U.S. patent application number 12/740663 was filed with the patent office on 2010-11-25 for transdermal delivery system.
This patent application is currently assigned to Acrux DDS Pty Ltd.. Invention is credited to Kerrie Setiawan, Adam Watkinson.
Application Number | 20100297032 12/740663 |
Document ID | / |
Family ID | 40590452 |
Filed Date | 2010-11-25 |
United States Patent
Application |
20100297032 |
Kind Code |
A1 |
Setiawan; Kerrie ; et
al. |
November 25, 2010 |
TRANSDERMAL DELIVERY SYSTEM
Abstract
A transdermal delivery system comprising a composition
comprising a physiologically active agent and a penetration
enhancer wherein the penetration enhancer comprises a combination
of (i) an ester of salicylic acid, preferably selected from the
C.sub.6 to C.sub.30 aliphatic ester of salicylic acid and (ii)
polyethylene glycol (PEG) of average molecular weight no more than
300.
Inventors: |
Setiawan; Kerrie; (Victoria,
AU) ; Watkinson; Adam; (Victoria, AU) |
Correspondence
Address: |
FOLEY AND LARDNER LLP;SUITE 500
3000 K STREET NW
WASHINGTON
DC
20007
US
|
Assignee: |
Acrux DDS Pty Ltd.
|
Family ID: |
40590452 |
Appl. No.: |
12/740663 |
Filed: |
October 31, 2008 |
PCT Filed: |
October 31, 2008 |
PCT NO: |
PCT/AU08/01614 |
371 Date: |
August 9, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60984787 |
Nov 2, 2007 |
|
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|
Current U.S.
Class: |
424/43 ; 514/170;
514/179; 514/182; 514/214.02; 514/567; 514/570; 604/310 |
Current CPC
Class: |
A61P 5/30 20180101; A61K
31/205 20130101; A61K 31/568 20130101; A61K 31/565 20130101; A61P
5/00 20180101; A61P 5/24 20180101; A61P 15/10 20180101; A61M 35/003
20130101; A61K 31/56 20130101; A61K 9/0014 20130101; A61K 47/32
20130101; A61P 29/00 20180101; A61K 47/10 20130101; A61P 15/16
20180101; A61K 47/14 20130101; A61K 9/12 20130101; A61P 25/24
20180101; A61P 5/26 20180101; A61P 15/18 20180101; A61P 5/44
20180101; A61K 31/573 20130101; A61P 15/00 20180101; A61K 31/192
20130101; A61K 31/57 20130101 |
Class at
Publication: |
424/43 ; 514/170;
514/179; 514/182; 514/570; 514/567; 514/214.02; 604/310 |
International
Class: |
A61K 9/12 20060101
A61K009/12; A61K 31/5685 20060101 A61K031/5685; A61K 31/566
20060101 A61K031/566; A61K 31/192 20060101 A61K031/192; A61K 31/57
20060101 A61K031/57; A61K 31/196 20060101 A61K031/196; A61K 31/55
20060101 A61K031/55; A61P 25/24 20060101 A61P025/24; A61P 5/00
20060101 A61P005/00; A61P 15/18 20060101 A61P015/18; A61M 35/00
20060101 A61M035/00 |
Claims
1-22. (canceled)
23. A transdermal delivery system comprising a composition
comprising a physiologically active agent and a penetration
enhancer wherein the penetration enhancer comprises a combination
of (i) an ester of salicylic acid, and (ii) polyethylene glycol
(PEG) of average molecular weight no more than 300.
24. A transdermal delivery system according to claim 23 wherein the
ester of salicylic acid is a C.sub.6 to C.sub.12 alkyl ester.
25. A transdermal delivery system according to claim 23 wherein the
ester of salicylic acid is ethylhexylester.
26. A transdermal delivery system according to claim 23 wherein the
ester of salicylic acid is present in an amount of from 0.1 to 10%
by weight of the total transdermal composition.
27. A transdermal delivery system according to claim 23 wherein the
PEG of average molecular weight of no more than 300 is present in
an amount in the range of from 0.1 to 40% by weight of the total
composition.
28. A transdermal delivery system according to claim 23 wherein the
weight ratio of ester of salicylic acid to polyethylene glycol of
average molecular weight no more than 300 is in the range of from
to 1:10 to 10:1.
29. A transdermal delivery system according to claim 23 wherein the
composition comprises a solvent selected from C.sub.2 to C.sub.4
alkanol.
30. A transdermal delivery system according to claim 29 wherein the
volatile solvent is preferably present in the composition in an
amount in the range of from 70% to 95% by weight of the total
composition.
31. A transdermal delivery system according to claim 23 wherein the
composition consists essentially of: (i) the physiolocically active
agent component which may include one or more physiologically
active agents; (ii) the penetration enhancer component consisting
of a C.sub.6 to C.sub.12 alkyl ester of salicylic acid and a
polyethylene glycol of average molecular weight no more than 300;
(iii) a volatile solvent consisting of one or more of ethanol and
isopropanol; and (iv) optionally a propellant.
32. A transdermal delivery system according to claim 23 wherein the
total water content of the composition is less than 10% by weight
of the total composition.
33. A transdermal delivery system according to claim 23 which is
non-occlusive.
34. A transdermal delivery system according to claim 23 wherein the
weight ratio of penetration enhancer to active is in the range of
from 500:1 to 1:10.
35. A transdermal delivery system according to claim 23 wherein the
physiologically active agent comprises one or more selected from
the group consisting of antidepressants; women's health actives and
hormones.
36. A transdermal delivery system according to claim 23 wherein the
physiologically active agent comprises one or more of mirtazapine,
metabolites, salts, enantiomers (including esmirtazapine),
solvents, non-covalent complexes, chelates, hydrates, crystalline
or amorphous forms thereof.
37. A transdermal delivery system according to claim 23 wherein the
physiologically active agent comprises one or more hormones
selected from the group consisting of: androgens, estrogens,
selective estrogen receptor modulators, aromatase inhibitors,
gonadotropins, progesterone, progestins, selective progesterone
receptor modulators, antiprogestogen, antigonadotropins,
GnRH:(receptor) agonists, antidiarrhoeals, cardiovascular system
agents, antihypertensives, calcium channel blockers, proton pump
inhibitors, antiarrhyrthmics, antiangina, beta-adrenergic blocking
agents, cardiotonic glycosides, adrenergic stimulants,
vasodilators, antimigraine preparations, anticoagulants,
haemostatic agents, analgesics, antipyretics, hypnotics,
antianxiety, neuroleptic and antipsychotic drugs, antidepressants,
CNS stimulants such as caffeine, anti-alzheimer's agents,
antiparkinson agents, lipid regulating drugs, anticonvulsants,
antiemetics, antinauseants, non-steroidal antiinflammatory agents,
antirheumatoid, muscle relaxants, agents used in gout and
hyperuricaemia, diuretics, antidiuretics, obstetric drugs,
prostaglandins, antimicrobials, antituberculosis drugs,
antimalarials, antiviral agents, anthelmintics, cytotoxic agents,
anorectics, agents used in hypercalcaemia, antitussives,
expectorants, decongestants, bronchospasm relaxants,
antihistamines, local anaesthetics, stratum corneum lipids,
H2-receptor antagonists, neuromuscular blocking agents, smoking
cessation agents, insecticides and other pesticides, dermatological
agents, allergens, nutraceutically active compounds, keratolytics,
psychicenergisers, anti-acne agents, anti-psoriasis agents,
anti-itch agents, anticholinergic agents, and mixtures thereof.
38. A transdermal delivery system according to claim 36 comprising
a plurality of hormones from one or more of these groups preferably
a contraceptive active agent comprising one or more estrogens and
one or more progestins.
39. A transdermal delivery system according to claim 37 wherein the
drug delivery system comprises on a weight basis from about 0.1 to
about 10% of the hormone, from about 0.1 to 12% of the penetration
enhancer and from about 70 to 99.8% ethanol, isopropanol or mixture
thereof.
40. A method of transdermal administration of an active agent to an
animal subject comprising application to dermal surface of the
animal a transdermal system according to claim 23.
41. A method of transdermal administration according to claim 40
wherein the animal subject is in need of male hormone replacement
in testosterone deficient hypogonadal men, female hormone
replacement therapy for postmenopausal women, androgen replacement
therapy for females lacking libido using an androgen such as
testosterone, male contraception and female contraception.
42. A transdermal delivery system according to claim 23 further
comprising a spray apparatus comprising a container containing the
transdermal composition a spray nozzle and an actuator for
delivering a metered dose of spray from the container via the
nozzle.
Description
FIELD
[0001] This invention relates to a transdermal delivery system and
to a method of transdermal delivery of a physiologically active
agent.
BACKGROUND
[0002] Administration of physiologically active agents through the
skin (transdermal delivery) has received increased attention
because it not only provides a relatively simple dosage regime but
it also provides a relatively slow and controlled route for release
of a physiologically active agent into the systemic circulation.
However, transdermal drug delivery is complicated by the fact that
the skin behaves as a natural barrier and therefore transport of
agents through the skin is a complex mechanism.
[0003] Structurally, the skin consists of two principle parts, a
relatively thin outermost layer (the `epidermis`) and a thicker
inner region (the `dermis`). The outermost layer of the epidermis
(the `stratum corneum`) consists of flattened dead cells which are
filled with keratin. The region between the flattened dead cells of
the stratum corneum is filled with lipids which form lamellar
phases that are responsible for the natural barrier properties of
the skin.
[0004] For effective transdermal delivery of a physiologically
active agent that is applied to the surface of the skin (`topical
application`), the agent must partition firstly from the vehicle
into the stratum corneum, it must typically then diffuse within the
stratum corneum before partitioning from the stratum corneum to the
viable epidermis.
[0005] To overcome some of the problems with transdermal delivery
that are associated with transport across the dermal layers
(`percutaneous absorption`), physiologically active agents are
commonly formulated with dermal penetration enhancers (Finnin and
Morgan, J. Pharm. Sci., Vol 88, No. 10, October 1999, pp 955-958)
which are often lipophilic chemicals that readily partition into
the stratum corneum whereupon they exert their effects on improving
the transport of drugs across the skin barrier.
[0006] A transdermal "patch" typically consists of a matrix or
reservoir containing the drug to be administered, together with a
backing layer, an adhesive and a protective release liner. Release
membranes may also be incorporated. The delivery of drugs through
these systems is either through passive diffusion, controlled by a
semi-permeable release membrane, or is controlled by the
adhesive/adhesive matrix. The system may also incorporate drug
penetration enhancers to increase the flux of the drug through the
skin.
[0007] One of the drawbacks of the current approaches is that the
formulations are typically in continuous contact with the skin.
Creams and ointments or adhesives used in patches can cause skin
irritation and sensitisation. A significant proportion of patch
users suffer from skin irritation and sensitisation due to
adhesives used in the patch.
[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), 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 acetamide is not
clinically acceptable for these reasons. Although Deet and Azones
have lower reported toxicities, their toxicity is still such that
they are not widely used. It is possible that Azone and dimethyl
sulfoxide 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 compositions of the present invention are suitable for
use as vehicles for the topical application of specific compounds
to the skin using pharmaceutical, nutraceutical, cosmetic or
veterinary preparations. Such topical application enables the
specific compounds to penetrate the skin and enter the circulatory
system thereby enabling the active compound (s) to have a systemic
effect. The at least one active compound may be a pharmacologically
active compound. A "pharmacologically active compound" is a
compound that has a therapeutic effect on the human or animal body
in the treatment or prevention of a condition.
[0011] The discussion of documents, acts, materials, devices,
articles and the like is included in this specification solely for
the purpose of providing a context for the present invention. It is
not suggested or represented that any or all of these matters
formed part of the prior art base or were common general knowledge
in the field relevant to the present invention as it existed before
the priority date of each claim of this application.
SUMMARY
[0012] The invention provides a transdermal delivery system
comprising composition comprising a physiologically active agent
and a penetration enhancer wherein the penetration enhancer
comprises a combination of (i) an ester of salicylic acid,
preferably selected from the C.sub.6 to C.sub.30 aliphatic ester of
salicylic acid and (ii) polyethylene glycol of average molecular
weight no more than 300.
[0013] In a further aspect the invention provides a method of
transdermal administration of an active agent to an animal subject,
including a human, comprising application to dermal surface of the
animal of the above described transdermal delivery system.
[0014] In yet another aspect the invention provides use of (i) an
ester of salicylic acid, preferably selected from the C.sub.6 to
C.sub.30 aliphatic ester of salicylic acid and (ii) polyethylene
glycol (of average molecular weight no more than 300) in
manufacture of a medicament with a physiologically active agent for
transdermal administration of the physiologically active agent to
an animal by application of the medicament to an area of the skin
surface of the animal.
[0015] In a further aspect the invention provides a method of
preparing a transdermal delivery system for administration to an
area of dermal surface of an animal the method comprising combining
the physiologically active agent and a first penetration enhancer
component of an ester of salicylic acid, preferably selected from
the C.sub.6 to C.sub.30 aliphatic ester of salicylic acid and a
second penetration enhancer component of polyethylene glycol of
average molecular weight no more than 300.
[0016] In a further embodiment the invention comprises a
transdermal delivery system comprising a spray apparatus comprising
a container for a transdermal composition a spray nozzle and an
actuator for delivering a metered dose of spray from the container
via the nozzle, wherein the transdermal composition comprises a
physiologically active agent and a first penetration enhancer
component of an ester of salicylic acid, preferably selected from
the C.sub.6 to C.sub.30 aliphatic ester of salicylic acid, and a
second penetration enhancer component of polyethylene glycol of
average molecular weight no more than 300.
[0017] The transdermal delivery system will preferably be applied
in a dose sufficient to provide an effective amount of the
physiologically active agent in the bloodstream of the animal.
[0018] Preferably the animal is a human but the invention also
extends to the treatment of non-human animals.
Definitions
[0019] It will be understood by those skilled in the art that the
term polyethylene glycol does not include diethylene glycol
(although diethylene glycol may if desired be present as an
additional component). Polyethylene glycol of average molecular
weight no more than 300 includes polyethylene glycol of nominal
average molecular weight 200 and 300 wherein the average molecular
weight is not more than 110% and not less than 90% (preferably not
more than 105% and not less than 95%) of the nominated value.
Polyethylene glycol is of formula H--[OCH.sub.2CH.sub.2].sub.n--OH.
An average molecular weight of no more than 300 means the average
value of n is at least 3 and is generally from 3 to 6 such as 3, 4,
5 or 6 (although the average need not be an integer) and more
preferably 3 to 5. Polyethylene glycol (PEG) is widely available
from commercial suppliers in pharmaceutical grades and is sold in
specified nominal molecular weights which generally signify that
the average molecular weight is not more than 105% and not less
than 95% of the nominated value. The viscosities and methods for
molecular weight determination are disclosed in USP NF Official
Compendium of Standards Volume 11180-1182 [2007 Edition].
[0020] The term "physiologically active agent" is used herein to
refer to a broad class of useful chemical and therapeutic
agents.
[0021] 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. The term physiologically active agent includes
prodrugs of the agent which in vivo exerts the physiological
effect.
[0022] Steroids encompass compounds having the general
cyclopentanoperhydrophenanthrene ring system of formula:
##STR00001##
[0023] Steroids vary by the functional groups attached to these
rings and the oxidation state of the rings. The steroid may be in
the form of the active drug or may be a prodrug steroid which in
vivo provides a more active form of the steroid. The steroids
include drugs and prodrugs which provide eutrogenic, androgenic
glucocorticoid, adrenocortoid, anabolic or birth control activity.
Examples of steroids include, for example, dexamethasone,
dexamethasone acetate, dexamethasone sodium phosphate, cortisone,
cortisone acetate, hydrocortisone, hydrocortisone acetate,
hydrocortisone cypionate, hydrocortisone sodium phosphate,
hydrocortisone sodium succinate, prednisone, prednisolone,
prednisolone acetate, prednisolone sodium phosphate, prednisolone
tebutate, prednisolone pivalate, triamcinolone, triamcinolone
acetonide, triamcinolone hexacetonide, triamcinolone diacetate,
methylprednisolone, methylprednisolone acetate, methylprednisolone
sodium succinate, flunsolide, beclomethasone dipropionate,
betamethasone sodium phosphate, betamethasone, vetamethasone
disodium phosphate, vetamethasone sodium phosphate, betamethasone
acetate, betamethasone disodium phosphate, chloroprednisone
acetate, corticosterone, desoxycorticosterone, desoxycorticosterone
acetate, desoxycorticosterone pivalate, desoximethasone, estradiol,
fludrocortisone, fludrocortisone acetate, dichlorisone acetate,
fluorohydrocortisone, fluorometholone, fluprednisolone,
paramethasone, paramethasone acetate, androsterone,
fluoxymesterone, aldosterone, methandrostenolone,
methylandrostenediol, methyl testosterone, norethandrolone,
testosterone, testosterone enanthate, testosterone propionate,
equilenin, equilin, estradiol benzoate, estradiol dipropionate,
estriol, estrone, estrone benzoate, acetoxypregnenolone, anagestone
acetate, chlormadinone acetate, flurogestone acetate, hydroxymethyl
progesterone, hydroxymethylprogesterone acetate,
hydroxyprogesterone, hydroxyprogesterone acetate,
hydroxyprogesterone caproate, melengestrol acetate,
normethisterone, pregnenolone, progesterone, ethynyl estradiol,
mestranol, dimethisterone, ethisterone, ethynodiol diacetate,
norethindrone, norethindrone acetate, norethisterone, fluocinolone
acetonide, flurandrenolone, hydrocortisone sodium succinate,
methylprednisolone sodium succinate, prednisolone phosphate sodium,
triamcinolone acetonide, hydroxydione sodium, spironolactone,
oxandrolone, oxymetholone, prometholone, testosterone cypionate,
testosterone phenylacetate, estradiol cypionate, and
norethynodrel.
[0024] A "prodrug" is a pharmaceutically active agent which is
administered in an inactive or less active form and is metabilised
into an active form. The prodrug itself may have little or none of
the desired activity until it interacts with the systems of the
body such as the skin or circulatory systems. Nonetheless a
pharmaceutically active agent used in the transdermal delivery
system of the invention include agents which are prodrugs which on
administration form a more active agent in vivo during or after the
process of transdermal administration.
[0025] In yet another preferred embodiment, a prodrug or a
composition of prodrug mixed with the parent composition has a
permeation rate that is faster or slower than an identical
composition having a pharmacologically equivalent amount of the
parent drug. In still another preferred embodiment, the composition
has a duration of the therapeutic effect that is longer or shorter
than a composition having a pharmacologically equivalent amount of
the parent drug alone. In another preferred embodiment, the prodrug
is more lipophilic than the parent drug and the prodrug has a
greater permeation rate through the skin. Generally prodrugs are
variations or derivatives of the parent drugs which have groups
cleavable under metabolic conditions. Prodrugs become the parent
drugs which are pharmaceutically active or more active in vivo,
when they undergo solvolysis under physiological conditions or
undergo enzymatic degradation. Prodrugs commonly known in the art
include acid esters prepared by reaction of the parent acids or
alcohol with a suitable alcohol or acid respecctively, or amides
prepared by reaction of the parent acid or amine compound with an
amine or acid respectively, or basic groups reacted to form an
acylated base derivative. Examples of prodrugs are discussed in,
Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam
1985; Silverman, The Organic Chemistry of Drug Design and Drug
Action, pp. 352-401, Academic Press, San Diego, Calif., 1992 and
Burger's Medicinal Chemistry and Drug Chemistry, Fifth Ed., Vol. 1,
pp. 172-178, 949-982 (1995). The other method for controlling the
blood plasma profile of subject is in the selection of the prodrug,
such as based on its molecular weight or polarity. By increasing
the molecular weight of the prodrug, the time to the onset of
permeation of effective amounts of the prodrug will increase
relatives to the parent drug. One example of this effect is in the
use of norethindrone and norethindrone acetate. The permeation rate
of norethindrone rapidly peaks after application, whereas
norethindrone acetate having a higher molecular weight reaches a
maximum after the norethindrone permeation rate begins to decline.
steroids having a free hydroxy group at a position on the steroid
ring, such as the 17-position, the 3-position, or at the
11-position on the fused ring. Particularly preferred are steroidal
hormones such as estrogens, progestins, and androgens. The
corresponding steroid prodrug (prosteroid) is defined as a
corresponding structure to the steroid where the free hydroxy at
the 3,11 or 17 position has been reacted with an alcohol reactive
moiety. Particularly preferred are steroid derivatives acylated at
the 17 position hydroxyl for example by a C1-C12 alkanoyl group.
Regardless of whether the steroid or the corresponding prosteroid
derivative is incorporated in the carrier composition as the
dominant drug, each provides a source of steroid in the bloodstream
to achieve the intended physiological effect which, in the case of
the corresponding prosteroid, occurs through metabolic conversion
of the derivative. A steroid ester is the corresponding structure
to the steroid where the free hydroxy group on the ring has been
esterified. Examples of a steroid and its corresponding ester
include estradiol and estradiol benzoate, estradiol 17-beta
cypionate, estradiol 17 propionate, estradiol hemisuccinate
(eutocol), estradiol enanthate, estradiol undecylate, estradiol
acetate, and estradiol proprionate, etc. Another example is
testosterone and its corresponding ester of testosterone such as 17
beta-cypionate, testosterone enanthate, testosterone nicotinate,
testosterone phenylacetate, testosterone proprionate, etc. Also
included are non-esters that have groups on the 17 position such as
testosterone 17-chloral hemiacetal, or ethers that have groups on
the 3-position such as estradiol 3-methyl ether.
[0026] The terms "percutaneous" and "transdermal" are used herein
in the broadest sense to refer to being able to pass through
unbroken skin.
[0027] 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.
[0028] 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. It is particularly preferred that the transdermal delivery
system of the invention is non-occlusive.
[0029] 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.
[0030] 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.
[0031] 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.
[0032] The term "aliphatic" includes straight chain, branched chain
and cyclic aliphatic and may be saturated alkyl groups or
unsaturated aliphatic containing from 1 to 3 unsaturated groups
particularly 1 to 3 double bonds.
[0033] The 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.
[0034] A "nutraceutically active compound" is a compound, derived
from a natural origin (animal or vegetable) that has a beneficial
and/or therapeutic effect on the human or animal body in the
treatment of a condition. Such compounds may be regarded as
nutrients.
[0035] Throughout the description and the claims of this
specification the word "comprise" and variations of the word, such
as "comprising" and "comprises" is not intended to exclude other
additives, components, integers or steps.
DETAILED DESCRIPTION
[0036] The present inventors have found that the use of a
penetration enhancer which is a combination of (i) an ester of
salicylic acid, preferably selected from the C.sub.6 to C.sub.30
aliphatic esters of salicylic acid and (ii) polyethylene glycol (of
average molecular weight no more than 300) shows a synergistic
improvement in penetration enhancement.
[0037] The weight ratio of ester of salicylic acid to polyethylene
glycol (of average molecular weight no more than 300) is preferably
in the range of from 95 : 5 to 5:95 and preferably from to 1:10 to
10:1 such as 1:10 to 5:1 and 1:5 to 2:1. The optimal ratio may vary
depending on the nature and concentration of the active agent and
the concentration of the penetration enhancer combination.
[0038] The ester of salicylic acid is preferably a C.sub.6 to
C.sub.18 aliphatic ester, more preferably a C.sub.6 to C.sub.12
alkyl ester and still more preferably is C.sub.8 alkyl and most
preferably is 2-ethylhexylester known by the common name Octyl
salicylate or simply Octisalate.
[0039] Typically the ester of salicylic acid will be present in an
amount of from 0.1 to 10% by weight of the total transdermal
composition of the invention and more preferably from 0.5 to 5%
such as 0.5, 0.7, 0.8, 0.9, 1.0, 1.2, 1.5, 1.7, 2.0, 3.0, 3.5, 4.0,
4.5 and 5.0.
[0040] Typically the PEG of average molecular weight less than 300
will be present in an amount in the range of from 0.1 to 40%by
weight of the total composition and preferably from 0.5 to 20% such
as 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 6%, 7%, 8%, 9%, 10%,
11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%.
[0041] The composition of the invention preferably comprises PEG
200 in an amount in the range of from 0.1 to 40% by weight of the
total composition and preferably from 0.5 to 20% such as 1%, 1.5%,
2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%,
14%, 15%, 16%, 17%, 18%, 19%, 20%.
[0042] The composition of the invention may and preferably will
contain a volatile solvent. Preferably the volatile solvent has a
vapour pressure above 35 mm Hg at atmospheric pressure and normal
skin temperature of 32 degrees Celsius. In a particularly preferred
form of the invention the solvent preferably a C.sub.2 to C.sub.4
alkanol and more preferably is ethanol or isopropanol, or a mixture
thereof.
[0043] Known dermal penetration enhancers may also be employed in
the transdermal drug delivery system. The use of 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-pyrollidone and those dermal
penetration enhancers given in U.S. Pat. No. 5,082,866, particulary
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. Preferably the composition will comprise
no more than 5% by weight of the non-volatile penetration enhancers
other than PEG and the salicylic acid esters more preferably no
more than 1% and most preferably no more than 0.5% by weight of the
composition of non-volatile penetration enhancers other than PEG of
molecular weight of no more than 300 and salicylic acid esters.
[0044] The volatile solvent is preferably present in the
composition of the invention in an amount in the range of from 40
to 95% by weight of the composition and more preferably from 50 to
95%, still more preferably from 60 to 95% by weight such as 65% to
95% by weight 70% to 95%, 70 to 90% and 75 to 90% by weight of the
total composition.
[0045] The composition of the invention may if desired contain one
or more additional adjuvants such as those selected from the group
consisting of penetration enhancers, surfactants, thickeners and
solvents. Examples of suitable thickeners include polyacrylic
acids; and acylic acid copolymers agor, carrageenan, food starch,
gelatins, germ Arabic, guorgem, hydroxyethyl cellulose
hydroxypropymethyl cellulose, protein and polyvinyl pyrrolidone.
The content of thickener may be from 0 to 5%. It is however a
particularly preferred aspect of the invention that the composition
consists essentially of: [0046] (i) an physiolocically active agent
component which may include one or more physiologically active
agents; [0047] (ii) a penetration enhancer component consisting of
an ester of salicylic acid and a polyethylene glycol of average
molecular weight no more than 300; [0048] (iii) a volatile solvent
consisting of one or more of ethanol and isopropanol; and [0049]
(iv) optionally a propellant.
[0050] It will be understood by those skilled in the art that
alcohols and polyols contain a certain amount of water. Typically
the total water content of the composition is less than 20% by
weight and preferably less than 10% by weight of the total
composition.
[0051] The composition of the invention may be in a range of forms
from a liquid, cream, paste, gel, lotion, patch (matrix and
reservoir), tape, plaster or film former. In the more preferred
embodiment the transdermal delivery system is in the form of a
liquid for application to a defined area of skin.
[0052] The compositions of the present invention may be in any form
suitable for topical application to the skin. Suitable forms
include sprayable liquids; gels; liquids that may be applied using
a roll-on device; lacquers; and sustained release matrices of
transdermal delivery devices such as patches. The compositions are
usually administered alone but, under some circumstances,
administration may be further modified by using other delivery
mechanisms such as iontophoresism, ultrasound and microneedles to
enhance penetration. Non-occlusive application and in particular
Spray application are preferred.
[0053] Suitable pharmacologically active compounds may be selected
from:
[0054] Alimentary System Antidiarrhoeals such as diphenoxylate,
loperamide andhyoscyamine;
[0055] Cardiovascular system agents including:
[0056] Antihypertensives such as hydralazine, minoxidil, captopril,
enalapril, clonidine, prazosin, debrisoquine, diazoxide,
guanethine, methyldopa, reserpine, trimetaphan;
[0057] Calcium channel blockers such as diltiazem, felodopine,
amlodipine, nitrendipine, nifedipine and verapamil;
[0058] Proton pump inhibitors such as lansoprazole; omeprazole; and
pantaprazole;
[0059] Antiarrhyrthmics such as amiodarone, flecainide,
disopyramide, procainamide, mexiletene and quinidine;
[0060] Antiangina agents such as glyceryl trinitrate, erythritol
tetranitrate, pentaerythritol tetranitrate, mannitol hexanitrate,
perhexilene, isosorbide dinitrate and nicorandil;
[0061] Beta-adrenergic blocking agents such as alprenolol,
atenolol, bupranolol, carteolol, labetalol, metoprolol, nadolol,
nadoxolol, oxprenolol, pindolol, propranolol, sotalol, timolol and
timolol maleate;
[0062] Cardiotonic glycosides such as digoxin and other cardiac
glycosides andtheophylline derivatives;
[0063] Adrenergic stimulants such as adrenaline, ephedrine,
fenoterol, isoprenaline,orciprenalihe, rimeterol, salbutamol,
salmeterol, terbutaline, dobutamine, phenylephrine,
phenylpropanolamine, pseudoephedrine and dopamine;
[0064] Vasodilators such as cyclandelate, isoxsuprine, papaverine,
dipyrimadole, isosorbide dinitrate, phentolamine, nicotinyl
alcohol, co-dergocrine, nicotinic acid, glyceryl trinitrate,
pentaerythritol tetranitrate and xanthinol; and
[0065] Antimigraine preparations such as ergotamine,
dihydroergotamine, methysergide, pizotifen and sumatriptan.
[0066] Drugs affecting blood and haemopoietic tissues
including:
[0067] Anticoagulants and thrombolytic agents such as warfarin,
dicoumarol, low molecular weight heparins such as enoxaparin;
streptokinase and its active derivatives.
[0068] Haemostatic agents such as aprotinin, tranexamic acid and
protamine.
[0069] Drugs affecting the Central Nervous System including:
[0070] Analgesics;
[0071] antipyretics including the opiod analgesics such as
buprenorphine, dextromoramide, dextropropoxyphene, fentanyl,
alfentanil, sufentanil, hydromorphone, methadone, morphine,
oxycodone, papaveretum, pentazocine, pethidine, phenoperidine,
codeine and dihydrocodeine. Others include acetylsalicylic acid
(aspirin), paracetamol, and phenazone;
[0072] Hypnotics and sedatives such as the barbiturates,
amylobarbitone, butobarbitone and pentobarbitone and other
hypnotics and sedatives such as choral hydrate, chlormethiazole,
hydroxyzine and meprobamate; and
[0073] Antianxiety agents such as the benzodiazepines, alprazolam,
bromazepam, chlordiazepoxide, clobazam, chlorazepate, diazepam,
flunitrazepam, flurazepam, lorazepam, nitrazepam, oxazepam,
temazepam and triazolam.
[0074] Agents to treat food allegies such as sodium
cromoglicate.
[0075] 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.
[0076] Antidepressants such as the tricyclic antidepressants
amitryptyline, clomipramine, desipramine, dothiepin, doxepin,
imipramine, nortriptyline, opipramol, protriptyline and
trimipramine; tetracyclic antidepressants such as mianserin;
monoamine oxidase inhibitors such as isocarboxazid, phenelizine,
tranylcypromine and moclobemide; selective serotonin re-uptake
inhibitors such as fluoxetine, paroxetine,titalopram, fluvoxamine
and sertraline; and tetracyclic antidepressants such as mirtazapine
and any metabolites, salts enantiomers (including esmirtazapine),
solvents, non-covalent complexes, chelates, hydrates, crystalline
or amorphous forms thereof.
[0077] CNS stimulants such as caffeine.
[0078] Anti-alzheimer's agents such as tacrine.
[0079] Antiparkinson agents such as amantadine, benserazide,
carbidopa, levodopa,benztropine, biperiden, benzhexol, procyclidine
and dopamine-2 agonists such as
S(-)-2-(N-propyl-N-2thienylethylamino)-5-hydroxytetralin
(N-0923).
[0080] Lipid regulating drugs such as statins.
[0081] Drugs affecting bone metabolism such as calcitonin and
bisphosphonates.
[0082] Anticonvulsants such as phenytoin, valproic acid, primidone,
phenobarbitone, methylphenobarbitone and carbamazepine,
ethosuximide, methsuximide, phensuximide, sulthiame and
clonazepam.
[0083] 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.
[0084] Musculoskeletal system drugs:
[0085] Non-steroidalanti-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;
[0086] 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;
[0087] Antirheumatoid agents such as penicillamine,
aurothioglucose, sodium aurothiomalate, methotrexate and
auranofin;
[0088] Muscle relaxants such as baclofen, diazepam, cyclobenzaprine
hydrochloride, dantrolene, methocarbamol, orphenadrine and quinine;
and
[0089] Agents used in gout and hyperuricaemia such as allopurinol,
colchicine, probenecid and sulphinpyrazone.
[0090] Hormones and Steroids including:
[0091] Estrogens such estradiol, estriol, estradiol benzoate,
estradiol 17.beta.-cypionate, estradiol enanthate, estradiol
propionate, estrone, ethinylestradiol, Fosfestrol, Dienestrol
mestranol, stilboestrol, dienoestrol, epioestriol, estropipate
Diethylstilbestrol, Chlorotrianisene, conjugated estrogenic
hormones, Polyestradiol phosphate and zeranol and mixtures
thereof;
[0092] Progesterone and progestins such as norethisterone,
norethisterone acetate, gestodene, levonorgestrel, allylestrenol,
anagestone, desogestrel, dimethisterone, dydrogesterone,
ethisterone, ethynodiol, Ethynodiol diacetate, Etonogestrel,
gestodene, ethinylestradiol, haloprogesterone,
17-hydroxy-16-methylene-progesterone,
17.alpha.-hydroxyprogesterone, lynestrenol, medroxyprogesterone,
melengestrol, norethindrone, norethynodrel, norgesterone,
Gestonorone, Norethisterone, norgestimate, norgestrel,
Levonorgestrel, norgestrienone, norvinisterone, pentagestrone, MENT
(7-methyl-19-testosterone); Norelgestromin, and trimigestone
Drospirenone, Tibolone, and megestrol and mixtures thereof;
[0093] Antiandrogens such as cyproterone acetate and danazol;
[0094] Antiestrogens such as tamoxifen and epitiostanol and the
aromatase inhibitors, exemestane and 4-hydroxy-androstenedione and
its derivatives;
[0095] Androgens and anabolic agents such as androisoxazole,
androstenediol, bolandiol, bolasterone, clostebol, ethylestrenol.
formyldienolone, 4-hydroxy-19-nortestosterone, methandriol,
methenolone, methyltrienolone, nandrolone, norbolethone,
oxymesterone, stenbolone and trenbolone. Androgenic steroids can
include boldenone, fluoxymesterone, mestanolone, mesterolone,
methandrostenolone, 17-methyltestosterone,
17.alpha.-methyltestosterone 3-cyclopentyl enol ether,
norethandrolone, normethandrone, oxandrolone, oxymesterone,
oxymetholone, prasterone, stanlolone, stanozolol, testosterone,
testosterone 17-chloral hemiacetal, testosterone proprionate,
testosterone enanthate tiomesterone dehydroepiandrosterone (DHEA),
androstenedione (Andro): an androstenediol, androsterone,
dihydrotestosterone (DHT) and androstanolone and derivatives
thereof;
[0096] 5-alpha reductase inhibitors such as finasteride,
turosteride, LY-191704 and MK-306;
[0097] 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;
[0098] Further examples of steroidal antiinflammatory agents for
use in the instant compositions include 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;
[0099] Pituitary hormones and their active derivatives or analogs
such as corticotrophin, thyrotropin, follicle stimulating hormone
(FSH), luteinising hormone (LH) and gonadotrophin releasing hormone
(GnRH);
[0100] Hypoglycaemic agents such as insulin, chlorpropamide,
glibenclamide, gliclazide, glipizide, tolazamide, tolbutamide and
metformin;
[0101] Thyroid hormones such as calcitonin, thyroxine and
liothyronine and antithyroid agents such as carbimazole and
propylthiouracil; and
[0102] Other miscellaneous hormone agents such asoctreotide.
[0103] Pituitary inhibitors such as bromocriptine.
[0104] Ovulation inducers such as clomiphene.
[0105] Genitourinary system including:
[0106] 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 pottasium sparing diuretics,
spironolactone, amiloride and triamterene.
[0107] Antidiuretics such as desmopressin, lypressin and
vasopressin including their active derivatives or analogs.
[0108] Obstetric drugs including agents acting on the uterus such
as ergometrine, oxytocin and gemeprost.
[0109] Prostaglandins such as alprostadil (PGEi), prostacyclin
(PGI2), dinoprost (prostaglandin F2-alpha) and misoprostol.
[0110] Antimicrobials including:
[0111] Antimicrobials including the cephalosporins such
ascephaiexin, cefoxytin and cephalothin;
[0112] Penicillins such as amoxycillin, amoxycillin with clavulanic
acid, ampicillin, bacampicillin, benzathine penicillin,
benzylpenicillin, carbenicillin, cloxacillin, methicillin,
phenethicillin, phenoxymethylpenicillin, flucloxacillin,
mezlocillin, piperacillin, ticarcillin and azlocillin;
[0113] Tetracyclines such as minocycline, chlortetracycline,
tetracycline, demeclocycline, doxycycline, methacycline and
oxytetracycline and other tetracycline-type antibiotics;
[0114] Aminoglycosides such as amikacin, gentamicin, kanamycin,
neomycin, netilmicin and tobramycin;
[0115] Antifungals 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;
[0116] Quinolones such as nalidixic acid, cinoxacin, ciprofloxacin,
enoxacin andnorfloxacin;
[0117] Sulphonamides such as phthalylsulphthiazole, sulfadoxine,
sulphadiazine, sulphamethizole and sulphamethoxazole;
[0118] Sulphones such as dapsone; and
[0119] 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
andd iiodohydroxyquin; hexachlorophene; chlorhexidine; chloroamine
compounds; benzoylperoxide.
[0120] Antituberculosis drugs such as ethambutol, isoniazid,
pyrazinamide, rifampicin and clofazimine.
[0121] Antimalarials such as primaquine, pyrimethamine,
chloroquine, hydroxychloroquine, quinine, mefloquine and
halofantrine.
[0122] Antiviral agents such as acyclovir and acyclovir prodrugs,
famciclovir, zidovudine, didanosine, stavudine, lamivudine,
zalcitabine, saquinavir, indinavir, ritonavir, ndocosanol,
tromantadine and idoxuridine.
[0123] Anthelmintics such as mebendazole, thiabendazole,
niclosamide, praziquantel, pyrantel embonate and
diethylcarbamazine.
[0124] 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.
[0125] Metabolism agents including:
[0126] Anorectic and weight reducing agents including
dexfenfluramine, fenfluramine, diethylpropion, mazindol and
phentermine; and
[0127] Agents used in hypercalcaemia such as calcitriol,
dihydrotachysterol and their active derivatives or analogs;
[0128] Respiratory system agents including:
[0129] Antitussives such as ethylmorphine, dextromethorphan and
pholcodine;
[0130] Expectorants such as acetylcysteine, bromhexine, emetine,
guaiphenesin, ipecacuanha ans saponins;
[0131] Decongestants such as phenylephrine, phenylpropanolamine ans
pseudoephedrine; and
[0132] 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 andtheophylline and
theophylline derivatives.
[0133] Allergy and immune system agents including:
[0134] 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.
[0135] Local anaesthetics such as bupivacaine, amethocaine,
lignocaine, cinchocaine, dibucaine, mepivacaine, prilocaine and
etidocaine.
[0136] Stratum corneum lipids, such as ceramides, cholesterol and
free fatty acids, for improved skin barrier repair [Man, et al. J.
Invest. Dennatol., 106(5), 1096, 1996].
[0137] H2-receptor antagonists such as cimetidine; and
ranitidine;
[0138] Neuromuscular blocking agents such assuxamethonium,
alcuronium, pancuronium, atracurium, gallamine, tubocurarine and
vecuronium.
[0139] Smoking cessation agents such as nicotine, bupropion and
ibogaine.
[0140] Insecticides and other pesticides which are suitable for
local or systemic application.
[0141] Dermatological agents, such as vitamins A and E, vitamin E
acetate and vitamin E sorbate.
[0142] Allergens for desensitisation such as house dust mite
allergen.
[0143] nutraceutically active compounds include carotenoids such as
lycopene, lutein, astaxanthin and [beta]-carotene; glucosamine or
N-acylglucosamine; ubiquinone;--Vitamins such as vitamins A, C, D
and E; Rosmarinic acid; Honokiol; Magnolol; Chlorogenic acid;
Oleuropein; Methylsulphonylmethane ("MSM"); Collagen and
Chondroitin; Boswellin and boswellic acid;
[0144] Keratolytics such as the alpha-hydroxy acids, glycollic acid
and salicylic acid.
[0145] Psychicenergisers, such as 3-(2-aminopropyl) indole,
3-(2-aminobutyl)indole, and the like.
[0146] Anti-acne agents such as isotretinoin, tretinoin and benzoyl
peroxide.
[0147] Anti-psoriasis agents such as etretinate, cyclosporin and
calcipotriol.
[0148] Anti-itch agents such as capsaicin and its derivatives such
as nonivamide [Tsai, et al. Drug. Dev. Ind. Pharm., 20(4), 719,
1994].
[0149] 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
acyloxymethylammnonium salts [described, for example, by Bodor et
al, J. Med. chem. 23, 474 (1980) and also in United Kingdom
Specification No. 2010270, published 27 Jun. 1979].
[0150] The optimal ratio of penetration enhancer to active will
differ depending on the nature of the active and the specific
identity and composition of the combination which makes up the
penetration enhance. Typically the weight ratio of penetration
enhancer to active will be in the range of from 1000:1 to 1:1000
and preferably from 500:1 to 1:10 and most preferably from 20:1 to
1:1.
[0151] The penetration enhancer of the invention is particularly
useful in transdermal administration of antidepressants, women's
health actives and hormones. Hormones that may be used in the drug
delivery system of the present invention include systemically
active hormones which can be delivered through the skin with the
assistance of the dermal penetration enhancer to achieve a desired
effect.
[0152] Suitable hormones include:
[0153] androgens such as:
[0154] testosterone. dehydroepiandrosterone (DHEA), androstenedione
(Andro): an androstenediol, androsterone, dihydrotestosterone (DHT)
androstanolone, fluoxymesterone, mesterolone, methyltestosterone
and derivatives thereof;
[0155] estrogens such as:
[0156] Estradiol, Estriol, Estrone, Chlorotrianisene, Dienestrol,
Diethylstilbestrol, Ethinylestradiol, Fosfestrol, Mestranol,
Polyestradiol phosphate.
[0157] Selective estrogen receptor modulators such as:
[0158] Bazedoxifene, Clomifene, Fulvestrant, Lasofoxifene,
Raloxifene, Tamoxifen, Toremifene
[0159] Aromatase inhibitor such as:
[0160] Aminogluthetimide, Anastrozole, Exemestane, Formestane,
Letrozole and Vorozole.
[0161] Gonadotropins such as:
[0162] Clomifene and Urofollitropin.
[0163] Progestogens such as:
[0164] progesterone;
[0165] progestins such as: [0166] those selected from the group
consisting of Desogestrel, Drospirenone, Dydrogesterone,
Ethisterone, Etonogestrel, Ethynodiol diacetate, Gestodene,
Gestonorone, Levonorgestrel, Lynestrenol, Medroxyprogesterone,
Megestrol, Norelgestromin, Norethisterone, Norethynodrel,
Norgestimate, Norgestrel, Norgestrienone, ethinylestradiol,
Tibolone, megestrol and MENT (7-methyl-19-testosterone);
[0167] Selective progesterone receptor modulators such as:
[0168] Asoprisnil, CDB-4124
[0169] Antiprogestogen such as Mifepristone;
[0170] Antigonadotropinssuch as:
[0171] Danazol and Gestrinone; and
[0172] GnRH:(receptor) agonis such as:
[0173] Buserelin, Goserelin, Histrelin, Leuprorelin, Nafarelin and
Triptorelin.
[0174] GnRH antagonist: Abarelix, Cetrorelix and Ganirelix.
[0175] Compositions of the invention may include a plurality of
hormones from one or more of these groups. For example it may be
desirable for contraceptive formulations to comprise one or more
estrogens and one or more progestins.
[0176] The treatment system may be used for local or systemic
administration in an effective amount. In one embodiment the
transdermal delivery system is administered to provide a
pharmaceutically effective amount of the active in the systemic
circulation. In one preferred form of the invention the drug
delivery system comprises on a weight basis from about 0.1 to about
10% of active agent (partially a hormone), from about 0.1 to 12% of
the at least one dermal penetration enhancer and from about 78 to
99.8% ethanol, isopropanol or mixture thereof.
[0177] In another preferred form of the invention the drug delivery
system comprises, on a weight basis, from about 1 to 3% of a
hormone, from about 1 to 15% of the dermal penetration enhancer
combination, from about 45 to 90% ethanol, isopropanol or mixture
thereof, 5 to 45% water.
[0178] Another group of preferred drugs are antidepressants
including noradrenergic and specific serotonergic antidepressants
(N.sub.aSSA); more preferably tetracyclic antidepressants and most
preferably mirtazapine and any metabolites, salts, enantiomers
(including esmirtazapine), solvants, non-covalent complexes,
chelates, hydrates, crystalline or amorphous forms thereof.
[0179] 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 using for example estradiol, androgen
replacement therapy for females lacking libido and/or to treat
depression using an androgen such as testosterone, male
contraception (for example using a progestin such etonogestrel
optionally with testosterone) and female contraception (for example
using a progestin optionally in combination with an estrogen).
Steroidal hormones particularly estrogens may be used to treal
premenstrual syndrome (PMS) symptoms in women for example
estradiol. PMS symptoms include (but are not limited to) abdominal
bloating, abdominal cramps, headache or migraine, breast tenderness
or swelling, anxiety, insomnia, joint or muscle pain and mood
swings.
[0180] In one embodiment the transdermal delivery system comprises
a spray apparatus comprising a container for a transdermal
composition, a spray nozzle and an actuator for delivering a
metered dose of spray from the container via the nozzle, wherein
the transdermal composition comprises a physiologically active
agent and a first penetration enhancer component of an ester of
salicylic acid, preferably selected from the C.sub.6 to C.sub.30
aliphatic ester of salicylic acid, and a second penetration
enhancer component of polyethylene glycol of average molecular
weight no more than 300.
[0181] The transdermal delivery system will preferably be applied
in a dose sufficient to provide an effective amount of the
physiologically active agent in the bloodstream of the animal.
[0182] Preferably, the applicator provides a metered dose
application such as a metered dose aerosol, a stored-energy metered
dose pump or a manual metered dose pump. Preferably the drug
delivery system is applied to the skin of the animal covering a
delivery surface area between about 10 and 800 cm.sup.2, more
preferably between about 10 and 400.sup.2, and most preferably
between about 10 and 200 cm.sup.2. The application is most
preferably performed by means of a topical metered dose spray
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 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 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.
[0183] The invention will now be described with reference to the
following examples. It is to be understood that the examples are
provided by way of illustration of the invention and that they are
in no way limiting to the scope of the invention.
Examples
[0184] The compositions of the Examples and their performance are
compared with reference to the drawings.
BRIEF DESCRIPTION OF DRAWINGS
[0185] In the drawings:
[0186] FIG. 1 is a column chart comparing the permeation of a
progestin from a control with progestin transdermal delivery
composition of the invention of Example 1.
[0187] FIG. 2 is a column chart comparing the permeation of an
estrogen from a control with a transdermal delivery composition of
the invention of Example 1.
[0188] FIGS. 3a and 3b are column charts showing the effect on
progestin permeation of comparative transdermal compositions
containing different progestins and PEG400 rather than PEG 200 as
described in Example 2.
[0189] FIG. 4 is a column chart comparing the permeation of a
progestin from a control composition with a transdermal delivery
compositions of the invention containing PEG200 pursuant to Example
2.
[0190] FIG. 5 is a column chart comparing the permeation of an
estrogen from transdermal delivery compositions 2 to 7 of the
invention with the control composition of 1 of Example 2.
[0191] FIG. 6 is a column chart comparing the effect of PEG200 on
permeation of an androgen from transdermal delivery compositions 1
to 4 of Example 3.
[0192] FIG. 7 is a column chart comparing permeation of an androgen
from transdermal delivery compositions 2 to 3 with the control
composition 1 of Example 4.
[0193] FIGS. 8 and 9 are column charts comparing permeation of the
non-steroidal anti-inflamatory drug (NASAID) ketoprofen from a
commercial product with transdermal delivery spray compositions
containing each of OS and PEG alone and in combination (in
accordance with the invention) as described in Example 5.
[0194] FIGS. 10 and 11 are column charts comparing permeation of
the non-steroidal anti-inflamatory drug (NASAID) diclofenac from a
commercial product with transdermal delivery spray compositions
containing each of OS and PEG200 and PEG 400 alone and OS in
combination with the different PEG compositions as described in
Example 6.
[0195] FIG. 12 is a column chart which compares the effect of each
of PEG 200 and PEG 400 on the permeation of the estrogen estradiol
from compositions containing OS penetration enhancer as described
in Example 7.
Example 1
[0196] Investigation of the Effect of PEG200 on Cumulative
Norethisterone Acetate and Estradiol Permeation Through Human Skin
In Vitro
Methods:
[0197] Finite-dose in vitro diffusion studies were undertaken using
dermatomed human female abdominal skin (500 .mu.m).
[0198] These experiments were performed over 24 hours using
Franz-type cells. Pre-cut skin membranes were mounted as a barrier
between the halves of greased (high vacuum grease, BDH) horizontal
Franz-type permeation cells in the middle of the receptor chamber
of the cell with the stratum corneum facing the donor chamber. The
area available for permeation was approximately 0.925 cm2. The
receptor chambers of the permeation cells were filled with the
receptor phase (Phosphate Buffered Saline pH 7.4) and capped. The
permeation cells were immersed in a constant temperature water bath
such that the receptor chambers were maintained at 35.degree. C.
Receptor chamber contents were continuously agitated by small
PTFE-coated magnetic stirrer bars driven by submersible magnetic
stirrers. The skin was allowed to equilibrate to temperature with
receptor solution for 1 h in the water bath prior to dosing.
[0199] The formulations were applied to the skin at a dose of 3.6
.mu.L/cm2. The applied formulation was spread over the skin area
using an Eppendorf positive displacement pipette tip without
breaking the skin membrane.
[0200] The formulations consisted of: [0201] Comparison composition
1: 2.8% Norethisterone Acetate (NETA), 0.55% Estradiol (E2), 5%
Octyl Salicylate (OS) [0202] Composition 2: 2.8% NETA, 0.55% E2, 5%
Polyethylene Glycol 200 (PEG200) [0203] Composition 3: 2.8% NETA,
0.55% E2, 5% OS, 5% PEG200 [0204] Composition 4: 2.8% NETA, 0.55%
E2, 10% PEG200 [0205] Composition 5: 2.8% NETA, 0.55% E2, 5% OS,
10% PEG200
[0206] The amount of active that permeated the skin was quantified
using validated HPLC methods
[0207] FIG. 1 compares the penetration of comparative composition 1
with compositions 2-5 relating to invention. PEG200 in combination
with OS was found to significantly enhance the permeation of both
Norethisterone Acetate and estradiol through human epidermis in
vitro. Permeation of NETA is compared in FIG. 1 and permeation of
estradiol is compared in FIG. 2.
Example 2
[0208] Investigation into the Effect of PEG200 and PEG400 on
Cumulative Nestorone & Ethinylestradiol Permeation Through
Human Skin In Vitro
Methods:
[0209] Finite-dose in vitro diffusion studies were undertaken using
dermatomed human female abdominal skin(500 .mu.m).
[0210] These experiments were performed over 24 hours using
stainless steel, flow through diffusion cells based on those
described previously (Cooper, E. R. J. Pharm. Sci. 1984, 73,
1153-1156) except that the cell was modified to increase the
diffusion area to 1.0 cm2. The formulations were applied using a
finite dose technique (Franz, T. J. Curr. Probl. Dermatol., 1978,
7, 58-68) to mimic clinical dosing conditions at an applied dose
volume of 3.6 .mu.L/cm2. A piece of stainless steel wire mesh was
placed directly below the skin in the receptor chamber of the of
the diffusion cell to maintain a turbulent flow of receptor
solution below the skin. The diffusion cells were maintained at a
flow rate of approximately 0.5 mL/hr by a microcassette peristaltic
pump (Watson Marlow 505S UK). The cells were kept at
32.+-.0.5.degree. C. by a heater bar and the samples were collected
into appropriately sized glass vials for a period of 24 hr. The
receptor solutions (Phosphate Buffered Saline pH7.4) maintained
sink conditions below the skin.
[0211] The formulations consisted of: [0212] Composition (Comp) 1
(Control): 1.35% Nestorone (NES), 0.35% Ethinylestradiol (EE), 5%
Octyl Salicylate (OS) in Isopropyl Alcohol (IPA) [0213] Comp 2:
1.35% NES, 0.35% EE, 5% OS, 5% Polyethylene glycol 400 (PEG400) in
IPA [0214] Comp 3: 1.35% NES, 0.35% EE, 0.5% Polyethylene glycol
(PEG200) in IPA [0215] Comp 4: 1.35% NES, 0.35% EE, 5% OS, 0.5%
PEG200 in IPA [0216] Comp 5: 1.35% NES, 0.35% EE, 1% PEG200 in IPA
[0217] Comp 6: 1.35% NES, 0.35% EE, 5% OS, 1% PEG200 in IPA [0218]
Comp 7: 1.35% NES, 0.35% EE, 2.5% PEG200 in IPA [0219] Comp 8:
1.35% NES, 0.35% EE, 5% OS, 2.5% PEG200 in IPA [0220] Comp 9: 1.35%
NES, 0.35% EE, 5% PEG200 in IPA [0221] Comp 10: 1.35% NES, 0.35%
EE, 5% OS, 5% PEG200 in IPA [0222] Comp 11: 1.35% NES, 0.35% EE,
10% PEG200 in IPA [0223] Comp 12: 1.35% NES, 0.35% EE, 5% OS, 10%
PEG200 in IPA
[0224] The amount of active that permeated the skin was quantified
using validated HPLC methods
[0225] The effect of PEG400 on permeation of NES and EE is shown in
FIGS. 3a and 3b respectively. PEG200 in combination with OS was
found to enhance the permeation of both Nestorone and
Ethinylestradiol through human epidermis in vitro.
[0226] The addition of PEG400 to the formulation did not have a
significant effect (enhancing or inhibitory) on the permeation of
Nestorone through human epidermis in vitro. PEG400 was found to
inhibit the permeation of ethinylestradiol through human epidermis
in vitro.
[0227] The effect of PEG 200 in compositions 3 to 12 on permeation
of NES is compared with the Composition 1 control (containing no
PEG200) in FIG. 4.
[0228] The effect of PEG200 in compositions 3 to 12 on permeation
of EE is compared with the Composition 1 control in FIG. 5.
Example 3
[0229] Investigation Into the Effect of PEG200 on Cumulative
Testosterone Permeation Through Human Skin In Vitro.
Methods:
[0230] Finite-dose in vitro diffusion studies were undertaken using
dermatomed human female abdominal skin (500 .mu.m).
[0231] These experiments were performed over 24 hours using
stainless steel, flow through diffusion cells based on those
described previously (Cooper, E. R. J. Pharm. Sci. 1984, 73,
1153-1156) except that the cell was modified to increase the
diffusion area to 1.0 cm2. The formulations were applied using a
finite dose technique (Franz, T. J. Curr. Probl. Dermatol., 1978,
7, 58-68) to mimic clinical dosing conditions at an applied dose
volume of 15 .mu.L/cm2. A piece of stainless steel wire mesh was
placed directly below the skin in the receptor chamber of the of
the diffusion cell to maintain a turbulent flow of receptor
solution below the skin. The diffusion cells were maintained at a
flow rate of approximately 1.0 mL/hr by a microcassette peristaltic
pump (Watson Marlow 505S UK). The cells were kept at
32.+-.0.5.degree. C. by a heater bar and the samples were collected
into appropriately sized glass vials for a period of 24 hr. The
receptor solutions (0.002% w/v NaN3) maintained sink conditions
below the skin.
[0232] The formulations consisted of: [0233] Comp 1: 2%
Testosterone (TES), 5% Octyl Salicylate (OS), 2% polyvinyl
pyrrolidine (PVP), 30% isopropyl alcohol (IPA) in ethanol (95%)
[0234] Comp 2: 2% TES, 5% OS, 2% PVP, 30% IPA, 0.5% polyethylene
glycol 200 (PEG200) in ethanol (95%) [0235] Comp 3: 2% TES, 5% OS,
2% PVP, 30% IPA, 1.0% PEG200 in ethanol (95%) [0236] Comp 4: 2%
TES, 5% OS, 2% PVP, 30% IPA, 2.5% PEG200 in ethanol (95%)
[0237] The amount of active that permeated the skin was quantified
using validated HPLC methods
[0238] The effect on permeation of TES from using the composition
as shown in FIG. 6. PEG200 in combination with OS was found to
significantly enhance the permeation of Testosterone through human
epidermis in vitro.
Example 4
[0239] Investigation Into the Effect of PEG200 on Cumulative
Testosterone Permeation Through Human Skin In Vitro
Methods:
[0240] Finite-dose in vitro diffusion studies were undertaken using
dermatomed human female abdominal skin (500 .mu.m).
[0241] These experiments were performed over 24 hours using
stainless steel, flow through diffusion cells based on those
described previously (Cooper, E. R. J. Pharm. Sci. 1984, 73,
1153-1156) except that the cell was modified to increase the
diffusion area to 1.0 cm2. The formulations were applied using a
finite dose technique (Franz, T. J. Curr. Probl. Dermatol., 1978,
7, 58-68) to mimic clinical dosing conditions at an applied dose
volume of 3.6 .mu.L/cm2. A piece of stainless steel wire mesh was
placed directly below the skin in the receptor chamber of the of
the diffusion cell to maintain a turbulent flow of receptor
solution below the skin. The diffusion cells were maintained at a
flow rate of approximately 1.0 mL/hr by a microcassette peristaltic
pump (Watson Marlow 505S UK). The cells were kept at
32.+-.0.5.degree. C. by a heater bar and the samples were collected
into appropriately sized glass vials for a period of 24 hr. The
receptor solutions (0.002% w/v NaN3) maintained sink conditions
below the skin.
[0242] The formulations consisted of: [0243] Comp 1: 5%
Testosterone (TES), 5% Octyl Salicylate (OS) in ethanol (95%)
[0244] Comp 2: 5% TES, 5% OS, 1.0% polyethylene glycol 200 (PEG200)
in ethanol (95%) [0245] Comp 3: 5% TES, 5% OS, 2.5% PEG200 in
ethanol (95%)
[0246] The amount of active that permeated the skin was quantified
using validated HPLC methods
[0247] The effect of the combination of PEG200 and OS in
Compositions 2 and 3 is compared with a control Composition 1 in
FIG. 7. As shown in FIG. 7, PEG200 in combination with OS was found
to significantly enhance the permeation of Testosterone through
human epidermis in vitro.
Example 5
[0248] Ketoprofen Transdermal Spray: Investigation into the Effect
of PEG200 and PEG 400 on Ketoprofen Permeation through Human Skin
In Vitro
Methods:
[0249] Finite-dose in vitro diffusion studies were undertaken
dermatomed skin (Padgett Model B or S electric dermatome set at 500
.mu.m) prepared from excised female, abdominal skin.
[0250] These experiments were conducted over 24 hours using
flow-through systems with a 1-cm2 administration area. A piece of
stainless steel wire mesh was placed directly below the skin in the
receptor chamber of the of the diffusion cell to maintain a
turbulent flow of receptor solution below the skin. The diffusion
cells were maintained at a flow rate of approximately 0.5 mL/hr by
a peristaltic pump (Watson Marlow 520S Peristaltic Pump with 313A
adaptor and 308MC 8 roller pump-head; Stauff Corporation,
Australia). The cells were kept at 32.+-.0.5.degree. C. by a heater
bar and the samples were collected into appropriately sized glass
vials for a period of 24 hr.
[0251] Following a 2-h equilibration of the skin with the receptor
solution (RS) of 0.002% sodium azide (NaN3), the stratum corneum
surface was dosed with a volume of 3.6 .mu.L/cm2 (unless otherwise
indicated) of a test formulation using a positive displacement
pipette. The formulation was spread evenly over the skin area using
the pipette tip.
[0252] The Ketoprofen Transdermal Spray formulations were as
follows: [0253] 5.0% Ketoprofen (KETO) in Isopropyl alcohol (IPA)
[no enhancer] [0254] 5.0% KETO, 5% Octyl Slaicylate (OS) in IPA
[OS] [0255] 5.0% KETO, 2.5% Polyethylene glycol 200 (PEG 200) in
IPA [PEG 200] [0256] 5.0% KETO, 5% OS, 2.5% PEG 200 in IPA [OS +PEG
200]
[0257] A commercially available ketoprofen gel (approximately 5
mg/cm2) was used as a control. The commercially available gel was
applied using a solid cap to simulate the rubbing action required
when using the product. Approximately 7 mg gel was applied to the
circular surface of a black polypropylene cylindrical cap (Alltech
catalogue # 98105, diameter 11 mm). The cap was weighed before the
gel was rubbed onto the surface of the skin. The gel was rubbed on
for 30 seconds (s) and the cap was left on the skin for a further 1
minute with a 3.5 g weight on top. The cap was then re-weighed to
determine the actual amount of gel applied. The actual weights of
the commercially available gel were used to adjust the permeation
data to the levels that would have been achieved with 5 mg/cm2 of
KETO applied.
[0258] The amount of active that permeated the skin was quantified
using validated HPLC methods.
[0259] FIG. 8 compares the permeation of ketoprofen from a
commercially available transdermal gel with the above spray
formulations containing 5% ketoprofen 0 or 5% OS and 0 or 2.5%
PEG200 in isopropyl alcohol.
[0260] FIG. 9 compares the transdermal permeation of 2.5%
ketoprofen composition where the penetration enhancer is PEG200 or
PEG400 and where PEG200 and PEG400 are used in combination with
OSAL (2.sup.nd and 3.sup.rd columns).
Results:
[0261] PEG200 in combination with OS was found to significantly
enhance the permeation of KETO through human epidermis in vitro.
PEG 400, either alone or in combination with OS, did not enhance
the permeation of KETO.
Example 6
[0262] Diclofenac Transdermal Spray: Investigation into the Effect
of PEG200 and PEG 400 on Diclofenac Permeation through Human Skin
In Vitro
Methods:
[0263] Finite-dose in vitro diffusion studies were undertaken
dermatomed skin (Padgett Model B or S electric dermatome set at 500
.mu.m) prepared from excised female, abdominal skin.
[0264] These experiments were conducted over 24 hours using
flow-through systems with a 1-cm.sup.2 administration area. A piece
of stainless steel wire mesh was placed directly below the skin in
the receptor chamber of the of the diffusion cell to maintain a
turbulent flow of receptor solution below the skin. The diffusion
cells were maintained at a flow rate of approximately 0.5 mL/hr by
a peristaltic pump (Watson Marlow 520S Peristaltic Pump with 313A
adaptor and 308MC 8 roller pump-head; Stauff Corporation,
Australia). The cells were kept at 32.+-.0.5.degree. C. by a heater
bar and the samples were collected into appropriately sized glass
vials for a period of 24 hr.
[0265] Following a 2-h equilibration of the skin with the receptor
solution (RS) of phosphate-buffered saline (PBS) pH 7.4, the
stratum corneum surface was dosed with a volume of 3.6
.mu.L/cm.sup.2 (unless otherwise indicated) of a test formulation
using a positive displacement pipette. The formulation was spread
evenly over the skin area using the pipette tip.
[0266] The Diclofenac Transdermal Spray formulations were as
follows: [0267] 0.1-2.0% Diclofenac (DIC) diethylamine in Isopropyl
alcohol (IPA) [no enhancer] [0268] 0.1-2.0% DIC diethylamine, 5%
Octyl Salicylate (OS) in IPA [OS alone] [0269] 0.1-2.0% DIC
diethylamine, 2.5% Polyethylene glycol 200 (PEG 200) in IPA [PEG
200 alone] [0270] 0.1-2.0% DIC diethylamine, 5% OS, 2.5% PEG 200 in
IPA [OS+PEG 200]
[0271] A commercially available Diclofenac gel (approximately 5
mg/cm2) was used as a control. The commercially available gel was
applied using a solid cap to simulate the rubbing action required
when using the product. Approximately 7 mg gel was applied to the
circular surface of a black polypropylene cylindrical cap (Alltech
catalogue #98105, diameter 11 mm). The cap was weighed before the
gel was rubbed onto the surface of the skin. The gel was rubbed on
for 30 seconds (s) and the cap was left on the skin for a further 1
minute with a 3.5 g weight on top. The cap was then re-weighed to
determine the actual amount of gel applied. The actual weights of
the commercially available gel were used to adjust the permeation
data to the levels that would have been achieved with 5 mg/cm.sup.2
of DIC applied.
[0272] The amount of active that permeated the skin was quantified
using validated HPLC methods.
[0273] FIG. 10 compares diclofenac DIC permeation from a
commercially available gel with compositions containing 2% DIC
diethylamine with each of 0% enhancer, 5% OS, 2.5% PEG 200 and 5%
OS plus 2.5% PEG 200 (each in isopropyl amine (IPA)).
[0274] FIG. 11 comprises the effect of PEG 400 on enhancement with
OS.
Results:
[0275] PEG200 in combination with OS was found to significantly
enhance the permeation of DIC through human epidermis in vitro. PEG
400, either alone or in combination with OS, was found to decrease
the DIC permeation.
Example 7
[0276] Estradiol Spray: Investigation into the Effect of PEG200 and
PEG 400 on Estradiol Permeation Through Human Skin In Vitro
Methods:
[0277] Finite-dose in vitro permeation studies were undertaken
using dermatomed skin (Padgett Model B or S electric dermatome set
at 500 .mu.m) prepared from excised female, abdominal skin.
[0278] These experiments were conducted over 24 hours (h) using
flow-through systems with a 1-cm2 administration area. A piece of
stainless steel wire mesh was placed in the receptor chamber of the
of each permeation cell to support the skin and to maintain a
turbulent flow of receptor solution below the skin. The receptor
solution was maintained at a nominal flow rate of 0.5 mL/h by a
peristaltic pump (Watson Marlow 520S Peristaltic Pump with 313A
adaptor and 308MC 8 roller pump-head; Stauff Corporation,
Australia). The cells were placed on a heater bar to keep the
temperature of the skin at 32.+-.1.degree. C.
[0279] Following a 2-h equilibration of the skin with the receptor
solution (RS; 0.002% sodium azide), the stratum corneum surface was
dosed with 3.6 .mu.L/cm.sup.2 of an Estradiol Transdermal Spray
formulation using a positive displacement pipette. The formulation
was spread evenly over the skin area using the pipette tip.
Permeation samples were collected into appropriately sized glass
vials for a period of 24 h.
[0280] The Estradiol transdermal spray formulations contained:
[0281] Estradiol (E2)+Octyl Salicylate (OS) in Isopropyl Alcohol
IPA [0282] E2+OS+Polyethylene glycol (PEG200) in Isopropyl Alcohol
IPA [0283] E2+OS+Polyethylene glycol 400 (PEG400) in IPA
[0284] The amount of active that permeated the skin was quantified
using validated HPLC methods.
[0285] FIG. 12 shows the effect of PEG200 and PEG400 on estradiol
permeation.
Results:
[0286] PEG200 combined with OS synergistically enhanced the
permeation of estradiol through human skin in vitro. PEG400 had no
significant effect on the permeation of Estradiol when compared
with the control formulation--this was true for formulations
containing PEG400 alone and PEG400+OS.
* * * * *