U.S. patent application number 10/925583 was filed with the patent office on 2005-01-27 for low peak exotherm curable compositions.
Invention is credited to Cipolla, Anthony J., Montgomery, Robert Eric.
Application Number | 20050020696 10/925583 |
Document ID | / |
Family ID | 24207684 |
Filed Date | 2005-01-27 |
United States Patent
Application |
20050020696 |
Kind Code |
A1 |
Montgomery, Robert Eric ; et
al. |
January 27, 2005 |
Low peak exotherm curable compositions
Abstract
Compositions having a curable unsaturated compound, an adhesion
promoter and curing agent which have a peak exotherm of less than
50.degree. C. are disclosed. The compositions when cured are
flexible bioadhesives which are also disclosed. Non-curable
diluents can be included in the compositions. Flexible bioadhesives
formed on biological structures and having low peak exotherms upon
curing of curable compositions to form the flexible bioadhesives
are disclosed. Compositions having a curable unsaturated compound
and a curing agent and a peak exotherm of less than 50.degree. C.
are included in the invention.
Inventors: |
Montgomery, Robert Eric;
(Lee, MA) ; Cipolla, Anthony J.; (Trout Run,
PA) |
Correspondence
Address: |
MAYER, BROWN, ROWE & MAW LLP
190 SOUTH LASALLE ST
CHICAGO
IL
60603-3441
US
|
Family ID: |
24207684 |
Appl. No.: |
10/925583 |
Filed: |
August 25, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10925583 |
Aug 25, 2004 |
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09552994 |
Apr 21, 2000 |
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6800671 |
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Current U.S.
Class: |
514/772.4 |
Current CPC
Class: |
C09D 175/16 20130101;
C08L 75/04 20130101; C08G 18/48 20130101; C08L 75/04 20130101; C08J
2333/14 20130101; A61L 26/0019 20130101; C08J 3/28 20130101; C08G
18/672 20130101; A61L 24/046 20130101; C08G 18/672 20130101; A61L
24/046 20130101; C09J 175/16 20130101; C08L 75/16 20130101; A61L
26/0019 20130101; A61K 9/006 20130101 |
Class at
Publication: |
514/772.4 |
International
Class: |
A61K 047/30 |
Claims
1-55. (Cancelled).
56. A composition comprising: a compound having an unsaturation
index of at least about 500; a curing agent; an adhesion promoter;
and a therapeutic ingredient; wherein the composition is curable
and has a peak exotherm of less than about 50.degree. C.
(120.degree. F.).
57. A composition according to claim 56, further comprising a
non-curable diluent.
58. A composition according to claim 56, wherein the curable
unsaturated compound comprises at least one unsaturated group
selected from the group consisting of methacrylate, acrylate, vinyl
and combinations thereof.
59. A composition according to claim 58, wherein the unsaturated
group is methacrylate.
60. A composition according to claim 56, wherein the curable
unsaturated compound is an oligomer.
61. A composition according to claim 60, wherein the oligomer is a
dimethacrylate oligomer.
62. A composition according to claim 61, wherein the dimethacrylate
oligomer is a dimethacrylate polyetherurethane oligomer.
63. A composition according to claim 56, wherein the peak exotherm
is from about 20.degree. C. to about 45.degree. C.
64. A composition according to claim 56, wherein the peak exotherm
is from about 35.degree. C. to about 40.degree. C.
65. A composition according to claim 56, wherein the adhesion
promoter is selected from the group consisting of poly(acrylic
acid), poly(ethylene oxide), poly(vinyl pyrollidone), poly(maleic
anhydride-co-methyl vinyl ether), karaya gum, guar gum, acacia gum,
carboxypolymethylene, chitosan, hydroxyethyl cellulose, sodium
carboxymethylcellulose, hydroxypropyl cellulose, polycarbophil,
poly(vinyl alcohol), hydroxypropylmethyl cellulose and compatible
combinations thereof.
66. A composition according to claim 56, wherein the adhesion
promoter is polycarbophil.
67. A composition according to claim 56, wherein the curing agent
is a photoinitiator.
68. A composition according to claim 56, further comprising a
bioadhesion synergist.
69. A composition according to claim 68, wherein the bioadhesion
synergist is a divalent metal or an alkali metal ion.
70. A composition according to claim 56, wherein after curing the
composition is a flexible bioadhesive.
71. A composition according to claim 56, further comprising a
curing agent synergist.
72. A composition according to claim 71, wherein the curing agent
synergist is ethyl-4-dimethylaminobenzoate.
73. A composition according to claim 56, further comprising a
silica thickener.
74. A composition according to claim 56, wherein the composition is
substantially free of monomers.
75. A composition according to claim 56, wherein the composition is
monomer free.
76. A composition according to claim 57, wherein the non-curable
diluent has a viscosity of from about 1 centipoise to about 2000
centipoise.
77. A curable composition according to claim 56, further comprising
a light-attenuating pigment.
78. A curable composition according to claim 77, wherein the
light-attenuating pigment is selected from the group consisting of
titanium dioxide and zinc oxide.
79. A composition according to claim 77, wherein the
light-attenuating pigment is present from about 0.0001 percent to
about 10 percent by weight of the composition.
80. A composition according to claim 56, wherein the therapeutic
ingredient is an active drug.
81. A composition according to claim 56, wherein the therapeutic
ingredient is a medicament.
82. A two-part system comprising: a) a first part which comprises a
curing agent; and b) a second part which comprises a curing agent
synergist of the curing agent of the first part, wherein the first
part or the second part or both further comprises a compound having
an unsaturation index of at least 500, a therapeutic ingredient,
and an adhesion promoter, and wherein upon mixing of the first part
and the second part, curing is achieved with a peak exotherm of
less than about 50.degree. C. (120.degree. F.).
83. A composition according to claim 82, wherein the curing agent
is a benzoyl peroxide and the curing agent synergist is
N,N-dimethyl-p-toluidine.
84. A composition according to claim 82, wherein the therapeutic
ingredient is an active drug.
85. A composition according to claim 82, wherein the therapeutic
ingredient is a medicament.
86. A method for forming a flexible bioadhesive on a tissue,
comprising: contacting the tissue with a composition comprising a
compound having an unsaturation index of at least about 500, a
curing agent, a therapeutic ingredient, and an adhesion promoter,
wherein the composition is curable and has a peak exotherm of less
than about 50.degree. C. (120.degree. F.), and curing the
composition to form the flexible bioadhesive on the tissue.
87. A composition according to claim 86, wherein the therapeutic
ingredient is an active drug.
88. A composition according to claim 86, wherein the therapeutic
ingredient is a medicament.
89. A method according to claim 86, wherein the tissue is selected
from the group consisting of skin, mucosa, internal organs, bone,
tendon, cartilage, enamel, dentin, and fingernails.
90. A flexible bioadhesive on a tissue surface prepared by the
method of claim 86.
91. A composition comprising a methacrylated polyetherurethane
oligomer, capric/caprylic triglyceride, polycarbophil,
camphorquinone, and ethyl-4-dimenthylaminobenzoate.
92. A composition according to claim 91, further comprising fumed
silica.
93. A composition according to claim 91, further comprising zinc
oxide.
94. A composition according to claim 91, wherein the composition
comprises a methacrylated polyetherurethane oligomer in an amount
from about 25 percent to about 98 percent by weight based on the
total weight of the composition, capric/caprylic triglyceride in an
amount from about 2 percent to about 50 percent by weight based on
the total weight of the composition, polycarbophil in an amount
from about 10 percent to about 50 percent by weight based on the
total weight of the composition, camphorquinone in an amount from
about 0.05 percent to about 0.30 percent by weight based on the
total weight of the composition, and ethyl-4-dimethylaminobenzoate
in an amount from about 0.1 percent to about 1.0 percent by weight
based on the total weight of the composition.
95. A composition according to claim 91, further comprising a
therapeutic ingredient.
96. A composition according to claim 95, wherein the therapeutic
ingredient is an active drug.
97. A composition according to claim 95, wherein the therapeutic
ingredient is a medicament.
98. A composition comprising a compound having less than about 40%
monomers, an unsaturation index of at least about 500, a curing
agent, a therapeutic ingredient, and an adhesion promoter, wherein
the composition is curable and has a peak exotherm of less than
about 50.degree. C. (120.degree. F.).
99. A method of making a composition comprising the steps of:
selecting a compound having an unsaturation index of at least 500;
and mixing said compound with a curing agent, a therapeutic
ingredient, and an adhesion promoter, wherein the mixture is
curable and has a peak exotherm of less than about 50.degree. C.
(120.degree. F.).
100. The method of claim 99, wherein the curable unsaturated
compound comprises less than about 40% monomers.
101. The method of claim 99, wherein the curable unsaturated
compound is monomer-free.
102. A composition according to claim 99, wherein the therapeutic
ingredient is an active drug.
103. A composition according to claim 99, wherein the therapeutic
ingredient is a medicament.
Description
[0001] The present invention relates to low peak exotherm curable
compositions that upon curing are useful as bioadhesives. The
compositions of the invention call be placed in contact with one or
more skin or mucosal surfaces, or other tissue surfaces, in an
initially liquid or malleable form, then subsequently cured or
polymerized in place to a final flexible solid or rubbery form.
BACKGROUND OF THE INVENTION
[0002] A broad spectrum of bioadhesives and bioadhesive
compositions have been developed, for example, to adhere
transdermal patches to the skin and to affix transmucosal patches
to mucosal surfaces. In general, the purpose of such bioadhesives
is to maintain intimate and prolonged contact with the underlying
living tissue surface, in order to allow for the migration of
medicinals into the body. In addition, bioadhesive compositions
include those that merely adhere a physical barrier, such as a
bandage, to living tissue (primarily for the purpose of protecting
an underlying wound or compromised tissue surface from potential
environmental insults, such as microorganisms). The majority of
such bioadhesives are provided as films of varying thicknesses
that, upon contact with a biological substrate such as skin or
mucosa, display adhesive characteristics suitable for the intended
use. For example, a transdermal patch comprises several layers,
which may include a protective backing, a drug reservoir and/or
matrix, an adhesive layer, and a release film layer. Each layer
serves a unique purpose in the delivery of the active drug from the
patch to the patient. The adhesive layer provides for the intimate
and prolonged contact of the patch with the underlying skin, in
order that the active drug may efficiently migrate from the patch
reservoir and/or matrix into the skin.
[0003] Transmucosal patches are similar in construction, but differ
in their adhesion specificity. Since mucosal surfaces (lining of
the oral cavity, nasal passages, etc) are relatively moist,
effective adhesives generally contain high molecular weight,
water-soluble or -swellable polymers that become entangled with
tissue surface polymers (such as mucins) upon contact with the
moist mucosal surface. Varying the composition of the adhesive
layer of the patch can control the strength and duration of contact
with the mucosal surface. Transmucosal patches (also known as
buccal patches when placed in the oral cavity) can be
unidirectional (that is, it releases a drug only in the direction
of the mucosal surface to which it is attached) or bidirectional
(releases a drug, or other active substance, both in the direction
of the mucosal surface, as well as into the rest of the oral
cavity). A more thorough review of the subject of bioadhesion to
mucosal surfaces can be found in Peppas, N. A. and Sahlin, J. J.,
Hydrogels as Mucoadhesive and Bioadhesive Materials: A Review,
Biomaterials 17 (1996), 1553-1561, which is herein incorporated by
reference.
[0004] Transdermal and transmucosal patches must also display
physical characteristics appropriate to their intended use. Since
the underlying biological substrate to which the patches become
attached is flexible, patient comfort must be provided for by also
formulating and constructing the patches from flexible components.
Patch flexibility also allows for movement of the tissue underlying
the patch without detachment or separation of the adhesive layer
and subsequent loss of the patch.
[0005] One drawback of existing transdermal and transmucosal
patches is their limited ability to conform to biological
substrates that are not relatively flat. For instance, many
transdermal patches are adhered to the upper arm, which is a
relatively flat surface that provides an easy attachment point for
a flat, flexible film patch. However, attachment of such a patch to
a more contoured surface, such as on the knuckles of the hand,
would be problematical without the ability of the patch to flex and
conform in multiple dimensions, especially during movement of the
underlying skin.
[0006] Transmucosal patches suffer from the same limitations of
underlying tissue surface topography, made more difficult by the
complexity and difficulty of adhering to a moist substrate, such as
the oral mucosa lining the inside of the mouth. For this reason,
transmucosal patches are generally small in order to allow them to
be placed in a location that may be relatively flat, thus
increasing the likelihood of successful, long-term adhesion.
[0007] Oral mucosal barrier compositions that are placed in contact
with gingival tissue and cured in place to provide a physical
barrier against contact of the underlying soft tissue with dental
compositions such as tooth bleaching agents and acid etching
compositions have been disclosed. Photopolymerizable dental resins
have been used for this purpose in the past, generally comprising a
curable monomer or blend of monomers (such as bis-GMA and
triethyleneglycol dimethacrylate), together with a curing system
(such as camphorquinone and dimethylaminomethyl methacrylate).
Compositions such as these are described in U.S. Pat. No. 6,048,202
and in WO 98/36700 and are believed to be commercially available
from Ultradent Products, Inc (South Jordan, Utah) under the trade
name OpalDam.TM..
[0008] Clinical evaluation of OpalDam.TM. shows poor adhesion to
the oral mucosa unless the underlying tissue surface is air-dried
and kept free of saliva prior to application of the barrier. In
addition, the cured barrier is rigid, which results in frequent
detachment of the cured barrier during lengthy dental procedures
(such as power bleaching, which employs a heat or light source to
assist in the tooth bleaching process). Barrier failure
(detachment) can result in contact of the underlying soft tissue
with potentially harmful dental agents (such as the high-strength
hydrogen peroxide used in tooth bleaching procedures or phosphoric
acid, used in acid-etching of tooth surfaces prior to bonding
procedures). Yet another disadvantage of OpalDam.TM. is its high
peak exotherm during the curing process. Although temperature
detection and pain threshold limits vary from patient to patient,
it is generally accepted that most individuals can tolerate
temperatures up to about 126.degree. F. on the oral mucosa for only
short periods of time.
[0009] Another disadvantage of currently available dental "resin
dams", as they are called, comes from the inclusion of low
molecular weight monomers, such as triethylene glycol
dimethacrylate, urethane dimethacrylate, and hydroxyethyl
methacrylate. Low molecular weight monomers are known skin
sensitizers and can penetrate quickly into the oral mucosa both
before and after the composition has "cured." See, for example,
Hemmer et al., Journal of the. American Academy of Dermatology, 35,
377-380 (1996); Toby et al., Arch. Dermatol. 120, 1202-1205 (1984);
Kanerva et al., Contact Dermatitis 37, 255-258 (1997); Kanerva et
al., Contact Dermatitis 28, 268-275 (1993); Kanerva et al., Contact
Dermatitis 33, 84-89 (1995). Since a typical free radical
polymerization of low molecular weight monomers will never proceed
to 100 percent completion, there are always residual monomers that
do not participate in the polymerization reaction and thus can
leach out from the polymerized material to cause unwanted skin
reaction and possible health problems.
[0010] U.S. Pat. No. 5,900,245 discloses barriers and coatings
formed by polymerization of polymerizable materials on the surface
of tissue. When formed, these barriers or coatings are compliant
with the tissue, as well as adherent, i.e., are capable of
conforming to the tissue. In order to attain bioadhesion to the
underlying tissue, the compositions described by the inventors must
be polymerized from the tissue surface up; that is, a
polymerization initiator is first placed on the tissue surface,
which is then contacted with a polymerizable composition. When
polymerization is initiated, the reaction starts at the tissue
surface and progresses through the bulk of the polymerizable
composition until the polymerization process is complete. The
inventors claim improved adhesive characteristics for their methods
and products by process. The inventors do not disclose a means for
placing a polymerizable composition on a tissue surface, curing
said polymerizable composition in situ, and obtaining a cured,
adherent material.
[0011] There is a need for compositions that can be placed on a
tissue surface in an initial malleable state, allowed to conform
well to the underlying tissue, and then subsequently cured to a
final flexible bioadhesive. Also, there is a need for a bioadhesive
that has excellent bioadhesive qualities and that is flexible.
Moreover, there is a need for a curable composition that forms a
bioadhesive on a tissue surface upon curing and that does not
generate much heat during the curing process, thus providing for
patient comfort during the curing process. Finally, there is a need
for a bioadhesive that can actively adhere well to both wet and dry
tissue surfaces, obviating the need for extensive tissue
preparation prior to application.
SUMMARY OF THE INVENTION
[0012] These and other objectives are achieved by the present
invention, which provides low peak exotherm curable compositions
which comprise a curable unsaturated compound, a curing agent and
an adhesion promoter, and wherein the composition has a peak
exotherm of less than about 50.degree. C. (120.degree. F.).
[0013] In one embodiment of the invention, the invention provides a
composition which comprises a curable unsaturated compound, a
curing agent and an adhesion promoter, wherein curing takes place
with a peak exotherm of less than about 50.degree. C. (120.degree.
F.).
[0014] In another embodiment of the invention, the invention
provides a composition which comprises a curable unsaturated
compound and a curing agent and wherein curing takes place with a
peak exotherm of less than about 50.degree. C. (120.degree. F).
[0015] Another embodiment of the invention provides a two part
composition which comprises a first part comprising a curable
polymerizable compound comprising unsaturated groups, an adhesion
promoter and a curing agent, and a second part comprising a curable
polymerizable compound comprising unsaturated groups, and a
adhesion promoter, and a curing agent synergist of the curing agent
of the first part, and wherein upon mixing of the first part and
the second part curing takes place with a peak exotherm of less
than about 50.degree. C. (120.degree. F.).
[0016] In another embodiment, the invention provides a method for
forming a flexible bioadhesive on a tissue, comprising contacting
the tissue surface with a composition comprising a curable
unsaturated compound, a curing agent and an adhesion promoter,
wherein the composition has a peak exotherm during curing of less
than about 50.degree. C. (120.degree. F.), and curing the
composition to form the flexible bioadhesive on the tissue.
[0017] Another embodiment of the invention is a flexible
bioadhesive on a tissue surface prepared by contacting the tissue
with a composition of the invention and then curing the composition
to form the flexible bioadhesive on the tissue.
[0018] The compositions of the invention are (1) curable, i.e., can
be transformed from a first liquid, gel, paste, or otherwise
shapeable or malleable form to a second solid or otherwise rubbery
form, (2) form bioadhesives to the underlying living tissue after
curing has occurred, (3) do not generate heat in excess of that
which is tolerable by or damaging to the living organism during the
curing process, and (4) provide a bioadhesive after curing that is
sufficiently flexible to conform to the movements of the underlying
living tissue during the period of time which the bioadhesive is in
use.
DETAILED DESCRIPTION OF THE INVENTION
[0019] In one embodiment, the present invention is directed to
curable compositions that have low peak exotherms. The compositions
of the invention, after curing, are useful as bioadhesives. The
bioadhesives of the invention, prepared by curing the compositions
of the invention, are flexible. In another embodiment of the
invention, the invention provides a method for forming a
bioadhesive on a tissue by curing the compositions of the invention
on the tissue.
[0020] In a preferred embodiment of the invention, the invention is
directed to a composition comprising a blend or mixture of a
curable component, an adhesion promoter, and a curing agent that
upon curing has a low peak exotherm and when cured is a flexible
bioadhesive. The curable component is capable of being cured from
an initial rubbery state, for instance, a liquid, gel, paste, or
putty, to a final non-rubbery state such as a flexible solid. The
adhesion promoter is preferably a water-soluble or water-swellable
polymer that is substantially insoluble in the curable component,
and dispersed throughout it in a finely divided (powdered or
granular) form. The adhesion promoter is thus included as a
plurality of solid particles suspended in a liquid, gel, paste or
semi-liquid matrix. The curing agent component comprises one or
more compounds capable of initiating and propagating a curing
reaction in the curable component. The curing reaction causes the
compositions of the invention to change from an initial malleable
state to a final flexible solid.
[0021] The invention solves the problem of there being too much
heat generated in curing reactions by providing compositions that
during the curing reaction have a low peak exotherm. Many curing
reactions, such as the free-radical polymerization of acrylate and
methacrylate monomers, generate heat as a result of the energetics
of bond formation. Each bond that is formed results in a net
increase in the temperature of the polymerizing mass, resulting in
an initial increase in temperature that peaks at some finite point,
the peak exotherm, after the initiation of polymerization. After
the peak exotherm is reached, the polymerization process may still
proceed, but it cannot sustain any further increase in the bulk
material temperature. The polymerization process effectively ends
when either all of the unsaturated groups have been used up or the
unsaturated groups are constrained within a polymer network that
prevents them from participating in any further reactions.
[0022] In another embodiment of the invention, compositions are
provided which contain a drug or active ingredient and that can be
placed on and allowed to conform to a tissue surface and then
subsequently cured on the tissue surface to become a bioadhesive.
The properties of the resulting bioadhesive allow it to remain
adherent to and compliant with the underlying tissue, which allows
for the effective migration of the contained drug or active
ingredient into the underlying tissue over a long period of
time.
[0023] In a preferred embodiment of the invention, the invention
provides a method of forming a bioadhesive on a tissue. The method
comprises applying compositions of the invention to a tissue
surface, allowing them to conform to the underlying substrate, and
subsequently curing them in situ. The method comprises placing the
compositions of the invention on the tissue surface and
subsequently curing in situ to provide a flexible and compliant
material that is adherent to the underlying tissue, i.e., a
flexible bioadhesive. Such bioadhesives are adherent to the
underlying tissue as a direct result of the flexibility and
compliance of the cured material.
[0024] The cured compositions of the invention (i.e., bioadhesives
of the invention) have a flexible and compliant character and are
able to adapt to the underlying living tissue as it moves and
provide for bioadhesive properties even in the absence of an
adhesion promoter. This adhesion is accomplished through conformity
to the tissue structure, rather than any specific chemical or
physiochemical interaction. The uniquely flexible behavior of the
bioadhesives of the invention enables them to have bioadhesive
properties even without the direct physical or chemical
interactions provided by the presence of an adhesion promoter.
Thus, in one embodiment of the invention, flexible bioadhesives can
be prepared without the presence of an adhesion promoter.
Embodiments of the invention having an adhesion promoter provide
bioadhesives that have an additional source of bioadhesion as
compared to those that do not include an adhesion promoter.
[0025] In general exothermic refers to a process, event, or
chemical reaction that gives off heat. For example, a chemical
reaction, such as a polymerization reaction, that produces heat
energy is exothermic. An exotherm is a graphical plot of the
temperature increase exhibited by an exotherm reaction versus the
time since the beginning of the reaction.
[0026] The exothermic reaction that occurs during a free radical or
addition polymerization process generates heat that is given off by
the bulk material undergoing polymerization. Each bond formation
that occurs as a result of two unsaturated moieties combining to
form a bond gives off a finite amount of heat (heat of reaction).
Thus, the heat given off by the bulk material is a multiple of the
heat of reaction for a single polymer bond formation, times the
number of bonds formed. Since the bond formation occurs over time
(the curing process), not all of the heat is given off at once. In
general, it is observed that the bulk material exhibits a rapid
rise in temperature to a peak exotherm, followed by a slower
decrease after that point in time. The peak exotherm temperature is
relevant to the inventive curable bioadhesive composition, due to
its intended placement in contact with a biological surface. The
biological surface may be damaged or may transmit pain signals if
the exothermic reaction exhibited by a curing composition is too
great.
[0027] Since polymerization peak exotherms can be sufficiently high
to cause discomfort when in direct contact with living tissue, care
must be taken to limit the peak exotherm to that which can be
easily and comfortably tolerated.
[0028] The inventor has made the surprising discovery that by
limiting the number of unsaturated moieties per a given molecular
weight of curable unsaturated compound, the heat generated or
released during curing can be reduced. Thus, the peak exotherm upon
curing of the compositions of the invention is reduced. This
achieves the goal of limiting any potential damage to the target
tissue surface.
[0029] Peak exotherms determined herein are the highest temperature
measured (during the exothermic curing reaction) by placing between
60 and 100 milligrams of a curable composition on a flat surface
temperature probe with a surface area of about 0.05 square inches
(28.4 square millimeters) and curing the composition. In this
specification peak exotherms are provided in both the Celsius
(.degree. C.) and Fahrenheit (.degree. F.) temperature scales. One
skilled in the art would understand that different experimental
conditions would obtain different peak exotherms and that for
comparison with the compositions of the invention, the above
technique and conditions should be employed.
[0030] As used herein, "bioadhesive" means capable of adhering to a
biological substrate such as skin and mucosa, or other tissue.
Bioadhesive can also mean a compound, material, or composition
having such adhesion properties to biological structures. The term
"adhesion promoter" means a specific ingredient added to a
composition to promote better adhesion to tissue.
[0031] As used herein, "flexible" means compliant, rubbery,
bendable, stretchable and/or otherwise deformable. For example, a
thin slab of material with dimensions of about one inch by one inch
and having a thickness of about 1 mm which can be displaced at
least 45 degrees out of plane without material failure or breakage,
preferably at least 90 degrees out of plane, and most preferably at
least 120 degrees out of plane is considered flexible. Flexible
also means compliant with tissue; a flexible material is one that
is able to change in concert with the change in shape of the
underlying tissue with which it is in contact. The compositions of
the invention when cured are flexible.
[0032] As used herein, the term "curable" means capable of
undergoing a physical change from an initial rubbery state to a
final non-rubbery state.
[0033] As used herein "malleable" means shapeable, formable,
moldable, or otherwise capable of being conformed to an underlying
substrate shape, texture, or topography.
[0034] As used herein, a curable unsaturated compound is any
compound or material that is capable of participating in a curing
or polymerization reaction. Unsaturated scompound generally include
aliphatic organic molecules having double bonds between carbon
atoms.
[0035] As used herein, "tissue" refers to any biological structure
of a living organism, including skin, mucosa, internal organs and
structures, as well as hard, mineralized, or partially mineralized
structures, such as bone, tendon, cartilage, enamel, dentin, and
fingernails. Tissue surfaces can be outer or inner surfaces of any
of the aforementioned structures.
[0036] As used herein, "water-soluble" means capable of being
dissolved, in part or in whole, in water or other aqueous
media.
[0037] As used herein, "water-swellable" means capable of
absorbing, but not actually dissolving in, water or other aqueous
media.
[0038] As used herein, "curing agent" means a compound or
combination of compounds capable or initiating or propagating a
chemical reaction that results in a composition's change of state
from rubbery to non-rubbery.
[0039] As used herein, "monomer" means a curable compound with one
or more polymerizable unsaturated moieties and a molecular weight
less than 1000.
[0040] As used herein, "oligomer" means a curable compound with one
or more polymerizable unsaturated moieties and a molecular weight
of greater than or equal to 1000. The terms "prepolymer" and
"oligomer" are used in this specification to mean the same type of
compound.
[0041] As used herein, "polymerize" means to undergo a chemical
reaction that results in the formation of higher molecular weigh
compounds from lower molecular weight unsaturated compounds.
[0042] The inventive compositions may be provided in either single-
or multiple-part forms. Single-part compositions are preferred
since no mixing is required prior to use. Formulating with curing
agents that are photoactive is one means of curing single-part
compositions. Preferably photoactive single-part compositions are
packaged in light-resistant containers, such as black plastic
syringes that are opaque to light.
[0043] Two-part compositions can be cured by providing a first part
containing a curing agent (such as benzoyl peroxide) and a second
part containing a curing agent synergist (such as
N,N-dimethyl-p-toluidine). The first and second part are kept
separated from one another until application to prevent premature
curing (i.e., polymerization). Preferably, the first and second
parts are packaged separately prior to use and mixed together just
prior to application to the tissue surface. Two-part compositions
of the present invention can be packaged in separate chambers of a
dual chamber tube or syringe, pushed simultaneously out of the
syringe with a dual barreled plunger into an attached static mixing
device, whereupon the two parts will mix prior to exiting said
static mixing device. The mixed composition that exits the static
mixing device will now contain both compounds of the curing agent,
and the curing reaction will begin. Preferably, the mixed
composition is rapidly placed upon a tissue surface to form a
bioadhesive of the invention.
[0044] Whether packaged as a single-part composition that requires
no mixing prior to application or as a two-part composition that
can be mixed just prior to application (as described above), the
inventive composition may be applied to a tissue surface by any
available and convenient means.
[0045] The compositions of the invention can be applied as a
liquid, gel, paste or putty that is shaped or is allowed to shape
itself to conform to the underlying tissue surface. Once the
desired shape, conformation and sufficient coverage is attained,
the composition can be cured. A particular advantage provided by
one-part compositions that are cured by exposing them to actinic
radiation (in general, light energy) is that the curing reaction
can be delayed until it is assured that conformation to the
underlying tissue surface is attained.
[0046] After curing the compositions of the invention on a tissue
surface, the compositions of the invention become bioadhesives
which adhere to the surface in order to provide short, medium, or
long-term contact for the purpose of releasing a medicinal
substance from the cured composition or acting as a protective
physical barrier for the underlying tissue. The bioadhesives of the
invention, prepared from the compositions of the invention, retain
a degree of flexibility that allows them to adjust to changes in
the underlying shape or conformation of the tissue. The flexibility
and bioadhesion provided by the bioadhesives of the invention
enables them to remain in full and intimate contact with tissue,
even while the tissue, such as skin, changes shape as the organism
moves, i.e., as a result of underlying joint, muscular, or tissue
movement.
[0047] The following Table 1 represents, in general, the percentage
range of curable bioadhesive compositions found to be most
suitable. It is not intended to be limiting in its scope, but
rather generally descriptive in nature.
1 Ingredient Percent (w/w) Curable unsaturated compound 25-98
Curing agent 0.01-5 Adhesion promoter 10-50 Non-curable diluent
(optional) 0-50
[0048] Curable Unsaturated Compounds
[0049] The curable unsaturated compounds of the compositions of the
invention can be any compound (molecule), chemical, or mixtures
thereof that are capable of undergoing a polymerization reaction.
Preferred curable unsaturated compounds have a molecular weight
greater than or equal to 1000, contain one or more unsaturated
moieties and are capable of being polymerized. The preferred
polymerizable moieties are unsaturated groups (methacrylate,
acrylate, vinyl, etc.) present either in monofunctional form (a
single polymerizable group per molecule) or multifunctional form
(two or more polymerizable groups per molecule). To reduce the
amount of heat generated during the curing process, preferred
compositions of the invention reduce the average number of
unsaturated groups per weight of composition by choosing relatively
high molecular weight monofunctional or multifunctional
constituents.
[0050] The curable unsaturated compounds of the invention can be
any mono-, di-, tri-, or multi-functional unsaturated compound, or
mixture thereof, capable of being polymerized through a free
radical and/or addition polymerization reaction. The preferred
unsaturated moiety is a methacrylate group, although any
biologically acceptable compound containing an unsaturated moiety
capable of participating in a polymerization reaction can be used
in the compositions of the invention.
[0051] Methacrylate-containing compounds are preferred, due to the
fact that they are generally less sensitizing (capable of inducing
skin allergies) than acrylate and vinyl containing compounds. The
most preferred curable unsaturated compounds are linear, end-capped
dimethacrylate oligomers with molecular weights greater than or
equal to 1000.
[0052] The compositions of the invention preferably comprise less
than about 40 percent of a monomer or mixture of monomers. More
preferably the compositions of the present invention are
substantially free of monomers. Substantially free of monomers
means that the compositions of the invention have less than about
30% by weight of a monomer or a mixture of monomers, preferably
less than about 20% by weight of a monomer or a mixture of
monomers, more preferably less than about 10% by weight of a
monomer or a mixture of monomers, and even more preferably less
than about 5% by weight of a monomer or a mixture of monomers.
[0053] Monomers (curable unsaturated compounds with molecular
weights less than 1000) tend to contribute to high peak exotherms,
are generally much more sensitizing to the skin and mucosal
surfaces than their higher molecular weight oligomeric
counterparts. In addition, when employed in oral or dental
applications low molecular weight monomers tend to contribute
undesirable tastes due to leaching and migration of monomer from
the cured material.
[0054] Completely monomer-free compositions are contemplated to be
within the scope of the present invention and are described in a
number of the examples to follow. Monomer-free composition are the
most preferred compositions of the invention. Monomer-free
compositions do not have any monomers present.
[0055] Most preferably, the curable unsaturated compounds of the
compositions of the invention are multifunctional oligomers
containing no more than about one unsaturated moiety (preferably a
methacrylate moiety) per 500 of molecular weight. The preferred
curable unsaturated compounds can therefore be described by the
numeric representation of their molecular weight per unsaturated
moieties. This numeric representation of the molecular weight of
the curable unsaturated compound per unsaturated moiety is defined
herein as an unsaturation index.
[0056] The unsaturation index is defined herein as the molecular
weight of an unsaturated compound divided by the number of
unsaturated moieties or groups. For example, a curable unsaturated
compound having a molecular weight of 1000 and two methacrylate
moieties would have an unsaturation index of 500 (1000 divided by
2). Two methacrylate groups in a curable unsaturated compound with
a molecular weight of 1700 would yield an unsaturation index of 850
(1700 divided by 2). Three methacrylate groups in a curable
unsaturated compound with a molecular weight of 2400 would have an
unsaturation index of 800 (2400 divided by 3). Preferred curable
unsaturated compounds of the invention have an unsaturation index
(as defined herein) greater than or equal to 500. More preferred
unsaturated compounds of the invention have an unsaturation index
of from about 600 to about 1500. Most preferred unsaturated
compounds of the invention have an unsaturation index of from about
600 to about 1000.
[0057] It should be noted that an average composition unsaturation
index can be affected by the inclusion of saturated compounds,
additives or diluents in addition to the curable unsaturated
compound. For example, if the unsaturation index of a curable
unsaturated compound is 600, but the composition is further diluted
by the inclusion of a saturated diluent at 50 percent w/w, the
resulting formulation will have an overall composition unsaturation
index of 1200 (600 divided by 0.50). Thus, saturated compounds,
additives and diluents may be used to increase the unsaturation
index.
[0058] Particularly preferred oligomers are dimethacrylates ranging
in molecular weight from 1,000 to about 3,000. Dimethacrylate
polyetherurethane oligomers commercially available from Echo
Resins, Inc (Versailles, Mo.) under the trade names MLU-340,
MLU-341, and MLU-342 are preferred oligomers for the invention.
[0059] Adhesion Promoters
[0060] Preferred curable compositions of the invention comprise an
adhesion promoter. Adhesion promoters are included in the
compositions of the invention to improve the adhesion of the cured
composition to biological tissues. Adhesion promoters are compounds
or substance that improve the peel or grab strength, to the
contacted biological surface, of the bioadhesive resulting from the
curing of the compositions of the invention. The chemical nature of
the adhesion promoter can be selected for the best bioadhesion to a
particular tissue, since tissues will vary in their surface
properties. For example, a moist mucosal surface can require a
different adhesion promoter than a relatively dry skin surface.
[0061] Preferred bioadhesives of the invention, formed by the
curing of the preferred curable compositions of the invention
attach well to wet field surfaces. Thus, the preferred bioadhesives
of the invention are especially useful in dental applications,
since it has been found that the bioadhesives of the invention are
particularly adherent to wet field tissue surfaces such as the oral
mucosa.
[0062] Preferably, in preparing compositions of the invention which
include an adhesion promoter, all of the components (other than the
adhesion promoter) are combined to form a curable composition or
matrix. The adhesion promoter is then added to form the final
composition of the invention. Most preferably, the adhesion
promoters are dispersed, but not actually dissolved, in the curable
composition in a finely divided form.
[0063] Preferred adhesion promoters include, for example, finely
divided poly(acrylic acid), poly(ethylene oxide), poly(vinyl
pyrrolidone), poly(maleic anhydride-co-methyl vinyl ether), karaya
gum, guar gum, acacia gum, carboxypolymethylene, chitosan,
hydroxyethyl cellulose, sodium carboxymethylcellulose,
hydroxypropyl cellulose, polycarbophil, poly(vinyl alcohol),
hydroxypropylmethyl cellulose, and the like. Other high molecular
weight synthetic and natural water-soluble or water-swellable
polymers can also be used as adhesion promoters. Combinations of
adhesion promoters can be used when compatible with each other.
Compatibility means that two or more adhesion promoters can be used
in combination without sacrificing or reducing the bioadhesive
properties of the cured composition in contact with a tissue
surface. More preferred adhesion promoters are polycarbophil with a
molecular weight in excess of about 100,000. Most preferred
adhesion promoters are polycarbophil with a molecular weight in
excess of about 1,000,000.
[0064] Curing Agent
[0065] Curing agents of the compositions of the invention include
both light- and heat-activated polymerization catalysts. Any
compound capable of being induced, either through the application
of an outside energy source or through the combination (at the time
of use) of two or more composition components, to initiate a
polymerization reaction can be used in the compositions of the
invention as a curing agent. Preferred curing agents are
photoinitiators that are capable of initiating a polymerization
reaction upon exposure to light energy. More preferred curing
agents are photoinitiators that are capable of initiating a
polymerization reaction upon exposure to specific wavelengths of
light energy in the visible, near infrared or ultraviolet spectrum.
Examples of photoinitiators useful with the compositions of the
invention include camphorquinone, benzoin methyl ether, benzoin
ethyl ether, benzoin butyl ether, 2-hydroxy-2-methyl-1-phenyl
propane-1-one, oligo[2-hydroxy-2-methy-
l-1-[4-(1-methylvinyl)phenyl]propanone], benzildimethylketal,
2-isopropylthioxanthone, 4-isopropylthioxanthone, benzophenone (and
derivatives), 9,10-anthraquinone, 1-hydroxycyclohexyl phenyl
ketone, and the like, and combinations (where compatible)
thereof.
[0066] Certain curing agents require the presence of a curing agent
synergist (within the composition either at the point of
manufacture or added to the composition at the time of use). A
curing agent synergist may act, along with the curing agent, to
initiate the polymerization reaction chemically within the
composition, without the use of an outside energy source such as
heat or light. Particularly useful curing synergists are amine
compounds. A curing agent synergist may also accelerate a
photoinitiated polymerization reaction. Specific examples of curing
agent synergists are dimethylaminomethyl methacrylate,
N,N-dimethyl-p-toluidine, and ethyl-4-dimethylamino benzoate.
[0067] Non-Curable Diluent
[0068] The increase in the molecular weight of the curable
unsaturated compound or compounds used in the compositions of the
invention often results in the concurrent increase in the viscosity
of the bulk material. Preferred compositions of the invention
comprise a non-curable diluent. In order to formulate a material
that can be readily shaped into a desired form (such as a thin film
on the surface of gingival tissue in the mouth), the viscosity of
the inventive composition must be low enough so that it may be, for
instance, easily pushed by a plunger mechanism from a syringe. The
compositions of the invention preferably comprise a non-curable
diluent capable of dissolving the curable unsaturated compound,
thereby resulting in a mixture that has a workable, extrudable,
malleable, or otherwise formable consistency.
[0069] Thus, if the viscosity rises above that which is suitable
for manipulation, i.e., extrusion, shaping, and forming the
composition prior to curing, a diluent should be included in the
curable compositions of the invention to reduce the composition's
viscosity to a range that may be manipulated.
[0070] One way of reducing the working viscosity of curable
compositions is to use lower molecular weight unsaturated diluents.
This approach is not preferred because it would lead to an increase
in the composition peak exotherm due to an increase in the number
of unsaturated moieties. Thus, it is preferred that a saturated or
otherwise non-polymerizable diluent be used to reduce the working
viscosity of the present inventive compositions.
[0071] Low molecular weight unsaturated monomers are preferably
kept to a minimum in the compositions of the invention for the
additional reasons, especially in the context of oral or dental
applications, that they have a detectable and often unpleasant
taste. Low molecular weight monomer leaching from the cured
composition, since there is inevitably at least a small amount of
monomer that does not polymerize during a free radical curing
reaction, leads to unacceptable organoleptic properties.
[0072] Non-curable diluents (hereinafter referred to as merely
diluents) that have utility in the preparation of the inventive
compositions must be able to dissolve and thereby reduce the
viscosity of the curable unsaturated oligomer. The diluent should
therefore have a viscosity that is lower than that of the curable
unsaturated oligomer at room temperature. Generally speaking,
preferred diluents are liquids. Suitable diluents also should have
a low level of toxicity for their intended use. Preferred diluents
are not easily extracted from the inventive composition after
curing. For example, when in contact with the moisture in saliva.
Therefore, preferred diluent for bioadhesives used in oral
applications are preferably water-insoluble. Preferred diluents
have a viscosity range of from about 1 centipoise to about 2000
centipoise. The viscosity of a diluent can be measured with a
Brookfield RVT DVII+ Viscometer (Brookfield Engineering,
Middleboro, Mass.) at 25.degree. C., using cylindrical spindle #4
at a spindle speed of 5 rpm. A particularly preferred diluent is
capric/caprylic triglyceride.
[0073] Suitable non-curable diluents include solvents,
plasticizers, emollients, and a broad range of liquid ester
compounds (the reaction product between an acid and an alcohol).
The type of non-curable diluent, as well as its concentration in
the final composition, will be dependent upon the oligomer
selected. Whereas one non-curable diluent may be a suitable solvent
for an oligomer with a molecular weight of 1500, that same diluent
may not be a suitable solvent for an oligomer with a molecular
weight of 4000. The oligomer should be soluble in the non-curable
diluent chosen.
[0074] Non-curable diluents include, for example, triglycerides
such as capric/caprylic triglyceride, liquid mono- and
diglycerides, vegetable oils such as avocado oil, safflower oil,
olive oil, and sweet almond oil, and other similar compounds.
[0075] Auxiliary Components
[0076] The inventive curable bioadhesive composition may also
contain a pigment or dye in order to allow for ease of visual
placement and detection, in addition to providing a means to
physically block out radiant energy from heat and light sources
that are frequently employed to accelerate, for instance, tooth
whiteners. Pigments such as titanium dioxide and zinc oxide, are
preferred, but any opacifying or light-attenuating pigment, dye, or
insoluble particle may be used. Pigments or dyes may optionally be
added to the composition in an amount from about 0.0001 percent to
about 10 percent by weight of the composition.
[0077] Preferred light attenuating pigments are titanium dioxide
(all particle sizes, include nanometer-sized powder particles) and
zinc oxide (also all particle sizes, including nanometer-sized
powder particles). Polymer particles, such as those from finely
ground high density polyethylene and poly(tetrafluoroethylene), are
also useful as light attenuating ingredients in the curable
compositions. They may also be used as "extenders", in order to
even further reduce the peak exotherm (by occupying "space" in the
formulation as a non-curable solid filler).
[0078] Pigments and dyes suitable for use in the compositions of
the invention are compounds that are biologically acceptable, for
example, in the oral cavity or on the surface of the skin.
[0079] Other auxiliary components include, for example, fragrance
and flavor additives, preservatives, antimicrobial agents, active
drugs and medicaments. Inhibitors, such as hydroquinone methyl
ether (MEHQ), hydroquinone (HQ) and butylated hydroxytoluene (BHT)
may be added to the compositions in order to prevent premature
polymerization before the time of use. Skin and mucosal penetration
enhancers, such as glyceryl triacetate (triacetin) can also be
included, especially when enhanced diffusion of a drug or active
ingredient into tissue is desired.
[0080] Bioadhesion Synergists
[0081] Surprisingly, it was found that certain compounds containing
divalent metal ions, such as zinc oxide and dicalcium phosphate
anhydrous, increased the bioadhesive strength of the inventive
compositions when used in conjunction with adhesion promoters that
contain carboxylic acid or anhydride group functionality. Thus, the
combination of a carboxylic acid or anhydride-functional adhesion
promoter with a divalent metal ion-containing compound resulted in
an unexpected increase in the bioadhesion of the compositions of
the invention after curing.
[0082] While not wishing to be bound by any particular theory, it
is hypothesized that upon contact with moisture, the carboxylate
moieties of the adhesion-promoting polymer create a low pH
environment at the interface between the bioadhesives of the
invention. This low pH environment is conducive to the
solubilization of, for example, zinc oxide, thereby releasing
divalent zinc ions into the interfacial environment. The available
zinc ions may create crosslinking between intermingling polymer
chains, particularly on mucosal surfaces that contain high
molecular weight mucins. Increased crosslinking between adhesion
promoter polymer chains and tissue surface polymer chains may
account for the improved adhesion at the interface between the
bioadhesives of the invention (the cured compositions of the
invention) and the underlying biological substrate.
[0083] Alternatively, while not wishing to be bound by theory, it
is hypothesized that divalent cations shield the charges provided
by carboxylate moieties and thereby enable the bioadhesive to
conform more closely to the tissue surface by reducing
charge-charge repulsion between carboxylate groups.
[0084] Thus, divalent or multivalent metal ion compounds that are
insoluble in the curable composition, or cured composition
resulting in the bioadhesives of the invention can be used in the
compositions of the invention. These compounds are called adhesion
promoter synergists. In particular, compounds containing zinc,
calcium, magnesium, or other divalent or multivalent metal ions
cause an unexpected increase in the adhesive properties of the
bioadhesives of the invention that also contain at least one
polymer having pendant carboxylic acid or anhydride moieties. In
other words, an adhesion promoter comprising at least one polymer
having pendant carboxylic acid or anhydride groups in combination
with at least one divalent or multivalent metal ion-containing
compound has been found to have surprising utility in the present
curable compositions of the invention.
[0085] Although not exhaustive, a list of divalent compounds
suitable for use with at least one polymer having pendant
carboxylic acid or anhydride groups includes zinc acetate, zinc
aspartate, zinc benzoate, zinc carbonate, zinc chloride, zinc
citrate, zinc cysteinate, zinc gluconate, zinc glutamate, zinc
lactate, zinc laurate, zinc myristate, zinc palmitate, zinc
phenolsulfonate, zinc-stearate, zinc sulfate, zinc undecylenate,
calcium acetate, calcium ascorbate, calcium aspartate, calcium
benzoate, calcium carbonate, calcium chloride, calcium citrate,
calcium dihydrogen phosphate, calcium disodium
ethylenediaminetetraacetat- e, calcium fluoride, calcium gluconate,
calcium glycerophosphate, calcium hydroxide, calcium lactate,
calcium laurate, calcium monofluorophosphate, calcium myristate,
calcium pantothenate, calcium paraben, calcium phosphate, calcium
propionate, calcium pyrophosphate, calcium saccharin, calcium
salicylate, calcium silicate, calcium sorbate, calcium stearate,
calcium sulfate, calcium tartarate, calcium undecylenate, magnesium
acetate, magnesium aluminum silicate, magnesium ascorbate,
magnesium ascorbyl phosphate, magnesium aspartate, magnesium
benzoate, magnesium carbonate, magnesium chloride, magnesium
fluoride, magnesium fluorosilicate, magnesium gluconate, magnesium
glycerophosphate, magnesium hydroxide, magnesium myristate,
magnesium oxide, magnesium palmitate, magnesium propionate,
magnesium salicylate, magnesium silicate, magnesium sodium
fluorosilicate, magnesium strearate, magnesium sulfate, and the
like.
[0086] The following Examples serve to provide further illustration
of tile invention by are not meant in any way to restrict the
effective scope of the invention.
EXAMPLES
Example I
[0087] The following composition is useful for isolating gingival
tissue in the oral cavity from therapeutic agents, such as
oxidizing tooth-whitening compositions. Such oxidizing compositions
are placed on the tooth enamel surface for a period of time from
about 5 minutes to about 2 hours, or until the desirable degree of
tooth whitening is achieved. When cured, the present inventive
composition protects the soft gingival tissue from the possible
harmful effects of the tooth whitening composition.
[0088] Composition 1A
2 Ingredient Function Percent (w/w) Methacrylated Curable 50.178
polyetherurethane oligomer unsaturated compound (MW 1200)
Capric/caprylic triglyceride Non-curable diluent 22.374
Polycarbophil Adhesion promoter 25.000 Pyrogenic silica Thickener
2.000 Camphorquinone Photoactive curing agent 0.100
Ethyl-4-dimethylamino Curing agent synergist 0.348 benzoate TOTAL
100.000
[0089] The above composition was prepared in a "light safe" room,
where all ambient light sources were filtered in order to remove
any spectral component below 500 nanometers (nm). This precaution
is necessary, due to the absorption peak for this particular
composition's photoactivator (camphorquinone), which has an
absorption maximum of 466-nm. Unfiltered light that included the
466-nm spectral component range would cause premature
polymerization of the composition prior to placing it in light safe
packaging.
[0090] The curing agents (camphorquinone and ethyl-4-dimethylamino
benzoate) were dissolved in the capric/caprylic triglyceride
diluent. This mixture was then combined with the oligomer in a
vacuum mixer, along with the silica thickener. The components were
mixed together, initially without drawing a vacuum in the mixing
vessel, until a homogeneous mixture was obtained. Subsequently, 20'
Hg of vacuum was drawn in the mixing vessel for a period of 5
minutes, whereupon a mixture free of entrapped air bubbles was
obtained. It should be noted that excessive mixing under a vacuum
is not recommended for compositions containing unsaturated
moieties. This is due to the propensity for unsaturated compounds
to undergo premature polymerization when deprived of oxygen
(O.sub.2), which acts in synergy with typical polymerization
inhibitors such as hydroquinone methyl ether (MEHQ), hydroquinone
(HQ) and butylated hydroxytoluene (BHT).
[0091] The finished composition above was then packaged into
opaque, black 3-gram plastic syringes under light-safe conditions.
The finished composition was an off-white, opaque gel that could be
easily extruded from the syringes. The opacity of the product most
likely resulted from the insolubility of the polycarbophil
particles in the curable matrix, since a composition prepared in a
similar fashion to Example I above that did not include the
polycarbophil was a transparent gel with a slight yellow color.
[0092] A modified version of the inventive composition above was
prepared that showed greater opacity due to the addition of zinc
oxide.
[0093] Composition Ib
3 Ingredient Percent (w/w) Methacrylated polyetherurethane
oligomer(MW 1200) 41.652 Capric/caprylic triglyceride 33.400
Polycarbophil 20.000 Pyrogenic silica 1.500 Camphorquinone 0.100
Ethyl-4-dimethylamino benzoate 0.348 Zinc oxide 3.000 TOTAL
100.000
Example II
[0094] A peak exotherm was determined, in accordance with the
following procedure, for the composition prepared in Example
Ia.
[0095] The peak exotherm attained was determined using a
standardized test procedure that accurately duplicates the in-use
placement, thickness, and curing conditions that one would employ
in situ. The method comprised the use of a flat surface disc
thermoprobe with a detection surface diameter of 0.31 inches, a
response time of 0.75 seconds, and a time constant of 0.15 seconds.
The probe was connected to a digital J-type thermocouple
thermometer (Digisense Type-J Thermometer, Cole-Palmer Corporation,
Vernon Hills, Ill.). A large enough bead of the above composition
was placed on the detection disc in order that the entire probe
surface was covered with the curable material. The bead of material
was then cured using a hand-held dental curing light (Optilux 500,
Demetron Corporation, Danbury, Conn.), the fiber optic probe of
which was positioned (with the help of a plastic spacer) 5-mm away
from the top of the material bead. A timer was used to determine
the time at which the peak exotherm was attained, along with the
digital readout from the thermometer. An average of three
measurements was used to determine the peak exotherm under the
conditions of the test. The above composition bead cured to a
solid, flexible bead that resisted permanent deformation when
manipulated by hand. The peak exotherm attained occurred at 23
seconds after the start of light exposure and was 40.6.degree. C.
(105.degree. F.).
[0096] The highest point on the material bead was measured to be
approximately 2 millimeters (mm), which approximates the thickness
(1 to 2 mm) that can be practically applied onto the gingival
surface without causing excessive material buildup. It is important
to somewhat overestimate the volume of material that may be in
contact with the biological surface, in order that a peak exotherm
for the material be estimated that greatly exceeds safety
parameters. It is generally accepted that a maximum temperature of
53.4.degree. C. (128.degree. F.) in the oral cavity is tolerated by
most. subjects; higher temperatures usually result in patient
discomfort. In the interest of providing a wide margin of safety,
it is preferred that the peak exotherm for the inventive
compositions, determined in accordance with the test method
outlined above, not exceed 50.degree. C. (120.degree. F.), and
preferably not exceed 43.4.degree. C. (110.degree. F.). Most
preferably, the peak exotherm is less than or equal to 40.degree.
C. (104.degree. F.).
[0097] A commercially available curable gingival isolation material
(OpalDam.TM., Ultradent Products, Inc., South Jordan, Utah) was
obtained and tested in accordance with the above procedure. The
commercial material bead reached its peak exotherm 26 seconds after
the start of light exposure and the peak exotherm was 124.degree.
F. The resulting material was a brittle solid that did not possess
the flexural properties that would allow it to "give" along with
minor movement that may occur in the underlying gingival tissue.
Rigidity in the final cured composition is more likely to cause
separation of the material from the gingival tissue, resulting in,
for instance, bleaching agent leakage and possible damage to the
tissue underlying the gingival barrier.
[0098] A further comparison of the peak exotherms of several
different compositions was performed. Table 2 below shows general
properties of the monomers and/or oligomers used to prepare the
compositions, which are further described in Table 3.
4TABLE 2 No. of Unsaturated Unsaturated Monomer/Oligomer MW Groups
Group Type UI Urethane Dimethacrylate 470 2 Methacrylate 235
Ethoxylated BisGMA 540 2 Methacrylate 270 MLU-340 1200 2
Methacrylate 600 Amount (w/w) Composition Composition Composition
Ingredient II a II b II c Urethane Dimethacrylate 99.55 Ethoxylated
BisGMA 99.55 MLU-340 99.55 Camphorquinone 0.10 0.10 0.10 Ethyl-4-
0.35 0.35 0.35 dimethylaminobenzoate TOTAL 100.00 100.00 100.00 MW
= Molecular weight UI = Unsaturation Index (MW divided by the # of
Unsaturated Groups)
[0099] Peak exotherms for the compositions IIa, IIb, and IIc above
were determined in accordance with the procedure outlined above.
The results are shown in Table 3 below, and clearly demonstrate the
superior limited exothermic properties of Compositions Ia, Ib and
IIc, which are representative of the inventive compositions.
5TABLE 3 Composition Start Temp (.degree. C.) Peak Temp (.degree.
C.) .DELTA. Temp (.degree. C.) II a 23.5 65.8 42.3 II b 22.5 61.6
39.1 OpalDam .RTM. 22.9 51.2 28.3 II c 23.2 46.8 23.6 Ia 23.4 40.6
17.2 Ib 22.7 33.4 11.0 None 22.4 51.0 28.6 (curing light only)
[0100] The following composition was clinically tested for its
general properties as a gingival barrier material during a
light-activated tooth whitening procedure. Zinc oxide was added to
increase the opacity of the cured composition in situ; the
increased opacity reduced the amount of light that could penetrate
through the gingival barrier during the tooth whitening procedure.
The composition below was prepared in a manner similar to that in
Example I. The final compositions was placed in 1-cc black syringes
and stored at room temperature until use.
[0101] Composition III
6 Ingredient Percent (w/w) Methacrylated polyetherurethane
prepolymer (MLU-340) 41.652 Capric/caprylic triglyceride 33.400
Polycarbophil 20.00 Fumed silica (Cab-O-Sil M5) 1.500
Camphorquinone 0.100 Ethyl-4-dimethylamino benzoate 0.348 Zinc
oxide 3.000 TOTAL 100.000
[0102] Four volunteer subjects were used to compare the in situ
properties of the above composition to those of a commercial
light-cured resin dam. The composition of the invention was applied
to the left half of the mouth, on both the upper and lower gingival
margins, while the commercial resin dam was applied to the right
half of the mouth in exactly the same fashion. The procedure was
performed as follows: a plastic syringe tip was attached to the
Leur-lock end of either a syringe of the above formulation or a
syringe of the commercial resin dam. Material from each respective
syringe was applied carefully along the margin between the gingiva
and the tooth enamel of one half of the upper (maxillary) teeth.
The same process was repeated for one half of the lower
(mandibular) teeth. While the composition of the invention had flow
properties that allowed for the entire half arch to be coated prior
to curing with the dental curing light, the commercial resin dam
tended to flow too easily, resulting in the need to cure the
material every so often to prevent the material from flowing down
and covering the hard surface of the tooth. The test materials were
left in place during a tooth whitening procedure that lasted,
depending upon the subject, between 20 and 60 minutes.
[0103] The subjects noted that the composition of the invention was
more comfortable for several reasons. First, the subjects noted
that the composition of the invention produced less heat than the
commercial resin dam material. Second, the composition of the
invention did not have the bitter taste that they identified as
originating from the commercial resin dam. The dental professionals
performing the procedure noted less gingival irritation after 60
minutes (the duration of the tooth whitening procedure), resulting
from the higher opacity of the inventive composition, together with
its reduced peak exotherm. Importantly, the dental professionals
noted that removal of the cured composition of the invention
following the tooth whitening procedure was much more comfortable
for the subjects than the OpalDam.TM., due to the fact that it came
out of undercuts better and was more flexible.
Example IV
[0104] A demonstration of the flexibility of the inventive
compositions in comparison to prior art compositions was conducted.
Representative compositions of the invention were prepared as in
the other examples. 1-mm thick cured fillets were prepared by
placing uncured material between two glass microscope slides that
were spaced apart from one another with two additional microscope
slides, in such a manner as to create a rectangular mold. The first
two slide were pressed together until material was spread through
the mold and until they touched the spacer slides. The material was
then cured for 3 minutes with a dental curing light, as described
above. The resulting cured rectangular fillets were exactly 1-mm
thick and varied tremendously in qualitative flexibility and
hardness.
[0105] To compare flexibility, the fillets were securely positioned
in a square edged clamp (one half of the fillet was clamped and the
other half was free). The free half was slowly bent out of plane
until the material failed and broke into two pieces. The
approximate angle of deflection at which failure occurred was
measured.
[0106] While the Compositions IIa, IIb, and the OpalDam.RTM.
material failed between 45 and 75 degrees from plane, the inventive
compositions I and IIc easily passed through the 90 degree out of
plane mark and did not fail when folded virtually in half (the
clamp prevented an angle greater than 160 degrees from plane being
attained).
Example V
[0107] The bioadhesive properties of various compositions were
evaluated qualitatively by coating the surface of the forefinger
with saliva and immediately placing a curable composition on the
wet surface. After 15 seconds, the composition was cured with a
dental curing light for 60 seconds and the bioadhesive quality of
the resulting cured mass determined by peeling slowly from the
surface of the skin. In some instances (Compositions IIa and IIb),
very little adhesion was observed, however, the compositions of the
invention, Ia and IIc, were difficult to remove and held to the
skin in a manner similar to very sticky tape. The Composition Ib
was clearly superior to any of the other compositions. The
commercial material, OpalDam.RTM., did not adhere well to saliva
moistened skin, but did adhere well to dry skin (this is consistent
with the clinical observation that OpalDam.RTM. works well only in
a dry field, i.e., if the mucosal surfaces have been air dried
prior to contact with the curable material.
Example VI
[0108] Composition III was also tested for its ability to attenuate
light energy. Since gingival barrier materials are often used
during light-activated tooth whitening procedures, it is important
that such materials be able to effectively reduce the amount of
light energy that reaches the underlying tissue. Excess light
energy that reaches the soft gingival tissue may cause damage in a
manner similar to sunburn, which, if occurring in the oral cavity,
can cause a tremendous amount of post-procedure pain for the
patient.
[0109] Light attenuation by gingival barrier compositions was
measured by taking a baseline measurement for a light source (in
this case, a metal halide source transmitted to a light delivery
construct through fiber-optic means) with a laser power meter
(Ophir Model AN/2). The baseline measurement for the light source
was 135 mW/cm.sup.2. Two standard glass microscope slides were
placed on top of one another and in the path between the light
source and the power meter detector well. This measurement was
taken in order to ascertain the light attenuation, if any, caused
by the glass slides. The measurement was taken again and found to
be the same, 135 mW/cm.sup.2, thus indicating that the glass slides
did not attenuate the light energy between the light source and the
detector well.
[0110] A bead of Composition III was placed in the center of one of
the glass slides and two cover slips were positioned as "spacers"
prior to placing tile second glass slide directly on top of the
first one. The bead of material was spread into a thin film by
pressing the slides together until the cover slip spacers would not
allow further compression. Before and after measurements of the
glass slides with and without the cover slip spacers showed the
material film thickness to be about 100 microns (1/10 of a
millimeter). The "sandwiched" material film was cured in place with
a standard dental curing light for 60 seconds.
[0111] The cured 100 micron film, sandwiched between two glass
slides, was then placed in the path between the light source and
the power meter detector well. The meter now read 62 mW/cm.sup.2, a
reduction in power density of approximately 54%.
[0112] The same test performed on a commercial gingival isolation
material (OpalDam.TM.) resulted in a reading of 93 mW/Cm.sup.2, a
reduction in power density of only 32%. The light-attenuating
ability of Composition III was almost 70 percent higher than the
commercial material.
Example VII
[0113] Additional compositions were prepared as follows, in
accordance with the general manufacturing procedures outlined
previously. These formulations are intended only to be
representative and by no means limiting.
[0114] Compositions VIIa-VIIe
7 Ingredient VIIa VIIb VIIc VIId VIIe Oligomer 1 (MLU-340) 41.652
41.652 Oligomer 2 (MLU-341) 25.300 Oligomer 3 (MLU-342) 30.000
30.000 Capric/caprylic triglyceride 33.400 33.400 41.000 45.552
49.552 Polycarbophil 20.000 20.000 Polyoxyethylene (High MW) 25.000
Polyyinylpyrollidone 20.000 Poly(methyl vinyl ether-co-maleic
15.000 anhydride) Fumed silica 1.500. 1.500 3.000 2.000 2.000
Camphorquinone 0.100 0.100 0.150 0.100 0.100 Ethyl-4-dimethylamino
beuzoate 0.348 0.348 0.550 0.348 0.348 Dicalcium phosphate
anhydrous 2.000 Zinc oxide 5.000 3.000 Titanium dioxide 3.000 1.000
2.000 TOTAL 100.000 100.000 100.000 100.000 100.000
Example VIII
[0115] To further demonstrate the advantages of utilizing an
oligomer as the curable component in a representative inventive
composition, a comparison of a formulation that contains an
oligomer as its curable unsaturated compound (VIIIa) was compared
to an identical that had as its only difference the use of a
monomer (urethane dimethacrylate) as its curable unsaturated
compound (VIIIb).
8 Composition Composition Ingredient VIIIa VIIIb Methacrylated
polyetherurethane 41.652 prepolymer (MLU-340) Urethane
dimethacrylate 41.652 Capric/caprylic triglyceride 33.400 33.400
(Crodamol GTCC) Poly(acrylic acid) 20.000 20.000 (Noveon AA-1)
Fumed silica 1.500 1.500 (Cab-O-Sil M5) Camphorquinone 0.100 0.100
Ethyl-4-dimethylamino benzoate 0.348 0.348 Zinc oxide 3.000 3.000
TOTAL 100.000 100.000
[0116] While the inventive Composition VIIIa demonstrated desirable
low peak exotherm properties, Composition VIIIb reached a peak
exotherm of52 degrees C. (125 degrees F.). In addition, Composition
VIIIb was extremely brittle, whereas Composition VIIIa was
flexible. Thus, the compositions of the invention achieve both low
peak exotherms and flexibility. This also demonstrates the
advantage of using oligomers rather than monomers in bioadhesive
compositions.
Example IX
[0117] A two-component curable composition suitable for use as a
tissue sealant was prepared; the individual parts 1 and 2 were
placed in separate chambers of a light resistant, dual-chambered
syringe (Plas-Pak Industries, Norwich, Conn.). The two components
are mixed together as they are forced out of the syringe with a
dual piston through a mixing baffle (also known in the art as a
static mixer) attached to the exit end of the syringe, opposite the
plunger. Upon being forced into one end of the static mixing
chamber, the two components become mixed by the time they emerge
from the other end. This particular static mixing chamber had 8
elements (which are like baffles or plates that direct the flow of
the materials through the chamber), although other designs and
numbers of elements are contemplated.
9 Ingredient Part 1 Part 2 Methacrylated polyetherurethane 37.540
37.540 prepolymer (MLU-341) Capric/caprylic triglyceride 35.960
41.960 Polycarbophil 20.000 Poly(vinyl pyrrolidone) (K30) 18.000
Fumed silica 2.000 2.200 Benzoyl peroxide 0.500
N,N-dihydroxy-p-toluidine 0.300 Dicalcium phosphate anhydrous 4.000
TOTAL 100.000 100.000
[0118] Although the invention has been described with references to
preferred embodiments and examples thereof, the scope of the
present invention is not limited to those described embodiments.
Those skilled in the art will realize that further embodiments can
be made without departing from the spirit of the invention, and it
is intended to include all such further modifications, adaptations
and changes as come within the scope of the claims set forth
herein.
* * * * *