U.S. patent application number 10/371538 was filed with the patent office on 2003-08-21 for transdermal administration of steroid drugs using hydroxide-releasing agents as permeation enhancers.
Invention is credited to Hsu, Tsung-Min, Luo, Eric C..
Application Number | 20030157157 10/371538 |
Document ID | / |
Family ID | 27739189 |
Filed Date | 2003-08-21 |
United States Patent
Application |
20030157157 |
Kind Code |
A1 |
Luo, Eric C. ; et
al. |
August 21, 2003 |
Transdermal administration of steroid drugs using
hydroxide-releasing agents as permeation enhancers
Abstract
A method is provided for increasing the permeability of skin or
mucosal tissue to transdermally administered steroid drugs. The
method involves use of a specified amount of a hydroxide-releasing
agent, the amount optimized to increase the flux of the drug
through a body surface while minimizing the likelihood of skin
damage, irritation or sensitization. Formulations and drug delivery
systems for co-administering a hydroxide-releasing agent with a
steroid drug are provided as well. Optimally, the steroid drugs are
a combination of an estrogen and progestin that may be administered
in female hormone replacement therapy, to provide female
contraception, and the like
Inventors: |
Luo, Eric C.; (Plano,
TX) ; Hsu, Tsung-Min; (San Diego, CA) |
Correspondence
Address: |
REED & EBERLE LLP
800 MENLO AVENUE, SUITE 210
MENLO PARK
CA
94025
US
|
Family ID: |
27739189 |
Appl. No.: |
10/371538 |
Filed: |
February 20, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10371538 |
Feb 20, 2003 |
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09737833 |
Dec 14, 2000 |
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6562370 |
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09737833 |
Dec 14, 2000 |
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09569889 |
May 11, 2000 |
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09569889 |
May 11, 2000 |
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09465098 |
Dec 16, 1999 |
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Current U.S.
Class: |
424/449 ;
514/169 |
Current CPC
Class: |
Y10S 514/946 20130101;
Y10S 514/947 20130101; A61K 31/137 20130101; Y10S 514/944 20130101;
A61K 9/7023 20130101; A61K 9/0014 20130101; A61K 9/7053 20130101;
A61K 47/02 20130101 |
Class at
Publication: |
424/449 ;
514/169 |
International
Class: |
A61K 031/56; A61K
009/70; A61K 009/14 |
Claims
We claim:
1. A composition of matter useful for the delivery of a steroid
drug through a body surface, comprising: (a) a therapeutically
effective amount of a steroid drug; (b) a hydroxide-releasing agent
in an amount effective to enhance the flux of the drug through the
body surface without causing damage thereto and effective to
provide a pH in the range of approximately 8.0 to 13 at the body
surface during drug administration, and wherein the amount of
hydroxide-releasing agent in the composition is the total of (a)
the amount required to neutralize any acidic species in the
composition plus (b) an amount equal to approximately 0.25 wt % to
25.0 wt % of the composition; and (c) a pharmaceutically acceptable
carrier suitable for topical or transdermal drug
administration.
2. The composition of claim 1, wherein the pH is within the range
of approximately 8.0 to 11.5.
3. The composition of claim 2, wherein the pH is within the range
of approximately 8.5 to 11.5.
4. The composition of claim 1, which is substantially free of
organic solvents.
5. The composition of claim 1, wherein the hydroxide-releasing
agent is selected from the group consisting of inorganic
hydroxides, inorganic oxides, metal salts of weak acids, and
mixtures thereof.
6. The composition of claim 5, wherein the hydroxide-releasing
agent is an inorganic hydroxide.
7. The composition of claim 6, wherein the inorganic hydroxide is
selected from the group consisting of ammonium hydroxide, alkali
metal hydroxides, alkaline earth metal hydroxides, and mixtures
thereof.
8. The composition of claim 7, wherein the inorganic hydroxide is
sodium hydroxide.
9. The composition of claim 7, wherein the inorganic hydroxide is
potassium hydroxide.
10. The composition of claim 6, wherein the amount of inorganic
hydroxide in the composition is the total of (a) the amount
required to neutralize any acidic species in the composition plus
(b) an amount equal to approximately 0.5 wt % to 4.0 wt % of the
composition.
11. The composition of claim 10, wherein the amount of inorganic
hydroxide in the composition is the total of (a) the amount
required to neutralize any acidic species in the composition plus
(b) an amount equal to approximately 0.75 wt % to 2.0 wt % of the
composition.
12. The composition of claim 5, wherein the hydroxide-releasing
agent is an inorganic oxide.
13. The composition of claim 12, wherein the inorganic oxide is
selected from the group consisting of magnesium oxide, calcium
oxide and mixtures thereof.
14. The composition of claim, 12, which contains up to
approximately 20 wt % of the hydroxide-releasing agent.
15. The composition of claim 5, wherein the hydroxide-releasing
agent is a metal salt of a weak acid.
16. The composition of claim 15, wherein the hydroxide-releasing
agent is selected from the group consisting of sodium acetate,
sodium borate, sodium metaborate, sodium carbonate, sodium
bicarbonate, tribasic sodium phosphate, dibasic sodium phosphate,
potassium carbonate, potassium bicarbonate, potassium citrate,
potassium acetate, dibasic potassium phosphate, tribasic potassium
phosphate, dibasic ammonium phosphate, and mixtures thereof.
17. The composition of claim 15, which contains up to approximately
20 wt % of the hydroxide-releasing agent.
18. The composition of claim 1, which is an aqueous
formulation.
19. The composition of claim 18, wherein the formulation is
selected from the group consisting of a cream, a gel, a lotion, and
a paste.
20. The composition of claim 19, wherein the formulation is a
cream.
21. The composition of claim 19, wherein the formulation is a
gel.
22. The composition of claim 1, which is a nonaqueous
formulation.
23. The composition of claim 22, wherein the formulation is an
ointment.
24. The composition of claim 1, wherein the steroid is a progestin
selected from the group consisting of acetoxypregneno lone,
allylestrenol, anagestone acetate, chlormadinone acetate,
cyproterone, cyproterone acetate, desogestrel, dihydrogesterone,
dimethisterone, ethisterone, ethynodiol diacetate, flurogestone
acetate, gestadene, hydroxyprogesterone, hydroxyprogesterone
acetate, hydroxyprogesterone caproate, hydroxymethylprogesterone,
hydroxymethyl-progesterone acetate, 3-ketodesogestrel,
levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone
acetate, megestrol, megestrol acetate, melengestrol acetate,
norethindrone, norethindrone acetate, norethisterone,
norethisterone acetate, norethynodrel, norgestimate,
d,1-norgestrel, 1-norgestrel, norgestrienone, normethisterone,
progesterone, and combinations thereof.
25. The composition of claim 24, wherein the progestin is selected
from the group consisting of progesterone, medroxyprogesterone
acetate, norethindrone, norethynodrel, d,1-norgestrel and
1-norgestrel.
26. The composition of claim 25, wherein the progestin is
progesterone.
27. The composition of claim 1, wherein the steroid is an estrogen
selected from the group consisting of 17.alpha.-estradiol,
17.beta.-estradiol, ethinyl estradiol, pharmaceutically acceptable
esters and ethers of 17.alpha.-estradiol, 17.beta.-estradiol and
ethinyl estradiol, estriol, estriol succinate, polyestrol
phosphate, estrone, estrone acetate, estrone sulfate, piperazine
estrone sulfate, quinestrol, mestranol and conjugated equine
estrogens.
28. The composition of claim 27, wherein the estrogen is
17.beta.-estradiol, ethinyl estradiol, or mestranol.
29. The composition of claim 27, which further comprises an
androgenic agent.
30. The composition of claim 29, wherein the androgenic agent is
testosterone or an ester thereof.
31. The composition of claim 27, which further comprises a
progestin.
32. A system for the topical or transdermal administration of a
steroidal drug through a body surface, comprising: (a) at least one
reservoir containing the drug and a hydroxide-releasing agent in an
amount effective to enhance the flux of the drug through the body
surface without causing damage thereto and effective to provide a
pH in the range of approximately 8.0 to 13 at the body surface
during drug administration, and wherein the amount of
hydroxide-releasing agent in the reservoir applied to the body
surface is the total of (a) the amount required to neutralize any
acidic species in the reservoir plus (b) an amount equal to
approximately 0.25 wt % to 25.0 wt % of the reservoir; (b) a means
for maintaining the system in drug and enhancer transmitting
relationship to the body surface; and (c) a backing layer that
serves as the outer surface of the system during use.
33. The system of claim 32, wherein the pH is within the range of
approximately 8.0 to 11.5.
34. The system of claim 33, wherein the pH is within the range of
approximately 8.5 to 11.5.
35. The system of claim 32, wherein the hydroxide-releasing agent
is selected from the group consisting of inorganic hydroxides,
inorganic oxides, metal salts of weak acids, and mixtures
thereof.
36. The system of claim 35, wherein the hydroxide-releasing agent
is an inorganic hydroxide.
37. The system of claim 36, wherein the inorganic hydroxide is
selected from the group consisting of ammonium hydroxide, alkali
metal hydroxides, alkaline earth metal hydroxides, and mixtures
thereof.
38. The system of claim 37, wherein the inorganic hydroxide is
sodium hydroxide.
39. The system of claim 37, wherein the inorganic hydroxide is
potassium hydroxide.
40. The system of claim 36, wherein the amount of inorganic
hydroxide in the reservoir is the total of (a) the amount required
to neutralize any acidic species in the reservoir plus (b) an
amount equal to approximately 0.5 wt % to 4.0 wt % of the
reservoir.
41. The system of claim 40, wherein the amount of inorganic
hydroxide in the reservoir is the total of (a) the amount required
to neutralize any acidic species in the reservoir plus (b) an
amount equal to approximately 0.75 wt % to 2.0 wt % of the
reservoir.
42. The system of claim 35, wherein the hydroxide-releasing agent
is an inorganic oxide.
43. The system of claim 42, wherein the inorganic oxide is selected
from the group consisting of magnesium oxide, calcium oxide and
mixtures thereof.
44. The system of claim 42, wherein the reservoir contains up to
approximately 20 wt % of the hydroxide-releasing agent.
45. The system of claim 35, wherein the hydroxide-releasing agent
is a metal salt of a weak acid.
46. The system of claim 45, wherein the hydroxide-releasing agent
is selected from the group consisting of sodium acetate, sodium
borate, sodium metaborate, sodium carbonate, sodium bicarbonate,
tribasic sodium phosphate, dibasic sodium phosphate, potassium
carbonate, potassium bicarbonate, potassium citrate, potassium
acetate, dibasic potassium phosphate, tribasic potassium phosphate,
dibasic ammonium phosphate, and mixtures thereof.
47. The system of claim 45, wherein the reservoir contains up to
approximately 20 wt % of the hydroxide-releasing agent.
48. The system of claim 32, wherein the backing layer is
occlusive.
49. The system of claim 32, wherein the reservoir is comprised of a
polymeric adhesive.
50. The system of claim 49, wherein the polymeric adhesive serves
as the means for maintaining the system in drug and enhancer
transmitting relationship to the body surface.
51. The system of claim 32, wherein the reservoir is comprised of a
hydrogel.
52. The system of claim 32, wherein the reservoir is comprised of a
sealed pouch containing the drug and hydroxide-releasing agent in a
liquid or semi-solid formulation.
53. The system of claim 32, wherein the steroid is a progestin
selected from the group consisting of acetoxypregnenolone,
allylestrenol, anagestone acetate, chlormadinone acetate,
cyproterone, cyproterone acetate, desogestrel, dihydrogesterone,
dimethisterone, ethisterone, ethynodiol diacetate, flurogestone
acetate, gestadene, hydroxyprogesterone, hydroxyprogesterone
acetate, hydroxyprogesterone caproate, hydroxymethylprogesterone,
hydroxymethyl-progesterone acetate, 3-ketodesogestrel,
levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone
acetate, megestrol, megestrol acetate, melengestrol acetate,
norethindrone, norethindrone acetate, norethisterone,
norethisterone acetate, norethynodrel, norgestimate,
d,1-norgestrel, 1-norgestrel, norgestrienone, normethisterone,
progesterone, and combinations thereof.
54. The system of claim 53, wherein the progestin is selected from
the group consisting of progesterone, medroxyprogesterone acetate,
norethindrone, norethynodrel, d,1-norgestrel and 1-norgestrel.
55. The system of claim 54, wherein the progestin is
progesterone.
56. The system of claim 32, wherein the steroid is an estrogen
selected from the group consisting of 17.alpha.-estradiol,
17.beta.-estradiol, ethinyl estradiol, pharmaceutically acceptable
esters and ethers of 17.alpha.-estradiol, 17.beta.-estradiol and
ethinyl estradiol, estriol, estriol succinate, polyestrol
phosphate, estrone, estrone acetate, estrone sulfate, piperazine
estrone sulfate, quinestrol, mestranol and conjugated equine
estrogens.
57. The system of claim 56, wherein the estrogen is
17.beta.-estradiol, ethinyl estradiol, or mestranol.
58. The system of claim 56, which further comprises an androgenic
agent.
59. The system of claim 58, wherein the androgenic agent is
testosterone or an ester thereof.
60. The system of claim 56, which further comprises a progestin.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This is a divisional application of U.S. Ser. No.
09/737,833, filed Dec. 14, 2000; which is a continuation-in-part of
U.S. Ser. No. 09/569,889, filed May 11, 2000, now abandoned; which
is a continuation-in part of U.S. Ser. No. 09/465,098, filed Dec.
16, 1999, now abandoned; the disclosures of which are incorporated
by reference.
TECHNICAL FIELD
[0002] This invention relates generally to transdermal
administration of pharmacologically active agents, and more
particularly relates to methods and compositions for transdermally
administering steroid drugs, particularly progestins and
estrogens.
BACKGROUND
[0003] The delivery of drugs through the skin provides many
advantages; primarily, such a means of delivery is a comfortable,
convenient and noninvasive way of administering drugs. The variable
rates of absorption and metabolism encountered in oral treatment
are avoided, and other inherent inconveniences , e.g.,
gastrointestinal irritation and the like, are eliminated as well.
Transdermal drug delivery also makes possible a high degree of
control over blood concentrations of any particular drug.
[0004] Skin is a structurally complex, relatively thick membrane.
Molecules moving from the environment into and through intact skin
must first penetrate the stratum corneum and any material on its
surface. They must then penetrate the viable epidermis, the
papillary dermis, and the capillary walls into the blood stream or
lymph channels. To be so absorbed, molecules must overcome a
different resistance to penetration in each type of tissue.
Transport acoss the skin membrane is thus a complex phenomenon.
However, it is the cells of the stratum corneum which present the
primary barrier to absorption of topical compositions or
transdermally administered drugs. The stratum corneum is a thin
layer of dense, highly keratinized cells approximately 10-15
microns thick over most of the body. It is believed to be the high
degree of keratinization within these cells as well as their dense
packing which creates in most cases a substantially impermeable
barrier to drug penetration. With many drugs, the rate of
permeation through the skin is extremely low and is particularly
problematic for high molecular weight drugs such as steroids.
Consequently, a means for enhancing the permeability of the skin is
desired to effect transport of a steroid drug into and through
intact skin.
[0005] In order to increase the rate at which a drug penetrates
through the skin, then, various approaches have been followed, each
of which involves the use of either a chemical penetration enhancer
or a physical penetration enhancer. Physical enhancement of skin
permeation include, for example, electrophoretic techniques such as
iontophoresis. The use of ultrasound (or "phonophoresis") as a
physical penetration enhancer has also been researched. Chemical
enhancers are compounds that are administered along with the drug
(or in some cases the skin may be pretreated with a chemical
enhancer) in order to increase the permeability of the stratum
corneum, and thereby provide for enhanced penetration of the drug
through the skin. Ideally, such chemical penetration enhancers (or
"permeation enhancers," as the compounds are referred to herein)
are compounds that are innocuous and serve merely to facilitate
diffusion of the drug through the stratum corneum.
[0006] Various compounds for enhancing the permeability of skin are
known in the art and described in the pertinent texts and
literature. Compounds that have been used to enhance skin
permeability include: sulfoxides such as dimethylsulfoxide (DMSO)
and decylmethylsulfoxide (C.sub.10MSO); ethers such as diethylene
glycol monoethyl ether (available commercially as Transcutol.RTM.)
and diethylene glycol monomethyl ether; surfactants such as sodium
laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide,
benzalkonium chloride, Poloxamer (231, 182, 184), Tween (20, 40,
60, 80) and lecithin (U.S. Pat. No. 4,783,450); the 1-substituted
azacycloheptan-2-ones, particularly
1-n-dodecylcyclazacycloheptan-2-one (available under the trademark
Azone.RTM. from Nelson Research & Development Co., Irvine,
Calif.; see U.S. Pat. Nos. 3,989,816, 4,316,893, 4,405,616 and
4,557,934); alcohols such as ethanol, propanol, octanol, benzyl
alcohol, and the like; fatty acids such as lauric acid, oleic acid
and valeric acid; fatty acid esters such as isopropyl myristate,
isopropyl palmitate, methylpropionate, and ethyl oleate; polyols
and esters thereof such as propylene glycol, ethylene glycol,
glycerol, butanediol, polyethylene glycol, and polyethylene glycol
monolaurate (PEGML; see, e.g., U.S. Pat. No. 4,568,343); amides and
other nitrogenous compounds such as urea, dimethylacetamide (DMA),
dimethylformamide (DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone,
ethanolamine, diethanolamine and triethanolamine; terpenes;
alkanones; organic acids, particularly salicylic acid and
salicylates, citric acid and succinic acid; and certain peptides,
e.g., peptides having Pro-Leu at the N-terminus and followed by a
protective group (see U.S. Pat. No. 5,534,496). Percutaneous
Penetration Enhancers, eds. Smith et al. (CRC Press, 1995) provides
an excellent overview of the field and further background
information on a number of chemical and physical enhancers.
[0007] Although many chemical permeation enhancers are known, there
is an ongoing need for enhancers that are highly effective in
increasing the rate at which a drug permeates the skin, do not
result in skin damage, irritation, sensitization, or the like, and
can be used to effect transdermal delivery of even high molecular
weight drugs such as steroid drugs. It has now been discovered that
hydroxide-releasing agents are highly effective permeation
enhancers, even when used without coenhancers, and provide all of
the aforementioned advantages relative to known permeation
enhancers. Furthermore, in contrast to conventional enhancers,
transdermal administration of drugs with hydroxide-releasing agents
as permeation enhancers, employed at the appropriate levels, does
not result in systemic toxicity.
[0008] Estrogen therapy is commonly used in the pharmacological
treatment of altered hormone profiles or sexual dysfunction in
women. Estrogen-based therapies are generally used to increase
mucous production, provide vasodilator effects, and/or to increase
the general health of the vagina. Nadelson et al., eds., Treatment
Interventions in Human Sexuality (New York: Plenum Press, 1983). In
such treatments, estrogen is administered orally, parenterally
(e.g., by injection), or topically. With oral administration, as is
true with the oral administration of many steroid hormones,
estrogens tend to be inactivated; estradiol, for example, is
converted to estriol and estrone and then conjugated to glucuronic
acid or sulfate. Additionally, estrogens also impair hepatic
secretory activity. This "first pass" effect may lead to an
undesirable increase in the production of certain coagulation
factors and other biologically important compounds by the liver.
Parenterally administered estrogen avoids the aforementioned
problems associated with oral administration, but as an invasive
mode of administration is generally undesirable.
[0009] Accordingly, there is a need in the art for an effective
method for administering estrogenic agents in a manner that does
not involve oral, parenteral or topical drug administration.
SUMMARY OF THE INVENTION
[0010] It is thus a primary object of the invention to address the
above-described need in the art by providing a method for
transdermally administering a steroid drug, particularly progestins
and/or estrogens.
[0011] It is another object of the invention to provide such a
method wherein a hydroxide-releasing agent is employed as a
permeation enhancer to increase the flux of the steroid drug
through a patient's skin or mucosal tissue.
[0012] It is still another object of the invention to provide such
a method wherein the amount of hydroxide-releasing agent employed
is optimized to enhance permeation while minimizing or eliminating
the possibility of skin damage, irritation or sensitization. It is
an additional object of the invention to provide formulations and
drug delivery systems for carrying out the aforementioned
methods.
[0013] Additional objects, advantages and novel features of the
invention will be set forth in part in the description that
follows, and in part will become apparent to those skilled in the
art upon examination of the following, or may be learned by
practice of the invention.
[0014] In one aspect of the invention, then, a method is provided
for increasing the rate at which a steroid drug permeates through
the body surface of a patient. The method involves administering
the drug to a predetermined area of the patient's body surface in
combination with a hydroxide-releasing agent in a predetermined
amount effective to enhance the flux of the agent through the body
surface without causing damage thereto. The predetermined amount of
the hydroxide-releasing enhancer is preferably an amount effective
to provide a pH at the body surface in the range of about 8.0 to
13, preferably about 8.0 to 11.5, more preferably about 8.5 to
11.5, during drug administration. If a skin patch is used, this is
the preferred pH at the interface between the basal surface of the
patch (i.e., the skin-contacting or mucosa-contacting surface of
the patch) and the body surface. The optimal amount (or
concentration) of any one hydroxide-releasing agent will, however,
depend on the specific hydroxide-releasing agent, i.e., on the
strength or weakness of the base, its molecular weight, and other
factors as will be appreciated by those of ordinary skill in the
art of transdermal drug delivery. This optimal amount may be
determined using routine experimentation to ensure that the pH at
the body surface is within the aforementioned ranges, i.e., in the
range of about 8.0 to 13, preferably about 8.0 to 11.5, more
preferably about 8.5 to 11.5. A conventional transdermal drug
delivery device or "patch" may be used to administer the active
agent, in which case the drug and hydroxide-releasing agent are
generally present in a drug reservoir or reservoirs. However, the
drug and hydroxide-releasing agent may also be administered to the
body surface using a liquid or semisolid formulation.
Alternatively, or in addition, the body surface may be pretreated
with the enhancer, e.g., treated with a dilute solution of the
hydroxide-releasing agent prior to transdermal drug administration.
Such a solution will generally be comprised of a protic solvent
(e.g., water or alcohol) and have a pH in the range of about 8.0 to
13, preferably about 8.0 to 11.5, more preferably about 8.5 to
11.5. Ideally the steroid drug is a progestin and/or an estrogen;
combinations of such steroids are useful, for example, in female
hormone replacement therapy (HRT) or as female contraceptive
compositions.
[0015] In a related aspect of the invention, a composition of
matter is provided for delivering a steroid drug through a body
surface using a hydroxide-releasing agent as a permeation enhancer.
Generally, the formulation comprises (a) a therapeutically
effective amount of a steroid drug, (b) a hydroxide-releasing agent
in an amount effective to enhance the flux of the drug through the
body surface without causing damage thereto, and (c) a
pharmaceutically acceptable carrier suitable for topical or
transdermal drug administration. The composition may be in any form
suitable for application to the body surface, and may comprise, for
example, a cream, lotion, solution, gel, ointment, paste or the
like, and/or may be prepared so as to contain liposomes, micelles,
and/or microspheres. The composition may be directly applied to the
body surface or may involve use of a drug delivery device. In
either case, it is preferred although not essential that water be
present in order for the hydroxide-releasing agent to generate
hydroxide ions and thus enhance the flux of the active agent
through the patient's body surface. Thus, a formulation or drug
reservoir may be aqueous, i.e., contain water, or may be nonaqueous
and used in combination with an occlusive overlayer so that
moisture evaporating from the body surface is maintained within the
formulation or transdermal system during drug administration. In
some cases, however, e.g., with an occlusive gel, a nonaqueous
formulation may be used with or without an occlusive layer.
[0016] In another aspect of the invention, a drug delivery system
is provided for the topical or transdermal administration of a
steroid drug using a hydroxide-releasing agent as a permeation
enhancer. The system will generally comprise: at least one drug
reservoir containing the drug and the hydroxide-releasing agent in
an amount effective to enhance the flux of the drug through the
body surface without causing damage thereto; a means for
maintaining the system in drug and enhancer transmitting
relationship to the body surface; and a backing layer that serves
as the outer surface of the device during use. The backing layer
may be occlusive or nonocclusive, although it is preferably
occlusive. The drug reservoir may be comprised of a polymeric
adhesive, which may serve as the basal surface of the system during
use and thus function as the means for maintaining the system in
drug and enhancer transmitting relationship to the body surface.
The drug reservoir may also be comprised of a hydrogel, or it may
be a sealed pouch within a "patch"-type structure wherein the drug
and hydroxide-releasing agent are present in the pouch as a liquid
or semi-solid formulation.
[0017] still another aspect of the invention, a method is provided
for administering a steroid drug to a patient using the
aforementioned drug delivery system and/or composition. The method
may be used in female contraception, in female HRT, or in contexts
in which the administration of a progestin and/or estrogen is
indicated.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 is a graph illustrating the cumulative amount of
estradiol from a matrix patch as described in Example 1.
[0019] FIG. 2 is a graph illustrating the cumulative amount of
estradiol from a matrix patch as described in Example 2.
[0020] FIG. 3 is a graph illustrating the cumulative amount of
estradiol from a matrix patch as described in Example 3.
[0021] FIG. 4 is a graph illustrating the cumulative amount of
estradiol from a matrix patch as described in Example 4.
DETAILED DESCRIPTION OF THE INVENTION
[0022] Definitions and Overview
[0023] Before describing the present invention in detail, it is to
be understood that this invention is not limited to specific drug
delivery systems, device structures, enhancers or carriers, as such
may vary. It is also to be understood that the terminology used
herein is for the purpose of describing particular embodiments
only, and is not intended to be limiting.
[0024] It must be noted that, as used in this specification and the
appended claims, the singular forms "a," "an" and"the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to "a steroid drug" includes a mixture
of two or more such drugs, reference to "a hydroxide-releasing
agent" includes mixtures of two or more hydroxide-releasing agents,
and the like.
[0025] In describing and claiming the present invention, the
following terminology will be used in accordance with the
definitions set out below.
[0026] The terms "drug" or"pharmacologically active agent" or
"active agent" as used herein refer to a compound or composition of
matter which, when administered to an organism (human or animal)
induces a desired pharmacologic and/or physiologic effect by local
and/or systemic action. The active agents herein are steroid
hormones, particularly progestins and estrogens.
[0027] The terms "treating" and "treatment" as used herein refer to
reduction in severity and/or frequency of symptoms, elimination of
symptoms and/or underlying cause, prevention of the occurrence of
symptoms and/or their underlying cause, and improvement or
remediation of damage. The present method of "treating" a patient,
as the term is used herein, thus encompasses both prevention of a
disorder in a predisposed individual and treatment of the disorder
in a clinically symptomatic individual.
[0028] The term "hydroxide-releasing agent" as used herein is
intended to mean an agent that releases free hydroxide ions in an
aqueous environment. The agent may contain hydroxide ions and thus
release the ions directly (e.g., an alkali metal hydroxide), or the
agent may be one that is acted upon chemically in an aqueous
environment to generate hydroxide ions (e.g., a metal
carbonate).
[0029] By "therapeutically effective" amount is meant a nontoxic
but sufficient amount of an active agent to provide the desired
therapeutic effect.
[0030] By "transdermal" drug delivery is meant administration of a
drug to the skin surface of an individual so that the drug passes
through the skin tissue and into the individual's blood stream,
thereby providing a systemic effect. The term "transdermal" is
intended to include "transmucosal" drug administration, i.e.,
administration of a drug to the mucosal (e.g., sublingual, buccal,
vaginal, rectal) surface of an individual so that the drug passes
through the mucosal tissue and into the individual's blood
stream.
[0031] The term "topical administration" is used in its
conventional sense to mean delivery of a topical drug or
pharmacologically active agent to the skin or mucosa, as in, for
example, the treatment of various skin disorders. Topical
administration, in contrast to transdermal administration, provides
a local rather than a systemic effect. Unless otherwise stated or
implied, the terms "topical drug administration" and "transdermal
drug administration" are used interchangeably.
[0032] The term "body surface" is used to refer to skin or mucosal
tissue.
[0033] By "predetermined area" of skin or mucosal tissue, which
refers to the area of skin or mucosal tissue through which a
drug-enhancer formulation is delivered, is intended a defined area
of intact unbroken living skin or mucosal tissue. That area will
usually be in the range of about 5 cm.sup.2 to about 200 cm.sup.2,
more usually in the range of about 5 cm.sup.2 to about 100
cm.sup.2, preferably in the range of about 20 cm.sup.2 to about 60
cm.sup.2. However, it will be appreciated by those skilled in the
art of drug delivery that the area of skin or mucosal tissue
through which drug is administered may vary significantly,
depending on patch configuration, dose, and the like.
[0034] "Penetration enhancement" or "permeation enhancement" as
used herein relates to an increase in the permeability of the skin
or mucosal tissue to the selected pharmacologically active agent,
i.e., so that the rate at which the agent permeates therethrough
(i.e., the "flux" of the agent through the body surface) is
increased relative to the rate that would be obtained in the
absence of permeation enhancement. The enhanced permeation effected
through the use of such enhancers can be observed by measuring the
rate of diffusion of drug through animal or human skin using, for
example a Franz diffusion apparatus as known in the art and as
employed in the Examples herein.
[0035] An "effective" amount of a permeation enhancer is meant a
nontoxic, nondamaging but sufficient amount of the enhancer to
provide the desired increase in skin permeability and,
correspondingly, the desired depth of penetration, rate of
administration, and amount of drug delivered.
[0036] "Carriers" or "vehicles" as used herein refer to carrier
materials suitable for transdermal drug administration. Carriers
and vehicles useful herein include any such materials known in the
art which are nontoxic and does not interact with other components
of the composition in a deleterious manner.
[0037] The term "aqueous" refers to a formulation or drug delivery
system that contains water or that becomes water-containing
following application to the skin or mucosal tissue.
[0038] Accordingly, the invention pertains to a method, composition
and drug delivery system for increasing the rate at which a steroid
drug permeates through the body surface of a patient, wherein the
method involves administering the agent to a predetermined area of
the patient's body surface in combination with a
hydroxide-releasing agent in an amount effective to enhance the
flux of the agent through the body surface without causing damage
thereto.
[0039] The Hydroxide-Releasing Agent
[0040] The "hydroxide-releasing agent" is a chemical compound that
releases free hydroxide ions in the presence of an aqueous fluid.
The aqueous fluid may be natural moisture at the skin surface, or a
patch or composition that is used may contain added water, and/or
be used in connection with an occlusive backing. Similarly, any
liquid or semisolid formulation that is used is preferably aqueous
or used in conjunction with an overlayer of an occlusive material.
In some cases, however, e.g., with an occlusive gel, a nonaqueous
formulation may be used with or without an occlusive layer.
[0041] Any hydroxide-releasing agent may be used provided that the
compound releases free hydroxide ions in the presence of an aqueous
fluid. Examples of suitable hydroxide-releasing agents include, but
are not limited to, inorganic hydroxides, inorganic oxides, and
alkali metal or alkaline earth metal salts of weak acids. Inorganic
hydroxides include, for example, ammonium hydroxide, alkali metal
hydroxide and alkaline earth metal hydroxides, such as sodium
hydroxide, calcium hydroxide, potassium hydroxide, magnesium
hydroxide, and the like. Inorganic oxides include, for example,
magnesium oxide, calcium oxide, and the like. Metal salts of weak
acids include, for example, sodium acetate, sodium borate, sodium
metaborate, sodium carbonate, sodium bicarbonate, sodium phosphate
(tribasic), sodium phosphate (dibasic), potassium carbonate,
potassium bicarbonate, potassium citrate, potassium acetate,
potassium phosphate (dibasic), potassium phosphate (tribasic),
ammonium phosphate (dibasic), and the like. Preferred
hydroxide-releasing agents are metal hydroxides such as sodium
hydroxide and potassium hydroxide.
[0042] It is important that the amount of hydroxide-releasing agent
in any patch or formulation is optimized so as to increase the flux
of the steroid drug through the body surface while minimizing any
possibility of skin damage. In general, this means that the pH at
the body surface in contact with a formulation or drug delivery
system of the invention (i.e., the interface between the body
surface and the formulation or delivery system) should be in the
range of approximately 8.0 to 13, preferably about 8.0 to 11.5,
more preferably about 8.5 to 11.5. This will typically although not
necessarily mean that the pH of the formulation or the drug
composition contained within a delivery system will be in the range
of approximately 8.0 to 13, preferably about 8.0 to 11.5, more
preferably about 8.5 to 11.5.
[0043] For inorganic hydroxides, the amount of hydroxide-releasing
agent will typically represent about 0.5 wt % to 4.0 wt %,
preferably about 0.5 wt % to 3.0 wt %, more preferably about 0.75
wt % to 2.0 wt % and optimally about 1.0 wt %, of a topically
applied formulation or of a drug reservoir of a drug delivery
system, or "patch." The aforementioned amount applies to
formulations and patches in which the drug is (1) an uncharged
molecule, either an uncharged, nonionizable compound or a basic
drug in nonionized, free base form, or (2) a basic addition salt of
an acidic drug, and where (3) there are no additional species in
the formulation or patch that could react with or be neutralized by
the inorganic hydroxide. For formulations and patches in which the
steroid drug can react with the hydroxide releasing agent, and/or
wherein there are additional species in the formulations or systems
that can be neutralized by or react with the hydroxide-releasing
agent (i.e., acidic inactive ingredients), the amount of the
inorganic hydroxide will be the total of (1) the amount necessary
to neutralize or react with the drug and/or other
base-neutralizable species, plus (2) about 0.5 wt % to 4.0 wt %,
preferably about 0.5 wt % to 3.0 wt %, more preferably about 0.75
wt % to 2.0 wt % and optimally about 1.0 wt %, of the formulation
or drug reservoir. That is, for drugs that react with the inorganic
hydroxide should be present in an amount just sufficient to
neutralize the drug, plus an additional amount (i.e., about 0.5 wt
% to 4.0 wt %, preferably about 0.5 wt % to 3.0 wt %, more
preferably about 0.75 wt % to 2.0 wt % and optimally about 1.0 wt
%) to enhance the flux of the drug through the skin or mucosal
tissue. For patches, the aforementioned percentages are given
relative to the total dry weight of the formulation components and
the adhesive, gel or liquid reservoir. The aforementioned amount of
the inorganic hydroxide provides for a skin flux of transdermally
administered testosterone in the range of about 2 to 30
.mu.g/cm.sup.2/hr, preferably about 5 to 20 .mu.g/cm.sup.2/hr.
[0044] For other hydroxide-releasing agents such as inorganic
oxides and metal salts of weak acids, the amount of
hydroxide-releasing agent in the formulation or drug delivery
system may be substantially higher, as high as 20 wt %, in some
cases as high as 25 wt % or higher, but will generally be in the
range of about 2 wt % to 20 wt %.
[0045] Still greater amounts of hydroxide-releasing agent may be
used by controlling the rate and/or quantity of release of the
hydroxide-releasing agent preferably during the drug delivery
period itself.
[0046] However, for all hydroxide-releasing agents herein, the
optimum amount of any particular agent will depend on the strength
or weakness of the base, the molecular weight of the base, and
other factors such as the number of ionizable sites in the drug
administered and any other acidic species in the formulation or
patch. One skilled in the art may readily determine the optimum
amount for any particular agent by ensuring that a formulation or
drug delivery system should in all cases be effective to provide a
pH at the skin surface in the range of about 8.0 to 13, preferably
in the range of about 8.0 to 11.5, more preferably in the range of
about 8.5 to 11.5, during application to reach the desired pH at
the body surface. This in turn ensures that the degree of
enhancement is optimized while the possibility of damage to the
body surface is eliminated or at least substantially minimized.
[0047] The Steroid Drug
[0048] Suitable estrogens that may be administered using the
compositions and drug delivery systems of the invention include
synthetic and natural estrogens such as: estradiol (i.e.,
1,3,5-estratriene -3,17.beta.-diol, or "17.beta.-estradiol") and
its esters, including estradiol benzoate, valerate, cypionate,
heptanoate, decanoate, acetate and diacetate; 17.alpha.-estradiol;
ethinylestradiol (i.e., 17.alpha.-ethinylestradiol) and esters and
ethers thereof, including ethinylestradiol 3-acetate and
ethinylestradiol 3-benzoate; estriol and estriol succinate;
polyestrol phosphate; estrone and its esters and derivatives,
including estrone acetate, estrone sulfate, and piperazine estrone
sulfate; quinestrol; mestranol; and conjugated equine estrogens.
17.beta.-Estradiol, ethinylestradiol and mestranol are particularly
preferred synthetic estrogenic agents for use in conjunction with
the present invention.
[0049] Suitable progestins that can be delivered using the
compositions and systems of the invention include, but are not
limited to, acetoxypregnenolone, allylestrenol, anagestone acetate,
chlormadinone acetate, cyproterone, cyproterone acetate,
desogestrel, dihydrogesterone, dimethisterone, ethisterone
(17.alpha.-ethinyltestosterone), ethynodiol diacetate, flurogestone
acetate, gestadene, hydroxyprogesterone, hydroxyprogesterone
acetate, hydroxyprogesterone caproate, hydroxymethylprogesterone,
hydroxymethylprogesterone acetate, 3-ketodesogestrel,
levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone
acetate, megestrol, megestrol acetate, melengestrol acetate,
norethindrone, norethindrone acetate, norethisterone,
norethisterone acetate, norethynodrel, norgestimate, norgestrel,
norgestrienone, normethisterone, and progesterone. Progesterone,
medroxyprogesterone, norethindrone, norethynodrel, d,1-norgestrel
and 1-norgestrel are particularly preferred progestins.
[0050] It is generally desirable to co-administer a progestin along
with an estrogen in female HRT so that the estrogen is not
"unopposed." As is well known, estrogen-based therapies are known
to increase the risk of endometrial hyperplasia and cancer, as well
as the risk of breast cancer, in treated individuals.
Co-administration of estrogenic agents with a progestin has been
found to decrease the aforementioned risks. Preferred such
combinations include, without limitation: 17.beta.-estradiol and
medroxyprogesterone acetate; 17.beta.-estradiol and norethindrone;
17.beta.-estradiol and norethynodrel; ethinyl estradiol and
d,1-norgestrel; ethinyl estradiol and 1-norgestrel; and megestrol
and medroxyprogesterone acetate.
[0051] For female HRT, it may be desirable to co-administer a small
amount of an androgenic agent along with the progestin and the
estrogen, in order to reproduce the complete hormone profile of the
premenopausal woman, since low levels of certain androgens are
present in premenopausal women. Suitable androgenic agents include,
but are not limited to: the naturally occurring androgens and
derivatives thereof, including androsterone, androsterone acetate,
androsterone propionate, androsterone benzoate, androstenediol,
androstenediol-3-acetate, androstenediol-17-acetate,
androstenediol-3,17-diacetate, androstenediol-17-benzoate,
androstenediol-3-acetate-17-benzoate, androstenedione,
dehydroepiandrosterone (DHEA; also termed "prasterone"), sodium
dehydroepiandrosterone sulfate, 4-dihydrotestosterone (DHT; also
termed "stanolone"), 5.alpha.-dihydrotestosterone, dromostanolone,
dromostanolone propionate, ethylestrenol, nandrolone
phenpropionate, nandrolone decanoate, nandrolone furylpropionate,
nandrolone cyclohexanepropionate, nandrolone benzoate, nandrolone
cyclohexanecarboxylate, oxandrolone, stanozolol and testosterone;
pharmaceutically acceptable esters of testosterone and
4-dihydrotestosterone, typically esters formed from the hydroxyl
group present at the C-17 position, including, but not limited to,
the enanthate, propionate, cypionate, phenylacetate, acetate,
isobutyrate, buciclate, heptanoate, decanoate, undecanoate, caprate
and isocaprate esters; and pharmaceutically acceptable derivatives
of testosterone such as methyl testosterone, testolactone,
oxymetholone and fluoxymesterone. Testosterone and testosterone
esters, such as testosterone enanthate, testosterone propionate and
testosterone cypionate, are particularly preferred androgenic
agents. The aforementioned testosterone esters are commercially
available or may be readily prepared using techniques known to
those skilled in the art or described in the pertinent
literature.
[0052] Any of the aforementioned steroid drugs, i.e., progestins,
estrogens and androgens, may be naturally occurring steroids,
synthetic steroids, or derivatives thereof. The active agent(s) may
be incorporated into the present compositions and drug delivery
systems and administered in the form of a pharmaceutically
acceptable derivative, analog, ester, amide, salt, or prodrug, or
the agents may be modified by appending one or more appropriate
functionalities to enhance selected biological properties such as
penetration through the mucosal tissue. In general, esters are
preferred relative to salts or other derivatives. Preparation of
esters involves functionalization of hydroxyl and/or carboxyl
groups that may be present, as will be appreciated by those skilled
in the arts of pharmaceutical chemistry and drug delivery. Esters
can be reconverted to the free acids, if desired, by using
conventional hydrogenolysis or hydrolysis procedures. Amides and
prodrugs may also be prepared using techniques known to those
skilled in the art or described in the pertinent literature. For
example, amides may be prepared from esters, using suitable amine
reactants, or they may be prepared from an anhydride or an acid
chloride by reaction with ammonia or a lower alkyl amine. Prodrugs
are typically prepared by covalent attachment of a moiety which
results in a compound that is therapeutically inactive until
modified by an individual's metabolic system.
[0053] To administer any one of the active agents in salt form,
suitable pharmaceutically acceptable salts can be prepared using
standard procedures known to those skilled in the art of synthetic
organic chemistry and described, for example, by J. March, Advanced
Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed.
(New York: Wiley-Interscience, 1992). Acid addition salts are
prepared from an active agent in the free base form (e.g.,
compounds having a neutral --NH.sub.2 group) using conventional
means, involving reaction with a suitable acid. Suitable acids for
preparing acid addition salts include both organic acids, e.g.,
acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic
acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric
acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,
mandelic acid, methanesulfonic acid, ethanesulfonic acid,
p-toluenesulfonic acid, salicylic acid, and the like, as well as
inorganic acids, e.g., hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like. An acid
addition salt may be reconverted to the free base by treatment with
a suitable base. Preparation of basic salts of acid moieties which
may be present (e.g., carboxylic acid groups) are prepared in a
similar manner using a pharmaceutically acceptable base such as
sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium
hydroxide, magnesium hydroxide, trimethylamine, or the like.
[0054] For those active agents that are chiral in nature and can
thus be in enantiomerically pure form or in a racemic mixture, the
drug may be incorporated into the present dosage units either as
the racemate or in enantiomerically pure form.
[0055] Formulations
[0056] The method of delivery of the steroid drug may vary, but
necessarily involves application of a formulation or drug delivery
system containing the drug(s) and a hydroxide-releasing agent to a
predetermined area of the skin or other tissue for a period of time
sufficient to provide the desired local or systemic effect. The
method may involve direct application of the composition as an
ointment, gel, cream, or the like, or may involve use of a drug
delivery device. In either case, water must be present in order for
the hydroxide-releasing agent to generate hydroxide ions and thus
enhance the flux of the active agent through the patient's body
surface. Thus, a formulation or drug reservoir may be aqueous,
i.e., contain water, or may be nonaqueous and used in combination
with an occlusive overlayer so that moisture evaporating from the
body surface is maintained within the formulation or transdermal
system during drug administration. In some cases, however, e.g.,
with an occlusive gel, a nonaqueous formulation may be used with or
without an occlusive layer.
[0057] Suitable formulations include ointments, creams, gels,
lotions, pastes, and the like. Ointments, as is well known in the
art of pharmaceutical formulation, are semisolid preparations that
are typically based on petrolatum or other petroleum derivatives.
The specific ointment base to be used, as will be appreciated by
those skilled in the art, is one that will provide for optimum drug
delivery, and, preferably, will provide for other desired
characteristics as well, e.g., emolliency or the like. As with
other carriers or vehicles, an ointment base should be inert,
stable, nonirritating and nonsensitizing. As explained in
Remington: The Science and Practice of Pharmacy, 19th Ed. (Easton,
Pa..: Mack Publishing Co., 1995), at pages 1399-1404, ointment
bases may be grouped in four classes: oleaginous bases;
emulsifiable bases; emulsion bases; and water-soluble bases.
Oleaginous ointment bases include, for example, vegetable oils,
fats obtained from animals, and semisolid hydrocarbons obtained
from petroleum. Emulsifiable ointment bases, also known as
absorbent ointment bases, contain little or no water and include,
for example, hydroxystearin sulfate, anhydrous lanolin and
hydrophilic petrolatum. Emulsion ointment bases are either
water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, and
include, for example, cetyl alcohol, glyceryl monostearate, lanolin
and stearic acid. Preferred water-soluble ointment bases are
prepared from polyethylene glycols of varying molecular weight;
again, see Remington: The Science and Practice of Pharmacy for
further information.
[0058] Creams, as also well known in the art, are viscous liquids
or semisolid emulsions, either oil-in-water or water-in-oil. Cream
bases are water-washable, and contain an oil phase, an emulsifier
and an aqueous phase. The oil phase, also called the "internal"
phase, is generally comprised of petrolatum and a fatty alcohol
such as cetyl or stearyl alcohol. The aqueous phase usually,
although not necessarily, exceeds the oil phase in volume, and
generally contains a humectant. The emulsifier in a cream
formulation is generally a nonionic, anionic, cationic or
amphoteric surfactant.
[0059] As will be appreciated by those working in the field of
pharmaceutical formulation, gels are semisolid, suspension-type
systems. Single-phase gels contain organic macromolecules
distributed substantially uniformly throughout the carrier liquid,
which is typically aqueous, but also, preferably, contain an
alcohol and, optionally, an oil. Preferred "organic
macromolecules," i.e., gelling agents, are crosslinked acrylic acid
polymers such as the "carbomer" family of polymers, e.g.,
carboxypolyalkylenes that may be obtained commercially under the
Carbopol.RTM. trademark. Also preferred are hydrophilic polymers
such as polyethylene oxides, polyoxyethylene-polyoxypropylene
copolymers and polyvinylalcohol; cellulosic polymers such as
hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl
methylcellulose, hydroxypropyl methylcellulose phthalate, and
methyl cellulose; gums such as tragacanth and xanthan gum; sodium
alginate; and gelatin. In order to prepare a uniform gel,
dispersing agents such as alcohol or glycerin can be added, or the
gelling agent can be dispersed by trituration, mechanical mixing or
stirring, or combinations thereof.
[0060] Lotions, which are preferred for delivery of cosmetic
agents, are preparations to be applied to the skin surface without
friction, and are typically liquid or semiliquid preparations in
which solid particles, including the active agent, are present in a
water or alcohol base. Lotions are usually suspensions of solids,
and preferably, for the present purpose, comprise a liquid oily
emulsion of the oil-in-water type. Lotions are preferred
formulations herein for treating large body areas, because of the
ease of applying a more fluid composition. It is generally
necessary that the insoluble matter in a lotion be finely divided.
Lotions will typically contain suspending agents to produce better
dispersions as well as compounds useful for localizing and holding
the active agent in contact with the skin, e.g., methylcellulose,
sodium carboxymethyl-cellulose, or the like.
[0061] Pastes are semisolid dosage forms in which the active agent
is suspended in a suitable base. Depending on the nature of the
base, pastes are divided between fatty pastes or those made from a
single-phase aqueous gels. The base in a fatty paste is generally
petrolatum or hydrophilic petrolatum or the like. The pastes made
from single-phase aqueous gels generally incorporate
carboxymethylcellulose or the like as a base.
[0062] Formulations may also be prepared with liposomes, micelles,
and microspheres. Liposomes are microscopic vesicles having a lipid
wall comprising a lipid bilayer, and can be used as drug delivery
systems herein as well. Generally, liposome formulations are
preferred for poorly soluble or insoluble pharmaceutical agents.
Liposomal preparations for use in the instant invention include
cationic (positively charged), anionic (negatively charged) and
neutral preparations. Cationic liposomes are readily available. For
example, N[1-2,3-dioleyloxy) propyl]-N,N,N-triethylammonium (DOTMA)
liposomes are available under the tradename Lipofecting (GIBCO BRL,
Grand Island, N.Y.). Similarly, anionic and neutral liposomes are
readily available as well, e.g., from Avanti Polar Lipids
(Birmingham, ala.), or can be easily prepared using readily
available materials. Such materials include phosphatidyl choline,
cholesterol, phosphatidyl ethanolamine, dioleoylphosphatidyl
choline (DOPC), dioleoylphosphatidyl glycerol (DOPG),
dioleoylphoshatidyl ethanolamine (DOPE), among others. These
materials can also be mixed with DOTMA in appropriate ratios.
Methods for making liposomes using these materials are well known
in the art.
[0063] Micelles are known in the art as comprised of surfactant
molecules arranged so that their polar headgroups form an outer
spherical shell, while the hydrophobic, hydrocarbon chains are
oriented towards the center of the sphere, forming a core. Micelles
form in an aqueous solution containing surfactant at a high enough
concentration so that micelles naturally result. Surfactants useful
for forming micelles include, but are not limited to, potassium
laurate, sodium octane sulfonate, sodium decane sulfonate, sodium
dodecane sulfonate, sodium lauryl sulfate, docusate sodium,
decyltrimethylammonium bromide, dodecyltrimethylammonium bromide,
tetradecyltrimethylammonium bromide, tetradecyltrimethylammonium
chloride, dodecylammonium chloride, polyoxyl 8 dodecyl ether,
polyoxyl 12 dodecyl ether, nonoxynol 10 and nonoxynol 30. Micelle
formulations can be used in conjunction with the present invention
either by incorporation into the reservoir of a topical or
transdermal delivery system, or into a formulation to be applied to
the body surface.
[0064] Microspheres, similarly, may be incorporated into the
present formulations and drug delivery systems. Like liposomes and
micelles, microspheres essentially encapsulate a drug or
drug-containing formulation. They are generally although not
necessarily formed from lipids, preferably charged lipids such as
phospholipids. Preparation of lipidic microspheres is well known in
the art and described in the pertinent texts and literature.
[0065] Various additives, known to those skilled in the art, may be
included in the topical formulations. For example, solvents,
including relatively small amounts of alcohol, may be used to
solubilize certain drug substances. Other optional additives
include opacifiers, antioxidants, fragrance, colorant, gelling
agents, thickening agents, stabilizers, surfactants and the like.
Other agents may also be added, such as antimicrobial agents, to
prevent spoilage upon storage, i.e., to inhibit growth of microbes
such as yeasts and molds. Suitable antimicrobial agents are
typically selected from the group consisting of the methyl and
propyl esters of p-hydroxybenzoic acid (i.e., methyl and propyl
paraben), sodium benzoate, sorbic acid, imidurea, and combinations
thereof.
[0066] For those drugs having an unusually low rate of permeation
through the skin or mucosal tissue, it may be desirable to include
a second permeation enhancer in the formulation in addition to the
hydroxide-releasing agent, although in a preferred embodiment the
hydroxide-releasing agent is administered without any other
permeation enhancers. Any other enhancers should, like the
hydroxide-releasing agent itself, minimize the possibility of skin
damage, irritation and systemic toxicity. Example of suitable
secondary enhancers (or co-enhancers) include, but are not limited
to: ethers such as diethylene glycol monoethyl ether (available
commercially as Transcutol.RTM.) and diethylene glycol monomethyl
ether; surfactants such as sodium laurate, sodium lauryl sulfate,
cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer
(231, 182, 184), Tween (20, 40, 60, 80) and lecithin (U.S. Pat. No.
4,783,450); alcohols such as ethanol, propanol, octanol, benzyl
alcohol, and the like; fatty acids such as lauric acid, oleic acid
and valeric acid; fatty acid esters such as isopropyl myristate,
isopropyl palmitate, methylpropionate, and ethyl oleate; polyols
and esters thereof such as polyethylene glycol, and polyethylene
glycol monolaurate (PEGML; see, e.g., U.S. Pat. No. 4,568,343);
amides and other nitrogenous compounds such as urea,
dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone,
1-methyl-2-pyrrolidone, ethanolamine, diethanolamine and
triethanolamine; terpenes; alkanones; and organic acids,
particularly citric acid and succinic acid. Azone.RTM. and
sulfoxides such as DMSO and C.sub.10MSO may also be used, but are
less preferred. As noted earlier herein, Percutaneous Penetration
Enhancers, eds. Smith et al. (CRC Press, 1995) provides an
excellent overview of the field and further information concerning
possible secondary enhancers for use in conjunction with the
present invention.
[0067] The formulation may also contain irritation-mitigating
additives to minimize or eliminate the possibility of skin
irritation or skin damage resulting from the drug, the enhancer, or
other components of the formulation. Suitable irritation-mitigating
additives include, for example: -tocopherol; monoamine oxidase
inhibitors, particularly phenyl alcohols such as 2-phenyl
-1-ethanol; glycerin; salicylic acids and salicylates; ascorbic
acids and ascorbates; ionophores such as monensin; amphiphilic
amines; ammonium chloride; N-acetylcysteine; cis-urocanic acid;
capsaicin; and chloroquine. The irritant-mitigating additive, if
present, may be incorporated into the present formulations at a
concentration effective to mitigate irritation or skin damage,
typically representing not more than about 20 wt %, more typically
not more than about 5 wt %, of the formulations.
[0068] The concentration of the active agent in the formulation can
vary a great deal, and will depend on a variety of factors,
including the disease or condition to be treated, the nature and
activity of the active agent, the desired effect, possible adverse
reactions, the ability and speed of the active agent to reach its
intended target, and other factors within the particular knowledge
of the patient and physician. Preferred formulations will typically
contain on the order of about 0.5 wt % to 50 wt %, optimally about
1 wt % to 30 wt %, active agents.
[0069] Drug Delivery Systems
[0070] An alternative and preferred method involves the use of a
drug delivery system, e.g., a topical or transdermal "patch,"
wherein the active agent is contained within a laminated structure
that is to be affixed to the skin. In such a structure, the drug
composition is contained in a layer, or "reservoir," underlying an
upper backing layer. The laminated structure may contain a single
reservoir, or it may contain multiple reservoirs.
[0071] In one embodiment, the reservoir comprises a polymeric
matrix of a pharmaceutically acceptable adhesive material that
serves to affix the system to the skin during drug delivery;
typically, the adhesive material is a pressure-sensitive adhesive
(PSA) that is suitable for long-term skin contact, and which should
be physically and chemically compatible with the active agent,
hydroxide-releasing agent, and any carriers, vehicles or other
additives that are present. Examples of suitable adhesive materials
include, but are not limited to, the following: polyethylenes;
polysiloxanes; polyisobutylenes; polyacrylates; polyacrylamides;
polyurethanes; plasticized ethylene-vinyl acetate copolymers; and
tacky rubbers such as polyisobutene, polybutadiene,
polystyrene-isoprene copolymers, polystyrene-butadiene copolymers,
and neoprene(polychloroprene). Preferred adhesives are
polyisobutylenes.
[0072] The backing layer functions as the primary structural
element of the transdermal system and provides the device with
flexibility and, preferably, occlusivity. The material used for the
backing layer should be inert and incapable of absorbing drug,
hydroxide-releasing agent or components of the formulation
contained within the device. The backing is preferably comprised of
a flexible elastomeric material that serves as a protective
covering to prevent loss of drug and/or vehicle via transmission
through the upper surface of the patch, and will preferably impart
a degree of occlusivity to the system, such that the area of the
body surface covered by the patch becomes hydrated during use. The
material used for the backing layer should permit the device to
follow the contours of the skin and be worn comfortably on areas of
skin such as at joints or other points of flexure, that are
normally subjected to mechanical strain with little or no
likelihood of the device disengaging from the skin due to
differences in the flexibility or resiliency of the skin and the
device. The materials used as the backing layer are either
occlusive or permeable, as noted above, although occlusive backings
are preferred, and are generally derived from synthetic polymers
(e.g., polyester, polyethylene, polypropylene, polyurethane,
polyvinylidine chloride, and polyether amide), natural polymers
(e.g., cellulosic materials), or macroporous woven and nonwoven
materials.
[0073] During storage and prior to use, the laminated structure
includes a release liner. Immediately prior to use, this layer is
removed from the device so that the system may be affixed to the
skin. The release liner should be made from a drug/vehicle
impermeable material, and is a disposable element which serves only
to protect the device prior to application. Typically, the release
liner is formed from a material impermeable to the
pharmacologically active agent and the hydroxide-releasing agent,
and which is easily stripped from the transdermal patch prior to
use.
[0074] In an alternative embodiment, the drug-containing reservoir
and skin contact adhesive are present as separate and distinct
layers, with the adhesive underlying the reservoir. In such a case,
the reservoir may be a polymeric matrix as described above.
Alternatively, the reservoir may be comprised of a liquid or
semisolid formulation contained in a closed compartment or "pouch,"
or it may be a hydrogel reservoir, or may take some other form.
Hydrogel reservoirs are particularly preferred herein. As will be
appreciated by those skilled in the art, hydrogels are
macromolecular networks that absorb water and thus swell but do not
dissolve in water. That is, hydrogels contain hydrophilic
functional groups that provide for water absorption, but the
hydrogels are comprised of crosslinked polymers that give rise to
aqueous insolubility. Generally, then, hydrogels are comprised of
crosslinked hydrophilic polymers such as a polyurethane, a
polyvinyl alcohol, a polyacrylic acid, a polyoxyethylene, a
polyvinylpyrrolidone, a poly(hydroxyethyl methacrylate)
(poly(HEMA)), or a copolymer or mixture thereof. Particularly
preferred hydrophilic polymers are copolymers of HEMA and
polyvinylpyrrolidone.
[0075] Additional layers, e.g., intermediate fabric layers and/or
rate-controlling membranes, may also be present in any of these
drug delivery systems. Fabric layers may be used to facilitate
fabrication of the device, while a rate-controlling membrane may be
used to control the rate at which a component permeates out of the
device. The component may be a drug, a hydroxide-releasing agent,
an additional enhancer, or some other component contained in the
drug delivery system.
[0076] A rate-controlling membrane, if present, will be included in
the system on the skin side of one or more of the drug reservoirs.
The materials used to form such a membrane are selected to limit
the flux of one or more components contained in the drug
formulation. Representative materials useful for forming
rate-controlling membranes include polyolefins such as polyethylene
and polypropylene, polyamides, polyesters, ethylene-ethacrylate
copolymer, ethylene-vinyl acetate copolymer, ethylene-vinyl
methylacetate copolymer, ethylene-vinyl ethylacetate copolymer,
ethylene-vinyl propylacetate copolymer, polyisoprene,
polyacrylonitrile, ethylene-propylene copolymer, and the like.
[0077] Generally, the underlying surface of the transdermal device,
i.e., the skin contact area, has an area in the range of about 5
cm.sup.2 to 200 cm.sup.2, preferably 5 cm.sup.2 to 100 cm.sup.2,
more preferably 20 cm.sup.2 to 60 cm.sup.2. That area will vary, of
course, with the amount of drug to be delivered and the. flux of
the drug through the body surface. Larger patches will necessary to
accommodate larger quantities of drug, while smaller patches can be
used for smaller quantities of drug and/or drugs that exhibit a
relatively high permeation rate.
[0078] Such drug delivery systems may be fabricated using
conventional coating and laminating techniques known in the art.
For example, adhesive matrix systems can be prepared by casting a
fluid admixture of adhesive, drug and vehicle onto the backing
layer, followed by lamination of the release liner. Similarly, the
adhesive mixture may be cast onto the release liner, followed by
lamination of the backing layer. Alternatively, the drug reservoir
may be prepared in the absence of drug or excipient, and then
loaded by "soaking" in a drug/vehicle mixture. In general,
transdermal systems of the invention are fabricated by solvent
evaporation, film casting, melt extrusion, thin film lamination,
die cutting, or the like. The hydroxide-releasing agent will
generally be incorporated into the device during patch manufacture
rather than subsequent to preparation of the device.
[0079] In a preferred delivery system, an adhesive overlayer that
also serves as a backing for the delivery system is used to better
secure the patch to the body surface. This overlayer is sized such
that it extends beyond the drug reservoir so that adhesive on the
overlayer comes into contact with the body surface. The overlayer
is useful because the adhesive/drug reservoir layer may lose its
adhesion a few hours after application due to hydration. By
incorporating such an adhesive overlayer, the delivery system
remains in place for the required period of time.
[0080] Other types and configurations of transdermal drug delivery
systems may also be used in conjunction with the method of the
present invention, i.e., the use of a hydroxide-releasing agent as
a permeation enhancer, as will be appreciated by those skilled in
the art of transdermal drug delivery. See, for example, Ghosh,
Transdermal and Topical Drug Delivery Systems (Interpharm Press,
1997), particularly Chapters 2 and 8.
[0081] As with the topically applied formulations of the invention,
the composition containing drug and hydroxide-releasing agent
within the drug reservoir(s) of these laminated system may contain
a number of components. In some cases, the drug and
hydroxide-releasing agent may be delivered "neat," i.e., in the
absence of additional liquid. In most cases, however, the drug will
be dissolved, dispersed or suspended in a suitable pharmaceutically
acceptable vehicle, typically a solvent or gel. Other components
which may be present include preservatives, stabilizers,
surfactants, and the like.
[0082] UTILITY
[0083] The compositions and drug delivery systems are useful in a
method for administering a steroid drug or a combination of steroid
drugs transdermally. Administration of a combination of steroidal
active agents is useful in a variety of contexts, as will be
readily appreciated by those skilled in the art. For example, the
transdermal administration of a progestin with an estrogen may be
used in female hormone replacement therapy, so that the symptoms or
conditions resulting from altered hormone levels is mitigated or
substantially prevented. The present compositions and drug delivery
systems are in addition useful to administer progestins and
estrogens to treat other conditions and disorders that are
responsive to transdermal administration of the combination of
active agents. For example, the aforementioned combination is
useful to treat the symptoms of premenstrual stress and for female
contraception.
[0084] For female hormone replacement therapy, the woman undergoing
treatment will generally be of childbearing age or older, in whom
ovarian estrogen, progesterone and androgen production has been
interrupted either because of natural menopause, surgical
procedures, radiation, chemical ovarian ablation or extirpation, or
premature ovarian failure. For hormone replacement therapy, and for
the other indications described herein including female
contraception, the compositions or drug delivery systems are
preferably used consecutively so that administration of the active
agents is substantially continuous. Transdermal drug administration
according to the invention provides highly effective female hormone
replacement therapy. That is, the incidence and severity of hot
flashes and night sweats are reduced, postmenopausal loss of
calcium from bone is minimized, the risk of death from ischemic
heart disease is reduced, and the vascularity and health of the
vaginal mucosa and urinary tract are improved.
[0085] The amount of active agent(s) administered will depend on a
number of factors and will vary from subject to subject and depend
on the particular active agent administered, the particular
disorder or condition being treated, the severity of the symptoms,
the subject's age, weight and general condition, and the judgment
of the prescribing physician. Other factors specific to transdermal
drug delivery include the solubility and permeability of the
carrier and adhesive layer, and the period of time for which the
device will be fixed to the skin or other body surface. The minimum
amount of drug is determined by the requirement that sufficient
quantities of drug must be present in the device to maintain the
desired rate of release over the given period of application. The
maximum amount for safety purposes is determined by the requirement
that the quantity of drug present cannot exceed a rate of release
that reaches toxic levels. Generally, the maximum concentration is
determined by the amount of agent that can be received in the
carrier without producing adverse histological effects such as
irritation, an unacceptably high initial pulse of agent into the
body, or adverse effects on the characteristics of the delivery
device such as the loss of tackiness, viscosity, or deterioration
of other properties. However, preferred transdermal compositions
and systems for hormone replacement therapy are capable of
delivering about 0.5 to 10.0 mg progestin, e.g., norethindrone,
norethindrone acetate or the like, and about 10 to 200 .mu.g
estrogen, e.g., 17.beta.-estradiol, ethinyl estradiol, mestranol or
the like, over a period of about 24 hours. However, it will be
appreciated by those skilled in the art that the desired dose of
each individual active agent will depend on the specific active
agent as well as on other factors; the minimum effective dose of
each active agent is of course preferred.
[0086] The invention accordingly provides a novel and highly
effective means for increasing the flux of a steroid drug through
the body surface (skin or mucosal tissue) of a human or animal. The
hydroxide-releasing agents discussed herein, employed in specific
amounts relative to a formulation or drug reservoir, may be used as
permeation enhancers with a variety of steroid drugs, including,
but not limited to, testosterone and its esters. Surprisingly, the
increase in permeation is not accompanied by any noticeable tissue
damage, irritation, or sensitization. The invention thus represents
an important advance in the field of drug delivery.
[0087] It is to be understood that while the invention has been
described in conjunction with the preferred specific embodiments
thereof, the foregoing description, as well as the examples which
follow, are intended to illustrate and not limit the scope of the
invention. Other aspects, advantages and modifications will be
apparent to those skilled in the art to which the invention
pertains. All patents, patent applications, journal articles and
other references cited herein are incorporated by reference in
their entireties.
[0088] The following examples are put forth so as to provide those
of ordinary skill in the art with a complete disclosure and
description of how to make and use the materials of the invention,
and are not intended to limit the scope of what the inventors
regard as their invention. Efforts have been made to ensure
accuracy with respect to numbers (e.g., amounts, temperature, etc.)
but some errors and deviations should be accounted for. Unless
indicated otherwise, parts are parts by weight, temperature is in
.degree.C. and pressure is at or near atmospheric. EXAMPLE 1
[0089] An in vitro skin permeation study was conducted using three
estradiol transdermal systems. The formulations used to prepare
these systems are listed in Table 1, which includes weight and
weight percent of each component of the formulations. The weight of
sodium hydroxide was 0 g, 0.0155 g, and 0.025 g for formulation
#Est-P18, #Est-P19 and #Est-P20 respectively. Each formulation was
coated onto a release liner and dried in an oven at 55 .degree. C.
for two hours to remove water and other solvents. The dried
drug-in-adhesive/release liner film was laminated to a backing
film. The backing/drug-in-adhesive/release liner laminate was then
cut into discs with a diameter of {fraction (11/16 )} inch. The
theoretical percent weight for each ingredient after drying
(calculated assuming all volatile ingredients were completely
removed during drying) is set forth in Table 2.
[0090] The in vitro permeation of estradiol through human cadaver
skin from these discs was performed using Franz-type diffusion
cells with a diffusion area of 1 cm.sup.2. The volume of receiver
solution was 8 ml. Human cadaver skin was cut to a proper size and
placed on a flat surface with the stratum corneum side facing up.
The release liner was peeled away from the disc laminate. The
backing/drug-in-adhesive film was placed and pressed on the skin
with the adhesive side facing the stratum corneum. The
skin/adhesive/backing laminate was clamped between the donor and
receiver chambers of the diffusion cell with the skin side facing
the receiver solution. Three diffusion cells were used for each
formulation.
[0091] The cells were filled with 10% ethanol/90% water solution.
The receiver solution was completely withdrawn and replaced with
fresh ethanol/water solution at each time point. The samples taken
were analyzed by HPLC to determine the concentration of estradiol
in the receiver solution. The cumulative amount of estradiol that
permeated through the human cadaver skin was calculated using the
measured estradiol concentrations in the receiver solutions, which
were plotted versus time and shown in FIG. 1.
[0092] The pH of the patch was measured using the following
procedures. A 2.5 cm.sup.2 circular patch was punched out. Ten ml
of purified water was pipetted into a glass vial, and a stir bar
was added; the liner was removed from the patch and placed in the
vial along with the patch. The vial was then placed on a stir plate
and the water/patch/liner mixture was stirred for 5 minutes, at
which point the liner was removed from the vial and discarded. The
vial was again placed on a stir plate and stirring continued for an
additional 18 hours. After 18 hours, the stir bar was removed from
the vial and the pH of the solution determined using a calibrated
pH meter. The measured pHs for the estradiol transdermal systems
are listed in Table 3.
1TABLE 1 Weight and Weight Percent of Components (Based on Total
Solution Weight) for Three Estradiol Transdermal Systems Est-P18
Est-P19 Est-P20 Estradiol 0.0313 g (0.5%) 0.0322 g (0.5%) 0.0308 g
(0.5%) NaOH 0 0.0155 g (0.3%) 0.025 g (0.4%) DI water 0 0.4155 g
(6.9%) 0.425 g (7.0%) PIB* adhesive 4 g (66.3%) 4 g (66.0%) 4 g
(65.8%) (30% solid) Methylal 1.8 g (29.8%) 1.4 g (23.1%) 1.4 g
(23.0%) Ethanol 0.2 g (3.3%) 0.2 g (3.3%) 0.2 g (3.3%) *PIB =
polyisobutylene
[0093]
2TABLE 2 Weight and Theoretical Weight Percent of Components in the
Dried Film for Three Estradiol Transdermal Systems Est-P18 Est-P19
Est-P20 Estradiol 0.0313 g (2.5%) 0.0322 g (2.6%) 0.0308 g (2.5%)
NaOH 0 0.0155 g (1.2%) 0.025 g (2.0%) PIB adhesive 1.2 g (97.5%)
1.2 g (96.2%) 1.2 g (95.6%)
[0094]
3TABLE 3 pH for Three Estradiol Transdermal Systems Est-P18 Est-P19
Est-P20 pH 7.22 8.75 8.90
[0095] The cumulative amount of estradiol that permeated across
human cadaver skin at 24 hours increased from 0.22 .mu.g/cm.sup.2
to 7.01 .mu.g/cm.sup.2 when the calculated sodium hydroxide
concentration in the dried patch was increased from 0% to 2.0%. The
cumulative amount of estradiol that permeated across human cadaver
skin at 24 hours from the system containing 1.2% NaOH (Est-P19) was
4.55 .mu.g/cm.sup.2, which was about 20 times higher than that from
the formulation without NaOH (0.22 .mu.g/cm.sup.2, #Est-P 18).
[0096] The pH of the estradiol patch measured using the procedures
listed above increased from 7.22 to 8.90 when the calculated sodium
hydroxide concentration in the dried patch was increased from 0% to
2.0%.
EXAMPLE 2
[0097] An in vitro skin permeation study was conducted using four
estradiol transdermal systems. The formulations used to prepare
these systems are listed in Table 4, which includes weight and
weight percent of each component in the formulations. The weight of
potassium phosphate, tribasic (K.sub.3PO.sub.4) was 0 g, 0.1 g, 0.3
g, and 0.48 g for formulation #Est-PK1, -PK2, -PK3, and -PK4
respectively. The matrix patches were prepared and evaluated using
the same procedures as set forth in Example 1. The theoretical
percent weight for each ingredient after drying (calculated
assuming all the volatile ingredients were completely removed
during drying) is listed in Table 5. The cumulative amount of
estradiol across human cadaver skin was calculated using the
measured estradiol concentrations in the receiver solutions, which
are shown in Table 6 and FIG. 2. Since estradiol is not expected to
react with K.sub.3PO.sub.4, the K.sub.3PO.sub.4 concentration
listed in Table 5 equals the excess K.sub.3PO.sub.4 concentration.
The pH of each patch was determined using the procedure of Example
1 and the results are listed in Table 6.
4TABLE 4 Weight and Weight Percent of Each Component (Based on
Total Solution Weight) for Four Estradiol Transdermal Systems
Est-PK1 Est-PK2 Est-PK3 Est-PK4 Estradiol 0.03 g 0.03 g 0.03 g 0.03
g (0.5%) (0.5%) (0.5%) (0.4%) Methyl alcohol 0.5 g (8.0%) 0.5 g
(7.8%) 0.5 g (7.6%) 0.5 g (7.4%) K.sub.3PO.sub.4 0 0.1 g (1.6%) 0.3
g (4.6%) 0.48 g (7.1%) DI water 0.5 g (8.0%) 0.5 g (7.8%) 0.5 g
(7.6%) 0.5 g (7.4%) Propylene 0.25 g 0.25 g 0.25 g 0.25 g glycol
(4.0%) (3.9%) (3.8%) (3.7%) PIB adhesive 4 g (63.7%) 4 g (62.7%) 4
g (60.8%) 4 g (59.2%) (30% solid) Heptane 1 g (15.9%) 1 g (15.7%) 1
g (15.2%) 1 g (14.8%)
[0098]
5TABLE 5 Weight and Theoretical Weight Percent of Each Component in
the Dried Film for Four Estradiol Transdermal Systems Est-PK1
Est-PK2 Est-PK3 Est-PK4 Estradiol 0.03 g 0.03 g 0.03 g 0.03 g
(2.0%) (1.9%) (1.7%) (1.5%) K.sub.3PO.sub.4 0 0.1 g (6.3%) 0.3 g
0.48 g (16.9%) (24.5%) Propylene 0.25 g 0.25 g 0.25 g 0.25 g glycol
(16.9%) (15.8%) (14.0%) (12.8%) PIB adhesive 1.2 g 1.2 g 1.2 g 1.2
g (81.1%) (76.0%) (67.4%) (61.2%)
[0099]
6TABLE 6 Cumulative Amount of Estradiol Across Human Cadaver Skin
for Estradiol Transdermal Systems (.mu.g/cm.sup.2) Est-PK1 Est-PK2
Est-PK3 Est-PK4 5 hours 0.2 1.2 2.1 1.5 16.5 hours 0.4 3.9 7.6 3.7
20 hours 0.5 4.6 8.8 4.4 24 hours 0.6 5.6 10.2 5.3
[0100]
7TABLE 7 Excess K.sub.3PO.sub.4 Concentration and pH of Four
Estradiol Transdermal Systems Est-PK1 Est-PK2 Est-PK3 Est-PK4
Excess K.sub.3PO.sub.4 Concentration 0% 6.3% 16.9% 24.5% (wt %) pH
6.4 8.89 10.83 9.87
[0101] The cumulative amount of estradiol that permeated across the
human cadaver skin at 24 hours for Est-PK2 (5.6 .mu.g/cm.sup.2,
Table 6) with a calculated excess K.sub.3PO.sub.4 concentration of
6.3% was about nine times higher than that from the formulation
without K.sub.3PO.sub.4 (Est-PK1, 0.6 .mu.g/cm.sup.2). This result
indicated that the permeation of estradiol is enhanced by
K.sub.3PO.sub.4. The cumulative amount of estradiol across human
cadaver skin at 24 hours increased from 5.6 to 10.2 .mu.g/cm.sup.2
when the excess K.sub.3PO.sub.4 concentration in the dried patch
was increased from 6.3% to 16.9% (Tables 6 and 7). When the excess
K.sub.3PO.sub.4 concentration in the dried patch was further
increased from 16.9% to 24.5% (Table 7), the cumulative amount of
estradiol across human cadaver skin at 24 hours decreased from 10.2
to 5.3 .mu.g/cm.sup.2. This decrease in flux may be because the
high concentration of K.sub.3PO.sub.4 made the adhesive matrix more
hydrophobic and the amount of K.sub.3PO.sub.4 that could be
dissolved by the small amount of water on the top of the skin was
reduced.
[0102] The pH of the estradiol patch measured using the procedures
listed above increased from 6.4 to 10.83 when the K.sub.3PO.sub.4
concentration in the dried patch was increased from 0% to 16.9%.
However, the pH of the estradiol patch decreased from 10.83 to 9.87
when the K.sub.3PO4 concentration in the dried patch was further
increased from 16.9% to 24.5%.
EXAMPLE 3
[0103] An in vitro skin permeation study was conducted using four
estradiol transdermal systems. The formulations used to prepare
these systems are listed in Table 8, which includes weight and
weight percent of each component in the formulations. The weight of
sodium carbonate (Na.sub.2CO.sub.3) was 0 g, 0.11 g, 0.3 g, and
0.45 g for formulation #Est-PC1, -PC2, -PC3, and -PC4 respectively.
The matrix patches were prepared and evaluated using the same
procedures as set forth in Example 1. The theoretical percent
weight for each ingredient after drying (calculated assuming all
the volatile ingredients were completely removed during drying) is
listed in Table 9. The cumulative amount of estradiol across human
cadaver skin was calculated using the measured estradiol
concentrations in the receiver solutions, which are shown in Table
10 and FIG. 3. Since estradiol is not expected to react with
Na.sub.2CO.sub.3, the Na.sub.2CO.sub.3 concentration listed in
Table 9 equals the excess Na.sub.2CO.sub.3 concentration. The pH of
each patch was determined using the procedure of Example 1 and the
results are listed in Table 10.
8TABLE 8 Weight and Weight Percent of Each Component (Based on
Total Solution Weight) for Four Estradiol Transdermal Systems
Est-PC1 Est-PC2 Est-PC3 Est-PC4 Estradiol 0.03 g 0.03 g 0.03 g 0.03
g (0.5%) (0.4%) (0.4%) (0.4%) Na.sub.2CO.sub.3 0 0.11 g 0.3 g
(4.1%) 0.45 g (1.6%) (6.1%) DI water 0.5 g (8.0%) 1.2 g 1.2 g 1.2 g
(16.9%) (16.5%) (16.2%) Methyl alcohol 0.5 g (8.0%) 0.5 g (7.1%)
0.5 g (6.9%) 0.5 g (6.7%) PIB adhesive 4 g (63.7%) 4 g (56.4%) 4 g
(55.0%) 4 g (53.8%) (30% solid) Propylene 0.25 g 0.25 g 0.25 g 0.25
g glycol (4.0%) (3.5%) (3.4%) (3.4%) Heptane 1 g (15.9%) 1 g
(14.1%) 1 g (13.7%) 1 g (13.5%)
[0104]
9TABLE 9 Weight and Theoretical Weight Percent of Each Component in
the Dried Film for Four Estradiol Transdermal Systems Est-PC1
Est-PC2 Est-PC3 Est-PC4 Estradiol 0.03 g 0.03 g 0.03 g 0.03 g
(2.0%) (1.9%) (1.7%) (1.6%) Na.sub.2CO.sub.3 0 0.11 g 0.3 g 0.45 g
(6.9%) (16.9%) (23.3%) PIB adhesive 1.2 g 1.2 g 1.2 g 1.2 g (81.1%)
(75.5%) (67.4%) (62.2%) Propylene 0.25 g 0.25 g 0.25 g 0.25 g
glycol (16.9%) (15.7%) (14.0%) (13.0%)
[0105]
10TABLE 10 Cumulative Amount of Estradiol Across Human Cadaver Skin
for Estradiol Transdermal Systems (.mu.g/cm.sup.2) Est-PC1 Est-PC2
Est-PC3 Est-PC4 5 hours 0.1 0.4 0.1 0.1 16.5 hours 0.2 0.9 0.4 0.6
20 hours 0.3 1.1 0.6 1.0 24 hours 0.3 1.4 1.0 1.4
[0106]
11TABLE 11 Excess Na.sub.2CO.sub.3 Concentration and pH of Four
Estradiol Transdermal Systems Est-PC1 Est-PC2 Est-PC3 Est-PC4
Excess Na.sub.2CO.sub.3 Concentration 0% 6.9% 16.9% 23.3% (wt %) pH
7.48 9.87 10.51 10.49
[0107] The cumulative amount of estradiol that permeated across the
human cadaver skin at 24 hours for Est-PC2 (1.4 .mu.g/cm.sup.2,
Table 10) with a calculated excess Na.sub.2CO.sub.3 concentration
of 6.9% was about four times higher than that from the formulation
without Na.sub.2CO.sub.3 (Est-PC1, 0.3 .mu.g/cm.sup.2). This result
indicated that Na.sub.2CO.sub.3 could enhance the permeation of
estradiol.
[0108] The cumulative amount of estradiol across human cadaver skin
at 24 hours remained about the same when the excess
Na.sub.2CO.sub.3 concentration in the dried patch was increased
from 6.9% to 23.3% (Tables 10 and 11). This behavior may be because
the amount of Na.sub.2CO.sub.3 that could be dissolved by the small
amount of water on the top of the skin remained about the same for
Est-PC2, Est-PC3 and Est-PC4.
[0109] The pH of the estradiol patch measured using the procedures
listed above increased from 7.48 to 10.51 when the Na.sub.2CO.sub.3
concentration in the dried patch was increased from 0% to 16.9%.
However, when the Na.sub.2CO.sub.3 concentration in the dried patch
was further increased from 16.9% to 23.3%, the pH of the estradiol
patch remained about the same.
EXAMPLE 4
[0110] An in vitro skin permeation study was conducted using four
estradiol transdermal systems. The formulations used to prepare
these systems are listed in Table 12, which includes weight and
weight percent of each component in the formulations. The weight of
magnesium oxide (MgO) was 0 g, 0.11 g, 0.3 g and 0.45 g for
formulation #Est-PM1, -PM2, -PM3 and -PM4 respectively. The matrix
patches were prepared and evaluated using the same procedures as
set forth in Example 1. The theoretical percent weight for each
ingredient after drying (calculated assuming all the volatile
ingredients were completely removed during drying) is listed in
Table 13. The cumulative amount of estradiol across human cadaver
skin was calculated using the measured estradiol concentrations in
the receiver solutions, which are shown in Table 14 and FIG. 4.
Since estradiol is not expected to react with MgO, the MgO
concentration listed in Table 13 equals the excess MgO
concentration. The pH of each patch was determined using the
procedure of Example 1 and the results are listed in Table 15.
12TABLE 12 Weight and Weight Percent of Each Component (Based on
Total Solution Weight) for Four Estradiol Transdermal Systems
Est-PM1 Est-PM2 Est-PM3 Est-PM4 Estradiol 0.03 g 0.03 g 0.03 g 0.03
g (0.5%) (0.4%) (0.4%) (0.4%) MgO 0 0.11 g 0.3 g (4.1%) 0.45 g
(1.6%) (6.1%) DI water 0.5 g (8.0%) 1.2 g 1.2 g 1.2 g (16.9%)
(16.5%) (16.2%) Methyl alcohol 0.5 g (8.0%) 0.5 g (7.1%) 0.5 g
(6.9%) 0.5 g (6.7%) PIB adhesive 4 g 4 g 4 g 4 g (30% solid)
(63.7%) (56.4%) (55.0%) (53.8%) Propylene 0.25 g 0.25 g 0.25 g 0.25
g glycol (4.0%) (3.5%) (3.4%) (3.4%) Heptane 1 g (15.9%) 1 g
(14.1%) 1 g (13.7%) 1 g (13.5%)
[0111]
13TABLE 13 Weight and Theoretical Weight Percent of Each Component
in the Dried Film for Four Estradiol Transdermal Systems Est-PM1
Est-PM2 Est-PM3 Est-PM4 Estradiol 0.03 g 0.03 g 0.03 g 0.03 g
(2.0%) (1.9%) (1.7%) (1.6%) MgO 0 0.11 g 0.3 g 0.45 g (6.9%)
(16.9%) (23.3%) PIB adhesive 1.2 g 1.2 g 1.2 g 1.2 g (81.1%)
(75.5%) (67.4%) (62.2%) Propylene 0.25 g 0.25 g 0.25 g 0.25 g
glycol (16.9%) (15.7%) (14.0%) (13.0%)
[0112]
14TABLE 14 Cumulative Amount of Estradiol Across Human Cadaver Skin
for Estradiol Transdermal Systems (.mu.g/cm.sup.2) Est-PM1 Est-PM2
Est-PM3 Est-PM4 4.75 hours 0.08 0.09 0.05 0.02 15.75 hours 0.21
0.31 0.19 0.13 19.75 hours 0.26 0.41 0.26 0.19 23.75 hours 0.32
0.53 0.36 0.27
[0113]
15TABLE 15 Excess MgO Concentration and pH of Four Estradiol
Transdermal Systems Est-PM1 Est-PM2 Est-PM3 Est-PM4 Excess MgO 0%
6.9% 16.9% 23.3% Concentration (wt %) pH 7.48 8.95 9.66 10.28
[0114] The cumulative amount of estradiol that permeated across the
human cadaver skin at 24 hours for Est-PM2 (0.53 .mu.g/cm.sup.2,
Table 14) with a calculated excess MgO concentration of 6.9% was
slightly higher than that from the formulation without
K.sub.3PO.sub.4 (Est-PM1, 0.32 .mu.g/cm.sup.2). This result
indicated that MgO enhances the permeation of estradiol. The
cumulative amount of estradiol across human cadaver skin at 24
hours decreased from 0.53 to 0.27 .mu.g/cm.sup.2 when the excess
MgO concentration in the dried patch was increased from 6.9% to
23.3% (Tables 14 and 15). This behavior may be because the high
concentration of MgO made the adhesive matrix more hydrophobic and
the amount of MgO that could be dissolved by the small amount of
water on the top of the skin was reduced. The pH of the estradiol
patch measured using the procedures listed above increased from
7.48 to 10.28 when the MgO concentration in the dried patch was
increased from 0% to 23.3%.
* * * * *