U.S. patent application number 11/525684 was filed with the patent office on 2007-05-03 for transdermal norelgestromin delivery system.
Invention is credited to Jay Audett, Paul B. Foreman, Delphine C. Imbert, Allison Luciano, Eric N. Silverberg, Jane Stepic, Jianye Wen, Tyler D. Westcott.
Application Number | 20070098772 11/525684 |
Document ID | / |
Family ID | 37770404 |
Filed Date | 2007-05-03 |
United States Patent
Application |
20070098772 |
Kind Code |
A1 |
Westcott; Tyler D. ; et
al. |
May 3, 2007 |
Transdermal norelgestromin delivery system
Abstract
A system for transdermal delivery of norelgestromin (NGMN) to an
individual. The system has a high NGMN loading with suitable
permeation enhancers to effect therapeutic flux rate. Polyacrylate
drug reservoir with the NGMN and high loading of one or more of
permeation enhancers and NGMN dissolved therein provides desirable
adhesive characteristics and effective transdermal therapeutic
properties. Estrogen can be delivered with the NGMN.
Inventors: |
Westcott; Tyler D.; (San
Francisco, CA) ; Stepic; Jane; (San Carlos, CA)
; Imbert; Delphine C.; (Cupertino, CA) ; Audett;
Jay; (Mountain View, CA) ; Wen; Jianye; (Palo
Alto, CA) ; Luciano; Allison; (Lebanon, NJ) ;
Silverberg; Eric N.; (Summit, NJ) ; Foreman; Paul
B.; (Somerville, NJ) |
Correspondence
Address: |
PHILIP S. JOHNSON;JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
37770404 |
Appl. No.: |
11/525684 |
Filed: |
September 22, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60720200 |
Sep 23, 2005 |
|
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|
Current U.S.
Class: |
424/449 ;
156/242; 514/182 |
Current CPC
Class: |
A61K 9/7061 20130101;
C09J 2467/006 20130101; A61K 31/4439 20130101; C09J 7/255 20180101;
A61K 31/56 20130101; C09J 7/385 20180101; C09J 133/06 20130101 |
Class at
Publication: |
424/449 ;
514/182; 156/242 |
International
Class: |
A61K 9/70 20060101
A61K009/70; A61K 31/56 20060101 A61K031/56 |
Claims
1. A method of making a drug reservoir for transdermal (NGMN)
delivery, comprising: providing a solution of a noncrosslinked
acrylate polymer, dissolving NGMN and permeation enhancer in the
solution, drying the solution to form a drug reservoir with more
than 4 wt % of NGMN dissolved in the drug reservoir such that the
drug reservoir has permeation enhancer and can deliver the NGMN at
a flux for therapy, the polymer constitutes 45 wt % to 90 wt % of
the drug reservoir, wherein the drug reservoir maintains
appropriate pressure sensitive adhesive properties applicable to a
body surface.
2. The method of claim 1 comprising forming the reservoir with
carrier having NGMN and estrogen dissolved therein, the carrier
being a polymer consist of noncrosslinked polyacrylate and wherein
the NGMN flux is greater than 0.4 .mu.g/cm.sup.2-h.
3. The method of claim 2 wherein the estrogen is ethinyl estradiol
(EE) and the method comprising dissolving more than 15 wt % NGMN,
and dissolving EE and permeation enhancer in the solution such that
the NGMN together with EE (NGMN/EE) and permeation enhancer make up
greater than 30 wt % dissolved solids in the drug reservoir and
wherein the acrylate polymer has polar functionality.
4. The method of claim 2 wherein the estrogen is ethinyl estradiol
(EE) and the acrylate polymer has at least 10 wt % functional
monomer component, constitutes 45 wt % to 80 wt % of the drug
reservoir and can hold the NGMN/EE together with permeation
enhancer at a dissolved amount of at least 30 wt %, the acrylate
polymer having a T.sub.g of greater than -15.degree. C. if without
permeation enhancer and without NGMN/EE.
5. The method of claim 2 wherein the drug reservoir can deliver the
NGMN at a flux of larger than 150 mg per day at greater than 0.4
.mu.g/cm.sup.2-h and the estrogen has a flux of greater than 0.01
.mu.g/cm.sup.2-h.
6. The method of claim 2 wherein the NGMN flux is greater than 0.5
.mu.g/cm.sup.2-h and the permeation enhancer is more than 20 wt %
in the reservoir.
7. The method of claim 4 wherein the acrylate polymer has no more
than 60 wt % soft monomer component, has at least 40 wt % hard
monomer component at least a fraction of which being hard
functional monomer, and has 1 to 35 wt % functional monomer
component.
8. The method of claim 4 wherein the drug reservoir has a glass
transition temperature T.sub.g of less than -10.degree. C. whereas
the acrylate polymer has a T.sub.g of greater than -15.degree. C.
and a creep compliance of 6.times.10.sup.-5 cm.sup.2/dyn to
2.times.10.sup.-6 cm.sup.2/dyn.
9. The method of claim 4 wherein the acrylate polymer includes (i)
40 to 50 wt % of soft alkyl acrylate monomer component, in which
each soft alkyl acrylate monomer having a homopolymer T.sub.g
of--80.degree. C. to -20.degree. C., (ii) 40 to 60 wt % of hard
modifying monomer component, in which each hard modifying monomer
having a homopolymer T.sub.g of 0 to 250.degree. C., and (iii) up
to 30% by weight of functional monomer component, wherein soft
monomer is an alkyl acrylate monomer having 4 to 10 carbon atoms in
the alkyl group.
10. The method of claim 4 wherein the acrylate polymer includes a
soft acrylate monomer selected from the group consisting of butyl,
hexyl, 2-ethylhexyl, octyl, and dodecyl acrylates and isomers
thereof.
11. The method of claim 4 wherein the acrylate polymer includes 40
to 50 wt % of soft alkyl acrylate monomer component having a
homopolymer T.sub.g of less than -20.degree. C.
12. The method of claim 4 wherein the acrylate polymer has a
T.sub.g of 0 to -20.degree. C. if without NGMN and permeation
enhancer, and the drug reservoir having the dissolved NGMN/EE and
permeation enhancer has a T.sub.g of -10.degree. C. to -20.degree.
C., a creep compliance of 1.times.10.sup.-4 cm.sup.2/dyn to
6.times.10.sup.-4 cm.sup.2/dyn and storage modulus of
1.times.10.sup.5 dyn/cm.sup.2 to 8.times.10.sup.5 dyn/cm.sup.2.
13. The method of claim 4 comprising incorporating permeation
enhancer and NGMN/EE in the acrylate polymer to result in single
phase pressure sensitive adhesive, wherein the acrylate polymer has
a T.sub.g of 0 to -20.degree. C., storage modulus of
8.times.10.sup.5 dyn/cm.sup.2 or above if without the NGMN/EE and
permeation enhancer, and the drug reservoir with the NGMN/EE and
permeation enhancer has a T.sub.g of -10.degree. C. to -20.degree.
C., a creep compliance of 1.times.10.sup.-4 cm.sup.2/dyn to
6.times.10.sup.-4 cm.sup.2/dyn and storage modulus of
1.times.10.sup.5 dyn/cm.sup.2 to 8.times.10.sup.5 dyn/cm.sup.2.
14. The method of claim 4 comprising providing the acrylate polymer
having monomer components of 50 to 60 wt % vinyl acetate, 10-20 wt
% hydroxyethyl acrylate, and 20-40 wt % 2-ethylhexyl acrylate.
15. The method of claim 4 comprising providing the acrylate polymer
having monomer components of 55 to 65 wt % butyl acrylate, 5 to 15
wt % t-octyl acrylamide, 20 to 30 wt % hydroxyethyl or
hydroxypropyl acrylate and 5 to 10 wt % acid monomer.
16. A method of making a transdermal NGMN/EE delivery drug
reservoir, comprising: providing for a drug reservoir a
noncrosslinked polyacrylate proadhesive containing function group
and having a T.sub.g of greater than -15.degree. C., creep
compliance of 6.times.10.sup.-5cm.sup.2/dyn to 2.times.10.sup.-6
cm.sup.2/dyn, and storage modulus of 8.times.10.sup.5 dyn/cm.sup.2
or above, dissolving NGMN and permeation enhancer in the
proadhesive with a concentration of greater than 30 wt % solids of
NGMN and EE together with permeation enhancer such that the
resulting drug reservoir has adhesive properties appropriate for
transdermal drug delivery, the resulting drug reservoir having a
T.sub.g of -10.degree. C. to -30.degree. C., a creep compliance of
1.times.10.sup.-4 cm.sup.2/dyn to 6.times.10.sup.-4 cm.sup.2/dyn
and storage modulus of 1.times.10.sup.5dyn/cm.sup.2 to
8.times.10.sup.5 dyn/cm.sup.2.
17. A device for transdermal administration of NGMN/EE to an
individual in need thereof for therapy, comprising a backing and a
single phase drug reservoir comprising noncrosslinked acrylate
polymer having dissolved NGMN of greater than 5 wt %, and
permeation enhancer to deliver the NGMN and to deliver EE, wherein
the drug reservoir is applicable as a pressure sensitive adhesive
to a body surface.
18. The device of claim 17 wherein the acrylate polymer in the drug
reservoir is consisted essentially of noncrosslinked polyacrylate
and the reservoir has at least 30 wt % of NGMN/EE with permeation
enhancer together and the NGMN flux is greater than 0.5
.mu.g/cm.sup.2-h transdermally and wherein the noncrosslinked
polyacrylate include polar functionality.
19. The device of claim 17 further comprising estrogen in the drug
reservoir.
20. The device of claim 17 wherein the drug reservoir has 4 wt % or
more of NGMN/EE and greater than 30 wt % of NGMN/EE together with
permeation enhancer.
21. The device of claim 17 wherein the drug reservoir has at least
30 wt % of NGMN/EE with permeation enhancer together and the
acrylate polymer comprises 50 wt % to 90 wt % of the drug
reservoir, wherein the drug reservoir is applicable as a pressure
sensitive adhesive to a body surface.
22. The device of claim 17 wherein the acrylate polymer has no more
than 60 wt % soft monomer component, at least 40 wt % hard monomer
component at least a portion of which is functional hard monomer,
and 10 to 35 wt % functional monomer, the acrylate polymer
constituting 45 wt % to 80 wt % of the drug reservoir and having a
solubility of at least 30 wt % for the NGMN/EE together with
permeation enhancer, the acrylate polymer having a T.sub.g of
greater than -15.degree. C. if without permeation enhancer and
without NGMN/EE, the drug reservoir having pressure sensitive
adhesive properties applicable to the body surface for transdermal
delivery.
23. The device of claim 17 wherein the drug reservoir in the device
includes permeation enhancer wherein the drug reservoir is of a
composition having a creep compliance of 6.times.10.sup.-5
cm.sup.2/dyn to 2.times.10.sup.-6 cm.sup.2/dyn if the drug
reservoir is without NGMNIEE and without permeation enhancer.
24. The device of claim 17 wherein the acrylate polymer includes 10
to 35 wt % functional monomer component.
25. The device of claim 17 wherein the acrylate polymer includes an
acrylic copolymer resulting from (i) 40 to 50 wt % of one or more
soft alkyl acrylate monomers, each soft alkyl acrylate monomer
having a homopolymer T.sub.g of -80 to -20.degree. C., (ii) 5 to 15
wt % of one or more nonfunctional hard modifying monomers, each
hard modifying monomer having a homopolymer T.sub.g of 0 to
250.degree. C., and (iii) one or more functional monomers of 10 to
35 wt %.
26. The device of claim 17 wherein the acrylate polymer has (i) 40
to 50 wt % of one or more soft alkyl acrylate monomers, each soft
alkyl acrylate monomer having a homopolymer T.sub.g of -80 to
-20.degree. C., (ii) 5 to 15 wt % of one or more nonfunctional hard
modifying monomers, each hard modifying monomer having a
homopolymer T.sub.g of 0 to 250.degree. C., and (iii) one or more
functional monomers of 10 to 35 wt %, wherein the soft monomer is
an alkyl acrylate monomer having 4 to 10 carbon atoms in the alkyl
group.
27. The device of claim 17 wherein the acrylate polymer includes a
soft acrylate monomer selected from the group consisting of butyl,
hexyl, 2-ethylhexyl, octyl, and dodecyl acrylates and isomers
thereof.
28. The device of claim 17 wherein the acrylate polymer includes 40
to 50 wt % of soft alkyl acrylate monomer having a homopolymer
T.sub.g of less than -20.degree. C.
29. The device of claim 17 wherein the acrylate polymer includes 40
to 50 wt % of soft alkyl acrylate monomer having a homopolymer
T.sub.g of less than -20.degree. C., hard modifying monomer having
a homopolymer T.sub.g of higher than 20.degree. C., and functional
monomer having acidic group.
30. The device of claim 17 wherein the acrylate polymer includes
hard modifying monomer having a homopolymer T.sub.g of 0 to
250.degree. C., wherein the permeation enhancer and the NGMN/EE are
dissolved in the acrylate polymer and the acrylate polymer has a
T.sub.g of 0 to -20.degree. C. and a creep compliance of
6.times.10.sup.-5 cm.sup.2/dyn to 2.times.10.sup.-6 cm.sup.2/dyn
without the NGMN/EE and permeation enhancer, whereas the drug
reservoir with the dissolved NGMN/EE and permeation enhancer has a
creep compliance of less than 1.times.10.sup.-3 cm.sup.2/dyn and
storage modulus of 1.times.10.sup.5 dyn/cm.sup.2 to
8.times.10.sup.5 dyn/cm.
31. The device of claim 17 wherein the acrylate polymer includes
hard modifying monomer having a homopolymer T.sub.g of 40 to
100.degree. C.
32. The device of claim 17 wherein the acrylate polymer includes
hard modifying monomer selected from the group consisting of vinyl
acetate, methyl acrylate, and methyl methacrylate.
33. The device of claim 17 wherein the acrylate polymer has acidic
group and hydroxyl group therein and includes 5 to 15 wt %
nonfunctional hard monomer.
34. The device of claim 17 wherein the acrylate polymer is
consisted of monomer components of 50-60 wt % vinyl acetate, 10-20
wt % hydroxyethyl acrylate, and 20-40 wt % 2-ethylhexyl
acrylate.
35. The device of claim 17 wherein the acrylate polymer includes
functional monomer selected from the group consisting of acrylic
acid, hydroxyethyl acrylate, and hydroxypropyl acrylate.
36. The device of claim 17 wherein the permeation enhancer and the
NGMN/EE are dissolved in the acrylate polymer and the acrylate
polymer has a T.sub.g of 0 to -20.degree. C., a creep compliance of
6.times.10.sup.-5 cm.sup.2/dyn to 2.times.10.sup.-6 cm.sup.2/dyn if
without the NGMN/EE and permeation enhancer dissolved therein,
whereas with the disolved NGMN/EE and permeation enhancer the
acrylate polymer is a drug reservoir with a T.sub.g of -10 to
-20.degree. C., a creep compliance of less than 1.times.10.sup.-3
cm.sup.2/dyn and storage modulus of 1.times.10.sup.5 dyn/cm.sup.2
to 8.times.10.sup.5 dyn/cm.sup.2.
37. The device of claim 17 wherein the acrylate polymer has a
T.sub.g of 0 to -20.degree. C. if without NGMN/EE and permeation
enhancer, whereas the acrylate polymer with NGMN/EE and permeation
enhancer at above 30 wt % in a single phase forms a drug reservoir
with a T.sub.g of -10 to -20.degree. C., a creep compliance of
1.times.10.sup.-4 cm.sup.2/dyn to 6.times.10.sup.-4 cm.sup.2/dyn
and storage modulus of 1.times.10.sup.5 dyn/cm.sup.2 to
8.times.10.sup.5 dyn/cm.sup.2.
38. The device of claim 17 wherein the acrylate polymer has a
T.sub.g of 0 to -20.degree. C., storage modulus of 8.times.10.sup.5
dyn/cm.sup.2 or above .degree. C. if without NGMN/EE and permeation
enhancer, whereas the acrylate polymer with NGMN/EE and permeation
enhancer at above 30 wt % forms a drug reservoir with a T.sub.g of
-10 to -40.degree. C., a creep compliance of 1.times.10.sup.-4
cm.sup.2/dyn to 6.times.10 .sup.-4 cm.sup.2/dyn and storage modulus
of 1.times.10.sup.5 dyn/cm.sup.2 to 8.times.10.sup.5
dyn/cm.sup.2.
39. The device of claim 17 wherein the device can deliver 125 to
350 .mu.g/day of NGMN for 7 days and the area of the device
contacting the skin is 20-50 cm.
40. The device of claim 17 comprising permeation enhancer selected
from the group consisting of N-lauroyl sarcosine, Oleth-2, selachyl
alcohol, glyceryl monolaurate, ethyl palmitate, sorbitan oleate,
oleic acid, isopropyl myristate, lauramide DEA, laureth-2.
41. The device of claim 17 comprising permeation enhancer selected
from the group consisting of N-lauroyl sarcosine, and wherein the
device contains no thioglycerol.
42. A device for transdermal administration of NGMN/EE to an
individual for therapy, comprising a backing and a single phase
drug reservoir comprising a matrix of acrylate polymer having polar
functional group, dissolved NGMN of greater than 5 wt %, and
permeation enhancer to deliver the NGMN and EE at greater flux
(.mu.g/cm.sup.2-h) than ORTHO EVRA.RTM. patch, the acrylate polymer
being noncrosslinked and consisting of 5.2 wt % 2-hydroxyethyl
acrylate, vinyl acetate of 20 to 40 wt % and 2-ethylhexyl acrylate
of 55-75 wt %, the permeation enhancer either including N-lauroyl
sarcosine or including Oleth-2 and at least one other permeation
enhancing chemical, wherein the drug reservoir maintaining adhesive
properties applicable to a body surface for 7 days.
43. A device for transdermal administration of NGMN/EE to an
individual for therapy, comprising a rigid transparent occlusive
backing and a single phase drug reservoir comprising a matrix of
acrylate polymer having polar functional group, dissolved NGMN of
greater than 5 wt %, and permeation enhancer to deliver the NGMN
and EE at greater flux (.mu.g/cm.sup.2-h) than ORTHO EVRA.RTM.
patch, the acrylate polymer being noncrosslinked and consisting of
5.2 wt % 2-hydroxyethyl acrylate, vinyl acetate of 20 to 40 wt %
and 2-ethylhexyl acrylate of 55-75 wt %, the permeation enhancer
being one of (i) including N-lauroyl sarcosine, (ii) including
oleic acid and at least two other permeation enhancing chemicals,
and (iii) Oleth-2 and at least one other permeation enhancing
chemical, wherein skin color is visible through the device and the
drug reservoir maintaining adhesive properties applicable to a body
surface for 7 days without turning cloudy.
44. A device for transdermal administration of NGMN/EE to an
individual for therapy, comprising a transparent occlusive backing
and a single phase drug reservoir comprising a matrix of acrylate
polymer, dissolved NGMN of greater than 5 wt %, EE, and permeation
enhancer, the acrylate polymer being noncrosslinked and consisting
of 5.2 wt % 2-hydroxyethyl acrylate, vinyl acetate of 20 to 40 wt %
and 2-ethylhexyl acrylate of 55-75 wt % and having a storage
modulus of 2 to 5.times.10.sup.5 dyn/cm.sup.2, wherein the drug
reservoir has a storage modulus of 1.0.times.10.sup.5 to
1.5.times.10.sup.5 dyn/cm.sup.2 for pressure sensitive adhesive
applicable to a body surface to deliver the NGMN and EE at greater
flux (.mu.g/cm.sup.2-h) than ORTHO EVRA.RTM. patch surface for 7
days without turning cloudy.
Description
CROSS REFERENCE TO RELATED U.S. APPLICATION DATA
[0001] The present application is derived from and claims priority
to provisional application U.S. Ser. No. 60/720,200, filed Sep. 23,
2005, which is herein incorporated by reference in its
entirety.
TECHNICAL FIELD
[0002] This invention relates to a medical patch for transdermal
administration of norelgestromin (NGMN) and to a method of treating
a subject by administering norelgestromin (NGMN) thereto with the
medical patch. In particular, the invention relates to transdermal
systems for administration of NGMN preferably in combination with
an estrogen with adhesive system having high enhancer tolerance
when used in transdermal drug delivery.
BACKGROUND
[0003] Transdermnal devices for the delivery of biologically active
agents have been used for maintaining health and therapeutically
treating a wide variety of ailments. For example, analgesics,
steroids, etc., have been delivered with such devices. Such
transdermal devices include patches in which a biologically active
agent is delivered to the body tissue passively without use of an
additional energy source. Many such devices have been described,
for example, in U.S. Pat. Nos. 3,598,122, 3,598,123, 4,379,454,
4,286,592, 4,314,557, 4,568,343, and U.S. Application No.
2003002682, all of which are incorporated herein by reference in
their entireties.
[0004] A transdermal patch is typically a small adhesive bandage
that contains the drug to be delivered. A simple type of such
transdermal patches is an adhesive monolith including a
drug-containing reservoir disposed on a backing. The reservoir is
typically formed from a pharmaceutically acceptable pressure
sensitive adhesive. In some cases, the reservoir can be formed from
a non-adhesive material, the skin-contacting surface of which is
provided with a thin layer of a suitable adhesive. The rate at
which the drug is administered is dependent upon the rate at which
drug partitions from the patch into the skin and then diffuses
across the epidermis before being absorbed systemically.
[0005] Although the transdermal delivery of therapeutic agents has
been the subject of intense research and development for over 30
years, only a relatively small number of drug molecules are
suitable for transdermal delivery due to the fact that human skin
is an excellent barrier. Various techniques have been explored to
enhance the permeation of drug molecules that are not otherwise
suitable for transdermal delivery. Of these techniques, chemical
enhancement is the most established and is currently employed
commercially. Pressure sensitive adhesives, such as acrylic
adhesives, are used in most transdermal drug delivery devices as a
means of providing intimate contact between the drug delivery
device and the skin. The use of drugs and permeation enhancers
("enhancers"), especially at high concentrations, usually has a
significant impact on the properties of pressure sensitive
adhesives, such as cohesive strength, adhesive flow, tackiness and
adhesion strength. Therefore, pressure sensitive adhesives have to
be designed in a way that they can provide the needed performance
in the presence of enhancers.
[0006] Combinations of norelgestromin (NGMN), formerly known as
17-deacetyl norgestimate, and ethinyl estradiol (EE) have been
administered orally to women as a contraceptive. These two drugs
have also been described as deliverable transdermally, as
mentioned, for example, in U.S. Pat. No. 5,693,335; 5,876,746; and
5,972,377. Other patents related to transdermal delivery of sex
hormones are, for example, U.S. Pat. No. 4,906,169 and 5,422,119.
However, delivering the sex hormones through a body surface at an
adequate flux rate is a challenge.
[0007] Currently, transdermal patches for delivery of NGMN and EE
(once a week ORTHO EVRA.RTM. patches from Ortho-McNeil
Pharmaceutical) have three layers. The backing layer is composed of
a beige flexible film with a low-density pigmented polyethylene
outer layer and a polyester inner layer. The backing layer provides
structural support and protects the middle adhesive layer from the
environment. The middle layer contains polyisobutylehe/polybutene
adhesive, micronized crospovidone (an insoluble crosslinked
polyvinyl pyrrolidone), non-woven polyester fabric and lauryl
lactate. The micronized crospovidone serves as a hydrophilic filler
material that helps seven day wear by absorbing moisture at the
skin/adhesive interface. The other components in this layer are the
hormones, norelgestromin and ethinyl estradiol. The third layer is
the protective liner, which protects the adhesive layer during
storage and is removed just prior to patch application. It is a
transparent polyethylene terephthalate (PET) film with a
polydimethylsiloxane coating on the side that is in contact with
the middle adhesive layer.
[0008] The total amount of NGMN released from a 20 cm.sup.2 ORTHO
EVRA.RTM. patch over a seven-day wear period is 1.05 mg
(corresponding to 17.5% of the total NGMN load and to an hourly
average flux of about 0.3 .mu.g/cm.sup.2-h. The total amount of EE
released over the seven-day wear period is 0.14 mg (corresponding
to 18.7% of the total EE loading) and to an hourly average flux of
about 0.04 .mu.g/cm.sup.2-h. In this current system,
polyisobutylene (PIB) adhesive is highly plasticized and suffers
cold-flow during storage and wear, resulting in a black-border that
forms around the patch over the wear period. The inclusion of a
high level (20% wt/wt) of micronized crospovidone in the current
system also results in an adhesive formulation that becomes opaque
white over the wear period. During the seven day wear, as moisture
is absorbed, the adhesive drug layer changes from translucent to
opaque and white in appearance requiring the use of an opaque
backing layer to mask this phenomena during wear in the currently
commercially available systems. There continues to be a need for
improved delivery of sex hormones, especially sustained delivery
over a period of time, and especially for NGMN, an estrogen, or
NGMN in combination with an estrogen, for contraceptive effect or
hormone replacement via a product with better rheology, more
appealing appearance, and which is less obvious on most skin types
and easier to remove. Such better products will lead to improved
patient compliance.
SUMMARY
[0009] The present invention provides a method and a device for
transdermal delivery of an effective amount of NGMN, an estrogen,
or NGMN in combination with an estrogen (for contraceptive effect
or for providing hormone replacement) to an individual in need
thereof. In one aspect, a patch with polyacrylate reservoir
suitable for multiple day delivery of NGMN is provided. In another
aspect, a high loading of permeation enhancer enables high flux
rate with a relatively small area, suitable for a transdermal patch
that can be maintained adhesively on the body surface for an
extensive period of time, such as 3, 7 days, and even longer, with
acceptable rheological and adhesive properties and better
appearance.
[0010] The preparation of formulations with polyacrylate for
adhesion rather than PIB results in improved cold-flow resistance.
This feature in turn results in an improvement in both patch
aesthetics, ease of removal and improved patient compliance. The
use of polyacrylate also results in formulations that are and
remain translucent (versus opaque in appearance due to undissolved
PVP particles and moisture uptake during 7 day wear) which, when
combined with a transparent or translucent backing, have an
improved translucent appearance after application and during wear.
Although PVP, either dissolved, dispersed (e.g., in micronized
form), or combination thereof, can be used, it is not required for
the formulation of the present invention to adhere to the body
surface. Further, the increased drug flux per unit area also
results in a smaller patch size, again improving aesthetics and
patient acceptability, and reducing the likelihood of unintentional
detachment.
[0011] In the currently commercially available 7-day wear patches,
the amount of NGMN and EE loaded into the adhesive drug layer
resulting in adhesive layer about 0.006 inch (0.15 mm) to 0.008
inch (0.20 mm) thick. The thicker adhesive layer requires the
addition of a non-woven backing for structural support during
manufacturing, patch application and patch removal. The thicker
adhesive layer also results in severe cold flow during storage in
the pouch, and higher affinity for lint and dirt to adhere to the
edge of the patch during wear. The currently available ORTHO
EVRA.RTM. patches utilizes less than 20% of the NGMN and EE loaded
into the patch during 7 days of wear. The effective dose of NGMN
and EE in an ORTHO EVRA.RTM. contraceptive patch is 150 .mu.g/day
of NGMN and 20 .mu.g/day of EE having a basal surface area (i.e.
the area in diffusional contact with the skin) of 20 cm.sup.2.
ORTHO EVRA.RTM. patches deliver the NGMN at a flux of 0.3
.mu.g/cm.sup.2-h, and EE at a flux of 0.04 .mu.g/cm.sup.2-h.
[0012] The use of polyacrylates results in a simpler, less complex
manufacturing process as the drug/adhesive layer is thinner
removing the need for a non-woven. Thus, a transdermal NGMN or NGMN
and EE delivery patch can be made to have NGMN or NGMN/EE loading
of higher than 5 wt %, preferably from 5 to 20 wt %, more
preferably from 5 to 10 wt % of NGMN in the reservoir to deliver
NGMN about 125 to about 350 .mu.g/day, preferably from about 150 to
about 300 .mu.g/day, and more preferably from about 150 to about
250 .mu.g/day for 7 days. With the appropriate size, patches can be
made with NGMN/EE in the reservoir to deliver NGMN about 50 to
about 250 .mu.g/day and EE about 5 to 35 .mu.g/day, preferably from
about 75 to about 225 .mu.g/day NGMN and 10 to 30 .mu.g/day of EE,
and more preferably from about 125 to about 175 .mu.g/day of NGMN
and 15 to 25 .mu.g/day of EE for 7 days with acceptable rheology
such as cold flow property.
[0013] In one aspect of the invention, a novel technique is
provided for increasing adhesive enhancer tolerance. It has been
discovered that by increasing the glass transition temperature of
the acrylate polymer using the ratio of soft monomer and hard
monomer, it is possible to load enhancer concentrations into the
polymer at a high weight percent to obtain a formulation and still
achieve desirable adhesive characteristics. The loading of drug
and/or enhancer into the polymer composition can be, e.g., greater
than 20 dry weight %, greater than 30 dry weight % (or solids wt
%), even up to 40-50 wt %, and still provide adequate adhesion and
rheological characteristics for pressure sensitive adhesive (PSA)
application. With sufficient loadings of permeation enhancers in
such formulations, sustained high rates of drug delivery can be
achieved. With adequate adhesive properties, the resulting
reservoir with sufficient drug loading and permeation enhancers can
be used to achieve effective therapeutic results.
[0014] In one aspect of the invention, a clear multiple day patch
with 3 to 7-day dermal adhesion is provided. It has been discovered
that the use of a polyacrylate adhesive or proadhesive, having been
plasticized with permeation enhancers to have an elastic modulus
(storage modulus) of 1.times.10.sup.5 to 2.times.10.sup.5
dyn/cm.sup.2, i.e., 10,000 to 20,000 Pa (measured at 1 rad/s,
25.degree. C.), or more preferably 10,000 to 15,000 Pa (i.e.,
1.0.times.10.sup.5 to 1.5.times.10.sup.5 dyn/cm.sup.2), either with
or without PVP (e.g., up to about 6% PVP), when used with an
occlusive nonporous backing, such as 0.5 mil PET/1.5 mil EVA
results in superior skin adhesion for 7 days. The resultant
polyacrylate formulations further result in a reduction in measured
residue upon patch removal relative to existing commercial
PIB-based products while providing comparable wearing performance.
With the use of transparent backing such as the PET/EVA laminate, a
clear patch that would not turn cloudy after multiple day use
(e.g., 3 days, 7 days) can be achieved.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 illustrates a cross-section through a schematic,
perspective view of one embodiment of a transdermal therapeutic
system according to the present invention.
[0016] FIG. 2 illustrates a cross-section view through another
embodiment of a transdermal therapeutic system of this
invention.
[0017] FIG. 3 illustrates the flux profile of a NGMN formulation
with permeation enhancers GMO and NLS according to the present
invention compared to NGMN in other formulations.
[0018] FIG. 4 illustrates the flux profile of another NGMN
formulation with EE and permeation enhancers GMO and NLS according
to the present invention compared to NGMN in other
formulations.
[0019] FIG. 5 illustrates the flux profile of EE with the NGMN
formulation of FIG. 4.
DETAILED DESCRIPTION
[0020] The present invention relates to transdermal delivery of
norelgestromin (NGMN), an estrogen, or NGMN in combination with an
estrogen, with the help of permeation enhancers for loading
adequate amount of NGMN, an estrogen, or NGMN in combination with
an estrogen with desirable flux. It is further understood that a
progestin, which may be NGMN or different from NGMN (such as
norgestimate) or an estrogen, which may be EE or different from EE
(such as 17.beta. estradiol), either alone or in combination, can
be made into a transdermal delivery system. The design of female
sex hormone patches with polyacrylate reservoir matrix results in
product attributes that are greatly improved, e.g., thinner
reservoir matrix layer, smaller surface area, and better esthetics.
According to the present invention, polyacrylates and polyacrylates
in combination with permeation enhancers improve drug utilization
resulting in patches with such improved product attributes. Using
polyacrylate adhesives or proadhesives, clear patches for NGMN and
EE delivery can be made. In a clear patch, the color of the skin is
visible through the patch when applied to the skin, regardless of
the race and color of the user. In such patches, the backing is
preferably a clear pigmentless backing, e.g., EVA/PET backing known
to those skilled in the art.
[0021] Traditionally a transdermal drug delivery system was
formulated with a pressure sensitive adhesive that has a glass
transition temperature (T.sub.g) in the range of -40.degree. C. to
-10.degree. C. According to the present invention, a useful
reservoir material is acrylate polymer. In one aspect of the
present invention, one type of useful acrylate polymer for making a
norelgestromin transdermal delivery patch is one that comprises,
and preferably is consisted of 2-hydroxyethyl acrylate, vinyl
acetate and 2-ethylhexyl acrylate. In another aspect of the present
invention, a preferred starting acrylate polymeric material (which
can be formulated into an adhesive material having pharmaceuticals
and/or enhancers) is a stiffer material that has a glass transition
temperature (T.sub.g) in the range of about -20.degree. C. or
higher, preferably -15 .degree. C. or higher, more preferably
-15.degree. C. to 0.degree. C., and even more preferably
-10.degree. C. to 0.degree. C.; creep compliance of about
7.times.10.sup.-5 cm.sup.2/dyn (at 3600 second) or below; and
modulus G' of about 8.times.10.sup.5 dyn/cm.sup.2 or above. The
polymeric material can be formulated into a transdermal reservoir
matrix (including carrier structure) with a combined drug and/or
enhancer concentration greater than 20 dry weight percent (wt %),
greater than 30 wt %, or even greater than 40 dry weight percent.
The resulting transdermal adhesive formulation with pharmaceutical
agent(s) and/or enhancers will provide excellent adhesion with no
cold flow, i.e., no cold flow of an amount that is noticeable by an
average person when the device is removed from the pouch and would
affect the normal use of the delivery system.
[0022] Some of the more preferred starting proadhesive acrylate
polymers without enhancer or drug have poor adhesive properties
because the glass transition temperature is too high. Once
plasticized in the transdermal formulation, the glass temperatures
of such formulations drop into the pressure sensitive range, about
-10.degree. C. to -40.degree. C., and the resulting creep
compliance and storage modulus enable the achievement of good tack,
with little or no cold flow. Creep compliance is an important
parameter to evaluate cold flow behavior of a pressure sensitive
adhesive (PSA). In a transdermal drug delivery system, if the creep
compliance is large, the adhesive will have cold flow with time,
i.e., the adhesive may lose its shape because the weight of the
material in the device is under gravity.
[0023] In describing the present invention, the following terms
will be employed, and are intended to be defined as indicated
below. As used in this specification and the appended claims, the
singular forms "a," "an" and "the" include plural references unless
the content clearly dictates otherwise.
[0024] As used herein, the term "transdermal" refers to the use of
skin, mucosa, and/or other body surfaces as a portal for the
administration of drugs by topical application of the drug thereto
for passage into the systemic circulation.
[0025] "Biologically active agent" is to be construed in its
broadest sense to mean any material that is intended to produce
some biological, beneficial, therapeutic, or other intended effect,
such as enhancing permeation, hormone replacement, or
contraception. As used herein, the term "drug" refers to any
material that is intended to produce some biological, beneficial,
therapeutic, or other intended effect, such as relieving symptoms
of a health disorder, but not agents (such as permeation enhancers)
the primary effect of which is to aid in the delivery of another
biologically active agent such as the therapeutic agent
transdermally.
[0026] As used herein, the term "therapeutically effective" refers
to the amount of drug or the rate of drug administration needed to
produce the desired therapeutic result. As used herein, the term
"permeation enhancement" intends an increase in the permeability of
skin to a drug in the presence of a permeation enhancer as compared
to permeability of skin to the drug in the absence of a permeation
enhancer. A "permeation-enhancing amount" of a permeation-enhancer
is an amount of the permeation enhancer sufficient to increase the
permeability of the body surface of the drug to deliver the drug at
a therapeutically effective rate.
[0027] "Acrylate", "polyacrylate" or "acrylic polymer", when
referring to a polymer for an adhesive or "proadhesive", refers to
polymer or copolymer of acrylic acid, ester(s) thereof, acrylamide,
or acrylonitrile. Unless specified otherwise, it can be a
homopolymer, copolymer, or a blend of homopolymers and/or
copolymers. In some embodiments, prior to incorporation of drugs
and ingredients, the polymeric materials are not suitable PSAs "as
is" because of the stiffness of the polymer and insufficient
adhesiveness or tackiness. These polymeric materials become
adhesive and have the desired PSA characteristics after
incorporating drugs, permeation enhancer and optionally other
ingredients in suitable quantities. Such polymeric materials, which
are not suitable as a PSA as is (prior to incorporation of drugs
and ingredients) but will have the desired PSA characteristics
after incorporating drugs and/or other ingredients, can be called
"proadhesive" herein.
[0028] As used in the present invention, "soft" monomers refer to
the monomers that have a T.sub.g of about -80.degree. C. to
-10.degree. C. after polymerization into homopolymer; "hard"
monomers refer to the monomers that have a T.sub.g of about 0 to
250.degree. C. after forming homopolymer; and "functional" monomers
refer to the monomers that contain hydrogen bonding functional
groups such as hydroxyl, carboxyl or amino groups (e.g., alcohols,
carboxylic acid, or amines), these polar groups tend to increase
the hydrophilicity of the acrylate polymer and increase polar drug
solubility.
[0029] The present invention relates to transdermal delivery of
NGMN, an estrogen, or NGMN in combination with an estrogen, from a
polyacrylate adhesive or proadhesive and various permeation
enhancers for desirable flux. A suitable transdermal delivery patch
according to the present invention can deliver NGMN, an estrogen,
or NGMN in combination with an estrogen through about 5-100
cm.sup.2, preferably 5-50 cm.sup.2, and preferably about 5-25
cm.sup.2, especially about 10 to 20 cm.sup.2 of intact skin over an
extended period of time.
[0030] Progestins and estrogens both inhibit ovulation, albeit by
separate pathways. NGMN, as a progestin, inhibits the release of
luteinizing hormone (LH), whereas the predominant effect of
estrogen is to inhibit the secretion of follicle-stimulating
hormone (FSH). Thus, when a combination of NGMN and estrogen is
administered according to the invention, ovulation is prevented by
inhibiting the ovulatory stimulus and/or by inhibiting the growth
of follicles. NGMN administration is believed to be advantageous
relative to the parent compound (norgestimate) or its other
metabolites in that NGMN inhibits little or no androgenic
activity.
[0031] The transdermal patches of the invention can be used for
contraception for women and they can be adapted for hormone
replacement therapy. The patches can be used to deliver NGMN and,
optionally an estrogen, to the skin continuously for an extended
time period, typically 1-7 days and preferably for 7 days. When the
patches are worn for contraception, a patch will typically be
placed on the skin on the fifth day of the menstrual cycle, and
replaced as needed until 21 days of wearing have elapsed. For
instance, in the case of a 7-day patch, three patches will be
required to deliver the drug(s) for the 21-day period. If desired,
a placebo patch may be worn thereafter until the fifth day of the
succeeding menstrual cycle. This regimen is repeated for each
menstrual cycle.
[0032] The effective dose of NGMN for inhibiting ovulation is
normally in the range of about 125 to about 350 .mu.g/day,
preferably from about 150 to about 300 .mu.g/day, and more
preferably from about 150 to about 250 1.mu.g/day. The patches of
the invention will typically have a basal surface area (i.e. the
area in diffusional contact with the skin) between 10 and 50
cm.sup.2. The effective dose of estrogen for inhibiting ovulation
will depend upon the particular estrogen being co-administered. For
instance, when the estrogen is ethinyl estradiol, the dose will
normally be at least 2 .mu.g/day, from about 2 .mu.g/day to about
200 .mu.g/day, and preferably from about 5 .mu.g/day to 150
.mu.g/day of EE, preferably from about 5 to 35 .mu.g/day, and more
preferably approximately 5 to 20 .mu.g/day. The patches will
contain sufficient amounts of NGMN and, when present, estrogen, to
provide such daily doses for the intended patch wear time. Thus,
the patches can deliver the NGMN at a flux of greater than 0.2
.mu.g/cm.sup.2-h, preferably about 0.2 to 1 .mu.g/cm.sup.2-h, more
preferably about 0.2 to 0.4 .mu.g/cm.sup.2-h and can deliver EE at
a flux of greater than 0.01 .mu.g/cm.sup.2-h, preferably about 0.01
to 0.1 .mu.g/cm.sup.2-h, more preferably about 0.01 to 0.04
.mu.g/cm.sup.2-h.
[0033] If a larger patch size is used, a smaller quantity of
hormones per unit area would be adequate. When a prolonged
therapeutic effect is desired, the patch is removed at the end of
the wear period and a fresh system applied to a new location. In
such cases, blood levels will remain reasonably constant.
[0034] Estrogens that may be combined with NGMN in the matrix
include estradiol and esters thereof such as estradiol valerate,
estradiol cypionate, estradiol acetate, estradiol benzoate, and
ethinyl estradiol (EE). EE is a preferred estrogen for use in
combination with NGMN. EE/NGMN combinations may favorably affect
metabolic parameters such as elevation of serum high density
lipoprotein and reduction of the low density lipoprotein/high
density lipoprotein ratio in serum.
[0035] The matrix may contain other additives depending upon the
particular adhesive used. For instance, materials, such as
polyvinyl pyrrolidone (PVP), hygroscopic agents that improve the
duration of wear, or additives that improve the physical (e.g.,
cold flow) or adhesive (e.g., tack, cohesive strength) properties
of the matrix may be included.
[0036] The patches are also useful for providing hormone
replacement therapy. When used to provide hormone replacement
therapy, the drug reservoir is constructed so as to provide an
effective amount of NGMN, or estrogen, or a combination, for the
intended purpose. Typically, the reservoir and therefore the patch
is constructed to provide from about 125 to about 350 .mu.g/day,
and preferably from about 150 to about 300 .mu.g/day NGMN
co-administered with from about 5 to 45 .mu.g/day and preferably
from about 10 to 35 .mu.g/day of EE. In an alternative embodiment,
the patch will administer from about 120 to 350 .mu.g/day, and
preferably from about 150 to 300 .mu.g/day NGMN co-administered
with from about 20 to 175 .mu.g/day and preferably from about 30 to
150 .mu.g/day of 17-.beta. estradiol. The patch is applied for 7
days and replaced with a new patch (for 7 days) for the duration of
the therapy. Alternatively, patches for 3 days can be made and
used.
[0037] Exemplary transdermal NGMN delivery systems of the present
invention are illustrated by the embodiments shown in FIGS. 1 and
2. As shown in FIGS. 1 and 2, an embodiment of the transdermal
monolithic patch 1 according to this invention has a backing layer
2, a drug reservoir 3 (containing NGMN, an estrogen, or NGMN in
combination with an estrogen) disposed on the backing layer 2, and
a peelable protective layer 5. In the reservoir 3, which can be a
layer, at least the skin-contacting surface 4 is an adhesive. The
reservoir is a matrix (carrier) that is suitable for carrying NGMN,
an estrogen or NGMN in combination with an estrogen for transdermal
delivery. Preferably, the whole matrix, with drugs and other
optional ingredients, is a material that has the desired adhesive
properties. The reservoir 3 can be either a single phase polymeric
composition or a multiple phase polymeric composition. In a single
phase polymeric composition the drug and all other components are
present at concentrations no greater than, and preferably less
than, their saturation concentrations in the reservoir 3. This
produces a composition in which all components are dissolved. The
reservoir 3 is formed using a pharmaceutically acceptable polymeric
material that can provide acceptable adhesion for application to
the body surface. In a multiple phase polymeric composition, at
least one component, for example, the therapeutic drug NGMN, an
estrogen, or NGMN in combination with an estrogen, is present in
amount more than the saturation concentration. In some embodiments,
more than one component, e.g., a drug and a permeation enhancer, is
present in amounts above saturation concentration. In the
embodiment shown in FIG. 1, the adhesive acts as the reservoir and
includes NGMN and EE.
[0038] In the embodiment shown in FIG. 2, the reservoir 3 is formed
from a material that does not have adequate adhesive properties if
without drug or permeation enhancer. In this embodiment of a
monolithic patch 1, the skin-contacting surface of the reservoir 4
may be formulated with a thin adhesive coating 6. The reservoir 3
may be a single phase polymeric composition or a multiple phase
polymeric composition as described earlier, except that it may not
contain an adhesive with adequate adhesive bonding property for
skin. The adhesive coating can contain the drug and permeation
enhancer, as well as other ingredients.
[0039] The drug reservoir 3 is disposed on the backing layer 2. At
least the skin-contacting surface of the reservoir is adhesive. As
mentioned, the skin-contacting surface can have the structure of a
layer of adhesive. The reservoir 3 may be formed from drug (or
biological active agent) reservoir materials as known in the art.
For example, the drug reservoir is formed from a polymeric material
in which the drug has reasonable solubility for the drug to be
delivered within the desired range, such as, a polyurethane,
ethylene/vinyl acetate copolymer (EVA), acrylate, styrenic block
copolymer, and the like. In preferred embodiments, the reservoir 3
is formed from a pharmaceutically acceptable adhesive or
proadhesive, preferably acrylate copolymer-based, as described in
greater detail below. The drug reservoir or the matrix layer can
have a thickness of about 1-10 mils (0.025-0.25 mm), preferably
about 2-5 mils (0.05-0.12 mm), more preferably about 2-3 mils
(0.05-0.075 mm).
[0040] Preferred materials for making the adhesive reservoir or
adhesive coating, and for making proadhesives according to the
present invention include acrylates, which can be a copolymer of
various monomers ((i) "soft" monomer, (ii) "hard" monomer, and
optionally (iii) "fanctional" monomer) or blends including such
copolymers. The acrylates (acrylic polymers) can be composed of a
copolymer (e.g., a terpolymer, i.e., made with three monomers; or a
tetrapolymer, i.e., made with four monomers) including at least two
or more exemplary components selected from the group including
acrylic acids, alkyl acrylates, methacrylates, copolymerizable
secondary monomers or monomers with functional groups. Functional
monomers are often used to adjust drug solubility, polymer cohesive
strength, or polymer hydrophilicity. Examples of functional
monomers are acids, e.g., acrylic acid, methacrylic acid and
hydroxy-containing monomers such as hydroxyethyl acrylate,
hydroxypropyl acrylate, acrylamides or methacrylamides that contain
amino group and amino alcohols with amino group protected.
Functional groups, such as acid and hydroxyl groups can also help
to increase the solubility of basic ingredients (e.g., drugs) in
the polymeric material. Additional useful "soft" and "hard"
monomers include, but are not limited to, methoxyethyl acrylate,
ethyl acrylate, butyl acrylate, butyl methacrylate, hexyl acrylate,
hexyl methacrylate, 2-ethylbutyl acrylate, 2-ethylbutyl
methacrylate, isooctyl acrylate, isooctyl methacrylate,
2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate,
decyl methacrylate, dodecyl acrylate, dodecyl methacrylate,
tridecyl acrylate, tridecyl methacrylate, acrylonitrile,
methoxyethyl acrylate, methoxyethyl methacrylate, and the like.
Additional examples of acrylic adhesive monomers suitable in the
practice of the invention are described in Satas, "Acrylic
Adhesives," Handbook of Pressure-Sensitive Adhesive Technology, 2nd
ed., pp. 396-456 (D. Satas, ed.), Van Nostrand Reinhold, New York
(1989). Examples of acrylic adhesives are commercially available
from National Starch and Chemical Company, Bridgewater, N.J.
[0041] The acrylate polymers can include cross-linked and
non-cross-linked polymers. The polymers can be cross-linked by
known methods to provide the desired polymers. However,
cross-linking is hard to control and may result in polymeric
materials that are too stiff or too soft. According to the present
invention, it is preferred that the polymeric material for
incorporation of drugs and other ingredients to be polymers without
crosslinking and no cross-linking agent is used in forming the
polymeric material. It is further preferred that the monomers do
not self cross-link during polymerization. In the present
invention, it was found that, instead of cross-linking to form a
matrix adhesive with desired PSA properties for incorporating drugs
and enhancers, good control of the PSA properties can be achieved
by selecting polymeric materials, and in one aspect related to
proadhesive, selecting materials that are too stiff prior to
incorporation of drugs and other ingredients and subsequently
incorporating such drugs and ingredients.
[0042] It has been found that, in the case of proadhesive, in a
preferred embodiment, an acrylate polymer composition with a creep
compliance (J) of 7.times.10.sup.-5 cm.sup.2/dyn or below and
elastic modulus G' of 8.times.10.sup.5 dyn/cm.sup.2 or above,
although too stiff as a PSA as is, after formulating with drug or
enhancer or a combination thereof at a relative high concentration
will achieve the desirable adhesive properties. The plasticizing or
tackifying effect of the drug(s) and/or other ingredients on the
polymeric material provides a means to achieve the desired adhesive
properties in the reservoir.
[0043] Acrylate polymers, when the main monomer of which has the
general formula CH.sub.2.dbd.CH--COOR, are particularly useful as
proadhesives. Typical main monomers are normally alkyl acrylates of
4 to 1 carbon atoms, preferably 4-10 carbons. Useful alkyl
acrylates include ethyl acrylate, butyl acrylate, amyl acrylate,
hexyl acrylate, 2-ethylhexyl acrylate, octyl acrylate, isooctyl
acrylate, decyl acrylate, dodecyl acrylates, with 2-ethylhexyl
acrylate, butyl acrylate, and iso-octyl acrylate being preferred.
Such "soft" monomers if polymerized into homopolymer generally have
a T.sub.g of less than about 0.degree. C., preferably about
-10.degree. C. to -80.degree. C., preferably about -20.degree. C.
to -80.degree. C. Preferably, they are present in an amount of
about 10 to 70 wt % (i.e., dry weight % or solids wt %), more
preferably no more than about 60% by weight, more preferably no
more than about 50 wt % of the total monomer weight and more
preferably about 40 to 50 wt %. As used herein, when a monomer is
said to be present in the acrylate polymer at a certain percentage,
it is meant that the monomer has been polymerized in the acrylate
polymer at that percentage of polymerization monomer
ingredients.
[0044] "Hard" modifying monomers are mainly used to modify the
adhesive properties, mainly glass transition temperature (e.g., to
increase the T.sub.g and to make the resulting polymer stiffer at
room temperature), to meet various application requirements. A hard
monomer, if polymerized into homopolymer, has a T.sub.g of about 0
to 250.degree. C., preferably about 20 to 250.degree. C., more
preferably in the range of about 30 to 150.degree. C. (for
convenience, this is referred to as the "homopolymer T.sub.g"
herein). The hard monomer component (or content in the polymer) is
present in an amount of about 10 wt % or more, preferably in the
range of about 30 to 60 wt %, preferably about 35 to 60 wt %, more
preferably about 40 to 60 wt %, even more preferably about 40 to 50
wt % in the polymerization. Examples of hard modifying monomers are
methyl acrylate, vinyl acetate, methyl methacrylate, isobutyl
methacrylate, vinyl pyrrolidone, substituted acrylamides or
methacrylamides. Homopolymers of these monomers generally have
higher glass transition temperature than homopolymers of the soft
monomers.
[0045] Certain nitrogen containing monomers can be included in the
polymerization to raise the T.sub.g. These include N-substituted
acrylamides or methacrylamides, e.g., N-vinyl pyrrolidone, N-vinyl
caprolactam, N-tertiary octyl acrylamide(t-octyl acrylamide),
dimethyl acrylamide, diacetone acrylamide, N-tertiary butyl
acrylamide(t-butyl acrylamide and N-isopropyl acrylamide(i-propyl
acrylamide). Further examples of monomers that can be used in
polymerization to modify and raise the T.sub.g of the polymer
include cyanoethylacrylates, N-vinyl acetamide, N-vinyl formamide,
glycidyl methacrylate and allyl glycidyl ether.
[0046] Functional monomers can be used to either provide needed
functionality for solubilizing agents in the polyacrylate or
improve cohesive properties. Examples of functional monomers are
organic acids, e.g., acrylic acid, methacrylic acid, and
hydroxyl-containing monomers such as hydroxyethyl acrylate.
Preferred functional monomers when incorporated into the polymer
result in acid groups, i.e., --COOH, hydroxyl groups, i.e., --OH,
or amino groups in the polymer for affecting the solubility of
basic agents such as basic drugs. Examples of hydroxy functional
monomers include hydroxyethyl acrylate, hydroxypropyl acrylate,
hydroxyethyl methacrylate and hydroxypropyl methacrylate. The
hydroxyl groups can be primary, secondary or tertiary hydroxyl. In
some cases, the acrylate polymer can includes at least one
non-primary hydroxyl functional monomer component to provide
orientation of the functional group in the polymer. Suitable
non-primary hydroxyl functional monomers are secondary hydroxyl
functional monomers such as hydroxypropyl acrylate. Useful
carboxylic acid monomers to provide the functional group preferably
contain from about 3 to about 6 carbon atoms and include, among
others, acrylic acid, methacrylic acid, itaconic acid, and the
like. Acrylic acid, methacrylic acid and mixtures thereof are
particularly preferred as acids.
[0047] A functional monomer can also be a hard monomer, if its
homopolymer has the high T.sub.g. Such functional monomers that can
also function as hard monomers include, e.g., hydroxyethyl
acrylate, hydroxypropyl acrylate, acrylic acid, dimethylacrylamide,
dimethylaminoethyl methacrylate, tert-butylaminoethyl methacrylate,
methoxyethyl methacrylate, and the like.
[0048] The functional monomer(s) are preferably present in the
acrylate polymer in an amount of about at least 5 wt %, preferably
at least 10 wt %, preferably 10 to 40 wt %, more preferably about
10 to 30 wt %, more preferably about 10 to 20 wt %, even more
preferably 10 to 15 wt %, even though some of the functional
monomer(s) may be hard monomers. Examples of preferred functional
monomer component include acrylic acid and hydroxyethyl acrylate,
acrylamides or methacrylamides that contain amino group and amino
alcohols with amino group protected. One of the applications of
using functional monomers is to make a polar proadhesive having
higher enhancer tolerance, in that, for example, the resulting PSA
with the enhancers and/or drug will not phase separate or have
excessive cold flow.
[0049] In certain embodiments, the hard monomer(s) that are not
also functional monomers can constitute about 10 to 60 wt %,
preferably about 40 to 60 wt % of the acrylate monomer, especially
in cases in which no acidic functional hard monomer and less than
about 20 wt % of hydroxyl functional hard monomer are included in
the acrylate polymer. In other embodiments, the hard monomer(s)
that are not also functional monomer can constitute about 5 to 15
wt %, e.g., about 10 wt % of the acrylate monomer, especially in
cases in which a large amount (e.g., about 25 wt % or more) of
functional hard monomer(s) are included, such as when more than
about 5 wt % acidic hard functional monomers and 10 or more wt %
(e.g., about 10-25 wt %) hydroxyl functional hard monomer(s) are
included in the acrylate polymer.
[0050] In an embodiment, useful polyacrylates have at least about
10 wt %, preferably at least about 20 wt %, preferably at least
about 30 wt % acrylic monomers having hydroxyl group, acid group,
or a combination thereof. One example is a polyacrylate having
about 30 wt % hydroxyl group containing (--OH) monomer and about 3
wt % acid containing (--COOH) monomer. Another contains about 26 wt
% --OH monomer and about 6 wt % --COOH monomer. Another useful
polar polyacrylate contains about 10 wt % --OH monomer. Yet another
useful polar polyacrylate contains about 20 wt % --OH monomer. The
preferred --OH monomer is hydroxyethyl acrylate and hyderoxylpropyl
acrylate. The preferred --COOH monomer is acrylic acid.
Proadhesives were made with such functional amounts.
[0051] Table 1 shows the T.sub.g of exemplary soft and hard
homopolymers the monomers of which are useful for making adhesive
and proadhesive of the present invention. Some of the monomers
(e.g., acrylic acid, hydroxyethyl acrylate) are also functional
monomers. TABLE-US-00001 TABLE 1 Examples of soft and hard
homopolymers poly(hydroxyethyl acrylate) (hard/functional monomer)
about 100.degree. C. poly(acrylic acid) (hard/functional monomer)
106.degree. C. poly(vinyl acetate) (hard monomer) 30.degree. C.
poly(ethylhexyl acrylate) (soft monomer) -70.degree. C.
poly(isopropyl acrylate) (soft monomer) -8.degree. C. poly(n-propyl
acrylate) (soft monomer) -52.degree. C. poly(isobutyl acrylate)
(soft monomer) -40.degree. C. poly(n-butyl acrylate) (soft monomer)
-54.degree. C. poly(n-octyl acrylate) (soft monomer) -80.degree.
C.
[0052] It has been found that the soft monomers 2-ethylhexyl
acrylate and butyl acrylate are especially suitable to polymerize
with functional monomers hydroxyethyl acrylate or acrylic acid
either alone or in combination to form the acrylate polymer of the
present invention. Further, the hard monomer vinyl acetate has been
found to be very useful to polymerize with the soft monomers
2-ethylhexyl acrylate and butyl acrylate, either alone or in
combination to form the proadhesive. Thus, the acrylate proadhesive
polymer of the present invention is especially suitable to be made
from 2-ethylhexyl acrylate or butyl acrylate copolymerized with
hydroxyethyl acrylate, acrylic acid, or vinyl acetate, either alone
or in combination. Another preferred hard monomer is t-octyl
acrylamide, which can be used alone or in combination with other
hard monomers such as acrylic acid and hydoxyethyl acrylate.
[0053] In an embodiment, the adhesive or proadhesive is made by
polymerizing monomers including about 20 to 75 wt % vinyl acetate,
about 5-40 wt % hydroxyl functional monomer and about 10-75 wt %
soft monomer such as 2-ethylhexyl acrylate or butyl acrylate,
preferably about 30 to 75 wt % vinyl acetate, about 10-40 wt %
hydroxyl ftmctional monomer and about 10-70 wt % soft monomer such
as 2-ethylhexyl acrylate or butyl acrylate. In a preferred
embodiment, the proadhesive is made by polymerizing monomers
including about 50 to 60 wt % vinyl acetate, about 10-20 wt %
hydroxyethyl acrylate, and about 20-40 wt % 2-ethylhexyl acrylate.
In some cases, no carboxyl(acid) group is used. Hydroxyethyl
acrylate or hydroxypropyl acrylate can be used to provide hydroxyl
functionality. In certain embodiments, the adhesive or proadhesive
is a terpolymer consisted of monomer components of vinyl acetate,
2-ethylhexyl acrylate and hydroxyethyl acrylate. For example, one
embodiment is a proadhesive having about 50 wt % vinyl acetate,
about 10 wt % hydroxyethyl acrylate, and about 40 wt % 2-ethylhexyl
acrylate. As used herein, when a specific percentage is mentioned,
it is contemplated there may be slight variations, e.g., of plus or
minus 5% of the specific percentage (i.e., about 10 wt % may
included 10 wt %.+-.0.5wt %). One other embodiment is a proadhesive
having about 60 wt % vinyl acetate, about 20 wt % hydroxyethyl
acrylate, and about 20 wt % 2-ethylhexyl acrylate.
[0054] In another embodiment, the proadhesive is made by
polymerizing monomers including both monomer with hydroxyl group
and monomer with carboxyl group. For example, certain preferred
monomer combination for polymerization include an alkyl acrylate,
an acrylamide, a monomer with hydroxyl group and a monomer with
carboxyl group, e.g., making a proadhesive by polymerizing butyl
acrylate, 2-hydroxyethyl acrylate or 2 hydroxypropyl acrylate or
hydroxypropyl methacrylate, t-octyl acrylamide, and acrylic acid.
In an embodiment, greater than 3 wt % of a hydroxypropyl acrylate
or hydroxylpropyl methacrylate is used in making the acrylate
polymer.
[0055] In certain cases for making a proadhesive in which both
monomers with hydroxyl groups and monomer with carboxyl groups are
to be polymerized with a soft monomer, e.g., butyl acrylate, the
monomer proportions in the polymerization includes about 55 to 65
wt % soft monomer (e.g., butyl acrylate), about 5 to 15 wt %
t-octyl acrylamide, about 20 to 30 wt % hydroxyethyl or
hydroxypropyl acrylate and about 5 to 10 wt % acid monomer such as
acrylic acid. In one embodiment, the acrylate polymer includes
about 59 wt % butyl acrylate, about 10 wt % t-octyl acrylamide,
about 25 wt % hydroxypropyl acrylate and about 6 wt % acrylic acid.
In another embodiment, the hydroxypropyl acrylate is replaced with
hydroxyethyl acrylate.
[0056] It is desirable that with the incorporation of a large
amount of permeation enhancers, the T.sub.g of the resulting
reservoir (with the drug, permeation enhancers and other
ingredients) is such that the resulting reservoir would have good
PSA properties for application to the body surface of an
individual. Further, the resulting reservoir should not have cold
flow that affects the normal application of the transdermal
delivery. In one aspect of the present invention, an acrylate
polymer (or a blend of acrylate polymers) constitutes preferably
about 40 wt % to 90 wt %, more preferably about 45 wt % to 80 wt %
of the reservoir. It is possible to load drug and/or enhancer into
the polymer composition to a high concentration, e.g., at or
greater than about 20 dry weight %, at or greater than about 30 dry
weight % (or solids wt %), even up to about 40 or above, without
adversely impacting the adhesion and rheological characteristics
for pressure sensitive adhesive (PSA) application.
[0057] In one aspect, preferred acrylate polymers or blends thereof
provide the acrylic pressure sensitive properties in the delivery
system glass transition temperature of about -10.degree. C. to
-40.degree. C., preferably about -20.degree. C. to -30.degree. C.
at application on a surface. The T.sub.g of an acrylate polymer can
be determined by differential scanning calorimetry (DSC) known in
the art. Also, theoretical ways of calculating the T.sub.g of
acrylate polymers are also known. Thus, one having a sample of an
acrylate polymer will be able to experimentally determine the
T.sub.g, for example, by DSC. One can also determine the monomer
composition of the acrylate polymer and estimate theoretically the
T.sub.g by calculation. From the knowledge of the monomer
composition of an acrylate polymer having drugs and enhancers, one
can also make the acrylate polymer without the drug and enhancer
and determine the T.sub.g. According to the present invention, the
acrylate materials, before dissolving the drug(s), permeation
enhancers, etc., have T.sub.gs that are in the range of about -20
to 10.degree. C., and have rheological properties that are not
quite suitable for use directly as a PSA to skin because of the
stiffness of the material. The acrylate polymers preferably have a
molecular weight in a range of about 200,000 to 600,000. Molecular
weight of acrylate polymers can be measured by gel permeation
chromatography, which is known to those skilled in the art.
[0058] To control the physical characteristics of the acrylate
polymer and the polymerization, it is preferred that monomers of
molecular weight of below 500, even more preferably below 200 be
used in the polymerization. Further, although optionally larger
molecular weight monomers (linear macromonomers such as
ELVACITE.TM. from ICI) can be used in the polymerization, it is
preferred that they are not used. Thus, preferably no monomer of
molecular weight (MW) above 5000, more preferably no monomer of MW
above 2000, even more preferably no monomer of MW above 500, is to
be included in the polymerization to form the acrylate polymer. The
adhesives and proadhesives of the present invention can be formed
without such macromonomers. The adhesives and proadhesives of the
present invention can be formed without such macromonomers. Thus,
in an aspect of the present invention, preferably, proadhesive
polymers can be formed without macromonomers, or substantially
without macromonomers, to have adhesive properties too stiff for
PSA as is without incorporation of a large amount of permeation
enhancers and drug. However, such proadhesives will become suitable
for adhering to the skin as PSA in patch application after the
appropriate amount of permeation enhancers and drug are dissolved
therein.
[0059] However, if desired, in certain embodiments, optionally, the
reservoir can include diluent materials capable of reducing quick
tack, increasing viscosity, and/or toughening the reservoir
structure, such as polybutylmethacrylate (ELVACITE, manufactured by
ICI Acrylics, e.g., ELVACITE 1010, ELVACITE 1020, ELVACITE 20),
polyvinylpyrrolidone, high molecular weight acrylates, i.e.,
acrylates having an average molecular weight of at least 500,000,
and the like.
[0060] The acrylate polymers of the present invention can dissolve
a large amount of permeation enhancer and allow the resulting drug
and permeation enhancer-containing adhesive to have the desired
adhesive and cohesive property without the drug or permeation
enhancer separating out of the acrylate polymer matrix either as
crystals or as oil. The resulting composition will be in the
T.sub.g and compliance range that it can be applied to a body
surface without leaving an undesirable amount of residue material
on the body surface upon removal of the device. The preferred
acrylate polymer is not cross-linked. It is contemplated, however,
that if desired, a nonsubstantial amount of cross-linking may be
done, so long as it does not change substantially the T.sub.g,
creep compliance and elastic modulus of the acrylate polymer. In
one aspect, it is also found that higher T.sub.g and higher
molecular weight of the acrylate are important for a preferred
acrylate polymer tolerating high enhancer loading. Since the
measurement of the molecular weight of an acrylate polymer is
difficult, precise or definite values are often not obtainable.
More readily obtainable parameters that relate to molecular weight
and drug and enhancer tolerance (i.e., solubility) are creep
compliance and elastic modulus.
[0061] Enhancers typically behave as plasticizers to acrylate
adhesives. The addition of an enhancer will result in a decrease in
modulus as well as an increase in creep compliance, the effect of
which is significant at high enhancer loading. A high loading of
enhancers will also lower the T.sub.g of the acrylate polymer.
Thus, to achieve a proadhesive that is tolerant of high enhancer
loading, other than increasing the T.sub.g by using a higher ratio
of hard monomer to soft monomer and the selection of suitable
monomers, it is desirable to provide suitable higher molecular
weight such that chain entanglement would help to achieve the
desirable rheology. As a result, selecting a higher T.sub.g and
higher molecular weight for a proadhesive will increase the elastic
modulus and decrease the creep compliance of the acrylate, making
the proadhesive more enhancer tolerant. The measurement of the
molecular weight of an acrylate polymer is often method-dependant
and is strongly affected by polymer composition, since acrylate
polymers discussed here are mostly copolymers, not homopolymers.
More readily obtainable parameters that relate to molecular weight
and drug and enhancer tolerance (i.e., solubility) are creep
compliance and elastic modulus.
[0062] According to the present invention, preferred useful
proadhesive polymeric materials for forming drug-containing PSA are
acrylate polymers that, before the incorporation of drugs,
enhancers, etc., and other ingredients for transdermal formation,
have creep compliance (measured at 30.degree. C. and 3600 second)
of about 7.times.10.sup.-5 cm.sup.2/dyn or below and storage
modulus G' about 8.times.10.sup.5 dyn/cm.sup.2 or above. Preferably
the creep compliance is about 6.times.10.sup.-5 cm.sup.2/dyn to
2.times.10.sup.-6 cm.sup.2/dyn, more preferably about
5.times.10.sup.-5 cm.sup.2/dyn to 4.times.10.sup.-6 cm.sup.2/dyn.
Preferably the storage modulus is about 8.times.10.sup.5
dyn/cm.sup.2 to 5.times.10.sup.6 dyn/cm.sup.2, more preferably
about 9.times.10.sup.5 dyn/cm.sup.2 to 3.times.10.sup.6
dyn/cm.sup.2. Such creep compliance and modulus will render these
acrylate polymers too stiff and unsuitable "as is" for dermal PSA
applications. However, it was found that after formulating into a
transdermal system with drugs, permeation enhancers, and the like,
which produce plasticizing effect as well as tackifying effect, the
acrylate polymers plasticized with permeation enhancers and/or drug
would have a desirable storage modulus and creep compliance that
are suitable for transdermal PSA applications. For a desirable
acrylate matrix applicable to skin with good adhesive property, the
material plasticized with drug and permeation enhancers would have
a resulting creep compliance that is about 1.times.10.sup.-3
cm.sup.2/dyn or less, preferably more than about 7.times.10.sup.-5
cm.sup.2/dyn, preferably from about 7.times.10.sup.-5 cm.sup.2/dyn
to 6.times.10.sup.-4 cm.sup.2/dyn, more preferably about
1.times.10.sup.-4 cm.sup.2/dyn to 6.times.10.sup.-4 cm.sup.2/dyn.
The preferred storage modulus of the plasticized acrylate polymer
is about 1.times.10.sup.5 dyn/cm.sup.2 to 8.times.10.sup.5
dyn/cm.sup.2, preferably about 1.2.times.10.sup.5 dyn/cm.sup.2 to
6.times.10.sup.5 dyn/cm.sup.2, more preferably about
1.4.times.10.sup.5 dyn/cm.sup.2 to 5.times.10.sup.5
dyn/cm.sup.2.
[0063] It was found that incorporating the proper selection of drug
(including NGMN alone, an estrogen alone, and NGMN in combination
with an estrogen) and other ingredients (such as permeation
enhancer) and the appropriate amounts thereof into a preferred
polyacrylate can change the T.sub.g, storage modulus G', and creep
compliance the appropriate amounts to result in an effective
transdermal drug delivery system with the right adhesive properties
for the desirable length of time, such as 24 hours, 3 day, or even
7 day application on a body surface. Such transdermal drug delivery
systems will have little or no cold flow. As used herein, "little
cold flow" means that any shape change of the device caused by cold
flow is not noticeable by an average person when the device is
removed from the pouch and on which the device is applied over the
time of use. Useful for forming adhesives incorporating an
increased amount of beneficial agents (including drugs and
permeation enhancers) over prior adhesives in transdermal drug
delivery are the proadhesive acrylic formulations containing a
relatively lower percentage of soft monomers. It has been found
that increasing the molecular weight increases the modulus of
elasticity and decreases the polymer chain mobility via chain
entanglements. Also, increasing hard monomer content increases the
glass transition temperature.
[0064] Acrylates are preferred materials for making the reservoir.
It is contemplated that the reservoir 3 or the adhesive coating 6
can also be formed from or include other material that has pressure
sensitive adhesives characteristics so that the reservoir can have
drug and permeation enhancers incorporated therein. Examples of
reservoir material and pressure sensitive adhesives include, but
are not limited to, acrylates, polysiloxanes, polyisobutylene
(PIB), polyisoprene, polybutadiene, styrenic block polymers, and
the like. Examples of styrenic block copolymer-based adhesives
include, but are not limited to, styrene-isoprene-styrene block
copolymer (SIS), styrene-butadiene-styrene copolymer (SBS),
styrene-ethylenebutene-styrene copolymers (SEBS), and di-block
analogs thereof. As mentioned, a preferred reservoir material is
acrylate polymer.
[0065] Permeation enhancers are useful for increasing the skin
permeability of the drug NGMN, an estrogen or NGMN in combination
with an estrogen drug combinations to achieve delivery at
therapeutically effective rates. Such permeation enhancers can be
applied the skin by pretreatment or delivering concurrently with
the drug, for example, by incorporation in the reservoir. A
permeation enhancer should have the ability to enhance the
permeability of the skin for one, or more drugs or other
biologically active agents. A useful permeation enhancer would
enhance permeability of the desired drug or biologically active
agent at a rate adequate for therapeutic level from a reasonably
sized patch (e.g., about 5 to 25 cm.sup.2). Some of the useful
permeation enhancers include non-ionic surfactant, one or more can
be selected from the group including glyceryl mono-oleate, glyceryl
mono-laurate, sorbitan mono-oleate, glyceryl tri-oleate, and
isopropyl myristate. The non-ionic surfactant can be used in the
amount of 0.1 about 20 wt % solids to the total composition of the
matrix layer. Examples of permeation enhancers include, but are not
limited to, fatty acid esters of alcohols, including fatty acid
esters of glycerin, such as capric, caprylic, dodecyl, oleic acids;
fatty acid esters of isosorbide, sucrose, polyethylene glycol;
caproyl lactylic acid; laureth-2; laureth-2 acetate; laureth-2
benzoate; laureth-3 carboxylic acid; laureth-4; laureth-5
carboxylic acid; oleth-2; glyceryl pyroglutamate oleate; glyceryl
oleate;; N-myristoyl sarcosine; N-octyl-2-pyrrolidone;
lauraminopropionic acid; polypropylene glycol-4-laureth-2;
polypropylene glycol-4-laureth-5dimethy-1 lauramide; lauramide
diethanolamine (DEA). Preferred enhancers include, but are not
limited to, N-lauroyl sarcosine, pyroglutamate (such as octyl-,
ethyl-, lauryl pyroglutamate (LP)), glyceryl monolaurate (GML),
glyceryl monocaprylate, glyceryl monocaprate, glyceryl monooleate
(GMO) and sorbitan monolaurate. Additional examples of suitable
permeation enhancers are described, for example, in U.S. Pat. Nos.:
5,785,991; 5,843,468; 5,882,676; and 6,004,578.
[0066] In some embodiments, especially some in which the reservoir
does not necessarily have adequate adhesive properties and a
separate adhesive layer is used, a dissolution assistant can be
incorporated in the reservoir to increase the concentration of the
drug or biologically active ingredient within the reservoir layer.
Suitable dissolution assistants include small acids as lauric acid,
oleic acid, etc. Permeation enhancers can also act as solubization
assistants. Non-ionic surfactants and dissolution assistants can be
used in combination to increase the delivery rate of female sex
hormones.
[0067] The permeation enhancers that are particularly useful in the
transdermal delivery of progestrin (e.g., NGMN) and estrogen (e.g.,
EE) include, fatty acid esters: ascorbyl palmitate (ASP), glyceryl
caprylate (GCP), lauryl lactate (LL), ethyl myristate (EM),
isopropyl Myristate (IPM), oleic acid (OA), Sorbitan Oleate (SMO),
glycerol monolaurate (GMO) octyldodecanol (OYD); aromatic ester:
benzyl benzoate (BB), tocopherol (TOC); alcohols: dipropyleneglycol
(DPG), 1,2,3-hexanetriol (HEX); amides: ethyl pyroglutamate (EPG),
lauramide DEA (LDA); acid: hydroxycaprylic acid (HCP); fatty acid:
N-lauroyl sarcosine (NLS); and fatty alcohol ethers: selachyl
alcohol (SAL), laureth-4 (LTH) and oleth-4 (OL), oleth-2 (OL2).
[0068] In the preferred embodiments, we have found that with the
appropriate permeation enhancers, no significant amount of
thioglycerol, preferably no thioglycerol need to be added as
permeation enhancer in the reservoir. Thus, preferably, less than 2
wt %, and more preferably less than 1 wt % of thioglycerol is to be
included.
[0069] The present invention is especially suitable for transdermal
delivery systems in which a large amount of permeation enhancer is
needed to aid the transdermal delivery of NGMN, an estrogen, NGMN
in combination with an estrogen or similar drugs. As used herein,
"permeation enhancers" is meant to include dissolution assistants,
unless specified otherwise in context. One or more permeation
enhancers, alone or in combination, can constitute about 5 to 40 wt
%, can constitute greater than 10 wt %, preferably about 10 to 35
wt %, more preferably about 15 to 30 wt % solids of the resulting
reservoir that has adequate pressure sensitive adhesive properties.
Further, with a proadhesive, the permeation enhancer(s) can
constitute preferably 20 to 35 wt % of the resulting reservoir.
[0070] For an adhesive that has usable adhesive property before
drug and enhance addition, such as DURO-TAK.RTM. 87-4287, the
enhancer(s) is preferably in the 15 to 25 wt % range. When such an
adhesive is used, the adhesive before the dissolution of drug and
enhancer preferably has a storage modulus of about 2 to
5.times.10.sup.5 dyn/cm.sup.2, and a creep compliance of about
4.times.10.sup.-5 to 6.times.10.sup.-5 cm.sup.2/dyn. After
dissolution of drug and enhancer wherein the drug reservoir
preferably has a storage modulus of 1.0.times.10.sup.5 to
1.5.times.10.sup.5 dyn/cm.sup.2. DURO-TAK.RTM. adhesives such as
DURO-TAK.RTM. 87-4287 are available from National Starch &
Chemicals, Bridgewater, N.J. in 2005 and at the time of the filing
of the present application and their chemical and physical
properties are assessable by those skilled in the art.
[0071] With the inclusion of the suitable permeation enhancer(s), a
progestin preferably NGMN, an estrogen, or progestin (e.g., NGMN)
in combination with an estrogen can be delivered at high flux when
solubilized in the matrix of the drug reservoir to a loading of
higher than 5 wt %, preferably from 5 to 20 wt %, more preferably
from 5 to 10 wt %.
[0072] Other than NGMN and estrogen, it is understood that the
reservoir can also contain other drugs, preferably in a single
phase polymeric composition, free of undissolved components. Other
drugs that can be contained in the drug reservoir include, for
example, those disclosed in U.S. Pat. No. 6,004,578. One skilled in
the art will be able to incorporate such drugs based on the
disclosure of the present invention.
[0073] In certain embodiments, optionally, certain other
plasticizer or tackifying agent is incorporated in the polyacrylate
composition to improve the adhesive characteristics. Examples of
suitable tackifying agents include, but are not limited to,
aliphatic hydrocarbons; aromatic hydrocarbons; hydrogenated esters;
polyterpenes; hydrogenated wood resins; tackifying resins such as
ESCOREZ, aliphatic hydrocarbon resins made from cationic
polymerization of petrochemical feedstocks or the thermal
polymerization and subsequent hydrogenation of petrochemical
feedstocks, rosin ester tackifiers, and the like; mineral oil and
combinations thereof. The tackifying agent employed should be
compatible with the polymer or blend of polymers.
[0074] The backing layer 2 may be formed from any material suitable
for making transdermal delivery patches, such as a breathable or
occlusive material including fabric or sheet, made of polyvinyl
acetate, polyvinylidene chloride, polyethylene, polyurethane,
polyester, ethylene vinyl acetate (EVA), polyethylene terephthalate
(PET), polybutylene terephthalate, coated paper products, aluminum
sheet and the like, or a combination thereof. In certain
embodiments, the backing layer includes low density polyethylene
(LDPE) materials, medium density polyethylene (MDPE) materials or
high density polyethylene (HDPE) materials, e.g., SARANEX (Dow
Chemical, Midland, Mich.). The backing layer may be a monolithic or
a multilaminate layer. In preferred embodiments, the backing layer
is a multilaminate layer including polyester/ethylene vinyl acetate
(PET/EVA). Preferably the backing layer is translucent or
adequately transparent such that the color of the reservoir can
been observed and device can be seen to be clear (rather than
cloudy). The backing layer can have a thickness of about 0.012 mm
(0.5 mil) to 0.125 mm (5 mil); preferably about 0.025 mm (1 mil) to
0.1 mm (4 mil); more preferably about 0.0625 mm (1.5 mil) to 0.0875
mm (3.5 mil).
[0075] The protective layer of the transdermal device can be made
of a polymeric material that may be optionally metallized. Examples
of the polymeric materials include polyurethane, polyvinyl acetate,
polyvinylidene chloride, polypropylene, polycarbonate, polystyrene,
polyethylene, polyethylene terephthalate, polybutylene
terephthalate, paper, and the like, and a combination thereof. In
preferred embodiments, the protective layer includes a siliconized
polyester sheet.
[0076] A wide variety of materials that can be used for fabricating
the various layers of the transdermal delivery patches according to
this invention have been described above. It is contemplated that
the use of materials other than those specifically disclosed
herein, including those which may hereafter become known to the art
to be capable of performing the necessary functions is
practicable.
[0077] Transdermal flux can be measured with a standard procedure
using Franz cells or using an array of formulations. Flux
experiments were done on isolated human cadaver epidermis. With
Franz cells, in each Franz diffusion cell a disc of epidermis is
placed on the receptor compartment. A transdermal delivery system
is placed over the diffusion area (1.98 cm.sup.2) in the center of
the receptor. The donor compartment is then added and clamped to
the assembly. At time 0, receptor solution (between 21 and 24 ml,
exactly measured) is added into the receptor compartment and the
cell maintained at 35.degree. C. This temperature yields a skin
surface temperature of 30-32.degree. C. Samples of the receptor
compartment are taken periodically to determine the skin flux and
analyzed by HPLC. In testing flux with an array of transdermal
miniature patches, formulations are prepared by mixing stock
solutions of each of the mixture components of formulation in
organic solvents (typically 15 wt % solids), followed by a mixing
process. The mixtures are then aliquoted onto arrays as 4-mm
diameter drops and allowed to dry, leaving behind solid samples or
"dots." (i.e., mini-patches). The array of miniature patches is
then tested individually for skin flux using a permeation array,
whose principle is similar to that of an array of miniature Franz
cells. The test array has a plurality of cells, a piece of isolated
human epidermis large enough to cover the whole array, and a
multiple well plate with wells acting as the receptor compartments
filled with receptor medium. The assembled permeation arrays are
stored at 32.degree. C. and 60% relative humidity for the duration
of the permeation experiments. Receptor fluid is auto-sampled from
each of the permeation wells at regular intervals and then measured
by HPLC for flux of the drug.
Administration of the Drug(s)
[0078] On application to the skin, the drug in the drug reservoir
of the transdermal patch diffuses into the skin where it is
absorbed into the bloodstream to produce a systemic therapeutic
effect. When the patches are worn for contraception, a patch will
typically be placed on the skin on the fifth day of the menstrual
cycle, and replaced as needed until 21 days of wearing have
elapsed. For instance, in the case of a 7 day patch, three patches
will be required to deliver the drug(s) for the 21 day period. If
desired a placebo patch may be worn thereafter until the fifth day
of the succeeding menstrual cycle. This regimen is repeated for
each menstrual cycle. When patches are worn for hormone replacement
therapy, a patch will typically be placed on the skin once per
week.
Methods of Manufacture
[0079] The transdermal devices are manufactured according to known
methodology. For example, in an embodiment, a solution of the
polymeric reservoir material, as described above, is added to a
double planetary mixer, followed by addition of desired amounts of
the drug(s), permeation enhancers, and other ingredients that may
be needed. Preferably, the polymeric reservoir material is an
acrylate material. The acrylate material is solubilized in an
organic solvent, e.g., ethanol, ethyl acetate, hexane, and the
like. The mixer is then closed and activated for a period of time
to achieve acceptable uniformity of the ingredients. The mixer is
attached by means of connectors to a suitable casting die located
at one end of a casting/film drying line. The mixer is pressurized
using nitrogen to feed solution to the casting die. Solution is
cast as a wet film onto a moving siliconized polyester web. The web
is drawn through the lines and a series of ovens are used to
evaporate the casting solvent to acceptable residual limits. The
dried reservoir film is then laminated to a selected backing
membrane and the laminate is wound onto the take-up rolls. In
subsequent operations, individual transdermal patches are die-cut,
separated and unit-packaged using suitable pouchstock. Patches are
placed in cartons using conventional equipment. In another process,
the drug reservoir can be formed using dry-blending and thermal
film-forming using equipment known in the art. Preferably, the
materials are dry blended and extruded using a slot die followed by
calendaring to an appropriate thickness.
EXAMPLES
[0080] Below are examples of specific embodiments for carrying out
the present invention. The examples are offered for illustrative
purposes only, and are not intended to limit the scope of the
present invention in any way. In the following examples all
percentages are by weight unless noted otherwise. T.sub.g was
determined by DSC (Differential Scanning Calorimetry) with
10.degree. C./min heating rate. Modulus G' was storage modulus at
25.degree. C. and 1 rad/s frequency (Frequency sweep experiment was
conducted using AR-2000 rheometer from TA Instruments (TA
Instruments, 109 Lukens Drive, New Castle, Del. 19720). The test
conditions were: strain 1%, temperature 25.degree. C., frequency
range 0.1 to 100 rad/s, gap around 1000 micron). Creep compliance
tests were conducted using AR-2000 rheometer from TA Instruments.
The test conditions were: stress 1000 dyn/cm.sup.2, temperature
30.degree. C., time 3600 seconds, gap around 1000 microns. One
skilled in the art will know how to measure T.sub.g, creep
compliance, and storage modulus in view of the present
disclosure.
Example 1
[0081] A monomer mix containing butyl acrylate, 2-hydroxyethyl
acrylate, t-octyl acrylamide, acrylic acid, ethyl acetate
(solvent), and 2,2'-azobisisobutyronitrile (AIBN) (polymerization
initiator) was prepared. A fraction was charged to an appropriate
vessel and heated to reflux with stirring. The remainder was added
to the vessel over time. The ratios of the monomers and initiator
added totally, i.e., butyl acrylate: 2-hydroxyethyl acrylate:
t-octyl acrylamide: acrylic acid: AIBN were 59: 25.5: 9.5: 6: 2.
The material was then held at reflux for a suitable period of time.
At the end of the hold period, the contents were cooled to room
temperature and the solution polymer discharged. The dry film made
from this polyacrylate formulation had storage modulus of around
9.times.10.sup.5 dyn/cm.sup.2, creep compliance of around
7.times.10.sup.-5 cm.sup.2/dyn, and glass transition temperature of
-8.degree. C., and consequently was too stiff to provide adequate
adhesive properties alone. This formed a proadhesive.
Example 2
[0082] A monomer mix containing butyl acrylate, 2-hydroxypropyl
acrylate, t-octyl acrylamide, acrylic acid, ethyl acetate
(solvent), and 2,2'-azobisisobutyronitrile (AIBN) (polymerization
initiator) was prepared. A fraction was charged to an appropriate
vessel and heated to reflux with stirring. The remainder was added
to the vessel over time. The material was held at reflux for a
suitable period of time. The ratios of the monomers and initiator
added totally, i.e., butyl acrylate: 2-hydroxypropyl acrylate:
t-octyl acrylamide: acrylic acid: AIBN were 59: 25.5: 9.5: 6: 2. At
the end of the hold period, the contents were cooled to room
temperature and the solution polymer discharged. The dry film made
from this polyacrylate formulation had storage modulus of around
8.times.10.sup.5 dyn/cm.sup.2, creep compliance of around
4.times.10.sup.-5 cm.sup.2/dyn, and glass transition temperature of
-8.degree. C., and consequently was too stiff to provide adequate
adhesive properties alone. This formed a proadhesive.
Example 3
[0083] A monomer mix containing vinyl acetate, 2-hydroxyethyl
acrylate, 2-ethylhexyl acrylate, ethyl acetate (solvent), and
2,2'-azobisisobutyronitrile (AIBN) (polymerization initiator) was
prepared. A fraction was charged to an appropriate vessel and
heated to reflux with stirring. The remainder was added to the
vessel over time. The material was held at reflux for a suitable
period of time. The ratios of the monomers and initiator added
totally, i.e., vinyl acetate: 2-hydroxyethyl acrylate: 2-ethylhexyl
acrylate: AIBN were 50: 10: 40: 1.2. At the end of the hold period,
the contents were cooled to room temperature and the solution
polymer discharged. The dry film made from this polyacrylate
formulation had storage modulus of around 2.times.10.sup.6
dyn/cm.sup.2, creep compliance of around 4.times.10.sup.-6
cm.sup.2/dyn, and glass transition temperature of -14.degree. C.,
and consequently was too stiff to provide adequate adhesive
properties alone. This formed a proadhesive.
Example 4
[0084] A monomer mix containing vinyl acetate, 2-hydroxyethyl
acrylate, 2-ethylhexyl acrylate, ethyl acetate (solvent), and
2,2'-azobisisobutyronitrile (AIBN) (polymerization initiator) was
prepared. A fraction was charged to an appropriate vessel and
heated to reflux with stirring. The remainder was added to the
vessel over time. The ratios of the monomers and initiator added
totally, i.e., vinyl acetate: 2-hydroxyethyl acrylate: 2-ethylhexyl
acrylate: AIBN were 60: 20: 20: 1.2. The material was held at
reflux for a suitable period of time. At the end of the hold
period, the contents were cooled to room temperature and the
solution polymer discharged. The dry film made from this
polyacrylate formulation had storage modulus of around
4.times.10.sup.6dyn/cm.sup.2, creep compliance of around
2.times.10.sup.-6 cm.sup.2/dyn, and glass transition temperature of
-8.degree. C., and consequently was too stiff to provide adequate
adhesive properties alone. This formed a proadhesive.
Example 5
[0085] The combination of high capacity acrylate matrix with
certain unique combinations of permeation enhancers result in a
more acceptable transdermal contraceptive system with high drug and
permeation enhancers loading.
[0086] Various permeation enhancers were evaluated in two adhesives
(for the purpose of the Examples, the polyacryates of Examples 1 to
4 are called adhesive for ease of reference). Various combinations
of unique formulations were evaluated for flux of NGMN and EE,
comprised of unary (having a single enhancer), binary (having two
enhancers), and ternary (having three enhancers) combinations of
enhancers.
[0087] Forty-one permeation enhancers were selected based on the
evaluation of their unary, binary, and (in limited cases) ternary
performance enhancement, as indicated in Table 1. Combinations were
prepared by preparing mixtures of the permeation enhancers at
levels up to 80% of their solubility in the neat adhesives (except
where further limited due to toxicological constraints) and where
their combined weight fractions exceeded a rheologically acceptable
limit for each adhesive (20 wt % and 35 wt % total enhancer(s) in
National Starch DURO-TAK.RTM. 87-4287 adhesive and proadhesive from
Example 3 above, respectively), in which case the total combined
loading was limited to the limits proportionally to their
respective unary solubility limits. The NGMN solubility was then
predicted based upon the unary solubility estimates, and loaded
into the formulations at several fractions of saturated levels. EE
was also a component of every formulation, and was maintained in a
constant proportion to the NGMN level of 1:8 EE: NGMN.
TABLE-US-00002 TABLE 2 Evaluated Permeation Enhancers and their
combinations. Unary (U), Binary (B), Name Acronym Ternary (T)
Ascorbyl Palmitate ASP U, B Benzyl Benzoate BB U, B, T Ceteth-20
C20 U, B Dipropyleneglycol DPG U, B, T Ethyl Myristate EM U, B
Ethyl Palmitate EP U, B, T Farnesol FAN U, B Glyceryl Caprylate GCP
U, B Glycerol-tridecanoate GLT U, B Glyceryl Monolaurate GML U, B
Glycerol Monooleate GMO U, B, T Hydroxycaprylic Acid HCP U, B Hexyl
Decanol HD U, B 1,2,3-hexanetriol HEX U, B Isopropyl Laurate IPL U,
B Isopropyl Myristate IPM U, B, T Isosorbide ISO U, B Oleth-20 L20
U, B Laureth-2 LAU U, B Lauramide DEA LDA U, B, T Lauryl Lactate LL
U, B Lauryl Laurate LLA U, B Lauryl Alcohol LOL U, B Lauryl
Pyrrolidone LPY U, B Lauric Acid LRA U, B, T Laureth-4 LTH U, B, T
N-lauroyl Sarcosine NLS U, B, T Oleic Acid OA U, B, T Octyl
Pyroglutamate OCP U, B Octyldodecyl Lactate ODL U, B Oleth-4 OL U,
B Oleth-2 OL2 U, B, T Octyldodecanol OYD U, B, T Ethyl hexyl
dimethyl PABA PAD U, B Polyethylene glycol 400 PEG8 U, B PEG 200
monolaurate PML U, B Selachyl Alcohol SAL U, B, T Sorbitan Oleate
SMO U, B Stearyl Behenate STB U, B Succinic Acid SUC U, B
Tocopheryl Acetate TAC U, B Tetraethylene Glycol TEG U, B
Tocopherol TOC U, B, T
[0088] All formulations were prepared and evaluated for flux
through isolated human epidermis. Formulations were prepared by
mixing stock solutions of each of the mixture components in organic
solvents (typically 15 wt % solid content in ethyl acetate,
methanol and/or ethanol), followed by a mixing process. The
mixtures were then aliquoted onto 16.times.24 arrays as 4-mm
diameter drops and allowed to dry, leaving behind solid samples or
"dots." (i.e., mini-patches). The resulting 384 miniature patches
were then tested individually for skin flux using a 384-well
permeation array, whose principle is similar to that of an array of
miniature Franz cells, which is a standard tool for someone one
skilled in the art of transdermal formulation development. The
formulations could also have been tested on conventional Franz
cells and results would be expected to be similar. Each permeation
array consisted of the 384 miniature patch array, a piece of
isolated human epidermis large enough to cover the whole array, and
a 384-well plate acting as the receptor compartment and which was
filled with receptor medium. The assembled permeation arrays were
stored at 32.degree. C. and 60% relative humidity for the duration
of the permeation experiments and testing was conducting just like
with conventional Franz cells with standard procedure known to
people skilled in the art. Receptor fluid was auto-sampled from
each of the permeation wells at regular intervals and then measured
by HPLC for NGMN and EE content in order to determine the flux
profile and measure the flux at steady state. Every formulation was
replicated at least 3 times in order to ensure accuracy.
[0089] Selected NGMN-EE/enhancers formulations with flux in the
range of greater than 0.1 .mu.g/cm.sup.2h were each cast into a
film of 2-3 mils (0.05-0.075mm) on a siliconized polyester sheet,
and backed with a conformable and translucent or transparent
backing material. The examples were evaluated for transdermal flux.
All samples were monitored over time for crystal formation with
cross-polarizing filters under 4.times. magnification. Only
formulations that have not crystallized are included below in Table
3 (including Tables 3-1 to 3-2). TABLE-US-00003 TABLE 3-1 Example
compositions of transdermal matrix formulations yielding NGMN flux
of greater than 0.1 .mu.g/cm.sup.2h. Compositions given as percent
weight fraction. NGMN Example Flux Comp. NGMN EE Enhancer 1
Enhancer 2 Enhancer 3 Polyacrylate matrix (.mu.g/cm.sup.2h) 1 5.5%
0.7% 5.0% NLS 30.0% OA -- -- 58.8% from 0.95 Example3 2 7.5% 0.9%
5.0% NLS 27.0% IPM -- -- 59.5% from 0.69 Example3 3 10.0% 1.3% 5.0%
NLS 30.0% TOC -- -- 53.7% from 0.61 Example3 4 5.7% 0.7% 12.5% LTH
22.5% IPM -- -- 58.5% from 0.59 Example3 5 6.0% 0.8% 4.4% LDA 7.0%
SMO 23.6% IPM 58.2% from 0.59 Example3 6 7.5% 0.9% 4.0% NLS 16.0%
TOC -- -- 71.6% 87-4287 0.91 Adhesive 7 9.8% 1.2% 4.0% NLS 16.0% EP
-- -- 69.0% 87-4287 0.89 Adhesive 8 8.3% 1.0% 5.0% NLS 14.0% SMO --
-- 71.7% 87-4287 0.86 Adhesive 9 4.0% 0.5% 5.2% LDA 7.2% OL2 7.4%
OA 75.7% 87-4287 0.84 Adhesive 10 4.3% 0.5% 4.0% GMO 6.7% OA 9.3%
SMO 75.2% 87-4287 0.72 Adhesive Control 4.0% 0.5% none none none
95.5% 87-4287 0.05 Adhesive
[0090] TABLE-US-00004 TABLE 3-2 Example compositions of transdermal
matrix formulations yielding NGMN flux results in the greater than
0.1 .mu.g/cm.sup.2h. Compositions given as percent weight fraction.
NGMN Example Flux Comp. NGMN EE Enhancer 1 Enhancer 2 Enhancer 3
Polyacrylate matrix (.mu.g/cm.sup.2h) 1 8.8% 1.1% 15.6% GMO 1.1%
NLS 73.4% from 0.80 Example 3 2 7.7% 0.9% 5.0% NLS -- -- 86.4%
87-4287 0.51 Adhesive 3 10.5% 1.3% 16.2% GMO 2.7% SAL 69.3% from
0.50 Example 3 4 10.7% 1.3% 16.5% EP 1.0% NLS 70.5% from 0.44
Example 3 5 7.9% 1.0% 11.1% LAU 1.5% SAL -- -- 78.5% from 0.31
Example 3 6 15.9% 2.0% 30% OA -- -- 52.1% from 0.30 Example 3 7
8.0% 1.0% 12.0% SAL -- -- 79.0% 87-4287 0.22 Adhesive 8 8.9% 1.1%
29% LPY -- -- 61.0% 87-4287 0.13 Adhesive 9 5.0% 0.6% 20.2% LLPY --
-- -- -- 74.2% 87-4287 0.11 Adhesive Control 4.0% 0.5% none none
none 95.5% 87-4287 0.05 Adhesive
[0091] The data in Tables 3-1 and 3-2 show that with certain novel
acrylate matrix, it was able to dissolve more than 19 wt %
permeation enhancers to facilitate the delivery of NGMN and EE.
Such high loading of enhancers can facilitate the delivery of NGMN
flux significantly higher than about 0.05 .mu.g/cm.sup.2h, the
unenhanced flux of NGMN from an acrylate adhesive (in some cases
almost 20 times that of the unenhanced flux). The acrylate content
was as low as about 54 wt %. With the DURO-TAK.RTM. 87-4287,
generally for formulations with relatively high flux, the enhancer
loading was slightly lower than the enhancer loading possible with
the acrylate prolymer from Example 3, and the acrylate content was
about 69 wt % or greater. In one aspect of the present invention,
one type of useful acrylate polymer for making the transdermal
delivery patch is one that comprises, and preferably consists of
2-hydroxyethyl acrylate, vinlyl acetate and 2-ethylhexyl acrylate.
An example is DURO-TAK.RTM. 87-4287 polyacrylate adhesive, which is
a terpolymer having a monomer composition of 2-6 wt %
2-hydroxyethyl acrylate, with the rest being vinyl acetate (20-40
wt %) and 2-ethyihexyl acrylate (55-75 wt %). DURO-TAK.RTM. 87-4287
acrylate polymer has a T.sub.g of -38 C, storage modulus of
3.6.times.10.sup.5dyn/cm.sup.2 and creep compliance of about
5.times.10.sup.-5 cm.sup.2/dyn.
[0092] Tables 4-1 and 4-2 provide additional data for flux and
rheological property for formulations using DURO-TAK.RTM. 87-4287
acrylate adhesive. The data in Tables 4-1 and 4-2 show that the
formulations have rheological property suitable for adhesion on
skin for 1 day, 2 days, 3 days, even up to 7 day delivery. The
formulation examples with permeation enhancers shown in Tables 4-1
and 4-2 contain 70 to 80 wt % acrylate when no PVP was used. With
the inclusion of PVP, the acrylate content can be lowered to below
65 wt %. TABLE-US-00005 TABLE 4-1 Example compositions of
transdermal matrix formulations yielding NGMN flux of greater than
0.1 .mu.g/cm.sup.2h. Compositions given as percent weight fraction.
NGMN Example Flux Comp. NGMN EE Enhancer 1 Enhancer 2 Excipient
Polyacrylate matrix (.mu.g/cm.sup.2h) 1 7.5% 0.75% 5% NLS 14% SMO
72.8% 87-4287 Adhesive 0.62 2 5.0% 0.05% 4% NLS 16% IPM 75.0%
87-4287 Adhesive 0.29 3 8.5% 0.85% 4% NLS 16% DPG 7% PVP 63.7%
87-4287 Adhesive 0.41 4 4.0% 0.5% none none none 95.5% 87-4287
Adhesive 0.05 5 6.0% 0% 3% NLS 14% GMO 77.0% Example 3 adhesive
0.38 6 8.0% 0% none none none 92.0% Example 3 adhesive 0.02
[0093] TABLE-US-00006 TABLE 4-2 Rheological properties for
Transdermal Formulations in Table 4-1 Example Modulus creep
compliance Comp. (dyn/cm.sup.2) (cm.sup.2/dyn) 1 1.6 .times.
10.sup.5 1.4 .times. 10.sup.-4 2 1.1 .times. 10.sup.5 2.0 .times.
10.sup.-4 3 5.3 .times. 10.sup.5 5.8 .times. 10.sup.-5 4 3.4
.times. 10.sup.5 4.3 .times. 10.sup.-5 5 1.1 .times. 10.sup.6 1.3
.times. 10.sup.-5 6 3.0 .times. 10.sup.5 6.6 .times. 10.sup.-5
Example 6
[0094] Experiments were done to compare flux of formulation of the
present invention with commercially available ORTHO EVRAS patches.
ORTHO EVRA.RTM. patches have about 73.5 wt % polyisobutylene
adhesive, 4.25 wt % lauryl lactate, 20 wt % micronized
crospovidone, 2 wt % NGMN and 0.25 wt % EE similar to the
formulations in the U.S. Pat. No. 5,876,746 patent. Flux
experiments were done on isolated human cadaver epidermis using
conventional Franz cells with standard procedure known to people
skilled in the art. For each Franz diffusion cell a disc of
epidermis was placed on the receptor compartment. The NGMN or
NGMN/EE system was placed over the diffusion area (1.98 cm.sup.2)
in the center of the receptor. The donor compartment was then added
and clamped to the assembly. At time 0, receptor solution (between
21 and 24 ml, exactly measured) was added into the receptor
compartment and the cell maintained at 35.degree. C. This
temperature yields a skin surface temperature of 30-32.degree. C.
Samples of the receptor compartment were taken at about 24 hour
intervals for 120 hours to determine the skin flux and analyzed by
HPLC. The drug flux was calculated from the HPLC data.
[0095] FIG. 3 illustrates the NGMN flux profile of a NGMN
formulation with permeation enhancers GMO and NLS according to the
present invention compared to NGMN in certain other formulations.
The flux experiments were done using Franz cells. Curve A with the
diamond data points was obtained from a formulation according to
the present invention with 14.03 wt % GMO, 3.44 wt % NLS and 6.44
wt % NGMN in the polyacrylate proadhesive according to Example 3.
Curve C with the triangle data points was obtained using 7.63 wt %
NGMN without permeation enhancers in a polyacrylate proadhesive
made according to Example 3. Curve B with the circular dot data
points was obtained using the drug-containing matrix from a
commercially available ORTHO EVRA.RTM. patch (Lot 62M079). The
horizontal bars show the standard deviations based on replicates.
The data show that the formulation of the present invention had 2
to 4 times the NGMN flux compared to that by ORTHO EVRA.RTM. patch
and more than 5 times the flux without permeation enhancers.
[0096] FIG. 4 illustrates the NGMN flux profile of a NGMN
formulation with EE and permeation enhancers GMO and NLS according
to the present invention compared to NGMN in other formulations.
The flux experiments were done using Franz cells. The upper curve D
with the diamond data points was obtained from a formulation
according to the present invention with 6.4 wt % NGMN, 1.0 wt % EE,
14 wt % GMO, and 3 wt % NLS and in the polyacrylate proadhesive
made according to Example 3. The lower curve F with the diamond
data points was obtained using 7.6 wt % NGMN without permeation
enhancers in a polyacrylate proadhesive made according to Example
3. Curve E with the circular dot data points was obtained using the
drug-containing matrix from an ORTHO EVRA.RTM. patch. The data show
that the formulation of the present invention had 2 to 4 times the
NGMN flux compared to that by ORTHO EVRA.RTM. patch and more than 5
times the flux without permeation enhancers. Thus, comparison
experiments performed under the same setting showed that the
present system performed significantly better than the commercially
available ORTHO EVRA.RTM. patch reservoir.
[0097] FIG. 5 illustrates the EE flux profile of the formulations
of FIG. 4. The upper curve G with the diamond data points was
obtained from a formulation according to the present invention with
6.4 wt % NGMN, 1.0 wt % EE, 14 wt % GMO, and 3 wt % NLS and in the
polyacrylate proadhesive made according to Example 3. The lower
curve I with the diamond data points was obtained using 7.6 wt %
NGMN without permeation enhancers in a polyacrylate proadhesive
made according to Example 3. Curve H with the circular dot data
points was obtained using the drug-containing matrix from an ORTHO
EVRA.RTM. patch. Again the EE flux in the formulation with
permeation enhancers in the polyacrylate proadhesive made according
to Example 3 had an EE flux about 3 times that of the ORTHO
EVRA.RTM. patch and more than 10 times higher than that from the
patch without permeation enhancers.
Example 7
[0098] Further, wearing data showed that certain clear patches
without micronized PVP could be worn continuously for 3 to 7 days
with adequate adhesion, without becoming opaque white, and with
reduced adhesive residue upon removal. The backing used in these
clear patches was transparent. These clear patches had drug
reservoirs made with enhancer dissolved in either the National
Starch DURO-TAK.RTM. 87-4287 or with the proadhesive from Example
3, and 0 to 8% PVP K30 (uncrosslinked). It is expected that
including dissolved female sex hormones of therapeutic amounts in
such drug reservoirs will also result in comparable adhesion and
appearance. Comparatively, commercially available ORTHO EVRA.RTM.
patches, because of the presence of micronized PVP, turned cloudy
white with moisture absorption after 7 day wear. More particularly,
formulations made of National Starch DURO-TAK.RTM. 87-4287,
plasticized with permeation enhancers to have a modulus in the
range of 10,000 to 20,000 Pa, with up to 6 wt % PVP K30, combined
with a 0.5mil PET/1.5 mil EVA backing had superior wearing
characteristics, left reduced levels of residue, and did not become
cloudy or opaque white after 7 days.
Example 8
[0099] NGMN-EE/enhancers formulations are made using drug and
enhancer tolerant polyacrylates. These proadhesive are expected to
be capable of dissolving more NGMN, EE, and enhancer(s). Using the
same method as described in Example 5 above, formulation with 8 wt
% NGMN, 0.8 wt % EE, 5 wt % NLS, and 30 wt % SMO are prepared and
evaluated for flux through isolated human epidermis. The
polyacrylate is the polyacrylate of Example 3 (from National Starch
& Chemicals, Bridgewater, N.J.). This polyacrylate was a
copolymer and consisted of 10 wt % 2-hydroxyethyl acrylate, 50 wt %
vinyl acetate, and 40 wt % 2-ethylhexyl acrylate. Such systems are
expected to be still mono-phasic and result in transdermal flux
values of around 0.8 .mu.g/cm.sup.2-hr.
[0100] The entire disclosure of each patent, patent application,
and publication cited or described in this document is hereby
incorporated herein by reference. The practice of the present
invention will employ, unless otherwise indicated, conventional
methods used by those in pharmaceutical product development within
those of skill of the art. Embodiments of the present invention
have been described with specificity. The embodiments are intended
to be illustrative in all respects, rather than restrictive, of the
present invention. It is to be understood that various combinations
and permutations of various constituents, parts and components of
the schemes disclosed herein can be implemented by one skilled in
the art without departing from the scope of the present
invention.
* * * * *