U.S. patent application number 13/887719 was filed with the patent office on 2013-11-28 for transdermal delivery system for hormones and steroids.
This patent application is currently assigned to Acrux DDS Pty Ltd.. The applicant listed for this patent is Kerrie Setiawan, Adam Watkinson. Invention is credited to Kerrie Setiawan, Adam Watkinson.
Application Number | 20130317462 13/887719 |
Document ID | / |
Family ID | 40590452 |
Filed Date | 2013-11-28 |
United States Patent
Application |
20130317462 |
Kind Code |
A1 |
Setiawan; Kerrie ; et
al. |
November 28, 2013 |
TRANSDERMAL DELIVERY SYSTEM FOR HORMONES AND STEROIDS
Abstract
A transdermal delivery system comprising a composition
comprising a pharmacological agent and a penetration enhancer
wherein the penetration enhancer comprises polyethylene glycol
(PEG) of average molecular weight no more than 300.
Inventors: |
Setiawan; Kerrie; (West
Melbourne, AU) ; Watkinson; Adam; (West Melbourne,
AU) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Setiawan; Kerrie
Watkinson; Adam |
West Melbourne
West Melbourne |
|
AU
AU |
|
|
Assignee: |
Acrux DDS Pty Ltd.
West Melbourne
AU
|
Family ID: |
40590452 |
Appl. No.: |
13/887719 |
Filed: |
May 6, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12740666 |
Jul 13, 2010 |
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PCT/AU08/01613 |
Oct 31, 2008 |
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13887719 |
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60984787 |
Nov 2, 2007 |
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Current U.S.
Class: |
604/310 ;
514/178; 514/182 |
Current CPC
Class: |
A61K 31/565 20130101;
A61K 9/0014 20130101; A61P 5/00 20180101; A61P 15/00 20180101; A61K
31/568 20130101; A61K 31/205 20130101; A61K 31/56 20130101; A61K
31/192 20130101; A61P 15/10 20180101; A61P 5/26 20180101; A61K
31/57 20130101; A61P 15/18 20180101; A61P 25/24 20180101; A61P
29/00 20180101; A61P 5/24 20180101; A61P 5/30 20180101; A61K 9/12
20130101; A61K 47/32 20130101; A61K 47/10 20130101; A61P 15/16
20180101; A61M 35/003 20130101; A61K 47/14 20130101; A61P 5/44
20180101; A61K 31/573 20130101 |
Class at
Publication: |
604/310 ;
514/178; 514/182 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61M 35/00 20060101 A61M035/00; A61K 47/10 20060101
A61K047/10; A61K 31/573 20060101 A61K031/573; A61K 31/568 20060101
A61K031/568; A61K 31/565 20060101 A61K031/565 |
Claims
1.-18. (canceled)
19. A transdermal delivery system comprising a composition
comprising at least one pharmacological agent selected from
hormones and steroids; a penetration enhancer comprises a
polyethylene glycol (PEG) of average molecular weight no more than
300; and a solvent selected from C.sub.2 to C.sub.4 alkanol and
mixtures thereof in an amount in the range of from 70% to 95%, by
weight of the total composition.
20. A transdermal delivery system according to claim 19, wherein
the PEG of average molecular weight of no more than 300 is present
in an amount of at least 0.1% by weight of the total
composition.
21. A transdermal delivery system according to claim 19, wherein
the PEG of average molecular weight of no more than 300 is present
in the range of from 0.5% to 20% by weight of the total
composition.
22. A transdermal delivery system according to claim 19, wherein
the composition consists essentially of: (i) at least one
pharmacological agent selected from hormones and steroids; (ii) the
penetration enhancer component consisting of 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
optionally a propellant.
23. A transdermal delivery system according to claim 19, wherein
the total water content of the composition is less than 10% by
weight of the total composition.
24. A transdermal delivery system according to claim 19, which is
non-occlusive.
25. A transdermal delivery system according to claim 19, wherein
the weight ratio of penetration enhancer to pharmacological agent
is in the range of from 20:1 to 1:1.
26. A transdermal delivery system according to claim 19, wherein at
least one pharmacological agent comprises one or more selected from
the group consisting of steroidal hormones.
27. A transdermal delivery system according to claim 19, wherein at
least one pharmacological agent comprises one or more steroids
which provide eutrogenic, androgenic glucocorticoid, adrenocortoid,
anabolic or birth control activity.
28. A transdermal delivery system according to claim 27, wherein
the pharmacological agent comprises one or more steroids selected
from the group consisting of 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, fluorogestone acetate,
hydroxymethylprogesterone, 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
and the salts and prodrugs thereof.
29. A transdermal delivery system according to claim 19, for female
contraception comprising a comprising one or more estrogens and one
or more progestins.
30. A transdermal delivery system according to claim 19, wherein
the drug delivery system comprises on a weight basis from about 0.1
to about 10% of the steroid or hormone, from about 0.1 to 12% of
the penetration enhancer and from about 70 to 99.8% ethanol,
isopropanol or mixture thereof.
31. A transdermal delivery system according to claim 19, 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 spray
nozzle.
32. A transdermal delivery system according to claim 19, for
transdermal administration of at least one pharmacological agent
selected from hormones and steroids.
33. The transdermal delivery system according to claim 32, wherein
the transdermal administration is by application of the medicament
to an area of dermal surface of a subject.
34. The transdermal delivery system according to claim 32, wherein
the subject is in need of male hormone replacement in testosterone
deficient hypogonadal men, female hormone replacement therapy for
postmenopausal women, or androgen replacement therapy for females
lacking libido or suffering depression using an androgen, male
contraception, or female contraception.
35. A method of preparing a transdermal delivery system comprising
a composition for administration to an area of dermal surface of a
subject, the method comprising combining at least one
pharmacological agent selected from hormones and steroids and a
penetration enhancer comprising polyethylene glycol of average
molecular weight no more than 300 and 70% to 95%, by weight of the
total composition of solvent selected from C.sub.2 to C.sub.4
alkanols and mixtures thereof.
Description
FIELD
[0001] This invention relates to a transdermal delivery system and
to a method of transdermal delivery of hormones and steroids.
BACKGROUND
[0002] Steroids and hormones include sex hormones and certain
adrenocortical hormones (corticosteroids). The corticosteroids have
numerous and diversified physiological functions and
pharmacological effects. They influence carbohydrate, protein, fat,
and purine metabolism; electrolyte and water balance; and the
functions of the cardiovascular system, the kidney, skeletal
muscle, nervous system, and other organs and tissues.
Therapeutically, the corticosteroids are used for treating hormonal
insufficiencies, inflammation, and other conditions, whereas the
sex hormones are widely used for contraception and hormonal
insufficiencies, as well as for treating other conditions.
[0003] The two main classes of sex steroids are androgens and
estrogens, of which the most important human derivatives are
testosterone and estradiol (17.beta.-estradiol), respectively.
Other contexts will include progestagen as a third class of sex
steroids, distinct from androgens and estrogens. Progesterone is
the only naturally-occurring human progestagen. Progestins are
synthetic sex hormones used in contraception either alone or with
estradiol. Androgens are often referred to as "male sex hormones",
since they have masculinizing effects, while estrogens and
progestagens are considered "female sex hormones" although all
types are present in each gender, albeit at different levels.
Androgens may be used in treatment of reduced libido or in
treatment of depression in both men and women.
[0004] Administration of hormones and steroids through the skin
(`transdermal delivery`) has received increased attention because
it not only provides a potentially simple dosage regime but it also
provides a relatively controlled route for release of a hormone
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.
[0005] 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.
[0006] For effective transdermal delivery of a pharmacological
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.
[0007] 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.
[0008] One of the drawbacks of the current approaches to
administering hormones and steroids 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. Steroids and hormones, particularly the sex steroidal
hormones have a relatively poor skin permeation and many patches
require high loads of drug or large a surface area in order to
provide effective blood levels.
[0009] 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 dimethylacetamide.
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 because
the problem of irritation at the site of application and/or
difficulty in providing sufficient enhancement of transdermel
absorption.
[0010] 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
[0011] The invention provides a transdermal delivery system
comprising a composition comprising at least one agent selected
from hormones and steroids, and a penetration enhancer comprising a
polyethylene glycol of average molecular weight no more than
300.
[0012] 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 a dermal surface of
the animal of the above described transdermal delivery system.
[0013] In yet another aspect the invention provides use of (i)
polyethylene glycol of average molecular weight no more than 300
and (ii) at least one agent selected from hormones and steroids in
manufacture of a medicament for transdermal administration to a
subject by application of the medicament to an area of the skin
surface of the subject.
[0014] In one embodiment the medicament may be for treatment of an
insufficient level of a hormone such as a sex hormone or for
contraception.
[0015] In a further embodiment the invention comprises a
composition comprising a pharmacological agent selected from
steroids and hormones and a penetration enhance for application to
an area of skin of a subject. The composition may be for treatment
of an insufficient level of a hormone such as a sex hormone, for
hormone replacement therapy or contraception.
[0016] 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
at least one pharmacological agent selected from hormones and
steroids and a penetration enhancer comprising polyethylene glycol
of average molecular weight no more than 300.
[0017] 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 at
least one pharmacological agent selected from hormones and steroids
and a penetration enhancer component comprising polyethylene glycol
of average molecular weight no more than 300.
[0018] The transdermal delivery system will preferably be applied
in a dose sufficient to provide an effective amount of at least one
pharmacological agent in the bloodstream of the animal.
[0019] Preferably the animal is a human but the invention also
extends to the treatment of non-human animals.
DEFINITIONS
[0020] 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].
[0021] The term "pharmacological agent" is used herein to refer to
a broad class of useful chemical and therapeutic agents.
[0022] The term "pharmacological" 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 pharmacological agent includes prodrugs
of the agent which in vivo exerts the physiological effect.
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 tate 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, fluorogestone acetate,
hydroxymethylprogesterone, hydroxynnethylprogesterone 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 pharmacological drug 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 hormones and
steroids used in the transdermal delivery system of the invention
include hormones and steroids which are prodrugs which on
administration form a more active hormone or steroid 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 the Prohormones
and prosteroids are variations or derivatives of the parent
hormones or steroids which have groups cleavable under metabolic
conditions. Prodrugs become the parent drugs which are
pharmaceutically 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
respectively, 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
C.sub.1-C.sub.12 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 pharmacological agents selected
from hormones and steroids to be delivered through the skin to
achieve a desired systemic effect. The drug delivery system
preferably comprises at least one 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, at
least one active agent selected from hormones and steroids 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 at
least one 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] The subject to be treated with the transdermal delivery
system is generally a mammal, preferably a human being, male or
female. The term "therapeutically effective amount" means the
amount of the subject compound that will elicit the biological or
medical response of a tissue, system, animal or human that is being
sought.
[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
polyethylene glycol (of molecular weight no more than 300) as a
penetration enhancer shows a significant improvement in penetration
enhancement of the active agent.
[0037] Typically the PEG of average molecular weight less than 300
will be present in an amount in the range of from 0.5 to 20% such
as 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%.COPYRGT., 4.5%, 6%, 7%, 8%, 9%,
10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%.
Preferably the PEG of average molecular weight less than 300 is
present in an amount in the range of from 0.5 to 15% and most
preferably from 0.5 to 10% by weight of the composition.
[0038] 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%.
[0039] 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 is a C.sub.2 to
C.sub.4 alkanol and more preferably is ethanol or isopropanol, or a
mixture thereof.
[0040] 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 preferably from 50 to 95%,
more preferably from 60 to 95% by weight such as 65% to 95% by
weight, 70% to 95%, 70 to 90% or 75 to 90% by weight of the total
composition.
[0041] 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%.
[0042] In one embodiment the penetration enhancer component of the
composition may comprise one or more additional penetration
enhancers. Of particular note are esters of salicylic acid
preferably selected from the C.sub.6 to C.sub.30 aliphatic ester of
salicylic acid and more preferably C.sub.8 to C.sub.12 alkyl
salicylate and most preferably octyl salicylate particularly
2-ethylhexyl saliclate. When an ester of salicyclic acid is present
in combination with polyethylene glycol, the weight ratio of the
ester of salicylic acid to the 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.
[0043] Known dermal penetration enhancers may be included in
addition to PEG of molecular weight no more than 300. Examples of
known 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.
[0044] Preferably the composition will comprise no more than 5% by
weight of the other non-volatile penetration enhancer 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.
[0045] In a preferred embodiment of the invention the composition
consists essentially of: [0046] (i) at least one active selected
from hormones and steroids and more preferably steroidal sex
hormones; [0047] (ii) a penetration enhancer component consisting
essentially of 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; [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
such as 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 is preferred.
[0053] Suitable pharmacologically active hormones and steroids may
be selected from:
[0054] Estrogens such as 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;
[0055] 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;
[0056] Selective progesterone receptor modulators such as
Asoprisnil, CDB-4124 and mixtures thereof;
[0057] Selective estrogen receptor modulators such as Bazedoxifene,
Clomifene, Fulvestrant, Lasofoxifene, Raloxifene, Tamoxifen,
Toremifene and mixtures thereof;
[0058] Antiprogestogen such as Mifepristone and mixtures
thereof.
[0059] Antigonadotropins such as Danazol and Gestrinone and
mixtures thereof;
[0060] Antiandrogens such as cyproterone acetate and danazol and
mixtures thereof;
[0061] Antiestrogens such as tamoxifen and epitiostanol and the
aromatase inhibitors, exemestane and 4-hydroxy-androstenedione and
its derivatives and mixtures thereof.
[0062] 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;
[0063] 5-alpha reductase inhibitors such as finasteride,
turosteride, LY-191704 and MK-306 and mixtures thereof;
[0064] 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 and mixtures
thereof;
[0065] 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 and mixtures thereof;
[0066] Aromatase inhibitor such as Aminogluthetimide, Anastrozole,
Exemestane, Formestane, Letrozole and Vorozole;
[0067] Gonadotropins such as Clomifene and Urofollitropin;
[0068] GnRH:(receptor) agonists such as Buserelin, Goserelin,
Histrelin, Leuprorelin, Nafarelin and Triptorelin;
[0069] GnRH antagonist: Abarelix, Cetrorelix and Ganirelix;
[0070] Pituitary hormones and their active derivatives or analogs
such as corticotrophin, thyrotropin, follicle stimulating hormone
(FSH), luteinising hormone (LH) and gonadotrophin releasing hormone
(GnRH);
[0071] Thyroid hormones such as calcitonin, thyroxine and
liothyronine and antithyroid agents such as carbimazole and
propylthiouracil; and
[0072] Other miscellaneous hormone agents such asoctreotide; and
mixtures from two or more of the groups.
[0073] The optimal ratio of penetration enhancer to active will
differ depending on the nature of the active and the penetration
enhancer. 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.
[0074] The penetration enhancer of the invention is particularly
useful in transdermal administration of 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.
[0075] 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.
[0076] The transdermal delivery system may be used to deliver a
therapeutically effective amount of the hormone and/or steroid to a
local area or to the systemic circulation. In one embodiment the
system provides a pharmaceutically effective level of the
pharmacological agent in the systemic circulation, for example a
pharmaceutically effective blood level. In one preferred form of
the invention the drug delivery system comprises on a weight basis
from about 0.1 to about 10% of at least one pharmacological agent
selected from hormone and steroids in an amount of from about 0.1
to 12% of the dermal penetration enhancer and from about 78 to
99.8% ethanol, isopropanol or mixture thereof.
[0077] In another preferred form of the invention the drug delivery
system comprises, on a weight basis, from about 1 to 3% of at least
one pharmacological agent selected from hormone and steroids in an
amount of from about 1 to 15% of the dermal penetration enhancer
combination, from about 45 to 90% ethanol, isopropanol or mixture
thereof, and 5 to 45% water.
[0078] 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 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).
[0079] 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 at least one pharmacological
agent and a first penetration enhancer component of polyethylene
glycol of average molecular weight no more than 300; and optionally
a second penetration enhancer component of an ester of salicylic
acid.
[0080] The transdermal delivery system will preferably be applied
in a dose sufficient to provide an effective amount of the at least
one pharmacological agent in the bloodstream of the animal.
[0081] 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 cm.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.
[0082] 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
[0083] The compositions of the Examples and their performance are
compared with reference to the drawings.
BRIEF DESCRIPTION OF DRAWINGS
[0084] In the drawings:
[0085] FIG. 1 is a column chart comparing the permeation of a
progestin+an estrogen from a control with progestin transdermal
delivery composition of the invention containing PEG-200 pursuant
to Example 1.
[0086] FIGS. 2a and 2b 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.
[0087] FIG. 3 is a column chart which shows the effect of PEG 200
on the permeation of an androgen from transdermal delivery
compositions described in Example 3.
[0088] FIG. 4 and FIG. 5 are column charts which compare the effect
of PEG 200 and PEG 400 respectively on permeation of an androgen
from transdermal delivery compositions described in Example 4.
[0089] FIG. 6 is a column chart examining the effect of PEG 200 on
permeation of an androgen from compositions of Example 5.
[0090] FIG. 7 is a column chart examining the effect of PEG 200 on
the permeation of an estrogen from transdermal delivery
compositions described in Example 6.
[0091] FIG. 8 is a column chart showing the effect of PEG 200 on
the permeation of the androgen testosterone in the presence of
another permeation enhancer as described in Example 7.
EXAMPLE 1
Investigation of the Effect of PEG200 on Cumulative Permeation of
the progestin Norethisterone Acetate and the Estrogen Estradiol
Through Human Skin In Vitro
Methods:
[0092] Finite-dose in vitro diffusion studies were undertaken using
dermatomed human female abdominal skin (500 .mu.m).
[0093] 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 cm.sup.2. 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.
[0094] The formulations were applied to the skin at a dose of 3.6
.mu.L/cm.sup.2. The applied formulation was spread over the skin
area using an Eppendorf positive displacement pipette tip without
breaking the skin membrane.
[0095] The formulations consisted of:-- [0096] Comparison
composition 1: 2.8% Norethisterone Acetate (NETA), 0.55% Estradiol
(E2), 5% Octyl Salicylate (OS) [0097] Composition 2: 2.8% NETA,
0.55% E2, 5% Polyethylene Glycol 200 (PEG200) [0098] Composition 3:
2.8% NETA, 0.55% E2, 5% OS, 5% PEG200 [0099] Composition 4: 2.8%
NETA, 0.55% E2, 10% PEG200 [0100] Composition 5: 2.8% NETA, 0.55%
E2, 5% OS, 10% PEG200
[0101] The amount of active that permeated the skin was quantified
using validated HPLC methods
[0102] 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.
EXAMPLE 2
Investigation Into the Effect of PEG200 and PEG400 on Cumulative
Nestorone & Ethinylestradiol Permeation Through Human Skin In
Vitro
Methods:
[0103] Finite-dose in vitro diffusion studies were undertaken using
dermatomed human female abdominal skin (500 .mu.m).
[0104] 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 cm.sup.2. 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/cm.sup.2. 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.
[0105] The formulations consisted of:-- [0106] Composition (Comp) 1
(Control): 1.35% Nestorone (NES), 0.35% Ethinylestradiol (EE) in
Isopropyl Alcohol (IPA) [0107] Comp 2: 1.35% NES, 0.35% EE, 5%
Polyethylene glycol 400 (PEG400) in IPA Comp 3: 1.35% NES, 0.35%
EE, 0.5% Polyethylene glycol (PEG200) in IPA
[0108] The amount of active that permeated the skin was quantified
using validated HPLC methods.
[0109] The effect of PEG400 on permeation of NES and EE is shown in
FIGS. 2a and 2b respectively. FIGS. 2a and 2b: thus show Nestorone
and Ethinylestradiol permeation respectively obtained from the
application of Composition 2 (not of the invention) compared
against application of a control composition 1.
[0110] PEG200 in combination with OS was found to enhance the
permeation of both Nestorone and Ethinylestradiol through human
epidermis in vitro.
[0111] 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.
EXAMPLE 3
Investigation into the Effect of PEG200 on Cumulative Testosterone
Permeation Through Human Skin In Vitro
Methods:
[0112] Finite-dose in vitro diffusion studies were undertaken using
dermatomed human female abdominal skin (500 .mu.m).
[0113] 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 cm.sup.2. 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/cm.sup.2. 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 NaN.sub.3) maintained sink
conditions below the skin.
[0114] The formulations consisted of:-- [0115] Comp 1: 5%
Testosterone (TES), in ethanol (95%) [0116] Comp 2: 5% TES, 1.0%
polyethylene glycol 200 (PEG200) in ethanol (95%) [0117] Comp 3: 5%
TES, 2.5% PEG200 in ethanol (95%)
[0118] The amount of active that permeated the skin was quantified
using validated HPLC methods.
[0119] The effect of the combination of PEG200 in Compositions 2
and 3 is compared with a control Composition 1 in FIG. 3 As shown
in FIG. 3, PEG200 in was found to significantly enhance the
permeation of Testosterone through human epidermis in vitro.
EXAMPLE 4
Investigation into the Effect of PEG200 and PEG 400 on Cumulative
Permeation of the AndrogenTestosterone from a Lotion Through Human
Skin in Vitro
Methods:
[0120] 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 tissue.
[0121] These experiments were conducted over 24 hours (h) using
flow-through systems with a 1-cm.sup.2 administration area. A piece
of stainless steel wire mesh was placed in the receptor chamber 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 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 placed on a heater bar to keep the
temperature of the skin at 32.+-.1.degree. C.
[0122] Following a 2-h equilibration of the skin with the receptor
solution (RS; 0.002% sodium azide), the stratum corneum surface was
dosed with either 15 or 30 .mu.L/cm.sup.2 of an MD-Lotion
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.
[0123] The effect of the addition of Polyethylene glycol 200
(PEG200) or Polyethylene glycol 400 (PEG 400) on the permeation of
testosterone was investigated. 0.5-5% w/v PEG200 or PEG 400 was
added to the following Testosterone (TES) Lotion formulation:--
[0124] Formulation: 2% w/v TES, 2% w/v polyvinylpyrrolidone (PVP)
in isopropyl alcohol (IPA).
[0125] The amount of active that permeated the skin was quantified
using validated HPLC methods. Results for PEG 200 are shown in FIG.
4 and results for PEG 400 are shown in FIG. 5.
Results:
[0126] PEG200 significantly enhanced the permeation of TES through
human skin in vitro. PEG400 did not have any effect on the
permeation of TES through human skin in vitro.
EXAMPLE 5
Investigation into the Effect of PEG200 and PEG 400 on Cumulative
Permeation of the Androgen Testosterone Through Human Skin from a
Transdermal Testosterone Composition Applied as a Spray in
Vitro
Methods:
[0127] 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.
[0128] These experiments were conducted over 24 hours (h) using
flow-through systems with a 1-cm.sup.2 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.
[0129] 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 a Metered Dose Transdermal Spray
(MDTS) 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.
[0130] The Metered Dose Transdermal Spray formulations contained:
[0131] Testosterone (TES), Polyethylene glycol 200 (PEG 200) or
Polyethylene glycol 400 (PEG 400) isopropyl alcohol (IPA).
[0132] The amount of active that permeated the skin was quantified
using validated HPLC methods and the results for PEG 200 are shown
in FIG. 6.
Results:
[0133] PEG200 increased the permeation of TES through human skin in
vitro. The addition of Adding PEG 400 to the formulation did not
result in any significant difference in the permeation of TES when
compared with the control formulation.
EXAMPLE 6
Estradiol Spray: Investigation into the Effect of PEG200 and PEG
400 on Estradiol Permeation Through Human Skin in Vitro
Methods:
[0134] 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.
[0135] These experiments were conducted over 24 hours (h) using
flow-through systems with a 1-cm.sup.2 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.
[0136] 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.
[0137] The Estradiol Transdermal Spray formulations contained:--
[0138] Testosterone (TES), Polyethylene glycol 200 (PEG 200) or
Polyethylene glycol 400 (PEG 400) isopropyl alcohol (IPA)
[0139] The amount of active that permeated the skin was quantified
using validated HPLC methods and the results are depicted in FIG.
7.
Results:
[0140] In both the 0.25% and the 0.50% formulations PEG200 was
found to enhance the permeation of Estradiol through human skin in
vitro.
EXAMPLE 7
Investigation into the Effect of PEG200 on Cumulative Testosterone
Permeation Through Human Skin in Vitro
Methods:
[0141] Finite-dose in vitro diffusion studies were undertaken using
dermatomed human female abdominal skin (500 .mu.m).
[0142] 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 cm.sup.2. 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/cm.sup.2. 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 NaN.sub.3) maintained sink
conditions below the skin.
[0143] The formulations consisted of:-- [0144] Comp 1: 2%
Testosterone (TES), 5% Octyl Salicylate (OS), 2% polyvinyl
pyrrolidine (PVP), 30% isopropyl alcohol (IPA) in ethanol (95%)
[0145] Comp 2: 2% TES, 5% OS, 2% PVP, 30% IPA, 0.5% polyethylene
glycol 200 (PEG200) in ethanol (95%) [0146] Comp 3: 2% TES, 5% OS,
2% PVP, 30% IPA, 1.0% PEG200 in ethanol (95%) [0147] Comp 4: 2%
TES, 5% OS, 2% PVP, 30% IPA, 2.5% PEG200 in ethanol (95%)
[0148] The amount of active that permeated the skin was quantified
using validated HPLC methods
[0149] The effect on permeation of TES from using the composition
as shown in FIG. 8. PEG200 was found to significantly enhance the
permeation of Testosterone in combination with the permeation
enhancer octyl salicylate (OS) through human epidermis in
vitro.
* * * * *