose
aerosol, a stored energy metered dose pump, and a metered dose
pump.
55. The method of claim 54, wherein the non-occlusive percutaneous
or non-occlusive transdermal hormone composition is applied by an
aerosol or spray comprising a shroud adapted to keep an actuator
nozzle of the apparatus at a pre-determined height above the site
of application.
56. A method of supplementing hormone deficiency in a
postmenopausal woman comprising applying to the skin of a woman in
need thereof an effective amount of a non-occlusive percutaneous or
non-occlusive transdermal oestrogen composition comprising: (a)
oestrogen, (b) at least one dermal penetration enhancer, and (c) at
least one volatile liquid present in an amount to act as a vehicle
for the hormone and penetration enhancer, wherein the dermal
penetration enhancer is (i) adapted to transport the at least one
hormone across a dermal surface of an animal, when the volatile
liquid evaporates, to form a reservoir or depot of the at least one
hormone within said surface and (ii) is of low toxicity to and is
tolerated by the dermal surface of the animal; wherein said
composition is applied dermally using an apparatus comprising: a
container that contains said non-occlusive percutaneous or
non-occlusive transdermal oestrogen composition, and a metered dose
applicator selected from the group consisting of a metered dose
aerosol, a stored energy metered dose pump, and a metered dose
pump.
57. The method of claim 56, wherein the non-occlusive percutaneous
or non-occlusive transdermal oestrogen composition is applied by an
aerosol or spray comprising a shroud adapted to keep an actuator
nozzle of the apparatus at a pre-determined height above the site
of application.
58. A composition for the transdermal delivery of oestrogen
comprising (a) a therapeutically effective amount of oestrogen, (b)
at least one dermal penetration enhancer wherein the dermal
penetration enhancer is at least one of a safe skin-tolerant ester
sunscreen of formula (I): ##STR00002## wherein R.sup.1 is hydrogen,
lower alkyl, lower alkoxy, halide, hydroxyl, or NR.sup.3R.sup.4;
R.sup.2 is a C.sub.8 to C.sub.18 alkyl, R.sup.3 and R.sup.4 are
each independently hydrogen, lower alkyl, or R.sup.3 and R.sup.4
together with the nitrogen atom to which they are attached form a
5- or 6-membered heterocyclic ring; n is 0 or 1, and q is 1 or 2;
and (c) at least one volatile liquid present in an amount to act as
a vehicle for the oestrogen and penetration enhancer, wherein the
composition is a non-occlusive percutaneous or non-occlusive
transdermal composition that is administered to the skin in the
form of a mist or spray.
59. The composition of claim 58 consisting of (a) a therapeutically
effective amount of oestrogen, (b) at least one dermal penetration
enhancer wherein the dermal penetration enhancer is at least one of
a safe skin-tolerant ester sunscreen of formula (I): ##STR00003##
wherein R.sup.1 is hydrogen, lower alkyl, lower alkoxy, halide,
hydroxyl, or NR.sup.3R.sup.4; R.sup.2 is a C.sub.8 to C.sub.18
alkyl, R.sup.3 and R.sup.4 are each independently hydrogen, lower
alkyl, or R.sup.3 and R.sup.4 together with the nitrogen atom to
which they are attached form a 5- or 6-membered heterocyclic ring;
n is 0 or 1, and q is 1 or 2; and (c) at least one volatile liquid
present in an amount to act as a vehicle for the oestrogen and
penetration enhancer, wherein the composition is a non-occlusive
percutaneous or non-occlusive transdermal composition that is
administered to the skin in the form of a mist or spray.
60. The composition of claim 58, wherein the oestrogen comprises
oestradiol in an amount of about 2% (w/v) of the composition.
Description
[0001] This application is a continuation in part application based
on Ser. No. 09/910,780 filed on Jul. 24, 2001.
FIELD OF THE INVENTION
[0002] The present invention relates to percutaneous or transdermal
drug delivery. More specifically, the invention relates to a
topical absorption/penetration enhancing agent for use in the
delivery of a physiologically active agent to an animal, including
a human. The invention also relates to a system for the
non-occlusive delivery to an animal of a physiologically active
agent across a dermal surface or mucosal membrane of the animal.
Transdermal drug formulations of the present invention may be used
for local application or systemic delivery.
BACKGROUND OF THE INVENTION
[0003] The prevention or treatment of local or topical disease
states or conditions of the skin has traditionally used simple
non-occlusive delivery systems. These drug delivery systems usually
include a volatile and/or non-volatile medium whereby a composition
of the drug and medium is topically applied to the skin, generally
in the vicinity of or directly on the area of skin to be treated.
Such delivery systems usually take the form of emulsions, creams,
ointments, foams, gels, liquids, sprays and aerosols. These
delivery systems are generally used to treat skin inflammations,
soft-tissue contusions, parasites, fungal and bacterial topical
infection and topical analgesia. The limitation with this type of
delivery system is that systemic drugs are generally not suitable
for this type of administration. Some major problems with the
current state of the art relate to a lack of efficacy of systemic
drugs because of the low drug flux across the skin, as observed for
drugs such as testosterone, amlodipine, fentanyl, buprenorphine and
many others. Other drugs, such as glyceryl trinitrate, Nitrobid.TM.
(a drug for the treatment of angina), are difficult to deliver by
these systems due to the inability to adequately control the rate
of drug delivery, or the requirement for a very large application
area. Other problems with the poor dermal penetration of drugs is
that the drug can be easily washed off or transferred to clothes,
other surfaces or other animals.
[0004] The dermal delivery of drugs may represent the oldest form
of drug delivery in human history. Resins and animal fats were
probably used by humans in early times to treat damage to the skin
resulting from injuries and burns. Such substances for local
delivery of active substances remained largely unchanged until as
late as this century. The concept of transdermal systemic drug
delivery was first seriously advocated by Dr Alejandro Zaffaroni in
U.S. Pat. Nos. 3,598,122, 3,731,683 and 3,797,494 from the early
1970s. Transdermal systemic drug delivery provides an effective
method of achieving improved bioavailability for physiologically
active substances where the drugs are poorly absorbed by
traditional routes of delivery. It can also be used where oral
dosing is poorly tolerated or not possible.
[0005] Transdermal formulations are however limited. For example
polar drugs tend to penetrate the skin too slowly. Since most drugs
are of a polar nature this limitation is significant, as is the
fact that many drugs cause irritation at the site of topical
application.
[0006] Two main methods are known for assisting the rate of
penetration of drugs across the skin. The first is to increase the
thermodynamic activity of the drug. The thermodynamic activity of a
drug in a dermal formulation is proportional to the concentration
of the drug and the selection of the vehicle. According to the laws
of thermodynamics, the maximum activity of a drug is related to
that of the pure drug crystal. The second method involves the use
of compounds known as penetration enhancers to increase the
permeability of the dermal surface and has generally proven to be
more convenient and effective.
[0007] Since the early 1970s the main focus of transdermal systemic
drug delivery has been, and still is, on transdermal patch devices.
These patch devices are like bandages which are attached to the
surface of intact skin for prolonged periods of time to allow a
desired systemic delivery of a drug or other physiologically active
agent. These transdermal patch devices occlude the skin and trap
the drug, together with volatiles and vehicle excipients, between
the skin and an outer impermeable backing membrane. The membrane
prevents the evaporation or diffusion of vehicle excipients,
volatiles and drug into an environment other than the target skin
site. The prolonged length of time required for transfer of the
drug and excipients from the patch into the skin can and often does
result in local skin irritation. The irritation is caused by
prolonged contact on the skin by the drug, volatiles, vehicle
excipients, or the adhesive used to attach the patch device to the
skin. The occlusive nature of the patch device also restricts the
natural ability of the skin to "breathe", increasing the risk of
irritation. With added problems of complex and costly manufacturing
processes for transdermal patch devices there is a need for
improved transdermal drug delivery systems.
[0008] The rate of drug delivery across a dermal surface can be
increased by dermal penetration enhancers. The problem with most
known dermal penetration enhancers is that they are often toxic,
irritating or allergenic. These enhancers tend to be proton
accepting solvents such as dimethylsulfoxide and dimethyacetamide.
More recently, 2-pyrrolidine, N,N-diethyl-m-toluamide (Deet),
1-dodecal-azacycloheptane-2-one (Azone.RTM.),
N,N-dimethylformamide, N-methyl-2-pyrrolidine and calcium
thioglycolate have been reported as effective enhancers. However,
difficulties remain with such dermal enhancers because the problem
of irritation at the site of application has not been overcome.
[0009] The most critical problem with these compounds however is
their toxicity. If a compound when used as a dermal enhancer is
toxic, irritating or allergenic, then that compound is unsuitable
for application to the animal body. Dimethyl sulfoxide and dimethyl
acetamide are not clinically acceptable for these reasons. Although
Deet and Azone.RTM. have lower reported toxicities, their toxicity
is still such that they are not widely used. It is possible that
Azone.RTM. may be employed as a dermal penetration enhancer if the
amount applied is sufficiently small so as not to be appreciably
toxic, irritating or allergenic to the animal.
[0010] The thermodynamic activity of a drug can be increased by
employing supersaturated systems which give rise to unusually high
thermodynamic potentials [Coldman, et al., J. Pharm. Sci., 58(9),
119, 1969]. However, topical vehicles relying on supersaturation,
have the major limitation of formulation instability, both prior to
and during application to the skin. As such, they are of limited
clinical value within a non-occlusive volatile:non-volatile
delivery vehicle, because as soon as the formulation comes into
contact with a person's clothing or the like, the drug often
precipitates; hence the formulation is no longer supersaturated and
any enhanced percutaneous absorption ceases.
[0011] Other workers such as Kondo, et al., [J. Pharmacobio-Dyn.,
10, 743, 1987] who were using supersaturation to achieve enhanced
transdermal drug delivery, have relied on the use of
anti-nucleating polymers to stabilize the formulation. However, the
applied drug formulations stabilised with polymers formed an
appreciable surface mass on the skin which remained there over a
prolonged duration of many hours, not a few minutes. So while Kondo
advocated the use of a metered spray to deliver these formulations,
in reality it would be impossible to obtain a non-occlusive
delivery system with a short application time and still maintain a
clinically useful transdermal penetration enhancement.
[0012] German patent application DE 4334553-A1 to Jenapharm GmbH
discloses a pharmaceutical liquid system consisting of a drug
(diclofenac), a lipophilic phase, a volatile component and
appropriate antioxidants, preservatives or stabilisers. This system
relies on supersaturation to increase the flux rate of dermal
absorption. An application chamber is used to prevent accidental
precipitation of the supersaturated drug delivery system over the
application time of 150 minutes.
[0013] Japanese patent JP 61-268631 to Showa Denko KK discloses
dermal penetration enhancers suitable for use with water-soluble
drugs. The dermal penetration enhancers disclosed include 1-5
carbon fatty acid esters of para-aminobenzoic acid but their
chemical structures are quite distinct from the compounds used in
the present invention, and the physicochemical properties of the
1-5 carbon fatty acid esters of para-aminobenzoic acid are markedly
different to those of the present invention. For example the
octanol-water partition coefficients for all the 1-5 carbon fatty
acid esters of para-aminobenzoic acid are at least 200 fold lower
than those of the present invention. Also the preferred dermal
penetration enhancer disclosed in JP 61-268631 is the 2 carbon
fatty acid ester of para-aminobenzoic acid (or Benzocaine) which
has an octanol-water partition coefficient which is more than 8000
fold lower than those of the present invention. Unlike those of the
present invention, the preferred dermal penetration enhancer
disclosed in JP 61-268631 has significant pharmacological
properties in that it is a local anaesthetic, which has also been
reported to cause irritant and allergic skin reactions. The
compounds used in the present invention fulfil the ideal properties
of a dermal penetration enhancer in that they are non-irritant and
pharmacologically inert [Barry, B. W. Vehicle Effect: What Is an
Enhancer? In: Topical Drug Bioavailability, Bioequivalence, and
Penetration. Shah, V. P.; Maibach, H. I. Eds. Plenum Press: New
York, 1993; pp 261-276.].
[0014] It was not surprising then to find that in previous studies
[Feldmann, et al., Arch. Derm., 94, 649, 1996; Coldman, et al., J.
Pharm. Sci., 58(9), 119, 1969; and Bhatt, et al., Int. J. Pharm.,
50, 157, 1989] where low volumes of non-occlusive
volatile:non-volatile vehicles had been applied to the skin, the
extent of drug delivery was very limited. To date the only
formulations that have been employed clinically are either for
local therapies, such as topical minoxidil and topical
non-steroidal anti-inflammatories, or for transdermal drug delivery
of compounds which readily diffuse across the skin such as glyceryl
trinitrate and isosorbide dinitrate. As the permeability
coefficients of sex hormones, for example, are an order of
magnitude lower than glyceryl trinitrate, a marked penetration
enhancement effect would be needed to achieve clinically acceptable
transdermal drug delivery.
[0015] It is desirable to have a clinically acceptable
non-occlusive transdermal drug delivery system where the drug and
penetration enhancer undergoes rapid partitioning into the skin to
allow a convenient application time, leaving no residual
formulation on the skin surface, and maintaining good substantivity
within the skin. These characteristics can overcome problems such
as a loss of drug penetration or possibly a transfer of the drug
from the treated individual to another upon intimate contact, such
as that observed for a testosterone ointment being used for a male
patient, but which caused virilization in his female sexual partner
[Delance, et al., Lancet, 1, 276, 1984].
[0016] It is an object of the present invention to overcome or at
least alleviate one or more of the abovementioned disadvantages of
the prior art systems.
SUMMARY OF THE INVENTION
[0017] According to a first aspect of the present invention there
is provided a transdermal drug delivery system which comprises at
least one physiologically active agent or prodrug thereof and at
least one dermal penetration enhancer; characterised in that the
dermal penetration enhancer is a safe skin-tolerant ester
sunscreen.
[0018] The present invention also provides use of a safe
skin-tolerant ester sunscreen as a dermal penetration enhancer.
[0019] The present inventors have found a new class of dermal
penetration enhancers being skin-tolerant ester sunscreens, which
are generally considered safe by the FDA (U.S.). Compounds such as
octyl dimethyl-para-aminobenzoate (Padimate O) and octyl salicylate
have been extensively used over the last ten to twenty years as
safe and effective sunscreens in concentrations up to 8% v/v for
Padimate O and 5% v/v for octyl salicylate.
[0020] Dermal penetration enhancers of the present invention are
preferably esters of formula (I):
##STR00001##
[0021] wherein R.sup.1 is hydrogen, lower alkyl, lower alkoxy,
halide, hydroxy or NR.sup.3R.sup.4;
[0022] R.sup.2 is long chain alkyl;
[0023] R.sup.3 and R.sup.4 are each independently hydrogen, lower
alkyl or R.sup.3 and R.sup.4 together with the nitrogen atom to
which they are attached form a 5- or 6-membered heterocyclic
ring;
[0024] n is 0 or 1; and
[0025] q is 1 or 2.
[0026] More preferably the ester is a long chain alkyl
para-aminobenzoate, long chain alkyl dimethyl-para-aminobenzoate,
long chain alkyl cinnamate, long chain alkyl methoxycinnamate or
long chain alkyl salicylate; most preferably octyl
dimethyl-para-aminobenzoate, octyl para-methoxycinnamate, octyl
salicylate or isoamyl salicylate.
DETAILED DESCRIPTION OF THE INVENTION
[0027] The drug delivery systems according to the invention may
comprise any physiologically active agent together with the
penetration enhancer incorporated into a dosage form for topical
application to the skin or mucous membranes of animals. Suitable
dosage forms include creams, lotions, gels, ointments,
suppositories, mousses, spray, for example nasal sprays, aerosols,
buccal and sublingual tablets, gingival and buccal patches or any
one of a variety of transdermal devices for use in the continuous
administration of systematically active drugs by absorption through
the skin, oral mucosa or other membranes. Some examples of suitable
vehicles are given in U.S. Pat. Nos. 3,598,122, 3,598,123,
3,742,951, 3,814,097, 3,921,636, 3,993,072, 3,993,073, 3,996,934,
4,031,894, 4,060,084, 4,069,307, 4,201,211, 4,230,105, 4,292,299,
4,292,303, 5,323,769, 5,023,085, 5,474,783, 4,941,880 and U.S. Pat.
No. 4,077,407. These patents also disclose a variety of specific
systematically active agents which may also be useful in
transdermal delivery in adjunct to those of this invention. These
disclosures are thus hereby incorporated herein by reference.
[0028] Physiologically active agents that may be used in the
percutaneous or transdermal drug delivery system of the present
invention include any locally or systemically active agents which
are compatible with the dermal penetration enhancers of the present
invention and which can be delivered through the skin with the
assistance of the dermal penetration enhancer to achieve a desired
effect. These active agents (grouped by therapeutic class)
include:
[0029] Alimentary System
[0030] Antidiarrhoeals such as diphenoxylate, loperamide and
hyoscyamine.
[0031] Cardiovascular System
[0032] Antihypertensives such as hydralazine, minoxidil, captopril,
enalapril, clonidine, prazosin, debrisoquine, diazoxide,
guanethidne, methyldopa, reserpine, trimetaphan. Calcium channel
blockers such as diltiazem, felodopine, amlodipine, nitrendipine,
nifedipine and verapamil.
[0033] Antiarrhyrthmics such as amiodarone, flecamide,
disopyramide, procainamide, mexiletene and quinidine.
[0034] Antiangina agents such as glyceryl trinitrate, erythritol
tetranitrate, pentaerythritol tetranitrate, mannitol hexanitrate,
perhexylene, isosorbide dinitrate and nicorandil.
[0035] Beta-adrenergic blocking agents such as alprenolol,
atenolol, bupranolol, carteolol, labetalol, metoprolol, nadolol,
nadoxolol, oxprenolol, pindolol, propranolol, sotalol, timolol and
timolol maleate.
[0036] Cardiotonic glycosides such as digoxin and other cardiac
glycosides and theophylline derivatives.
[0037] Adrenergic stimulants such as adrenaline, ephedrine,
fenoterol, isoprenaline, orciprenaline, rimeterol, salbutamol,
salmeterol, terbutaline, dobutamine, phenylephrine,
phenylpropanolamine, pseudoephedrine and dopamine. Vasodilators
such as cyclandelate, isoxsuprine, papaverine, dipyrimadole,
isosorbide dinitrate, phentolamine, nicotinyl alcohol,
co-dergocrine, nicotinic acid, glyceryl trinitrate, pentaerythritol
tetranitrate and xanthinol.
[0038] Antimigraine preparations such as ergotamine,
dihydroergotamine, methysergide, pizotifen and sumatriptan.
[0039] Drugs Affecting Blood and Haemopoietic Tissues.
[0040] Anticoagulants and thrombolytic agents such as warfarin,
dicoumarol, low molecular weight heparins such as enoxaparin;
streptokinase and its active derivatives. Haemostatic agents such
as aprotinin, tranexamic acid and protamine.
[0041] Central Nervous System
[0042] Analgesics, antipyretics including the opiod analgesics-such
as buprenorphine, dextromoramide, dextropropoxyphene, fentanyl,
alfentanil, sufentanil, hydromorphone, methadone, morphine,
oxycodone, papavereturn, pentazocine, pethidine, phenoperidine,
codeine and dihydrocodeine. Others include acetylsalicylic acid
(aspirin), paracetamol, and phenazone.
[0043] Hypnotics and sedatives such as the barbiturates,
amylobarbitone, butobarbitone and pentobarbitone and other
hypnotics and sedatives such as choral hydrate, chlormethiazole,
hydroxyzine and meprobamate.
[0044] Antianxiety agents such as the benzodiazepines, alprazolam,
bromazepam, chlordiazepoxide, clobazam, chlorazepate, diazepam,
flunitrazepam, flurazepam, lorazepam, nitrazepam, oxazepam,
temazepam and triazolam. Neuroleptic and antipsychotic drugs such
as the phenothiazines, chlorpromazine, fluphenazine, pericyazine,
perphenazine, promazine, thiopropazate, thioridazine and
trifluoperazine and the butyrophenones, droperidol and haloperidol
and the other antipsychotic drugs such as pimozide, thiothixene and
lithium.
[0045] Antidepressants such as the tricyclic antidepressants
amitryptyline, clomipramine, desipramine, dothiepin, doxepin,
imipramine, nortriptyline, opipramol, protriptyline and
trimipramine and the tetracyclic antidepressants such as mianserin
and the monoamine oxidase inhibitors such as isocarboxazid,
phenelizine, tranylcypromine and moclobemide and selective
serotonin re-uptake inhibitors such as fluoxetine, paroxetine,
citalopram, fluvoxamine and sertraline.
[0046] CNS stimulants such as caffeine
[0047] Anti-alzheimer's agents such as tacrine
[0048] Antiparkinson agents such as amantadine, benserazide,
carbidopa, levodopa, benztropine, biperiden, benzhexyl,
procyclidine and dopamine-2 agonists such as
S(-)-2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetrali-n
(N-0923).
[0049] Anticonvulsants such as phenyloin, valproic acid, primidone,
phenobarbitone, methylphenobarbitone and carbamazepine,
ethosuximide, methsuximide, phensuximide, sulthiame and
clonazepam.
[0050] Antiemetics, antinauseants such as the phenothiazines,
prochloperazine, thiethylperazine and 5HT-3 receptor antagonists
such as ondansetron and granisetron and others such as
dimenhydrinate, diphenhydramine, metoclopramide, domperidone,
hyoscine, hyoscine hydrobromide, hyoscine hydrochloride, clebopride
and brompride.
[0051] Musculoskeletal System
[0052] Non-steroidal anti-inflammatory agents including their
racemic mixtures or individual enantiomers where applicable, such
as ibuprofen, flurbiprofen, ketoprofen, aclofenac, diclofenac,
aloxiprin, aproxen, aspirin, diflunisal, fenoprofen, indomethacin,
mefenamic acid, naproxen, phenylbutazone, piroxicam, salicylamide,
salicylic acid, sulindac, desoxysulindac, tenoxicam, tramadol and
ketoralac.
[0053] Additional non-steroidal antiinflammatory agents which can
be formulated in combination with the dermal penetration enhancers
include salicylamide, salicylic acid, flufenisal, salsalate,
triethanolamine salicylate, aminopyrine, antipyrine,
oxyphenbutazone, apazone, cintazone, flufenamic acid, clonixeril,
clonixin, meclofenamic acid, flunixin, colchicine, demecolcine,
allopurinol, oxypurinol, benzydamine hydrochloride, dimefadane,
indoxole, intrazole, mimbane hydrochloride, paranylene
hydrochloride, tetrydamine, benzindopyrine hydrochloide, fluprofen,
ibufenac, naproxol, fenbufen, cinchophen, diflumidone sodium,
fenamole, flutiazin, metazamide, letimide hydrochloride, nexeridine
hydrochloride, octazamide, molinazole, neocinchophen, nimazole,
proxazole citrate, tesicam, tesimide, tolmetin, and
triflumidate.
[0054] Antirheumatoid agents such as penicillamine,
aurothioglucose, sodium aurothiomalate, methotrexate and
auranofin.
[0055] Muscle relaxants such as baclofen, diazepam, cyclobenzaprine
hydrochloride, dantrolene, methocarbamol, orphenadrine and
quinine.
[0056] Agents used in gout and hyperuricaemia such as allopurinol,
colchicine, probenecid and sulphinpyrazone.
[0057] Hormones and Steroids
[0058] Oestrogens such as oestradiol, oestriol, oestrone,
ethinyloestradiol, mestranol, stilboestrol, dienoestrol,
epioestriol, estropipate and zeranol. Progesterone and other
progestagens such as allyloestrenol, dydrgesterone, lynoestrenol,
norgestrel, norethyndrel, norethisterone, norethisterone acetate,
gestodene, levonorgestrel, medroxyprogesterone and megestrol.
[0059] Antiandrogens such as cyproterone acetate and danazol.
[0060] Antioestrogens such as tamoxifen and epitiostanol and the
aromatase inhibitors, exemestane and 4-hydroxy-androstenedione and
its derivatives. Androgens and anabolic agents such as
testosterone, methyltestosterone, clostebol acetate, drostanolone,
furazabol, nandrolone oxandrolone, stanozolol, trenbolone acetate,
dihydro-testosterone, 17-.alpha.-methyl-19-nortestosterone and
fluoxymesterone. 5-alpha reductase inhibitors such as finasteride,
turosteride, LY-191704 and MK-306.
[0061] Corticosteroids such as betamethasone, betamethasone
valerate, cortisone, dexamethasone, dexamethasone 21-phosphate,
fludrocortisone, flumethasone, fluocinonide, fluocinonide desonide,
fluocinolone, fluocinolone acetonide, fluocortolone, halcinonide,
halopredone, hydrocortisone, hydrocortisone 17-valerate,
hydrocortisone 17-butyrate, hydrocortisone 21-acetate
methylprednisolone, prednisolone, prednisolone 21-phosphate,
prednisone, triamcinolone, triamcinolone acetonide.
[0062] Further examples of steroidal antiinflammatory agents for
use in the instant compositions include cortodoxone,
fluoracetonide, fludrocortisone, difluorsone diacetate,
flurandrenolone acetonide, medrysone, amcinafel, amcinafide,
betamethasone and its other esters, chloroprednisone,
clorcortelone, descinolone, desonide, dichlorisone, difluprednate,
flucloronide, flumethasone, flunisolide, flucortolone,
fluoromethalone, fluperolone, fluprednisolone, meprednisone,
methylmeprednisolone, paramethasone, cortisone acetate,
hydrocortisone cyclopentylpropionate, cortodoxone, flucetonide,
fludrocortisone acetate, flurandrenolone acetonide, medrysone,
amcinafal, amcinafide, betamethasone, betamethasone benzoate,
chloroprednisone acetate, clocortolone acetate, descinolone
acetonide, desoximetasone, dichlorisone acetate, difluprednate,
flucloronide, flumethasone pivalate, flunisolide acetate,
fluperolone acetate, fluprednisolone valerate, paramethasone
acetate, prednisolamate, prednival, triamcinolone hexacetonide,
cortivazol, formocortal and nivazol.
[0063] Pituitary hormones and their active derivatives or analogs
such as corticotrophin, thyrotropin, follicle stimulating hormone
(FSH), luteinising hormone (LH) and gonadotrophin releasing hormone
(GnRH).
[0064] Hypoglycaemic agents such as insulin, chlorpropamide,
glibenclamide, gliclazide, glipizide, tolazamide, tolbutamide and
metformin.
[0065] Thyroid hormones such as calcitonin, thyroxine and
liothyronine and antithyroid agents such as carbimazole and
propylthiouracil.
[0066] Other miscelaneous hormone agents such as octreotide.
[0067] Pituitary inhibitors such as bromocriptine.
[0068] Ovulation inducers such as clomiphene.
[0069] Genitourinary System
[0070] Diuretics such as the thiazides, related diuretics and loop
diuretics, bendrofluazide, chlorothiazide, chlorthalidone,
dopamine, cyclopenthiazide, hydrochlorothiazide, indapamide,
mefruside, methycholthiazide, metolazone, quinethazone, bumetanide,
ethacrynic acid and frusemide and potassium sparing diuretics,
spironolactone, amiloride and triamterene.
[0071] Antidiuretics such as desmopressin, lypressin and
vasopressin including their active derivatives or analogs.
[0072] Obstetric drugs including agents acting on the uterus such
as ergometrine, oxytocin and gemeprost.
[0073] Prostaglandins such as alprostadil (PGE1), prostacyclin
(PGl2), dinoprost (prostaglandin F2-alpha) and misoprostol.
[0074] Antimicrobials
[0075] Antimicrobials including the cephalosporins such as
cephalexin, cefoxytin and cephalothin.
[0076] Penicillins such as amoxycillin, amoxycillin with clavulanic
acid, ampicillin, bacampicillin, benzathine penicillin,
benzylpenicillin, carbenicillin, cloxacillin, methicillin,
phenethicillin, phenoxymethylpenicillin, flucloxacillin,
meziocillin, piperacillin, ticarcillin and azlocillin.
[0077] Tetracyclines such as minocycline, chlortetracycline,
tetracycline, demeclocycline, doxycycline, methacycline and
oxytetracycline and other tetracycline-type antibiotics.
[0078] Aminoglycosides such as amikacin, gentamicin, kanamycin,
neomycin, netilmicin and tobramycin.
[0079] Antifungais such as amorolfine, isoconazole, clotrimazole,
econazole, miconazole, nystatin, terbinafine, bifonazole,
amphotericin, griseofulvin, ketoconazole, fluconazole and
flucytosine, salicylic acid, fezatione, ticlatone, tolnaftate,
triacetin, zinc, pyrithione and sodium pyrithione.
[0080] Quinolones such as nalidixic acid, cinoxacin, ciprofloxacin,
enoxacin and norfloxacin. Sulphonamides such as
phthalylsulphthiazole, sulfadoxine, sulphadiazine, sulphamethizole
and sulphamethoxazole.
[0081] Sulphones such as dapsone.
[0082] Other miscellaneous antibiotics such as chloramphenicol,
clindamycin, erythromycin, erythromycin ethyl carbonate,
erythromycin estolate, erythromycin glucepate, erythromycin
ethylsuccinate, erythromycin lactobionate, roxithromycin,
lincomycin, natamycin, nitrofurantoin, spectinomycin, vancomycin,
aztreonam, colistin IV, metronidazole, tinidazole, fusidic acid and
trimethoprim; 2-thiopyridine N-oxide; halogen compounds,
particularly iodine and iodine compounds such as iodine-PVP complex
and diiodohydroxyquin; hexachlorophene; chlorhexidine; chloroamine
compounds; benzoylperoxide.
[0083] Antituberculosis drugs such as ethambutol, isoniazid,
pyrazinamide, rifampicin and clofazimine.
[0084] Antimalarials such as primaquine, pyrimethamine,
chloroquine, hydroxychloroquine, quinine, mefloquine and
halofantrine.
[0085] Antiviral agents such as acyclovir and acyclovir prodrugs,
famciclovir, zidovudine, didanosine, stavudine, lamivudine,
zalcitabine, saquinavir, indinavir, ritonavir, n-docosanol,
tromantadine and idoxuridine.
[0086] Anthelmintics such as mebendazole, thiabendazole,
niclosamide, praziquantel, pyrantel embonate and
diethylcarbamazine.
[0087] Cytotoxic agents such as plicamycin, cyclophosphamide,
dacarbazine, fluorouracil and its prodrugs [described, for example,
in International Journal of Pharmaceutics 111, 223-233 (1994)],
methotrexate, procarbazine, 6-mercaptopurine and mucophenolic
acid.
[0088] Metabolism
[0089] Anorectic and weight reducing agents including
dexfenfluramine, fenfluramine, diethylpropion, mazindol and
phentermine.
[0090] Agents used in hypercalcaemia such as calcitriol,
dihydrotachysterol and their active derivatives or analogs.
[0091] Respiratory System
[0092] Antitussives such as ethylmorphine, dextromethorphan and
pholcodine.
[0093] Expectorants such as acetylcysteine, bromhexine, emetine,
guaiphenesin, ipecacuanha ans saponins.
[0094] Decongestants such as phenylephrine, phenylpropanolamine ans
pseudoephedrine.
[0095] Bronchospasm relaxants such as ephedrine, fenoterol,
orciprenaline, rimiterol, salbutamol, sodium cromoglycate,
cromoglycic acid and its prodrugs [described, for example, in
International Journal of Pharmaceutics 7, 63-75 (1980)],
terbutaline, ipratropium bromide, salmeterol and theophylline and
theophylline derivatives.
[0096] Allergy and Immune System
[0097] Antihistamines such as meclozine, cyclizine, chlorcyclizine,
hydroxyzine, brompheniramine, chlorpheniramine, clemastine,
cyproheptadine, dexchlorpheniramine, diphenhydramine,
diphenylamine, doxylamine, mebhydrolin, pheniramine, tripolidine,
azatadine, diphenylpyraline, methdilazine, terfenadine, astemizole,
loratidine and cetirizine.
[0098] Local anaesthetics such as bupivacaine, amethocaine,
lignocaine, cinchocaine, dibucaine, mepivacaine, prilocalne and
etidocaine.
[0099] Stratum corneum lipids, such as ceramides, cholesterol and
free fatty acids, for improved skin barrier repair [Man, et al. J.
Invest. Dermatol., 106(5), 1096, 1996].
[0100] Neuromuscular blocking agents such as suxamethonium,
alcuronium, pancuronium, atracurium, gallamine, tubocurarine and
vecuronium.
[0101] Smoking cessation agents such as nicotine, bupropion and
ibogaine.
[0102] Insecticides and other pesticides which are suitable for
local or systemic application.
[0103] Dermatological agents, such as vitamins A and E, vitamin E
acetate and vitamin E sorbate.
[0104] Allergens for desensitisation such as house dust mite
allergen.
[0105] Nutritional agents, such as vitamins, essential amino acids
and essential fats.
[0106] Keratolytics such as the alpha-hydroxy acids, glycollic acid
and salicylic acid.
[0107] Psychicenergisers, such as 3-(2-aminopropyl)indole,
3-(2-aminobutyl)indole, and the like.
[0108] Anti-acne agents such as containing isotretinoin, tretinoin
and benzoyl peroxide.
[0109] Anti-psoriasis agents such as containing etretinate,
cyclosporin and calcipotriol.
[0110] Anti-itch agents such as capsaicin and its derivatives such
as nonivamide [Tsai, et al. Drug. Dev. Ind. Pharm., 20(4), 719,
1994].
[0111] Anticholinergic agents, which are effective for the
inhibition of axillary sweating and for the control of prickly
heat. The antiperspirrant activity of agents such as methatropine
nitrate, propantheline bromide, scopolamine, methscopolamine
bromide, and the new class of soft antiperspirants, quaternary
acyloxymethyl ammonium salts [described, for example, by Bodor et
al, J. Med. chem. 23, 474 (1980) and also in United Kingdom
Specification No. 2010270, published Jun. 27, 1979].
[0112] Other physiologically active peptides and proteins, small to
medium-sized peptides, e.g., vasopressin and human growth
hormone.
[0113] Whilst it is preferred that the active agent and penetration
enhancer be delivered by simultaneous administration, the
penetration enhancer may be applied before or after the application
of the physiologically active agent, if desired.
[0114] The present invention also provides a transdermal drug
delivery system which comprises at least one physiologically active
agent or prodrug thereof, at least one dermal penetration enhancer
and at least one volatile liquid; characterised in that the dermal
penetration enhancer is a safe skin-tolerant ester sunscreen.
[0115] According to a second aspect of the present invention there
is provided a non-occlusive, percutaneous or transdermal drug
delivery system which comprises:
[0116] (i) an effective amount of at least one physiologically
active agent or prodrug thereof;
[0117] (ii) at least one non-volatile dermal penetration enhancer;
and
[0118] (iii) at least one volatile liquid; characterised in that
the dermal penetration enhancer is adapted to transport the
physiologically active agent across a dermal surface or mucosal
membrane of an animal, including a human, when the volatile liquid
evaporates, to form a reservoir or depot of a mixture comprising
the penetration enhancer and the physiologically active agent or
prodrug within said surface or membrane; and the dermal penetration
enhancer is of low toxicity to, and is tolerated by, the dermal
surface or mucosal membrane of the animal.
[0119] The present invention also provides a method for
administering at least one systemic or locally acting
physiologically active agent or prodrug thereof to a animal which
comprises applying an effective amount of the physiologically
active agent in the form of a drug delivery system according to the
present invention.
[0120] Furthermore, the present invention provides a method for the
treatment or prophylaxis of a disease or condition in a animal
which comprises administering to a dermal surface or mucosal
membrane of said animal in need of such treatment a therapeutically
effective amount of a drug delivery system according to the present
invention.
[0121] The invention further provides apparatus for the controlled
application of an aerosol or spray composition to the dermal
surface or mucosal membrane of an animal, which comprises a shroud
as described hereinafter.
[0122] Preferably the animal is a human but the invention also
extends to the treatment of non-human animals.
[0123] Preferably the non-occlusive drug delivery system is not
supersaturated with respect to the physiologically active agent or
prodrug. As the volatile liquid of the non-occlusive drug delivery
system evaporates, the resulting non-volatile composition is
rapidly driven into the dermal surface or mucosal membrane. It is
possible that as the volatile liquid evaporates, the non-volatile
dermal penetration enhancer becomes supersaturated with respect to
the active agent. However, it is preferred that any supersaturation
does not occur before transport of the resulting non-volatile
composition across the epidermal surface has occurred.
[0124] It is most desirable that, after application of the
non-occlusive, percutaneous or transdermal drug delivery system,
the volatile component of the delivery system evaporates and the
area of skin to which the drug delivery system was applied becomes
touch-dry. Preferably said area of skin becomes touch-dry within 10
minutes, more preferably within 3 minutes, most preferably within 1
minute.
[0125] The group of dermal penetration enhancing ester sunscreen
compounds of the present invention are particularly suitable for
non-occlusive transdermal delivery of active agents through the
skin and membranes of a animal. These dermal penetration enhancing
compounds are of low toxicity to the skin and are excellent
promoters of percutaneous and oral mucosal (especially gingival)
absorption. In addition to the dermal penetration enhancers of the
present invention, known dermal penetration enhancers may be
employed in the non-occlusive transdermal drug delivery system of
the present invention. These known dermal penetration enhancers
include laurocapram (Azone.RTM.) and laurocapram derivatives, such
as those 1-alkylazacycloheptan-2-ones specified in U.S. Pat. No.
5,196,410, and oleic acid and its ester derivatives, such as
methyl, ethyl, propyl, isopropyl, butyl, vinyl and
glycerylmonooleate, and sorbitan esters such as sorbitan
monolaurate and sorbitan monooleate, and other fatty acid esters
such as isopropyl laurate, isopropyl myristate, isopropyl
palmitate, diisopropyl adipate, propylene glycol monolaurate and
propylene glycol monooleate, and long chain alkyl esters of
2-pyrrolidone, particularly the 1-lauryl, 1-hexyl and
1-(2-ethylhexyl) esters of 2-pyrollidene and those dermal
penetration enhancers given in U.S. Pat. No. 5,082,866,
particularly dodecyl (N,N-dimethylamino) acetate and dodecyl
(N,N-dimethylamino) propionate and in U.S. Pat. No. 4,861,764,
particularly 2-n-nonyl-1-3-dioxolane.
[0126] Preferred known dermal penetration enhancers are laurocapram
and laurocapram derivatives, such as those
1-alkylazacycloheptan-2-ones specified in U.S. Pat. No. 5,196,410,
and oleic acid and its ester derivatives, such as methyl, ethyl,
propyl, isopropyl, butyl, vinyl and glycerylmonooleate, and those
given in U.S. Pat. No. 5,082,866, particularly dodecyl
(N,N-dimethylamino) acetate and dodecyl (N,N-dimethylamino)
propionate and in U.S. Pat. No. 4,861,764, particularly
2-n-nonyl-1-3-dioxolane. Most preferred known dermal penetration
enhancers are oleic acid and its ester derivatives, such as methyl,
ethyl, propyl, isopropyl, butyl, vinyl and glycerylmonooleate, and
those given in U.S. Pat. No. 5,082,866, particularly dodecyl
(N,N-dimethylamino) acetate and dodecyl (N,N-dimethylamino)
propionate and in U.S. Pat. No. 4,861,764, particularly
2-n-nonyl-1-3-dioxolane.
[0127] Preferred volatile liquids of the present invention include
safe skin-tolerant solvents such as ethanol and isopropanol. An
aerosol propellant, such as dimethyl ether, may constitute a
volatile liquid for the purpose of the present invention.
[0128] Surprisingly the group of dermal penetration compounds
identified enhance the absorption of active agents and prodrugs
thereof through the skin and mucous membranes while avoiding the
significant pharmacological disadvantages and toxicities of prior
art enhancers. Additionally, the group of compounds of the
invention surprisingly exhibit appreciable penetration into and
substantivity for the outer layers of the skin, namely the stratum
corneum which has previously presented a formidable barrier to
percutaneous drug absorption.
[0129] In drug delivery systems according to the first aspect of
the present invention a pharmaceutical compounding agent,
co-solvent, surfactant, emulsifier, antioxidant, preservative,
stabiliser, diluent or a mixture of two or more of said components
may be incorporated in these systems as is appropriate to the
particular route of administration and dosage form. The amount and
type of components used should be compatible with the dermal
penetration enhancers of this invention as well as with the active
ingredient. A co-solvent or other standard adjuvant, such as a
surfactant, may be required to maintain the agent in solution or
suspension at the desired concentration.
[0130] The pharmaceutical compounding agents can include paraffin
oils, esters such as isopropyl myristate, ethanol, silicone oils
and vegetable oils. These are preferably used in the range 1 to
50%. Surfactants such as ethoxylated fatty alcohols, glycerol mono
stearate, phosphate esters, and other commonly used emulsifiers and
surfactants preferably in the range of 0.1 to 10% may be used, as
may be preservatives such as hydroxybenzoate esters for
preservation of the compound preferably in amounts of 0.01% to
0.5%. Typical co-solvents and adjuvants may be ethyl alcohol,
isopropyl alcohol, acetone, dimethyl ether and glycol ethers such
as diethylene glycol mono ethyl ether. These may be used in amounts
of 1 to 50%.
[0131] In drug delivery systems according to the second aspect of
the present invention, whilst a pharmaceutical compounding agent,
co-solvent, surfactant, emulsifier, antioxidant, preservative,
stabiliser, diluent or a mixture of two or more of said components
may be incorporated, these must be compatible with the ability of
the system to become touch-dry after application.
[0132] Because of the effect of the penetration enhancer of the
invention, the dosage of the physiologically active agent may often
be less than that conventionally used. It is proposed that, a
dosage near the lower end of the useful range of the particular
agent may be employed initially and increased as indicated from the
observed response if necessary.
[0133] The concentration of physiologically active agent used in
the drug delivery system will depend on its properties and may be
equivalent to that-normally utilised for the particular agent in
conventional formulations. Both the amount of physiologically
active agent and the amount of penetration enhancer will be
influenced by the type of effect desired. For example, if a more
localised effect is required in treating a superficial infection
with an antibacterial agent, lower amounts of physiologically
active agents and lower concentrations of enhancer may be
appropriate. Where deeper penetration is desired, as in the case of
local anaesthesia, a higher concentration of enhancer may be
appropriate.
[0134] Where it is desired to achieve systemic concentration of an
agent, proportionately higher concentrations of the enhancer of the
invention may be required in the transdermal drug delivery system
of the present invention, and the amount of active substance
included in the composition should be sufficient to provide the
blood level desired.
[0135] The concentration of absorption/penetration enhancer may be
in the range from 10-10,000 weight percent of
absorption/penetration enhancer based upon the weight of active
ingredient. The ratio of penetration enhancer to active ingredient
may vary considerably and will be governed as much as anything, by
the pharmacological results that are required to be achieved. In
principle, it is desirable that as little absorption enhancer as
possible is used. On the other hand, for some actives, it may well
be that the upper range of 10,000% by weight will be required. It
is preferred that the penetration enhancer and active are in
approximately equal proportions.
[0136] Surprisingly, it has been found that a large range of
systemic drugs can be delivered to a subject in need thereof by the
non-occlusive drug delivery system and methods of the present
invention. That is, the drug delivery system delivers the
physiologically active agent to a animal without the need for an
occlusive patch device. The efficacy of known systemic drug
delivery systems, and in particular transdermal patch devices is
maintained, and in some cases is increased by use of non-occlusive,
percutaneous or transdermal drug delivery systems of the present
invention.
[0137] A particular advantage of the non-occlusive drug delivery
system of the present invention is that patient compliance is
improved as the system does not occlude the skin or membrane and
therefore local irritation and allergic sensitisation problems
arising from prolonged exposure of the skin to both the delivery
system of occlusive transdermal patch devices and the adhesive used
to affix these patches to the skin are reduced.
[0138] The following definitions apply through this description and
the claims which follow.
[0139] The term "mucous membrane" refers generally to any of the
mucous membranes in the body, absorption through the mucous
membranes of the oral cavity which is of particular interest. Thus,
buccal, sublingual, gingival and palatal absorption are
specifically contemplated by the present invention. In a preferred
embodiment, the penetration enhancers of the present invention are
used to improve absorption through those oral tissues which most
resemble the skin in their cellular structure, i.e. the gingiva and
palate.
[0140] The term "physiologically active agent" is used herein to
refer to a broad class of useful chemical and therapeutic
agents.
[0141] The term "physiologically active" in describing the agents
contemplated herein is used in a broad sense to comprehend not only
agents having a direct pharmacological effect on the host, but also
those having an indirect or observable effect which is useful in
the medical arts.
[0142] A "prodrug" of a physiologically active agent herein means a
structurally related compound or derivative of an active compound
which in the animal body is converted to the desired
physiologically active compound. The prodrug itself may have little
or none of the desired activity.
[0143] The terms "percutaneous" and "transdermal" are used herein
in the broadest sense to refer to being able to pass through
unbroken skin.
[0144] The term "dermal penetration enhancer" is used herein in its
broadest sense to refer to an agent which improves the rate of
percutaneous transport of active agents across the skin for use and
delivery of active agents to organisms such as animals, whether it
be for local application or systemic delivery.
[0145] The term "non-occlusive" is used herein in its broadest
sense to refer to not trapping or closing the skin to the
atmosphere by means of a patch device, fixed reservoir, application
chamber, tape, bandage, sticking plaster, or the like which remains
on the skin at the site of application for a prolonged length of
time.
[0146] The term "stratum corneum" is used herein in its broadest
sense to refer to the outer layer of the skin, which is comprised
of (approximately 15) layers of terminally differentiated
keratinocytes made primarily of the proteinaceous material keratin
arranged in a `brick and mortar` fashion with the mortar being
comprised of a lipid matrix made primarily from cholesterol,
ceramides and long chain fatty acids. The stratum corneum creates
the rate-limiting barrier for diffusion of the active agent across
the skin.
[0147] The term "skin-depot" is used herein in its broadest sense
to refer to a reservoir or deposit of active agent and dermal
penetration enhancer within the stratum corneum, whether it be
intra-cellular (within keratinocytes) or inter-cellular.
[0148] The term "volatile:non-volatile liquid vehicle" is used in
the art to refer to a liquid pharmaceutical vehicle comprising a
volatile liquid mixed with a non-volatile liquid vehicle, such as a
dermal penetration enhancer. A system or vehicle comprising a
volatile liquid mixed with a non-volatile dermal penetration
enhancer when described herein is used in its broadest sense to
include those systems known as volatile:non-volatile liquid
vehicles.
[0149] Alkyl and alkoxy groups referred to herein may be either
straight chain or branched. The term "lower alkyl" means alkyl
groups containing from 1 to 5 arbon atoms. The term "lower alkoxy
has a similar meaning. The term "long chain alkyl" means alkyl
groups containing from 5 to 18 carbon atoms, more preferably 6 to
18 carbon atoms. The term "halide" means fluoride, chloride,
bromide or iodide. The term "heterocyclic ring" is herein defined
to mean a ring of carbon atoms containing at least one hetero atom,
and further the ring may be saturated or unsaturated to any
allowable degree.
[0150] The term "sunscreen" is used herein in its broadest sense to
refer to a chemical agent capable of filtering out ultraviolet
light.
[0151] The non-occlusive, percutaneous or transdermal drug delivery
system of the present invention enables a wide range of
physiologically active agents to be delivered through the skin to
achieve a desired systemic effect. The drug delivery system
preferably comprises the active agent intimately mixed with a
non-volatile dermal penetration enhancer and a volatile liquid.
Where the drug delivery system is applied to the skin, the active
agent and non-volatile liquid are thermodynamically driven into the
skin as the volatile liquid evaporates. Once within the skin the
non-volatile liquid may either disrupt the lipid matrix and/or act
as a solubilizer to allow an enhanced penetration rate of the
active agent through the skin and into the subject being treated.
In this way, the dermal penetration enhancer acts as a vehicle and
many systemic active agents are able to be transdermally
administered to an animal.
[0152] It is believed that the non-volatile dermal penetration
enhancer is readily absorbed into the stratum corneum in sufficient
quantities to form a reservoir or depot of the dermal penetration
enhancer within the stratum corneum. The dermal penetration
enhancer also contains the active agent to be administered and as
the dermal penetration enhancer crosses through the skin to form
the skin-depot, the active agent contained therein is transported
through the skin and contained within the depot. These depots are
believed to form within the lipid matrix of the stratum corneum
wherein the lipid matrix creates a rate-limiting barrier for
diffusion of the active agent across the skin and allows the
dermally administered active agent to be systemically released over
a period of time, usually up to 24 hours.
[0153] Once the volatile liquid of the non-occlusive drug delivery
system has evaporated, driving the mixture of non-volatile dermal
penetration enhancer and active agent into the stratum corneum, the
outer surface of the skin is then substantially free of active
agent and non-volatile dermal penetration enhancer. Normal
touching, wearing of clothes, rinsing or even washing of the skin
will not, to any significant extent, affect delivery of the drug or
displace either the active agent or the non-volatile dermal
penetration enhancer, once the volatile liquid has evaporated.
[0154] This is in contrast to prior-art systems where
supersaturated solutions are used to increase the rate of drug
permeation across the skin. Such supersaturated solutions are
susceptible to ready precipitation and require stabilization, such
as with polymers, or protection from external surfaces or objects
which may effect nucleation.
[0155] The rate of absorption of the physiologically active agent
via the stratum corneum is increased by the non-volatile dermal
penetration enhancer. The active agent may be dissolved or
suspended in the dermal penetration enhancer at the time when it is
being transported from the surface of the skin and into the stratum
corneum. The performance of the dermal penetration enhancer to
deliver a desired active agent varies with differences in both the
nature of the dermal penetration enhancer and active agent. It is
understood that different dermal penetration enhancers may need to
be selected to be appropriate for delivery of various active
agents.
[0156] Physiologically active agents that may be used in the
percutaneous or transdermal drug delivery system of the present
invention include any locally or systemically active agents which
are compatible with the non-volatile dermal penetration enhancers
and volatile liquids of the present invention and which can be
delivered through the skin with the assistance of the dermal
penetration enhancer to achieve a desired effect.
[0157] Preferred active agents include steroids and other hormone
derivatives, more preferably testosterone, oestradiol,
ethinyloestradiol, progesterone, norethisterone acetate and
gestodene; and non-steroidal anti-inflammatory drugs, preferably
ibuprofen, ketoprofen, flurbiprofen, naproxen and diclofenac; and
opioid analgesics, preferably fentanyl and buprenorphine; and
antinauseants, preferably prochlorperazine, metochlopramide,
ondansetron and scopolamine; and antioestrogens, preferably
tamoxifen and epitiostanol and the aromatase inhibitors, preferably
exemestane and 4-hydroxy-androstenedione and its derivatives; and
5-alpha reductase inhibitors, preferably finasteride, turosteride,
LY191704 and MK-306; and anxiolytics, preferably alprazolam; and
prostaglandins, preferably alprostadil and prostacylcin and their
derivatives; and melatonin; and anti-virals, preferably
n-docosanol, tromantadine and lipophilic pro-drugs of acyclovir;
and low molecular weight heparin, preferably enoxaparin; and
anti-migraine compounds, preferably sumatriptan; and
antihypertensives, preferably clonidine, amlodipine and
nitrendipine; and anti-malarials, preferably primaquine; and
minoxidil and minoxidil pro-drugs; and pilocarpine; and
bronchodilators, preferably salbutamol, terbutaline, salmeterol;
and anti-depressants, preferably ibogaine, bupropion and rolipram;
and anti-alzheimer's agents, preferably fluphenazine and
haloperidol; and anti-parkinson agents, preferably N-0923; and
antiandrogens, preferably cyproterone acetate; and anorectic
agents, preferably mazindol.
[0158] Diseases or conditions that may be treated by using the drug
delivery system and methods of the present invention include, but
are not limited to, male hormone replacement in testosterone
deficient hypogonadal men, female hormone replacement therapy for
postmenopausal women, androgen replacement therapy for females
lacking libido, male contraception, female contraception, soft
tissue injury, narcotic withdrawal, severe post-operative pain,
motion sickness, oestrogen dependent breast cancer, prostatic
enlargement and/or prostatic cancer, alopecia and acne, anxiety
disorders, male impotence, Raynauds syndrome and varicose veins,
sleep disorders such as jetlag, herpes virus infections, deep vein
thrombosis, migraine, high blood pressure, malaria, diagnosis of
cystic fibrosis and asthma, particularly nocturnal asthma, smoking
cessation, psychotic disorders, severe postnatal depression,
virilisation and obesity.
[0159] The foregoing lists are by no means intended to be
exhaustive and any physiologically active agent that is compatible
with the preferred volatile liquids and non-volatile dermal
penetration enhancers of the drug delivery system may be applied by
the method of the present invention to treat any appropriate
disease or condition.
[0160] The drug delivery system of the present invention may be
applied to the skin by means of an aerosol, spray, pump-pack,
brush, swab, or other applicator. Preferably, the applicator
provides either a fixed or variable metered dose application such
as a metered dose aerosol, a stored-energy metered dose pump or a
manual metered dose pump. The application is most preferably
performed by means of a topical metered dose aerosol combined with
an actuator nozzle shroud which together accurately control the
amount and/or uniformity of the dose applied. One function of the
shroud is to keep the nozzle at a pre-determined height above, and
perpendicular to, the skin or membrane to which the drug delivery
system is being applied. This function may also be achieved by
means of a spacer-bar or the like. Another function of the shroud
is to enclose the area above the skin or membrane in order to
prevent or limit bounce-back and/or loss of the drug delivery
system to the surrounding environment. Preferably the area of
application defined by the shroud is substantially circular in
shape.
[0161] The drug delivery system may be propelled by either pump
pack or more preferably by the use of propellants such as
hydrocarbons, hydro fluorocarbons, nitrogen, nitrous oxide, carbon
dioxide or ethers, preferably dimethyl ether. The non-occlusive,
drug delivery system is preferably in a single phase system as this
allows less complicated manufacture and ease of dose uniformity. It
may also be necessary to apply a number of dosages on untreated
skin to obtain the desired result.
[0162] The invention will now be described with reference to the
following examples and accompanying drawings. The examples and
drawings are not to be construed as limiting the invention in any
way. They are included to further illustrate the present invention
and advantages thereof.
[0163] In the drawings:
[0164] FIG. 1 is a diagrammatic representation showing the halves
of a stainless steel flow-through diffusion cell.
[0165] FIG. 2 is a graphical representation showing the effect of
pretreatment with various enhancers on the diffusion of ketoprofen
across shed snake skin.
[0166] FIG. 3 is a graphical representation showing the effect of
various enhancers on the diffusion of ketoprofen across shed snake
skin.
[0167] FIG. 4 is a graphical representation showing the diffusion
of ibuprofen from gel formulations across shed snake skin.
[0168] FIG. 5 is a graphical representation showing the plasma
profile of testosterone in domestic weanling pigs after a single
application of a metered dose topical aerosol. Error bars represent
standard error of the mean.
[0169] FIG. 6 is a graphical representation showing the plasma
profile of estradiol in domestic weanling pigs after a single
application of a metered dose topical aerosol. Error bars represent
standard error of the mean.
[0170] FIG. 7 is a graphical representation showing the plasma
profile of testosterone in castrated domestic weanling pigs after
the sixth once daily application of a metered dose topical aerosol.
Each point represents the mean of 4 individual values and the error
bars represent standard error of the mean. Testosterone levels
shown are baseline subtracted and the mean baseline (.+-.sem) on
Day 1 at 0 h was 0.8 ngml.sup.-1.+-.0.3 ngm.sup.-1.
[0171] FIG. 8 is a graphical representation showing the predicted
testosterone input across human skin in vivo and children's python
snake skin in vitro. Error bars represent standard error of the
mean.
[0172] FIG. 9 is a graphical representation showing the predicted
testosterone plasma concentration in hypogonadal males after once
daily dosing to steady-state with a metered dose topical spray.
[0173] In the examples, the effectiveness of the penetration
enhancers are illustrated by measuring the skin penetration of
formulations of a number of representative physiologically active
agents with the dermal penetration enhancers. Also, the skin
penetration of physiologically active agents was measured with
other prior art penetration enhancers as well as formulations of
the physiologically active agents with common adjuvants, which
serve as control formulations. The comparisons made generally
consisted of measuring the relative penetration through shed snake
skin of the various formulations. In every case, those formulations
which contained the dermal penetration enhancers delivered more of
the active agent through the skin than did the corresponding
control formulation or commercial preparation.
[0174] In Vitro Skin Diffusion Measurements
[0175] Shed Snake Skin
[0176] The Children's python shed snake skin was obtained during
natural shedding and the dorsal skin was used. Shed snake skin has
shown to be a suitable model membrane for human skin by Itoh, et
al., Use of Shed Snake Skin as a Model Membrane for In Vitro
Percutaneous Penetration Studies: Comparison with Human Skin,
Pharm. Res., 7(10), 1042-1047, 1990; and Rigg, et al., Shed Snake
Skin and Hairless Mouse Skin as Model Membranes for Human Skin
During Permeation Studies, J. Invest. Dermatol., 94; 235-240,
1990.
[0177] Full Thickness Skin
[0178] The animals used in these investigations were obtained from
the animal house at the Victorian College of Pharmacy, Monash
University, Parkville, Australia.
[0179] a. Hairless Mouse Skin
[0180] Hairless mice of 4-8 weeks of age were used. The mouse skin
was excised and full-thickness skin was isolated from the torso,
the subcutaneous fat and connective tissue removed and the skin cut
into circles of 2.0 cm.sup.2, then placed into the diffusion cells
for flux measurements.
[0181] b. Guinea Pig Skin
[0182] Adult guinea pigs of either sex (weight range 500 g-750 g)
were used. The hair on the back flank and back was removed with the
aid of depilatory wax (Arielle.RTM.) under halothane ahaesthesia.
Seven days later, after the stratum corneum had completely
regenerated, the guinea pigs were killed and the skin removed and
placed on a chilled slab. The subcutaneous fat and connective
tissue removed and the skin cut into circles and then placed into
the diffusion cells for flux measurements. For in vivo experiments
the guinea pigs were housed in individual cages and the topical
hydroquinone formulations were applied to the hair-free areas. Each
guinea pig received the test or control formulation on the
corresponding contralateral site, thus allowing each animal to act
as its own control.
[0183] In Vitro Skin Diffusion Experiments in Franz-Type Cells
[0184] The work using Hydroquinone was performed using vertical
Franz diffusion cells which had an effective diffusional area of
1.3 cm.sup.2, a receiver chamber temperature of 37 or 32 degrees
Celsius and receiver chamber volume of 13 mL of normal saline.
[0185] In Vitro Skin Diffusion Experiments in Horizontal Diffusion
Cells
[0186] A modified stainless steel flow-through diffusion cell
assembly based on that first shown by Cooper in J. Pharm. Sci.
73(8), 1984, was used to perform the experiments on diffusion of
the drugs from various donor compositions through the skin (either
snake or hairless mouse). The flow-through diffusion cell used to
perform the present experiments is shown in FIG. 1. The cell
consists of an upper section (1) and a lower section (2). A
stainless steel wire mesh support (4) is housed in a recess (5) in
the lower section of the cell. The skin sample (3), cut into a
circle, is gently placed over the support (4) and the two sections
(1, 2) of the cells are secured together by screws (not shown),
using the locating holes (9), to form a tight seal. An aperture (8)
in the upper section of the cell, which has an area of 0.79
cm.sup.2 (0.5 cm in diameter) forms a well above the skin into
which the topical formulation is applied. In most cases 400 microL
of formulation, solution or suspension containing the drug
substance to be tested was applied evenly over the skin. The bottom
section of the cell is provided with inlet (6) and outlet (7) tubes
which connect to the bottom of the recess (5) and through which a
receptor solution was pumped by a microcassette peristaltic pump
(Watson Marlow, UK) (not shown) at a constant flow rate to maintain
sink conditions. The receptor solution consisted of 50% propylene
glycol in water, made isotonic with 0.9% sodium chloride and
preserved with 0.1% sodium azide or 0.1% sodium fluoride. To
prevent air bubbles forming under the skin, the wire mesh (4)
ensures turbulent receptor flow. The recess (5) is filled with
receptor solution prior to placing the skin in the cell. The
receptor solution was degassed by spraying the solution into fine
droplets under vacuum while stirring at 40.degree. C. Degassing was
repeated three times. These precautions eliminated the need for a
bubble chamber in the diffusion cell. The diffusion cells were set
on a hollow metal heater bar which maintained normal skin
temperature of 32.degree. C. (.+-.0.5.degree. C.) means of heated,
circulating water (Thermomix, Braun, Germany). Each diffusion cell
had its receptor solution collected via tube (7) into polyethylene
vials (6 ml liquid scintillation vials, Packard instruments,
Netherlands) at two or four hour intervals for 24 hours, by means
of an automated rotating fraction collector (Retriever II, ISCO,
Australia). The amount of drug in each vial containing receptor
solution was determined by reverse phase HPLC. Prior to analysis
each vial was weighed with an analytical balance (Mettler AT261,
Australia) and the volume calculated from the density of the
receptor solution which was 1.0554 g/cm.sup.3 at 22.degree. C.
[0187] The concentration of applied drug in each diffusion cell
sample was measured using high pressure liquid chromatography
(HPLC). The receptor solution was assayed neat, with 20 microL
injected (WISP 712 autoinjector, Waters, Australia) into a freshly
prepared and degassed (by filtering) mobile phase. Each drug was
separated using a pre column fitted with a C18 insert and a
.mu.Bandapak C18 (30 cm.times.3.9 nm) HPLC column (Waters).
Absorbance was measured at the appropriate wavelength using a
Waters tuneable absorbance detector and peak area was plotted and
integrated using a Shimadzu C-R3A chromatopac integrator. The
results reported for each experiment are the average values of four
replicate diffusion cells unless stated otherwise. The assay
conditions used for each different drug are given in each
example.
EXAMPLE 1
[0188] The in vitro diffusion cell method described above was used
to compare the penetration of 400 microL of 2% w/v ketoprofen in
70% v/v aqueous ethanol applied to the shed snake skin following
the application of 400 microL of the different dermal penetration
enhancers in a 2% v/v solution in 70% ethanol, 2 hours prior to the
application of the ketoprofen. The control experiment involved
application of 400 microL of 70% aqueous ethanol alone for 2 hours,
followed by application of 400 microL of the 2% ketoprofen
solution. Samples were assayed according to the method described
previously. The detection wavelength was 255 nm and the mobile
phase consisted of acetonitrile:water (55:45) made to pH 3.0 with
orthophosphoric acid (BDH, Australia). Table 1 shows the mean flux
of ketoprofen across the snake skin over 24 hours as determined by
the linear regression of the cumulative amount of ketoprofen
crossing the skin versus time (Units=microg/cm.sup.2h). FIG. 2
shows the representative mean cumulative amount versus time plots
for ketoprofen.
TABLE-US-00001 TABLE 1 Mean flux +/- std p value error relative to
Enhancement Enhancer type (microg/cm.sup.2 h) control ratio Control
- no 0.96 .+-. 0.18 -- -- enhancer, n = 9 Azone, n = 2 2.58 .+-.
0.23 0.0029 2.7 Octyl dimethyl 2.25 .+-. 0.14 0.0068 2.3 PABA, n =
3 Octylmethoxy 3.22 .+-. 0.28 0.0003 3.35 cinnamate, n = 3 Octyl
salicylate, 27.66 .+-. 5.26 <0.0070 28.81 n = 2 NB. Enhancement
ratio = mean flux enhancer/mean flux control
[0189] Statistical significance was determined by means of a
Student's t-test. Azone was selected as the standard penetration
enhancer for comparison since it has been widely used in previous
percutaneous penetration experiments.
EXAMPLE 2
[0190] The in vitro diffusion cell method described above was used
to compare the penetration of 30 microL of the commercial
formulation Indospray.TM. (Rhone-Poulenc Rorer, Australia), which
is a 1.0% w/w solution of indomethacin in 95% v/v ethanol when
applied to the snake skin. 10 microL of increasing concentrations
of Octyl dimethyl PABA in absolute ethanol were applied 30 mins
prior to the application of the indomethacin formulation. The
control experiment involved application of 10 microL of absolute
ethanol alone 30 mins prior to the application of the indomethacin
formulation. Samples were assayed according to the method described
previously. The detection wavelength was 254 nm and the mobile
phase consisted of acetonitrile:water (55% v/v:45% v/v) made to pH
3.0 with orthophosphoric acid. Table 2 shows the mean flux of
indomethacin across the snake skin over 24 hours.
TABLE-US-00002 TABLE 2 Mean flux +/- p value Enhancer std error
relative Enhance- conc. (microg/ to ment Enhancer type (% v/v)
cm.sup.2 h) control ratio Control - no n/a 1.24 .+-. 0.05 -- --
Enhancer Octyl dimethyl 1.6 1.43 .+-. 0.14 ns 1.2 PABA as above, n
= 3 3.2 1.71 .+-. 0.32 ns 1.4 as above 6.4 1.94 .+-. 0.09 0.0005
1.6 ns = not statistically significantly different
[0191] These results demonstrate the ability of the dermal
penetration enhancers to be applied alone prior to exposure of the
skin to the physiologically active ingredient(s) formulations
without penetration enhancers. Enhancement of percutaneous
absorption is extensive, as well as being dose-dependent in manner,
such that the desired level of enhancement can be achieved by
utilising the appropriate dose of dermal penetration enhancer
applied to the skin.
EXAMPLE 3
[0192] The same protocol as Example 1 was repeated, except the
dermal penetration enhancers were included in the ketoprofen
formulation, such that 400 microL of 2% w/v ketoprofen and 2% v/v
dermal penetration enhancer in 70% v/v aqueous ethanol was applied
to the skin from the start of the diffusion experiment.
[0193] Table 3 shows the mean flux of ketoprofen across the snake
skin over 24 hours. FIG. 3 shows the representative mean cumulative
amount versus time plots for ketoprofen.
TABLE-US-00003 TABLE 3 Mean flux +/- std p value error relative to
Enhancement Enhancer type (microg/cm.sup.2 h) control ratio Control
- no 0.78 .+-. 0.07 -- -- enhancer, n = 10 Azone, n = 2 2.84 .+-.
0.11 <0.0001 3.6 Octyl dimethyl 2.71 .+-. 0.18 <0.0001 3.5
PABA, n = 2 Octylmethoxy 2.08 .+-. 0.39 0.0413 2.7 cinnamate, n = 2
Octyl salicylate, n = 4 61.68 .+-. 14.89 <0.0059 79.1
[0194] These results demonstrate the ability of the dermal
penetration enhancers to be applied together with the
physiologically active ingredient/s within the same formulation to
achieve their percutaneous absorption enhancement.
EXAMPLE 4
[0195] Table 4 shows the mean flux (% dose/h)+/- the standard error
of the mean of hydroquinone (HQ) penetrated across full-thickness
guinea pig skin in vitro from a gel formulation applied to the skin
at a dose of 15 mg/cm.sup.2. Radio labelled hydroquinone (C14,
Amersham) was added to each of the topical formulations. At
specified time intervals 200 microL of receptor solution was
withdrawn with a micro-pipette and replaced with 200 microL of
fresh normal saline. The 200 microL samples were added to 800
microL of water which in turn was added to 10 mL of scintillation
cocktail consisting of Toluene.TM. 1 L, PPO 5 g, POPOP 0.1 g and
Triton X.TM. 500 mL. The scintillation counting was performed on a
Packard Tricarb 460C instrument. Disintegrations per minute were
determined by an external standard procedure and calculated by the
data system of the instrument.
TABLE-US-00004 TABLE 4 Enhancement ratio Flux (enhancer/ Enhancer
type (% dose/h) control) PARSOL .RTM. MCX 3% v/v 0.93 .+-. 0.19*
2.7 ESCALOL .RTM. 507 3% v/v 1.02 .+-. 0.09* 2.9 AZONE 5% v/v, 1.48
.+-. 0.08* 43 PARSOL .RTM. MCX 3% v/v AZONE 5% v/v, 0.74 .+-. 0.02*
2.1 ESCALOL .RTM. 507 3% v/v PARSOL .RTM. MCX 3% v/v, 1.30 .+-.
0.10* 37 ESCALOL .RTM. 507 3% v/v 0.35 .+-. 0.10 -- Control (no
enhancer) n > or = 10,*statistically significantly different
from control, P < 0.01 following student t-test
[0196] Table 5 shows the effect of hydroquinone (HQ) penetration
across full-thickness guinea pig skin in vivo on the mean melanin
content (mg/cm.sup.2)+/-standard error of the mean following the
application of a finite dose solution (5 microL/cm.sup.2). Melanin
content was measured by reflectance absorbance from the treated and
untreated skin according to the methods outlined in the PhD thesis
of Anderson, J. R., titled The Development of Techniques for
Measuring the Bioavailability of Topical Depigmenting Agents
(School of Pharmaceutics, Victorian College of Pharmacy Ltd.,
Parkville, Victoria, Australia, December, 1985).
TABLE-US-00005 TABLE 5 Enhancement Melanin p value ratio content
relative to (enhancer/ HQ concentration/Enhancer type
(.mu.g/cm.sup.2) control control) HQ 1% w/v control * 57.5 .+-. 3.7
-- HQ 1% w/v, Octyl dimethyl 38.2 .+-. 3.1 0.002* 1.5 PABA 2% v/v
HQ 2% w/v control {circumflex over ( )} 36.8 .+-. 8.1 -- HQ 2% w/v,
Azone 2% v/v 39.5 .+-. 9.6 0.35{circumflex over ( )} 0.93 n = 8, *
statistically significant differences tested for using a Student
t-test.
EXAMPLE 5
[0197] Table 6 shows the median amount (.mu.g/cm.sup.2) of
ibuprofen penetrated across full-thickness hairless mouse skin in
vitro when 400 microL of a 2% w/v ibuprofen and 2% v/v dermal
penetration enhancer in 70% v/v aqueous ethanol is applied. Again
Azone was selected as the standard for comparison and the control
formulation contained no penetration enhancer. The detection
wavelength was 210 nm and the mobile phase consisted of
acetonitrile:water (55:45) made to pH 3.0 with orthophosphoric
acid.
TABLE-US-00006 TABLE 6 Enhancer type after 12 hours after 24 hours
Octyl methoxycinnamate 2% v/v 1099* 2458* Octyl dimethyl PABA 2%
v/v 1123* 2981* Azone 2% v/v 1036* 2684* Control (no enhancer) 474
1819 n = 8, *statistically significantly different from control, p
< 0.05 following ANOVA on Ranks.
EXAMPLE 6
[0198] Table 7 shows the mean amount (.mu./cm.sup.2)+/-standard
error of the mean of testosterone penetrated across dermatomed (300
.mu.m thickness) neonate porcine skin in vitro when 10 microL of a
12% w/v testosterone and 8% v/v of dermal penetration enhancer in
absolute ethanol was applied. The detection wavelength was 241 nm
and the mobile phase consisted of acetonitrile:water (55%:45%).
TABLE-US-00007 TABLE 7 Enhancer type after 4 hours after 24 hours
Octyl dimethyl PABA 8% v/v 72 .+-. 10* 227 .+-. 7* Control (no
enhancer) 4 .+-. 1 13 .+-. 2* Enhancement ratio 18 17 n = 3,
*statistically significantly different from control, P < 0.003
following Student t-test.
EXAMPLE 7
[0199] FIG. 4 shows the cumulative amount of ibuprofen transferred
across shed snake skin versus time for gel formulations of
ibuprofen. 5 mg of each gel was applied to the skin. Samples were
assayed by the HPLC method mentioned in Example 5. The gels were
made to a final concentration of 5% w/w ibuprofen and 2% w/w dermal
penetration enhancer by first dissolving them in 50% v/v aqueous
ethanol then adding 2% w/w Sepigel-305.TM. (SEPPIC, Paris, France)
as a gelling agent and stirring at room temperature until a gel was
formed. This formulation was compared with the commercial
IBUGEL.TM. (Dermal Laboratories, UK) formulation which contained 5%
w/w ibuprofen in a ethanolic gel base formed with carbopol. As
well, 2% w/w dermal penetration enhancer was added to the IBUGEL by
simple mixing. The ibuprofen contents of each gel were determined
by HPLC and were found to be 5.02, 5.75 and 5.43 mg/g for the gel
using Sepigel-305.TM. and enhancer, the IBUGEL and the IBUGEL with
enhancer; respectively.
[0200] Both the cumulative amounts at 12 an 24 h and the mean flux
over 24 h were significantly greater (p<0.05) for both the
enhanced gel formulations when compared to the commercial IBUGEL
formulation. The flux enhancement ratios were 6.15 and 2.61 for the
gel using Sepigel-305.TM. and enhancer and the IBUGEL with enhancer
(n=3) respectively when compared to the IBUGEL (p<0.05).
EXAMPLE 8
[0201] Table 8 shows the mean flux (g/cm.sup.2h) of hydrocortisone
penetrated across snake skin in vitro when 400 microL of 1% w/v
hydrocortisone and 2% v/v octyl dimethyl PABA in 70% v/v aqueous
ethanol was applied. The control formulation contained no
penetration enhancer. The detection wavelength was 242 nm and the
mobile phase consisted of acetonitrile:water (35%:65%).
TABLE-US-00008 TABLE 8 Mean flux +/- std p value error relative to
Enhancement Enhancer type (microg/cm.sup.2 h) control ratio Control
- no enhancer 0.14 .+-. 0.04 -- -- Octyl dimethyl PABA 0.79 .+-.
0.06 <0.0001 5.8 8% v/v
EXAMPLE 9
[0202] Table 9 shows the mean flux over 24 h of ketoprofen from a
transdermal patch using the enhancer octyl salicylate compared with
a control without enhancer. The patches were prepared by dissolving
300 mg of ketoprofen, 400 mg of penetration enhancer, 300 mg of
polyethylene glycol 400 and 800 mg of hydroxypropylcellulose in 20
mL of ethanol and stirring until viscous. This was then poured onto
a clean glass plate and dried at 40 degrees Celsius for 1 h. The
thickness of this film was approximately 1 mm. Circles of 0.8
cm.sup.2 were then cut out of this matrix and stuck onto the middle
of 2.0 cm.sup.2 circles of OPSITE.TM. adhesive bandage. This patch
was then stuck onto 2.0 cm.sup.2 pieces of snake skin and placed in
the diffusion cell. The ketoprofen content of each patch
formulation was determined by HPLC in triplicate and found to be
6.99+/-0.30 mg/cm.sup.2 and 6.76+/-0.24 mg/cm.sup.2, for the
control and octyl salicylate patches respectively (mean
content+/-std error, n=4).
TABLE-US-00009 TABLE 9 Mean flux +/- std p value error relative to
Enhancement Enhancer type (microg/cm.sup.2 h) control ratio Control
- no enhancer 0.47 .+-. 0.04 -- -- Octyl salicylate 11.70 .+-. 0.65
<0.0001 25.2
[0203] In order to further illustrate the present invention and the
advantages thereof, the following specific examples are given, it
being understood that same are intended only as illustrative and in
nowise limitative. In the examples, the effectiveness of the dermal
penetration enhancers are illustrated by measuring the skin
penetration of physiologically active agents. Also, the skin
penetration of the dermal penetration enhancers of this invention
were compared with that of other penetration enhancers as well as
formulations of bio-affecting agents with common adjuvants. The
comparisons made generally consisted of measuring the relative
penetration through shed snake skin of the various formulations. In
the examples, the in vitro skin penetration studies were performed
using the same in vitro diffusion cell apparatus as previously
mentioned.
EXAMPLE 10
[0204] FIG. 5 shows the mean cumulative amount of testosterone
which crosses the shed snake skin versus time.
[0205] The volume of each formulation applied to the skin was 5
microL/cm.sup.2. Each formulation contained 12% w/v testosterone in
absolute ethanol. The dose was applied with a GC syringe. All
except for the control formulation had a penetration enhancer added
at a concentration of 8% v/v.
[0206] Samples were assayed for testosterone by HPLC as shown
before in Example 6.
[0207] Table 10 shows the mean flux of testosterone over 24 h for
each of the formulations and the degree of enhancement expressed as
the ratio of the mean flux of the penetration enhancer formulation
divided by the mean flux of the control formulation.
TABLE-US-00010 TABLE 10 Mean flux +/- std p value error relative to
Enhancement Enhancer type (microg/cm.sup.2 h) control ratio Control
- no enhancer 0.70 .+-. 0.03 -- -- Oleic acid 2.09 .+-. 0.08
<0.0001 3.0 Azone 2.02 .+-. 0.27 <0.03 2.9 Octyl dimethyl
PABA 1.43 .+-. 0.25 <0.03 2.0 Octylsalicylate 4.18 .+-. 0.41
<0.03 6.0
EXAMPLE 11
[0208] Table 11 shows the mean flux over 24 h and the enhancement
ratios for a number of different preferred compounds after they are
applied to the skin at a dose of 5 microL/cm.sup.2. The two
penetration enhancers given as examples are octyl dimethyl PABA and
Azone. Both penetration enhancers were again at a concentration of
8% v/v within the formulations and control was without a
penetration enhancer. A concentration of 2% w/v oestradiol was used
in the formulation and detection wavelength was 212 nm and the
mobile phase consisted of acetonitrile:water (40%:60%). A
concentration of 6% w/v progesterone was used in the formulation,
the detection wavelength was 240 nm and the mobile phase consisted
of acetonitrile:water (55%:45%). A concentration of 6% w/v
norethisterone acetate was used in the formulation, the detection
wavelength was 240 nm and the mobile phase consisted of
acetonitrile:water (55%:45%) adjusted to pH 3.0 with
orthophosphoric acid. A concentration of 20% ibuprofen was used in
the formulation, the detection wavelength was 210 nm and the mobile
phase consisted of acetonitrile:water (55%:45%) adjusted to pH 3.0
with orthophosphoric acid. A concentration of 20% flurbiprofen was
used in the formulation, the detection wavelength was 247 nm and
the mobile phase consisted of acetonitrile water (55%:45%) adjusted
to pH 3.0 with orthophosphoric acid.
TABLE-US-00011 TABLE 11 Mean flux +/- std error p value Enhance-
(microg/ cf. ment Drug Enhancer type cm.sup.2 h) control ratio
Oestradiol Control, n = 3 0.06 .+-. 0.01 -- -- Azone 0.40 .+-. 0.05
<0.003 6.4 Octyldimethyl 0.26 .+-. 0.01 <0.0001 4.1 PABA
Progesterone Control, n .times. 3 0.40 .+-. 0.02 -- -- Azone, n = 3
2.17 .+-. 0.33 <0.05 5.4 Octyl dimethyl 0.95+/310.03 <0.0001
2.4 PABA Norethis- Control 0.14 .+-. 0.02 -- -- terone Azone 0.16
.+-. 0.02 -- 1.1 acetate 0.0001 Octyl dimethyl 1.85+/31 0.07
<0.0001 12.8 PABA Ibuprofen Control 5.39+/31 0.50 -- -- Azone
13.53 .+-. 1.38 0.0014 2.5 Octyl dimethyl 13.16 .+-. 1.21 0.001 2.4
PA0BA Flurbiprofen Control, n = 3 0.81 .+-. 0.05 -- -- Azone
2.05+/31 0.42 0.0559 2.5 Octyl dimethyl 2.91+/31 0.30 0.0023 3.6
PABA, n = 3
[0209] The flux values obtained for these drugs are clinically
relevant, given for example that in hormone replacement therapy for
postmenopausal women the current transdermal delivery systems aim
to provide 25 to 100 .mu.g of estradiol per day and 250 .mu.g of
norethisterone per day (Estracombi.TM.) and in testosterone
replacement therapies the goal ranges from replacing 0.1 to 0.3 mg
per day in women lacking testosterone (U.S. Pat. No. 5,460,820), to
5 to 6 mg per day in testosterone deficient hypogonadal men
(Androderm.TM.) and up to 6 to 10 mg per day for male contraception
(ref. J. Clin. Endocrinol. Metab., Vol. 81, 4113-4121, 1996). For
the NSAIDs, ibuprofen and flurbiprofen increased drug flux is
desirably predicated on the basis that this will lead to higher
local concentrations of the active drug at the target site of pain
and inflammation.
EXAMPLE 12
[0210] FIGS. 5 and 6 show the mean plasma levels of testosterone
and oestradiol respectively following application of the topical
transdermal aerosols (described previously in examples 15 and 14
respectively) to domestic weanling pigs (7 to 8 weeks old) in vivo.
Plasma testosterone and oestradiol levels were determined by high
specificity radioimmunoassays, using commercially available assay
kits. The oestradiol assay (Orion Diagnostica, Finland) was
conducted according to the manufacturers' directions. The
testosterone assay (Pantex, USA) was also conducted according to
the directions, with the procedure modified to include an
extraction step (90% diethylether/10% ethyl acetate) to remove any
species specific matrix effects. The control formulations were the
same aerosol systems as above, except they did not contain any
dermal penetration enhancer.
[0211] The male pigs receiving the testosterone dose were
surgically castrated 1 week prior to the commencement of the study
to remove any interference from endogenous testosterone production
and at the same time a cephalic cannula was inserted to facilitate
blood sampling. These procedures were performed under general
anaesthetic halothane (Fluothane.TM.).
[0212] The results shown are baseline subtracted, were the baseline
testosterone level at time zero was 4.3 nmol/L+/-1.1 nmol/L (mean
+/-std error mean) for the test group (n=4) and was <0.5 nmol/L
for every pig in the control group (n=7). A single application of 9
sprays over 180 cm.sup.2 was applied at 9 am and blood samples were
taken at the intervals shown over 24 h. The mean body weight of the
pigs were 19.9 kg+/-0.8 kg and 17.2 kg+/-0.4 kg for the test and
control groups respectively. The area under the plasma
concentration versus time curve (AUC) was 2.2 fold greater
(p<0.05) for the penetration enhancer formulation compared with
control. The calculated results for AUC were normalised to a body
weight of 20 kg assuming volume of distribution is directly
proportional to body weight.
[0213] The male pigs receiving the oestradiol dose had baseline
oestradiol levels of <0.02 nmol/L for every pig in the test
group (n=4) and <0.02 nmol/L for every pig in the control group
(n=6). A single application of 3 sprays over 30 cm.sup.2 was
applied at 9 am and blood samples were taken at the intervals shown
over 24 h. The mean body weights of the pigs were 21.3 kg+/-1.0 kg
and 17.5 kg+/-0.4 kg for the test and control group respectively.
The area under the plasma versus time curve (AUC) was 14.1 fold
greater (p<0.0003) for the penetration enhancer formulation
compared with control. The calculated results for AUC were
normalised to a body weight of 20 kg assuming volume of
distribution is directly proportional to body weight.
EXAMPLE 13
[0214] Male pigs were used as described above, and the testosterone
spray was applied daily over 180 cm.sup.2 as described previously.
Once daily testosterone application was performed at 9 am for 6
consecutive days, and on the sixth day blood samples were taken at
the intervals shown over 24 h in FIG. 7. A baseline blood sample
was taken at time=0 h, on day 1 and was 2.8 nmol/L+/-1.1 nmol/L
(mean +/-std error mean), n=4. FIG. 7 shows the mean plasma level
of testosterone versus time over 24 h. The results shown are
baseline testosterone subtracted and are representative of the
expected steady-state profile for testosterone.
[0215] FIG. 8 shows the mean cumulative amount of testosterone
crossing the domestic weanling pig skin in vivo, as determined by
Wagner-Nelson analysis, which says that Flux=Plasma
conc.times.Clearance (Berner B., John V. A., Pharmacokinetic
Characterisation of Transdermal Delivery Systems, Clin.
Pharmacokinet., 26(2): 121-134, 1994.). Clearance was determined
prior to study commencement by a bolus dose of intravenous
testosterone and was found to be 663 ml/hkg+/-139 ml/hkg which was
similar to the reported value for males of 655 ml/hkg (Mazer N. A.,
Heiber W. E., Moellmer J. F., Meikle A. W., Stringham J. D.,
Sanders S. W., Tolman K. G., Odell W. D., Enhanced transdermal
delivery of testosterone: a new physiological approach for androgen
replacement in hypogonadal men, J. Control. Releas., 19, 347-362,
1992). Also included for comparison in FIG. 8 are the expected in
vivo penetration across human skin and the in vitro penetration of
testosterone across shed snake skin. The in vivo penetration across
human skin was based on a 2.2 fold lower permeability of
testosterone in human skin compared with pig skin as determined in
vivo (Bartek M. J., LaBudde J., Maibach H. I., Skin Permeability In
Vivo: Comparison in Rat, Rabbit, Pig and Man, J. Invest. Dermatol.,
58(3): 114-123, 1972);
[0216] FIG. 8 shows the controlled nature of testosterone
penetration across the skin in vivo, as well as the good predictive
capability of the in vitro shed snake skin diffusion model for
ascertaining the likely penetration of the testosterone across
human skin. It is therefore envisaged that the flux values obtained
in examples 10 and 11 will be very similar to those obtained in
humans in a clinical setting.
[0217] Further to this FIG. 9 depicts the predicted plasma levels
of testosterone in male subjects of a nominal weight of 70 kg based
upon the clearance value of testosterone in males shown above. For
comparison the 95% confidence interval of the testosterone plasma
level in normal healthy adult males is given (Mazer, et al., J.
Control. Releas., 19, 347-362, 1992). As shown this delivery system
is quite capable of achieving the desired level of testosterone
replacement in testosterone deficient hypogonadal men based upon on
simple once daily application of the delivery system.
[0218] Aerosol Device
[0219] A plastic-coated glass aerosol container of 10 ml fill
volume was fitted with a pharmaceutical grade metered-dose valve of
a nominated discharge volume (50 .mu.l for the oestradiol aerosol
and 100 .mu.l for the testosterone aerosol).
[0220] A stainless steel O-ring locks the valve in place on the
aerosol container.
[0221] The aerosol container is charged with at least one
physiologically active agent, non-volatile dermal penetration
enhancer, volatile liquid carrier and optionally any other
diluents, carriers, surfactants or additives followed by the
propellant according to any suitable process.
[0222] A pharmaceutical grade spray nozzle and an aerosol shroud is
fitted to keep the spray nozzle perpendicular to the skin at a
height of 50 mm.
[0223] Method of Aerosol Use
[0224] 1. Hold the device upright in the palm of your preferred
hand with your thumb resting gently on the actuator button.
[0225] 2. Rest the shroud opening on the skin and depress the
actuator button once and release the button. Remove the device from
the skin.
[0226] 3. Repeat steps 1 and 2 on a new area of skin until the
correct number of doses have been given.
[0227] 4. Allow the applied formulation to dry on the skin for 1
minute.
[0228] During application of the spray, the nozzle shroud envelopes
the spray, providing an effective closed system which deposits the
active agent into the skin, and such that when the spray hits the
surface of the skin it does not undergo any appreciable bounce-back
into the atmosphere. A defined dose of active agent and penetration
enhancer is forced through a uniform spray nozzle at a constant
pressure form a defined height to give a uniform dose per
cm.sup.2.
EXAMPLE 14
TABLE-US-00012 [0229] 17-.beta.-Oestradiol Metered-Dose Transdermal
Aerosol Concentration Active ingredient: 17-.beta.-Oestradiol 2%
w/v Non-volatile dermal penetration enhancer: Octyl
dimethyl-para-aminobenzoate 8% v/v (Escalol 507, Padimate O)
Volatile liquid: Absolute ethanol (AR) 60% v/v Volatile propellant:
Dimethyl ether 30% v/v to give a final formulation pressure of 2.0
kp/cm.sup.2 (30 psi).
[0230] One spray of 50 .mu.l will apply 1 mg of
17-.beta.-oestradiol over an area of approximately 10 cmsup2. 3
sprays will be administered to the forearm skin, applying a dose of
3 mg over approximately 30 cm.sup.2.
EXAMPLE 15
TABLE-US-00013 [0231] Testosterone Metered-Dose Transdermal Aerosol
Concentration Active ingredient: Testosterone 12% w/v Non-volatile
dermal penetration enhancer: Octyl dimethyl-para-aminobenzoate 8%
v/v (Escalol 507, Padimate O) Volatile liquid: Absolute ethanol
(AR) 50% v/v Volatile propellant: Dimethyl ether to give a final
formulation pressure of 35% v/v 2.4 kp/cm.sup.2 (35 psi).
[0232] One spray of 100 .mu.l will apply 12 mg of testosterone over
an area of approximately 20 cm.sup.2. 9 sprays will be administered
to a defined area of skin on the torso (rib cage), applying a dose
of 108 mg over approximately 180 cm.sup.2.
EXAMPLE 16
TABLE-US-00014 [0233] Analgesic mousse with penetration enhancement
Ingredient: Concentration Ibuprofen 5% w/w
2-ethylhexyl-p-methoxycinnamate 5% w/w nonionic emulsifier 2.5% w/w
ethyl alcohol (95%) 32.5% w/w purified water 50% w/w hydrocarbon
propellant 5% w/w
[0234] Throughout this specification and the claims which follow,
unless the context requires otherwise, the word "comprise", or
variations such as "comprises" or "comprising", will be understood
to imply the inclusion of a stated integer or group of integers but
not the exclusion of any other integer or group of integers.
* * * * *