U.S. patent application number 09/752260 was filed with the patent office on 2002-09-12 for hot melt adhesives for dermal application.
Invention is credited to Paul, Charles W..
Application Number | 20020128345 09/752260 |
Document ID | / |
Family ID | 25025564 |
Filed Date | 2002-09-12 |
United States Patent
Application |
20020128345 |
Kind Code |
A1 |
Paul, Charles W. |
September 12, 2002 |
Hot melt adhesives for dermal application
Abstract
A pressure sensitive hot melt adhesive composition which
comprises a high molecular weight rubber and less than about 60
parts by weight of a liquid diluent, and has a G' of less than
about 15.times.10.sup.4 dynes/cm.sup.2 at 10 rad/s at 25.degree. C.
is useful for adhesive skin application (e.g., surgical tape),
including transdermal drug delivery applications.
Inventors: |
Paul, Charles W.; (Madison,
NJ) |
Correspondence
Address: |
Cynthia L. Foulke
National Starch and Chemical Company
Box 6500
Bridgewater
NJ
08807-0500
US
|
Family ID: |
25025564 |
Appl. No.: |
09/752260 |
Filed: |
December 29, 2000 |
Current U.S.
Class: |
523/112 |
Current CPC
Class: |
A61K 9/7076 20130101;
C09J 153/00 20130101; A61L 15/585 20130101; A61K 9/7053 20130101;
A61L 15/585 20130101; C08L 53/02 20130101 |
Class at
Publication: |
523/112 |
International
Class: |
C08K 003/00 |
Claims
1. An pressure sensitive hot melt adhesive composition comprising a
high molecular weight rubber and less than about 60 parts by weight
of a liquid diluent, and having a G' of less than about
15.times.10.sup.4 dynes/cm.sup.2 at 10 rad/s at 25.degree. C.
2. The adhesive of claim 1 comprising from about 1 to about 20
parts by weight of a rubber triblock or radial block copolymer,
from 0 to about 20 parts by weight of a high molecular weight
diblock rubber, 0 to about 10 parts by weight of other compatible
high molecular weight polymers, 0 to about 30 parts by weight of an
end block resin, 0 to less that about 60 parts by weight oil or
other liquid midblock diluent, 0 to about 50 parts by weight of a
solid tackifer and 0 to about 3 parts by weight of an
anti-oxidant.
3. The adhesive of claim 1 having a peel force of greater than
about 100 grams.
4. The adhesvie of claim 3 having a peel force of from about 100
grams to about 500 grams.
5. The adhesive of claim 1 which has a mid-block Tg of from about
-30.degree. C. to about 10.degree. C.
6. The adhesive of claim 2 wherein the triblock copolymer is
styrene-ethylene-butylene-styrene.
7. The adhesive of claim 2 wherein the triblock copolymer is
styrene-ethylene-butylene-propylene-styrene.
8. The adhesive of claim 2 which contains an A-B diblock
polymer.
9. The adhesive of claim 8 wherein the diblock copolymer is a
styrene ethylene propylene diblock polymer.
10. The adhesive of claim 2 containing an endblock resin.
11. The adhesive of claim 10 wherein the endblock resin is a homo
or copolymer of vinyl toluene, styrene, alpha-methyl styrene,
coumarone or indene
12. The adhesive of claim 1 wherein the liquid diluent is present
in an amount of from about 35 to about 55 parts by weight.
13. The adhesive of claim 1 wherein the liquid diluent is oil.
14. The adhesive of claim 1 further comprising a therapeutic
agent.
15. The adhesive of claim 14 wherein the therapeutic agent is a
pharmacologically active agent.
16. A transdermal drug delivery system comprising the adhesive of
claim 14.
17. The transdermal drug delivery system of claim 16 wherein the
adhesive serves as a carrier for the therapeutic agent.
18. The transdermal drug delivery system of claim 16 comprising an
adhesive layer, and a backing layer.
19. The transdermal drug delivery system of claim 18 further
comprising a release layer.
20. A method of administering a therapeutic agent to a patient
comprising applying to a body surface of a patient a transdermal
drug delivery system comprising the adhesive of claim 14 and a
therapeutic agent.
Description
FIELD OF THE INVENTION
[0001] The invention relates to an adhesive composition. In
particular, a hot melt pressure-sensitive adhesive for dermal
applications.
BACKGROUND OF THE INVENTION
[0002] Adhesives for application to the skin are permanently tacky
at room temperature, hold the adhered article to the skin with
gentle pressure, and should be easily removed without causing pain
or depositing adhesive residue. Useful adhesives need to adhere
well to human skin during perspiration, when the weather is hot, or
in an environment of draining wounds.
[0003] Painless removal of adhesive articles from hair-covered
regions of skin is especially difficult. For such regions, a soft
adhesive with minimal viscoelastic loss is required. Hydrogels have
been used effectively for such purposes, but have their own
disadvantages, including high price, special packaging and release
layers to retain the moisture (typically about 40% of the total
adhesive), as well as variations in properties during use in
response to changes in humidity.
[0004] Commonly assigned U.S. Pat. No. 5,559,165 improved upon the
state of the art by providing a hot melt pressure sensitive
adhesive having the desirable characteristics of a hydrogel, but
not the drawbacks associated with their use. While U.S. Pat. No.
5,559,165 represents a substantial contribution to the art, there
continues to be a need for improvements and modifications in hot
melt adhesives for use in dermal applications, in particular hot
melt adhesives which leave no residue upon removal from the
skin.
SUMMARY OF THE INVENTION
[0005] The invention provides a hot melt pressure sensitive
adhesive especially suited for adhesive skin application, including
transdermal drug delivery applications. The invention is based on
the discovery that hot melt pressure sensitive adhesives formulated
with higher mid-block Tg's and less liquid diluent, in particular
less liquid tackifier, than conventional hot melt pressure
sensitive adhesives heretofore known and used in the art give good
skin adhesion and leaves less adhesive residue on the skin.
[0006] One aspect of the invention is directed to a pressure
sensitive hot melt adhesive composition. The adhesive comprises
high molecular weight rubber and less than about 60 parts by
weight, more preferably from about 35 to about 55 parts by weight,
based on the total weight of the composition, of a liquid diluent.
Preferred adhesive compositions of the invention comprise from
about 1 to about 20 parts by weight of a high molecular weight
rubber triblock or radial block copolymer, from 0 to about 20 parts
by weight of a high molecular weight diblock rubber, 0 to about 10
parts by weight of other compatible high molecular weight polymers,
0 to about 30 parts by weight of an end block resin, 0 to less that
about 60 parts by weight oil or other liquid midblock diluent, 0 to
about 60 parts by weight of a solid tackifier and 0 to about 3
parts by weight of an anti-oxidant.
[0007] Another aspect of the invention is directed to a transdermal
drug delivery system comprising a pressure sensitive hot melt
adhesive and a therapeutic agent. The agent, while physiologically
active, may or may not be pharmaceutically active. In one
embodiment, the adhesive serves as a carrier for the
physiologically active agent.
[0008] Still another aspect of the invention is directed to a
transdermal drug delivery system comprising an adhesive layer, a
therapeutic agent and a backing layer. In one embodiment, the drug
delivery system also comprises a release layer. In another
embodiment of the drug delivery system the drug to be delivered is
incorporated into the adhesive.
[0009] Yet another aspect of the invention is directed to a method
of administering a therapeutic agent to a patient comprising
applying to a body surface of the patient a transdermal drug
delivery system comprising a pressure sensitive hot melt adhesive
and a physiologically active agent.
DETAILED DESCRIPTION OF THE INVENTION
[0010] The disclosures of all documents cited herein are
incorporated in their entireties by reference.
[0011] As used herein, the term "pressure-sensitive adhesive"
refers to a viscoelastic material which adheres instantaneously to
most substrates with the application of slight pressure and remains
permanently tacky. A polymer is a pressure-sensitive adhesive
within the meaning of the term as used herein if it has the
properties of a pressure-sensitive adhesive per se or functions as
a pressure-sensitive adhesive by admixture with tackifiers,
plasticizers or other additives.
[0012] Preferred adhesives will generally have a midbock Tg of from
about -30.degree. C. to about room temperature, more preferable
from about -30.degree. C. to about 10.degree. C. Useful adhesives
will preferably have a G' (storage modulus) less than about
15.times.10.sup.4 dynes/cm.sup.2 at 10 rad/s. (25.degree. C.),
preferably at least about 1.times.10.sup.4 and most preferably from
about 4 to 10.times.10.sup.4 dynes/cm.sup.2. Low G' provides a soft
adhesive that easily wets at rough surfaces such as skin. The
adhesives will also preferable have a G" (loss modulus) of about 1
to 6.times.10.sup.4 dynes/cm.sup.2. It has been found that
maintaining G" within this range ensures adequate hold while
ensuring painless removal. A tensile strength greater than 10 psi
is necessary to ensure that the adhesive does not fail cohesively
upon removal.
[0013] As used herein the term "high molecular weight rubbers" are
those having a viscosity at 25.degree. C. of above 1,000 cP in
toluene at a concentration of 20% by weight.
[0014] In the case of the high viscosity triblock copolymers
employed herein, they may have the more general configuration A-B-A
wherein the polymer blocks A are non-elastomeric polymer blocks
which, as homopolymers have glass transition temperatures above
20.degree. C., while the elastomeric polymer blocks B are isoprene,
or butadiene which may be partially or substantially hydrogenated
or mixtures thereof. Further, the copolymers may be linear or
branched. Typical branched structures contain an elastomeric
portion with at least three branches which can radiate out from a
central hub or can be otherwise coupled together. The amount of the
triblock component is preferably from about 1 to about 20 parts by
weight, more preferably about 3 to about 8 parts by weight.
[0015] The non-elastomeric blocks may comprise homopolymers or
copolymers of vinyl monomers such as vinyl arenes, vinyl pyridines,
vinyl halides and vinyl carboxylates, as well as acrylic monomers
such as acrylonitrile, methacrylonitrile, esters of acrylic acids,
etc. Monovinyl aromatic hydrocarbons include particularly those of
the benzene series such as styrene, vinyl toluene, vinyl xylene,
ethyl vinyl benzene as well as dicyclic monovinyl compounds such as
vinyl naphthalene and the like. Other non-elastomeric polymer
blocks may be derived from alpha olefins, alkylene oxides, acetals,
urethanes, etc. Styrene is preferred.
[0016] The elastomeric block component making up the remainder of
the copolymer is isoprene or butadiene which may be hydrogenated as
taught, for example, in U.S. Pat. No. 3,700,633. This hydrogenation
of butadiene may be either partially or substantially complete.
Selected conditions may be employed for example to hydrogenate the
elastomeric butadiene block while not so modifying the vinyl arene
polymer blocks. Other conditions may be chosen to hydrogenate
substantially uniformly along the polymer chain, both the
elastomeric and non-elastomeric blocks thereof being hydrogenated
to practically the same extent, which may be either partial or
substantially complete. Hydrogenated polymers are preferred to
minimize degradation during processing, which is a more severe
problem with higher molecular weight polymers.
[0017] The high viscosity triblock copolymer of the invention can
have a broad range of non-elastomeric end block to elastomeric
center block ratio of approximately about 5:95 or less to about
40:60 or higher. Examples of high viscosity triblock copolymers
that can be utilized to achieve one or more of the novel properties
of the present invention are styrene-ethylene-butylene-styrene
block copolymers (SEBS) available from Shell Chemical Company and
Pecten Chemical Company under trade designations Kraton G 1651,
Kraton G 1654, Kraton G 4600, Kraton G 4609 and the like. Other
grades of (SEBS) polymers can also be utilized in the present
invention provided such SEBS polymers exhibits the required high
viscosity. Such SEBS polymers include (high viscosity) Kraton G
1855X which has a Specific Gravity of 0.92, Brookfield Viscosity of
a 25 weight percent solids solution in toluene at 25.degree. C. of
about 40,000 cps or about 8,000 to about 20,000 cps at a 20 weight
percent solids solution in toluene at 25.degree. C. Although the
typical ratio values for Kraton G 1651, 4600, and 4609 are
approximately about 33:67 and for Kraton G 1855X approximately
about 27:73, as noted previously, these ratios can vary broadly
from the typical product specification values.
[0018] It is preferred that the adhesive additionally contain up to
20, preferably 3 to 8, parts by weight of a high molecular weight
(i.e., viscosity>1000 cps at 25.degree. C. at 20% in toluene)
diblock polymer of the general A-B configuration where A and B are
as described previously. Preferred are Kraton G 1701X or 1702X
which are both styrene ethylene propylene diblock polymers. Kraton
G1702X is most preferred While the adhesive formulation preferably
contains some diblock polymer, the diblock may be replaced entirely
or in part with another high molecular weight polymer that is
compatible with the system. For example, polyisobutylene (e.g.,
Vistanex from Exxon), polyisoprene (e.g., from Kuraray), or
styrene/butadiene copolymer (e.g., Plioflex from Goodyear) may be
used in amounts of about 2 to 10 parts by weight.
[0019] As will be described hereinbelow, various additives are
known to associate with the particular blocks (domains) of the
block polymer(s), altering the behavior of those portions
accordingly. In more detail, the mid-block portion or domain (i.e.,
the "B-block") of the polymer needs to have a Tg less than about
room temperature. As other mid-block compatible components such as
plasticizing oils and tackifiers are added, these components
associate with the B domains swelling them and generally resulting
in a change in the Tg thereof. For most pressure sensitive adhesive
applications, a Tg in the range of about 0.degree. C. to 25.degree.
C., preferably about 15.degree. C. is desirable; however, for use
herein mid-block Tg ranges from -30.degree. C. up to about
10.degree. C., more preferably from about -20.degree. C. to about
0.degree. C. are required.
[0020] The practice of the invention, the amount of liquid diluents
is less than about 60 parts by weight. In a preferred embodiment,
the majority of the liquid diluent is oil. Preferable any liquid
diluent used is an oil diluent. A useful diluent is primarily
aliphatic in character and is compatible with the polymer midblock.
Included in these materials are plasticizers such as paraffinic and
naphthenic petroleum oils, highly refined aromatic-free paraffinic
and naphthenic food and technical grade white petroleum mineral
oils, and liquid tackifiers such as the synthetic liquid oligomers
of polybutene, polypropene, polyterpene, etc. The synthetic series
process oils are high viscosity oligomers which are permanently
fluid liquid monolefins, isoparaffins or paraffins of moderate to
high molecular weight. Liquid plasticizing or tackifying diluents
include polyterpenes such as Wingtack 10 available from Goodyear,
and Escorez 2520 based on a C5 feed stream available from Exxon
Chemical. Other liquid diluents would include polyisoprene,
available as LIR 50 from Kuraray, Amoco's polybutenes available
under the name Indopol. Most preferred are white paraffinic
oils.
[0021] There may also be present up to 60 parts, preferably 30 to
50 parts by weight of a solid tackifier (i.e., one having a Ring
and Ball softening point above 25.degree. C.) which is compatible
with the midblock. Suitable tackifiers include any compatible
resins or mixtures thereof such as (1) natural or modified rosins
such, for example, as gum rosin, wood rosin, tall-oil rosin,
distilled rosin, hydrogenated rosin, dimerized rosin, and
polymerized rosin; (2) glycerol and pentaerythritol esters of
natural or modified rosins, such, for example as the glycerol ester
of pale, wood rosin, the glycerol ester of hydrogenated rosin, the
glycerol ester of polymerized rosin, the pentaerythritol ester of
hydrogenated rosin, and the phenolic-modified pentaerythritol ester
of rosin; (3) copolymers and terpolymers of natural terpenes, e.g.,
styrene/terpene and alpha methyl styrene/terpene; (4) polyterpene
resins having a softening point, as determined by ASTM method
E28,58T, of from about 80.degree. to 150.degree. C.; the latter
polyterpene resins generally resulting from the polymerization of
terpene hydrocarbons, such as the bicyclic monoterpene known as
pinene, in the presence of Friedel-Crafts catalysts at moderately
low temperatures; also included are the hydrogenated polyterpene
resins; (5) phenolic modified terpene resins and hydrogenated
derivatives thereof, for example, as the resin product resulting
from the condensation, in an acidic medium, of a bicyclic terpene
and phenol; (6) aliphatic petroleum hydrocarbon resins having a
Ball and Ring softening point of from about 70.degree. to
135.degree. C.; the latter resins resulting from the polymerization
of monomers consisting of primarily of olefins and diolefins; also
included are the hydrogenated aliphatic petroleum hydrocarbon
resins; (7) alicyclic petroleum hydrocarbon resins and the
hydrogenated derivatives thereof; and (8) aliphatic/aromatic or
cycloaliphatic/aromatic copolymers and their hydrogenated
derivatives.
[0022] Preferred tackifiers for use herein include polyterpenes
such as Piccolyte A125 from Hercules; aliphatic resins such as
Wingtack 95 from Goodyear; cycloaliphatic resins such as Eastotac
H100 from Eastman; and aliphatic/aromatic or
cycloaliphatic/aromatic resins such as ECR 149B or ECR 179A from
Exxon Chemical. Most preferred are the aliphatic or cycloaliphatic
resins while the least desirable are the rosin esters or phenolic
modified polyterpenes are least preferred.
[0023] The desirability and selection of the particular tackifying
agent is, in large part, dependent upon the specific block
copolymer employed.
[0024] Additionally, it may be desirable to incorporate in the
adhesive up to 30 parts by weight of an end block resin. End block
resins are those resins which reside predominantly in the
non-elastomer domains of the rubber after the adhesive is cooled.
Representative of such resins are the primarily aromatic resins
based on mixed C9 petroleum distillation streams such as the Picco
materials available from Hercules, or resins based on pure or mixed
monomer streams of aromatic monomers such as homo or copolymers of
vinyl toluene, styrene, alpha-methyl styrene, coumarone or indene.
Preferred are those based on alpha-methyl styrene available from
Hercules under the Kristalex trade name. If present, the end block
resin is generally used in an amount of 5 to 30 parts by weight,
preferably less than 20 parts.
[0025] Optionally there may also be present 0 to 5% by weight of a
wax component such as the polyethylene waxes available from
Allied-Signal under the A-C symbol. If used, the wax is generally
present in an amount of at least 2 parts by weight.
[0026] Finally, antioxidants typically used in the production of
rubber based pressure sensitive adhesives may be present in an
amount up to about 3 parts by weight. Among the applicable
stabilizers or antioxidants utilized herein are included high
molecular weight hindered phenols and multifunctional phenols such
as sulfur and phosphorous-containing phenols. Hindered phenols are
well known to those skilled in the art and may be characterized as
phenolic compounds which also contain sterically bulky radicals in
close proximity to the phenolic hydroxyl group hereof. In
particular, tertiary butyl groups generally are substituted onto
the benzene ring in at least one of the ortho positions relative to
the phenolic hydroxy group. The presence of these sterically bulky
substituted radicals in the vicinity of the hydroxyl group serves
to retard its stretching frequency and, correspondingly, its
reactivity; this steric hindrance thus providing the phenolic
compound with its stabilizing properties. Representative hindered
phenols include: 1,3,5-trimethyl 2,4,6-tris
(3,5-di-tert-butyl-4-hydroxybenzyl) benzene; pentaerythrityl
tetrakis-3(3,5-di-tert-butyl-4-hydroxyphenyl)-propionate;
4,4'-methylenebis (2,6-tert-butylphenol); 4,4'-thiobis
(6-tert-butyl-o-cresol); 2,6-di-tert-butylphenol;
6-(4-hydroxyphenoxy)-2,- 4-bis(n-octylthio)-1,2,5-triazine;
di-n-octadecyl 3,5-di-tert-butyl-4-hydr- oxybenzyl phosphonate;
2-(n-octylthio)ethyl 3,5-di-tert-butyl-4-hydroxyben- zoate; and
sorbitol hexa[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-propionate]-
.
[0027] As was noted above, there are a variety of ways to formulate
the particular raw materials in order to obtain an adhesive having
the desired midblock Tg, G' and G" values. Moreover, the particular
end use for which the adhesive is intended will also affect the
choice of materials and the ultimate Tg, G' and G" values. In
general, it has been found that the triblock rubber provides the
set of the adhesive into a gelatinous solid, while the diblock
rubber improves the tack of the formulation. The end block resin
provides strength to the adhesive formulation while lowering its
melt viscosity by reducing the self-association of the rubber end
blocks when molten. In formulating the adhesives, predominately
liquid diluents are used to ensure a low Tg for the matrix
(midblock portion) of the formulation. A low Tg leads to fast
polymer relaxation times which in turn lead to low pain upon
removal of the adhesive.
[0028] Using the above parameters as guidelines, it has been found
that particularly preferred adhesives may be prepared from about 10
parts of polymer, equally split between triblock and diblock,
preferably Kraton G 1651 and Kraton G1702, respectively. These
rubbers are used in combination with 5 to 30 parts, preferably
10-20 parts of end block resin, with Kristalex a-methyl styrene
resins most preferred. The remainder of the product is diluent and
tackifier. The lower the blend Tg of the remainder, the less tack
and lower peel the adhesive will exhibit. A particularly preferred
hot melt adhesive composition comprises 3 to 8 parts of the
triblock polymer, 3 to 8 parts diblock, 5 to 30 parts end block
resin, the remainder (to 100 parts) comprising an oil a solid
tackifier.
[0029] The resultant hot melt adhesives are useful as ostomy seals,
adhesive tapes and bandages, wound drainage adhesive seals, wound
dressings, as adherents for other products and the like that adhere
to human skin and remain adherent even in a moist environment. The
adhesive of the invention is particularly well-suited for use in
transdermal applications. The pressure sensitive adhesive of the
invention may be incorporated into a transdermal drug delivery
device designed to deliver a therapeutically effective amount of a
product to the skin of a patient, e.g., to cure a skin irritation
or to deliver a therapeutically effective amount of drug across the
skin of a patient.
[0030] The term transdermal refers to the use of the skin as a
portal for the administration of drugs by topical application. The
topically applied drug passes into and/or through the skin. The
terms skin, derma and epidermis are used interchangeably herein.
Thus "transdermal" is used broadly to refer to the topical
administration of a drug which acts locally, i.e., at the surface
or within the skin, such as, for example, a blemish patch used to
treat acne, and to the topical application of a drug which acts
systemically by diffusing through the skin and entering the blood
stream.
[0031] The term patient is used herein to include animals, both
human and non-human. Human patients include adults, children and
infants. Non-human patients include companion animals such as dogs,
cats and horses and livestock such as cattle and swine.
Agricultural and horticultural applications are also
contemplated.
[0032] The adhesive of the invention is contemplated for use in the
manufacture of liquid reservoir patches and matrix patches. Matrix
patches are particularly preferred embodiments since they are
easier to manufacture than liquid reservoir patches and are more
comfortable and convenient to wear.
[0033] Transdermal drug delivery devices of the invention comprise
a carrier (such as liquid, gel, or solid matrix, or a pressure
sensitive adhesive) into which the drug to be delivered is
incorporated, a distal backing layer and a proximal release layer.
When the patient peels the release liner from the adhesive and
applies the patch, the drug partitions into the stratum corneum
(outer skin layer) and permeates through the epidermis and
dermis.
[0034] While the invention will be described in more detail in
terms of a matrix-type patch, patches of the types described in
Pfister et al., Chemistry in Britain, January 1991, pages 43-46,
the disclosure of which is incorporated herein by reference,
including liquid reservoir-type systems, are encompassed by the
invention. Included are embodiments wherein the drug-containing
polymeric phase is laminated to a pressure sensitive adhesive or
used with an overlay adhesive or is the adhesive itself.
[0035] A matrix patch device according to the present invention is
a unit dosage form of a drug composition in a polymeric carrier.
The individual layers of the device include a substantially
drug-impermeable distal backing layer, the aforementioned drug
laden polymer carrier layer, also referred to herein as the
carrier, and, before transdermal application, a substantially
drug-impermeable proximal release layer or liner.
[0036] The portions of the carrier that are not in contact with the
skin are covered by a backing. The distal backing layer, in use,
defines the side of the patch that faces the environment, i.e.,
distal to the skin. The backing serves to protect the carrier and
the components contained in the carrier, including the drug, from
the environment by providing an impenetrable layer that prevents
loss of the drug to the environment. Thus, the material chosen
should be substantially impermeable to the drug. Advantageously,
the backing material can be opaque to protect the drug from
degradation from exposure to light. It may be desirable that the
backing have a relatively high vapor transmission rate, since this
results in the reduction of moisture buildup on the skin beneath
the device and in a corresponding reduction in the amount of skin
maceration that occurs. Conversely, to enhance drug flux, an
occlusive backing may be selected. Further, the backing layer
should be capable of binding to and supporting the other layers of
the device, yet should be pliable to accommodate the movements of a
person using the device since a stiff backing may cause mechanical
irritation. In order to maintain the health of the covered skin
during long term wear (e.g., for periods in excess of a day), it is
also desirable that the backing have a relatively high permeability
to oxygen. As the backing is in contact with the components of the
carrier, including the drug and any excipients, it is important
that the backing be stable to such components in order that the
backing retains its structural integrity and conformability. It is
also important that the backing not absorb the drug or excipients
from the carrier. In connection with the preparation of certain
reservoir type drug delivery devices, it is also desirable for the
backing to be heat sealable at a relatively low temperature to a
variety of other polymeric substrates.
[0037] Backings that have found use in drug delivery devices, and
which can be used in the practice of this invention include, with
or without modification, metal foils, metalized polyfoils,
composite foils or films containing poytetrafluoroethylene
(TEFLON.RTM.)-type materials or equivalents thereof, polyether
block amide copolymers, polyurethanes, polyvinylidene chloride,
nylon, silicone elastomers, rubber-based poylisobutylene styrene,
styrene-butadiene and styrene-isoprene copolymers, polyethylene,
polyester, and other such materials used in the art of transdermal
drug delivery. Particularly preferred are thermoplastic polymers
such as polyolefins, for example polyethylene and polypropylene,
and polyesters such as polyethyleneterephthalate.
[0038] The proximal release liner or peelable film covers the
skin-facing or proximal side of the device until the device is
used. A silicone-coated film is typically used for such
applications. Just prior to use of the device, the proximal release
liner is removed to expose the drug-containing polymer layer for
contact and adhesion to the skin surface. Thus, the proximal
release liner is adapted to be removed from the device and should
strip off the adhesive surface with minimal force.
[0039] In one embodiment, the release liner of a first patch also
serves as the backing layer of a second patch. This design allows
patches to be manufactured in a stacked format, and dispensed to
the patient in this manner. The first patch is removed, and applied
to the skin, with no excess waste generated for disposal.
[0040] The drug containing polymer layer is preferably a
pressure-sensitive skin contact adhesive of the invention which is
a pharmaceutically acceptable material that lacks functional groups
containing reactive hydrogen moieties and forms no new functional
groups upon storage. The adhesive of the invention, whether used as
a carrier contact adhesive or overlay contact adhesive for
transdermal patches is non-irritating, easy to apply, and easy to
remove.
[0041] The term "drug" is to be construed herein in its broadest
sense to mean any agent which is intended to produce some
therapeutic benefit. The agent may or may not be pharmaceutically
active, but will be "bioactive" in the sense that it has an effect
on the human body. The agent may be used to treat or alter a
condition, which may or may not be a pathological, i.e., a disease
state. "Drug", "bioactive agent," "preparation," "medicament,"
"therapeutic agent," "physiological agent" and "pharmaceutical
agent" are used interchangeably herein and include substances for
use in the diagnosis, cure, mitigation, arrest, treatment or
prevention of a condition or disease state or to affect the
structure or function of the body. Skin-wellness agents that
function to e.g., soften and moisturize are included in this term.
The term "treatment" is used broadly to encompass prevention,
alteration, cure and control of the condition.
[0042] The drug is present in a drug delivery device of the
invention in a therapeutically effective amount, i.e., an amount
effective to bring about a desired therapeutic result in the
treatment of a condition to which the preparation of this invention
is to be applied. Effective amount of a drug means a nontoxic but
sufficient amount of a drug to provide the selected effect over a
specific period of time. The amount that constitutes a
therapeutically effective amount varies according to the particular
drug incorporated in the device, the condition being treated, any
drugs being co-administered with the selected drug, desired
duration of treatment, the surface area of the skin over which the
device is to be placed, and other components of the drug delivery
device. Such an amount is readily determinable by the skilled
practitioner.
[0043] Drugs that can be included in the carrier of the invention
include substances capable of a local or a systemic effect when
administered to the skin. While it will be appreciated that the
invention enables the administration of drugs containing a reactive
functional group, which drugs have heretofore not been able to be
administered by the transdermal route using conventional acrylic
adhesives, the invention is not limited to the administration of
these types of drugs. Other drugs previously administered via the
transdermal route using conventional acrylic adhesives,
polyisobutylene-based adhesives or silicone adhesives may also be
administered using the adhesive of the invention, either alone or
in combination with another drug.
[0044] Treatment areas where the delivery device of the invention
finds use, and examples of pharmaceutical products which can be
incorporated in the devices of the invention, include treatment for
incontinence (oxybutinin), central nervous system conditions
(methylphenidate), hormone therapy and birth control (estradiol,
testosterone, progestin, progesterone, levonorgestrel)
cardiovascular (nitroglycerin, clonidine) and cardiotonics (e.g.,
digitalis, digoxin), pain management or anti-inflammatory
(fentanyl, lidocaine, diclofenac, flurbiprofen), cosmetic (benzoyl
peroxide, salicylic acid, vitamin C, vitamin E, aromatic oils),
antinauseants (scopalamine), smoking cessation (nicotine),
antiinflammatory conditions, both steroidal (e.g., hydrocortisone,
prednisolone, triamcinolone) and nonsteroidal (e.g., naproxen,
piroxicam) treatments, antibacterials (e.g., penicillins such as
penicillin V, cephalosporins such as cephalexin, erythromycin,
tetracycline, gentamycin, sulfathiazole, nitrofurantoin, and
quinolones such as norfloxacin, flumequine, and ibafloxacin),
antiprotazoals (e.g., metronidazole), antifungals (e.g. nystatin),
calcium channel blockers (e.g. nifedipine, diltiazem),
bronchodilators (e.g., theophylline, pirbuterol, salmeterol,
isoproterenol), enzyme inhibitors such as collagenase inhibitors,
protease inhibitors, elastase inhibitors, lipoxygenase inhibitors,
and angiotensin converting enzyme inhibitors (e.g., captopril,
lisinopril), other antihypertensives (e.g., propranolol),
leukotriene antagonists, anti-ulceratives such as H2 antagonists,
antivirals and/or immunomodulators (e.g.,
1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine,
1-(2-hydroxy-2-methyl-propy- l)-1
H-imidazo[4,5-c]quinoline-4-amine, and acyclovir), local
anesthetics (e.g., benzocaine, propofol), antitussives (e.g.,
codeine, dextromethorphan), antihistamines (e.g., diphenhydramine,
chlorpheniramine, terfenadine), narcotic analgesics (e.g.,
morphine, fentanyl), cardioactive products such as atriopeptides,
anticonvulsants (e.g., carbamazine), immunosuppressives (e.g.,
cyclosporine), psychotherapeutics (e.g., diazepam), sedatives
(e.g., phenobarbital), anticoagulants (e.g., heparin), analgesics
(e.g., acetaminophen), antimigrane agents (e.g., ergotamine,
melatonin, sumatriptan), antiarrhythmic agents (e.g., flecainide),
antiemetics (e.g., metaclopromide, ondansetron), anticancer agents
(e.g., methotrexate), neurologic agents such as anxiolytic drugs,
hemostatics, anti-obesity agents, and the like, as well as
pharmaceutically acceptable salts, esters, solvates and clathrates
thereof.
[0045] Veterinary drugs may also be conveniently applied using the
transdermal drug delivery device of the invention. In addition to
many of the above mentioned drugs, which can also be used in
veterinary applications, additional examples include e.g.,
diclazuril and lufenuron.
[0046] Agricultural and horticultural agents include, for example
orchid growth hormone.
[0047] It will be appreciated that transdermal drug delivery in
veterinary and horticultural applications enables more exact
dosing, and less waste than administration in the food/irrigation
water.
[0048] The skin presents a substantial barrier to ingress of
foreign substances into the body. The art has recognized that the
barrier to the transdermal or percutaneous delivery of drug through
the skin can be overcome or reduced by incorporating excipients
into the carrier that enhance the rate at which the drug passes,
i.e., penetrates, through the skin. Penetration enhancers are
well-known in the art. The terms "enhancement", "penetration
enhancement," and permeation enhancement" mean an increase in the
permeability of a biological membrane, e.g., skin, to a drug, so as
to increase the rate at which the drug permeates through the
membrane and accelerate drug delivery. These agents are commonly
referred to as penetration enhancers, accelerants, adjuvants and
absorption promoters, and will be collectively referred to herein
as "enhancers".
[0049] The drug delivery system of the invention, in addition to
the drug, may advantageously also contain an effective amount of a
penetration enhancer. An effective amount of a penetration enhancer
means an amount that provides a selected increase in membrane
permeability, rate of administration and amount of drug.
[0050] Some examples of enhancers are polyhydric alcohols such as
dipropylene glycol, propylene glycol, and polyethylene glycol; oils
such as olive oil, squalene, and lanolin; polyethylene glycol
ethers and fatty ethers such as cetyl ether and oleyl ether; fatty
acid esters such as isopropyl myristate; fatty acid alcohols such
as oleyl alcohol; urea and urea derivatives such as allantoin;
polar solvents such as dimethyidecylphosphoxide,
methyloctylsulfoxide, dimethyllaurylamide, didecylpyrrolidone,
isosorbitol, dimethylacetonide, dimethylsulfoxide,
decylmethylsulfoxide, and dimethylformamide; salicylic acid; amino
acids; benzyl nicotinate; bile salts; and higher molecular weight
aliphatic surfactants such as lauryl sulfate salts. Other agents
include oleic and linoleic acids, ascorbic acid, panthenol
butylated hydroxytoluene, tocopherol, tocopheryl acetate,
tocopheryl lineleate, propyloleate, isopropyl palmitate, oleamide,
polyoxyethylene (4) lauryl ether, polyoxyethylene (2) oleyl ether
and polyoxyethylene (10) oleyl ether sold under the trademarks Brij
30, 93 and 97 by ICI Americas, Inc., and polysorbate 20 sold under
the trademark Tween 20 by ICI Americas, Inc.
[0051] Some drugs function as plasticizers in the adhesive because
they are soluble to a certain degree in the polymers comprising the
adhesive. When a drug or enhancer modifies the adhesive character
of the formulated adhesive, it will generally be necessary to
reformulate the adhesive to compensate. For drug molecules which
are not sufficiently soluble in the polymer system, a co-solvent
for the drug can be added. Co-solvents, such as lecithin, retinol
derivatives, tocopherol, dipropylene glycol, triacetin, propylene
glycol, saturated and unsaturated fatty acids, mineral oil,
alcohols, butyl benzylphthalate, and the like are useful depending
on the solubility of the drug in the adhesive carrier.
[0052] The formulated component of a transdermal patch device may
also include, a controlled-viscosity composition, excipients,
diluents, emollients, plasticizers, anti-irritants, opacifiers,
fillers, such as clay and silica, pigments and mixtures thereof,
preservatives, as well as other components or additives that are
formulated for maintaining the drug composition in the polymeric
layer in a drug transferring relationship with the derma, e.g.,
skin, as appropriate for specific applications and which is adapted
to adhere to the skin at the application site.
[0053] The device of the invention is placed on the skin and
allowed to remain for a time sufficient to achieve or maintain the
intended therapeutic effect. The time that constitutes a sufficient
time can be selected by those skilled in the art with consideration
of the flux rate of the device of the invention and of the
condition being treated.
[0054] The transdermal delivery devices of the invention can be
made in the form of an article such as a tape, a patch, a sheet, a
dressing or any other form known to those skilled in the art. The
dosage system may be produced in any desirable unit form. A
circular form is convenient as it contains no corners which might
be easily detached from the skin. In addition to having various
shapes, the dosage units produced may come in various sizes.
[0055] Generally the device will be in the form of a patch of a
size suitable to deliver a preselected amount of drug through the
skin. A surface area in the range of 1 to 200 cm.sup.2 is
contemplated and preferred sizes are 5, 10, 15, 20, 25 and 30
cm.sup.2. The thickness may vary over a wide range, typically from
about 1 to about 5 mil, preferably 3 to 4 mil thick. The present
invention preferably incorporates enough pharmaceutically active
drug to provide efficacy with a dosage system having a 5 cm.sup.2
surface area and a thickness of about 3 to 4 Depending on the
design of the patch and the condition to be treated, the patch will
remain on the skin for up to an hour or more, up to about one week.
In a preferred embodiment, the patch is designed to remain on the
skin at the application site for about 24 hours, and to be changed
daily. Preferably, the patch will be placed on the skin at a site
different from the location of the previously used patches.
[0056] A drug delivery device of the invention can be prepared by
using conventional methods to apply an appropriate carrier to the
backing. For example, a matrix device can be manufactured by
preparing a coating formulation by mixing a solution of the
adhesive in a solvent with the drug and any excipients to form a
homogeneous solution or suspension; applying the formulation to a
substrate (a backing or a release liner) using well known knife or
bar or extrusion die coating methods; drying the coated substrate
to remove the solvent; and laminating the exposed surface to a
release liner or backing. The invention will be described further
in the following examples, which are included for purposes of
illustration and are not intended, in any way, to be limiting of
the scope of the invention.
[0057] In the examples which follow, unless otherwise specified,
all parts are by weight and all temperatures in degree Celsius.
[0058] All viscosities were measured using a Brookfield viscometer
with a #27 spindle.
EXAMPLES
[0059] All the formulations described herein were prepared in a 600
g Brabender mixer with sigma blades. The rubbers and about half the
oil in the formulation were added to the bowl preheated to about
325.degree. F. Once homogenous, solid tackifers were added followed
by additional oil. The formulations are shown in Table 1
wherein:
[0060] Septon 4055 is an SEBPS polymer with styrene end blocks and
a hydrogenated isoprene/butadiene mid block available from Kuraray.
At 5% by weight in toluene at 30.degree. C. it exhibits a viscosity
of 5800 cP.
[0061] Kraton G1702 is a diblock copolymer of styrene and
hydrogenated isoprene available from Shell Chemical. At 10% by
weight in toluene at 25.degree. C. it exhibits a viscosity of 3180
cP.
[0062] Kristalex 3085 and 5140 are alpha-methyl stryene/styrene end
block resins available from Hercules with softening points of
85.degree. C. and 140.degree. C., respectively.
[0063] Regalite R-10 is an aliphatic liquid resin with a softening
point of 10.degree. C. available from Hercules.
[0064] Luminol T350 is a paraffinic white oil available from
Petrocanada.
[0065] Kaydol is a napthenic white oil available from Witco.
[0066] Escorez 5340, 5400 and 5415 are cycloaliphatic resins
available from Exxon Chemical with softening points of 140.degree.
C., 103.degree. C. and 118.degree. C., respectively.
[0067] Irganox 1010 is a hindered phenol antioxidant available from
Ciba-Geigy.
1TABLE 1 ADHESIVE FORMULATIONS Compar- Compar- Compar- ative ative
ative Composition Example 1 Example 2 Example 3 Example 4 Example 5
Septon 4055 5 5 5 5 5 Kraton 5 5 5 5 5 G1702 Kristalex 15 15 -- 15
15 3085 Kristalex -- -- 5 -- -- 5140 Regalite 65 40 -- -- -- R-10
Luminol -- 20 -- 40 45 T350 Kaydol -- -- 65 -- -- Escorex -- -- 25
-- -- 5340 Escorex 15 -- -- -- -- 5400 Escorex -- 20 -- 40 35 5415
Iganox 1010 0.5 0.5 0.5 0.5 0.5
[0068] Test Procedures
[0069] A Rheometrics Dynamic Mechanical Analyzer (Model RDA 700)
was used to obtain the elastic (G') and loss (G") moduli versus
temperature. The instrument was controlled by Rhios software
version 4.3.2. Parallel plates 8 mm in diameter and separated by a
gap of about 2 mm were used. The sample was loaded and then cooled
to about -100.degree. C. and the time program started. The program
test increased the temperature at 5.degree. C. intervals followed
by a soak time at each temperature of 10 seconds. The convection
oven containing the sample was flushed continuously with nitrogen.
The frequency was maintained at 10 rad/s. The initial strain at the
start of the test was 0.05% (at the outer edge of the plates). An
autostrain option in the software was used to maintain an
accurately measurable torque throughout the test. The option was
configured such that the maximum applied strain allowed by the
software was 80%. The autostrain program adjusted the strain at
each temperature increment if warranted using the following
procedure. If the torque was below 200 g-cm the strain was
increased by 25% of the current value. If the torque was above 1200
g-cm it was decreased by 25% of the current value.
[0070] At torques between 200 and 1200 g-cm no change in strain was
made at that temperature increment. The shear storage or elastic
modulus (G') and the shear loss modulus (G") are calculated by the
software from the torque and strain data. Their ratio, G"/G', also
known as the tan delta, was also calculated.
[0071] The mid block Tg was taken as the maximum in tan delta.
[0072] Tensile strength was determined on 0.125" thick, 2.5" long
dogbone shaped portions with 1".times.1" end tabs and a
0.5".times.0.5" central gage portion. These were pulled on an
Instron with pneumatic grips at a speed of 20"/min. Strength was
taken as the maximum stress during the test.
[0073] Two mil thick adhesive drawdowns were made on 1.5 mil
polyester backing film. These were used to conduct loop tack tests
using a TMI loop tack tester on stainless steel plates.
[0074] Peel tests were conducted by bonding one inch wide strips of
adhesive to polished stainless steel using two passes of a 2 kg
roller. After a 20 minute dwell time the adhesive strips were
pulled at 2 inches/minute on an Instron and the average peel force
recorded.
[0075] Ghosting consists of residue left by the adhesive on the
stainless steel plates after the peel test. These determinations
were qualitative.
[0076] The adhesive properties of the resulting formulation are
shown in Table 2.
2TABLE 2 ADHESIVE PROPERTIES Comparative Comparative Comparative
Property Example 1 Example 2 Example 3 Example 4 Example 5
Viscosity (cP) @ 275.degree. F. 299,500 321,000 -- 229,000 -- @
325.degree. F. 10,900 10,525 18,400 9050 4,438 Loop tack
(oz/in.sup.2) 107 .+-. 8 68 .+-. 4 9 .+-. 1 64 .+-. 4 53 .+-. 8
Peel (g/in) 1370 .+-. 110 345 .+-. 25 10 .+-. 1 401 .+-. 39 172
.+-. 12 Ghosting (residue) Heavy Heavy Trace Light Trace G' 16.1
9.4 6.1 114 7.4 (10.sup.4 dynes/cm.sup.2; 25.degree. C.) G" 15.7
4.0 1.6 4.3 2.3 (10.sup.4 dynes/cm.sup.2; 25.degree. C.) Tan delta
(25.degree. C.) 1.0 0.4 0.3 0.4 0.3 Midblock Tg (.degree. C.) 6 -6
-32 -6 -8
[0077] Comparative Example 1 demonstrates that an adhesive with a
high level of liquid tackifer and a G' and G" outside the preferred
range exhibits peel which is too high for skin contact
applications(preferred peel values should be less that 1000 grams)
and heavy residue.
[0078] Comparative Examples 2 and 3 demonstrate that an adhesive
corresponding closely to prior art U.S. Pat. No. 5,559,165. In
Comparative Example 2, the majority of the liquid diluent is
tackifier rather than oil. Comparative Examples 2 and 3 exhibit
either high residue with good peel and tack or minimal residue with
peel and tack that is too low.
[0079] The adhesives of Examples 4 and 5, prepared in accordance
with the invention, show good peel (>100 grams) and tack (>20
oz/in.sup.2), exhibit good cohesive strength and leave minimal
residue.
[0080] Many modifications and variations of this invention can be
made without departing from its spirit and scope, as will be
apparent to those skilled in the art. The specific embodiments
described herein are offered by way of example only, and the
invention is to be limited only by the terms of the appended
claims, along with the full scope of equivalents to which such
claims are entitled.
* * * * *