U.S. patent application number 10/212666 was filed with the patent office on 2003-03-13 for sustained-release matrices for dental application.
This patent application is currently assigned to The Gillette Company, a Delaware corporation. Invention is credited to Philbrook, Carl M., Tseng, Mingchih M..
Application Number | 20030049209 10/212666 |
Document ID | / |
Family ID | 25012420 |
Filed Date | 2003-03-13 |
United States Patent
Application |
20030049209 |
Kind Code |
A1 |
Tseng, Mingchih M. ; et
al. |
March 13, 2003 |
Sustained-release matrices for dental application
Abstract
A sustained-release matrix for dental application includes
either an anti-microbial agent or a colorant that is released from
the matrix when the matrix contacts water. The preferred matrices
include a water-soluble polymer and a water-insoluble support
resin.
Inventors: |
Tseng, Mingchih M.;
(Hingham, MA) ; Philbrook, Carl M.; (Jamaica
Plain, MA) |
Correspondence
Address: |
FISH & RICHARDSON PC
225 FRANKLIN ST
BOSTON
MA
02110
US
|
Assignee: |
The Gillette Company, a Delaware
corporation
|
Family ID: |
25012420 |
Appl. No.: |
10/212666 |
Filed: |
August 5, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10212666 |
Aug 5, 2002 |
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09966798 |
Sep 27, 2001 |
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09966798 |
Sep 27, 2001 |
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09390963 |
Sep 7, 1999 |
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09390963 |
Sep 7, 1999 |
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09061546 |
Apr 16, 1998 |
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5998431 |
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09061546 |
Apr 16, 1998 |
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08262961 |
Jun 21, 1994 |
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5851551 |
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08262961 |
Jun 21, 1994 |
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07898471 |
Jun 15, 1992 |
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5340581 |
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07898471 |
Jun 15, 1992 |
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07749137 |
Aug 23, 1991 |
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Current U.S.
Class: |
424/49 ;
15/167.1; 433/80 |
Current CPC
Class: |
A61K 2800/43 20130101;
A46B 11/00 20130101; A61K 8/86 20130101; Y10T 428/2913 20150115;
Y10T 428/2929 20150115; A61Q 11/00 20130101; Y10T 428/2969
20150115; Y10T 428/2971 20150115; A61K 8/8135 20130101; A61K 8/43
20130101; Y10T 428/2938 20150115; Y10T 428/2967 20150115 |
Class at
Publication: |
424/49 ; 433/80;
15/167.1 |
International
Class: |
A61K 007/16; A46B
009/04; A61G 017/02 |
Claims
1. An oral brush comprising: a body comprising a handle and head; a
brush portion connected to the head of said body; and a
sustained-release matrix comprising a support resin, a
water-soluble substance, and an anti-microbial agent.
2. The oral brush of claim 1 wherein said matrix is a template
joined to said head.
3. The oral brush of claim 1 wherein said resin comprises ethylene
vinyl acetate.
4. The oral brush of claim 1 wherein said water soluble substance
comprises an organic polymer.
5. The oral brush of claim 4 wherein said polymer comprises
polyethylene oxide.
6. The oral brush of claim 1 wherein said anti-microbial agent
comprises chlorhexidine.
7. The oral brush of claim 1 wherein said resin comprises ethylene
vinyl acetate, said water soluble substance comprises polyethylene
oxide, and said anti-microbial comprises chlorhexidine.
8. The oral brush of claim 2 wherein said template is no greater
than 4 mm thick.
9. The oral brush of claim 1 wherein said template comprises
between 50 percent and 90 percent by weight ethylene vinyl acetate;
between 5 percent and 40 percent by weight polyethylene oxide; and
between 1 percent and 30 percent by weight anti-microbial
agent.
10. An oral brush comprising: a body including a head and a handle;
a brush portion attached to said head; and a sustained-release
matrix comprising a polymer and an anti-microbial agent.
11. The oral brush of claim 10 wherein said sustained-release
matrix is attached to said head.
12. The oral brush of claim 10 wherein said anti-microbial agent
comprises chlorhexidine.
13. The oral brush of claim 10 wherein said polymer comprises a
water-soluble polymer.
14. The oral brush of claim 13 wherein said water-soluble polymer
comprises polyethylene oxide.
15. The oral brush of claim 10 wherein said polymer comprises a
support resin.
16. The oral brush of claim 10 wherein said matrix comprises a. a
first layer including a water-soluble polymer and an anti-microbial
agent, and b. a second layer joined with said first layer and
comprising a support resin.
17. The oral brush of claim 16 wherein said water-soluble polymer
is polyethylene oxide.
18. The oral brush of claim 15 wherein said second layer further
comprises a support resin.
19. The oral bush of claim 18 wherein said support resin is
ethylene vinyl acetate.
20. The oral brush of claim 10 wherein said matrix comprises a. a
first layer comprises said polymer and said anti-microbial agent,
wherein said polymer is a support resin, and b. a second layer
joined with said first layer and comprising a support resin.
21. The oral brush of claim 20 wherein said support resin comprises
ethylene vinyl acetate.
22. A sustained-release matrix comprising: a resin comprising
ethylene vinyl acetate; a water-soluble polymer comprising
polyethylene oxide; and an anti-microbial agent.
23. The matrix of claim 22 comprising between 50 percent and 90
percent by weight ethylene vinyl acetate; between 5 percent and 30
percent by weight polyethylene oxide; and between 3 percent and 30
percent by weight anti-microbial agent.
24. The matrix of claim 22 wherein said anti-microbial agent
comprises chlorhexidine.
25. A sustained-release matrix comprising a first layer comprising
a polymer and an anti-microbial agent, and a second layer joined to
the first and comprising a support resin.
26. The matrix of claim 25 wherein said polymer in said first layer
comprises a support resin.
27. The matrix of claim 25 wherein said polymer in first layer
comprises a water soluble polymer.
28. A method of releasing an anti-microbial agent from an oral
brush, comprising providing an oral brush including a body with a
handle and a head, a brush portion attached to said head, and a
sustained-release matrix comprising a water insoluble resin, a
water-soluble polymer, and an anti-microbial agent; and contacting
the portion of said brush including said matrix with water, causing
said water-soluble polymer in said matrix to dissolve, thereby
releasing said anti-microbial agent into said water.
29. The method of claim 28 further comprising inserting said
portion of the brush including the matrix into the mouth of an
animal, the saliva of the animal including water that causes said
water-soluble polymer to dissolve thereby releasing said
anti-microbial agent into said mouth.
30. The method of claim 28 wherein said anti-microbial agent is
chlorhexidine.
31. The method of claim 28 wherein said resin comprises ethylene
vinyl acetate.
32. The method of claim 28 wherein said water-soluble polymer
comprises polyethylene oxide.
33. A method of releasing an anti-microbial agent into a mouth of
an animal, comprising providing a matrix including a resin, a
water-soluble substance, and an anti-microbial agent; and inserting
said matrix into a mouth of an animal, said matrix releasing said
anti-microbial agent into said mouth.
34. The method of claim 33 wherein said resin comprises ethylene
vinyl acetate.
35. The method of claim 34 wherein said water-soluble substance
comprises polyethylene oxide.
36. A wear-indicator oral brush, comprising a body comprising a
handle and head; a brush portion connected to the head of said
body; and a matrix that is attached to said head of said body, said
matrix comprising a colorant and a water-leachable substance that
leaches into water when the oral brush is used to cause said matrix
to change color after repeated uses.
37. The oral brush of claim 36 wherein said water-leachable
substance comprises a water-soluble polymer.
38. The oral brush of claim 37 wherein said water-soluble polymer
is selected from the group consisting of polyethylene oxide,
polyethylene glycol, and polyvinyl alcohol.
39. The oral brush of claim 36 wherein said matrix further
comprises a water-insoluble support resin.
40. The oral brush of claim 39 wherein said support resin comprises
ethylene vinyl acetate.
41. The oral brush of claim 39 wherein said water-leachable
substance comprises said colorant.
42. The oral brush of claim 36 wherein said matrix comprises a
first layer comprising said water-soluble substance; and a second
layer joined with said first layer and comprising a water-insoluble
support resin.
43. The oral brush of claim 42 wherein said second layer further
comprises said colorant.
44. The oral brush of claim 42 wherein said first layer comprises
said colorant.
Description
[0001] This application is a continuation-in-part of U.S. Ser. No.
07/749,137, filed Aug. 23, 1991.
BACKGROUND OF THE INVENTION
[0002] The invention relates to sustained-release matrices.
[0003] Most humans suffer from tooth decay and/or periodontal
disease caused by bacteria in the mouth. As a result, decreasing
the number of bacteria in the mouth has long been the target of
persons working in the health care field. The most common way of
minimizing the number of bacteria is to brush and floss the teeth
regularly, and to visit a dental hygienist to have the teeth and
gums cleaned thoroughly. Another prior approach is oral rinsing,
including with a solution containing a known anti-microbial agent
like chlorhexidine digluconate.
[0004] After a toothbrush has been used, there are a large number
of bacteria clinging to the bristles, even after the brush has been
rinsed. This, of course, is undesirable, and these bacteria
typically will multiply on the bristles between uses. To counter
this problem, self-sterilizing toothbrushes have been described in
the prior art. One such self-sterilizing toothbrush is described by
White et al., U.S. Pat. No. 2,216,333, and includes a combination
of a water soluble salt (e.g., sodium carbonate) with an
anti-microbial agent (e.g., sulfur). The two are fused to a solid
hard body and attached to the head of the toothbrush at the base of
the bristles. When exposed to water the sodium carbonate dissolves,
forming an alkaline solution that in turn dissolves some sulfur,
which kills bacteria.
[0005] Toothbrushes wear out with extended use. Breuer et al., U.S.
Pat. No. 4,802,255, describe a toothbrush that includes filaments
that release a dye, and thus change color, in response to increased
use of the filament. The change in color provides a means for
monitoring the degree of wear of the toothbrush.
[0006] Kent, U.S. Pat. No, 5,061,106, describes including capsules
or microspheres in the tuft holes in which the bristles of a
toothbrush are mounted. The capsules or microspheres include a
disinfectant or medicant that is released during use. A dye may
also be included in the structures. The dye also is released over
time to enable the user to become aware of when the contents of the
capsules are depleted.
SUMMARY OF THE INVENTION
[0007] The invention features sustained-release matrices that are
particularly suited for use with toothbrushes. The matrices can
include an anti-microbial agent that is released over time when the
matrices are exposed to water. The matrices may also include a
colorant and a water-leachable substance that is released over time
when the matrices are exposed to water to cause the matrix to
change color.
[0008] In one aspect the invention features an oral brush that
includes a sustained-release matrix made from a support resin, a
water-soluble substance (preferably a water-soluble polymer), and
an anti-microbial agent. When the matrix contacts water, the
water-soluble substance dissolves, causing the release of the
anti-microbial agent.
[0009] An oral brush, as used herein, is any brush that includes a
handle and a head attached to a brush designed for insertion into
the mouth. The brush portion preferably is made from the common
bristles found in toothbrushes, but can also be designed for
massaging the gums rather than the teeth. For example, Kaminski et
al., U.S. Ser. No. 07/724,129, which was filed on Jul. 1, 1991, is
assigned to the same assignee as the present application and is
hereby incorporated by reference, describes an interdental foam
brush in which the brush portion is made of a soft polyurethane
foam.
[0010] A support resin, as used herein, is an essentially
water-insoluble polymer that provides structural integrity to the
matrix as the other components of the matrix--the water-soluble
polymer and anti-microbial agent--dissolve or leach out. A further
description of what constitutes a support resin is included in the
Other Embodiments section. Preferably, the polymer used as the
support resin should have a low processing temperature (less than
130.degree. C.) so that it can be readily combined with
anti-microbial agents that are unstable at high temperature. Also,
the polymer should not become brittle as the other components
dissolve or leach out, so that the matrix does not break apart
readily when handled.
[0011] Preferred polymers for the support resin include
polystyrene, polyurethane, ethylene vinyl acetate, polyethylene,
styrene/rubber, and ethylene/propylene. The more preferred support
resin is an ethylene vinyl acetate polymer. Most preferably the
ethylene vinyl acetate polymer includes between 5% and 50% vinyl
acetate, and has a softening point of between 100.degree. C. and
35.degree. C., respectively.
[0012] A water-soluble substance, as used herein, is a substance
that is sufficiently soluble in water that it will dissolve out of
the matrix during contact with water to form channels in the matrix
through which the anti-microbial agent will leach into the water. A
further description of what constitutes a water-soluble substance
is provided in the Other Embodiments section.
[0013] The preferred water-soluble substances are polymers. The
preferred polymers are starches, polyvinyl alcohols, polyethylene
oxides, hydroxyalkyl starches, hydroxyethyl and hydroxypropyl
celluloses, and gelatins. The most preferred are polyethylene
oxides, most preferably a Polyox having a molecular weight of
between 100,000 and 5,000,000.
[0014] An anti-microbial agent is a substance that kills bacteria.
The preferred anti-microbial agent for use in the matrix is
chlorhexidine, most preferably the digluconate salt thereof; the
hydrochloride and diacetate salts of chlorhexidine can also be
used. Other anti-microbial agents that can be included in the
matrix include tetracycline (and other antibiotics), and domiphen
bromide.
[0015] Preferably, the matrix is a flat template having a thickness
of up to 4 mm and is attached to the head of the body at the base
of the bristles. The preferred templates have a surface area of at
least 0.01 in.sup.2, more preferably at least about 0.1 in.sup.2.
Most preferably, the template has the same surface area as the
toothbrush head (minus the bristles). In this position the template
is exposed to water when the brush is rinsed and to saliva when it
is inserted into the mouth, and can supply the anti-microbial agent
to the bristles for self-sterilization and to the mouth to kill
bacteria. The matrix can also be attached to any other part of the
brush (e.g., the back of the brush head or at the junction of the
brush head and handle), provided that the part of the brush it is
attached to is sufficiently close to the head end that it typically
is inserted into the mouth during use.
[0016] In other preferred embodiments, the matrix includes two
layers, joined together. By "two layers", it is meant that one
section of the template has a different composition than a second
section. The first outer layer includes a support resin or a
water-soluble polymer, and an anti-microbial agent; the second
inner layer includes the support resin. Significantly, the first
layer can include a large quantity of anti-microbial agent because
the layer includes less (or none) of the support resin, yet the
layer is stable because the co-extruded second layer provides the
necessary support. The second layer may also include, optionally,
some water-soluble polymer and/or anti-microbial agent.
[0017] The invention features, in another aspect, an oral brush
that includes a template including a water-soluble polymer and an
anti-microbial agent.
[0018] The invention features, in another aspect, a matrix
including ethylene vinyl acetate, polyethylene oxide, and an
anti-microbial agent such as chlorhexidine. The matrix can be
sized, shaped, and otherwise designed for short or long term
placement at some point in the mouth. The matrix can also be
designed as a template for inclusion on a toothbrush, or can be
used to coat dental floss, or other dental instrument(s).
[0019] The matrices of the invention provide a controlled release
of an anti-microbial agent into the mouth. When included on a
toothbrush, the matrix repeatedly supplies controlled dosages of
the agent to kill bacteria in the mouth and on the bristles of the
brush. The matrices are easy to manufacture, and their composition,
shape and thickness can be adjusted to provide the best properties
for the intended use. For example, the amount and type of
polyethylene oxide in the preferred embodiment can be modified so
that the viscosity of the released polymer in solution is less than
the viscosity of the saliva in the mouth.
[0020] Another aspect of the invention features a wear-indicator
oral brush that includes a matrix containing a colorant (e.g., a
dye) and a water-leachable substance that is released from the
matrix when the oral brush is used to cause the matrix to change
color after repeated (at least 5) typical uses. The preferred
matrix is a template that includes two co-extruded or co-molded
layers. The outer layer, which contacts water and saliva during
brushing, preferably includes the water-leachable substance, which
can be, for example, a water-soluble polymer like polyethylene
oxide, or the colorant itself, or a combination of the two. The
second, inner, layer preferably includes a support resin, and can
also include a colorant (e.g, TiO.sub.2) that provides the template
with a different color, or shade of color, than the colorant
included in the outer layer. The first layer preferably also
includes a support resin, although less than the amount included in
the second layer, and also can include an anti-microbial agent.
[0021] The oral brushes having a matrix including a colorant, i.e.,
pigment or dye, provide a means to monitor the degree of wear of
the brush. Where the water-leachable substance includes the
colorant, over time as the brush is used the colorant is released,
causing the matrix to change color. In those embodiments in which
the colorant is not water-leachable and thus is not released from
the matrix, typically the portion of the template including a
water-leachable substance dissolves away through repeated use of
the brush to expose the section of the matrix that includes the
colorant, providing an indication of wear. The amounts and types of
colorant in the matrix can be adjusted so that the color of the
matrix changes after the number of uses through which a typical
brush should be used. When the colored matrix also includes an
anti-microbial agent, the change of colorant can be designed to
correspond with the depletion of the agent in the matrix.
[0022] Other features and advantages of the invention will be
apparent from the description of the preferred embodiment thereof,
and from the claims.
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0023] FIG. 1 is a perspective view of the preferred
toothbrush.
[0024] FIGS. 2a-2e provide perspective views of some alternative
two-layer templates. FIG. 2f is a cross-sectional view of the
template of FIG. 2e, taken along line A-A. In these figures the
holes through which the bristles would be inserted are not
shown.
[0025] Referring to FIG. 1 a toothbrush 10 includes a plastic body
having a handle 12 and a head 14 attached to a bristle portion 16.
Also attached to the head at the base of the bristles is template
20, a sustained-release matrix.
[0026] The body of the toothbrush is formed by conventional methods
well-known in the art. The handle is shaped to be grasped by a
hand, but alternatively can be shaped to fit into an electric
toothbrush. The configuration of the head can vary and may be oval,
convex curved, flat trim, or serrated V, or any other desired
configuration. The shape and size of handle 12 and head 14 can vary
and the axes of the handle and head may be on the same or a
different plane. The bristle portion is formed of tufts of
individual filaments attached to the head in manners known to the
art. Preferred filaments are those formed of polyamide and
polyester. The filaments preferably have substantially uniform
longitudinal lengths of between 0.3 and 6 cm, and substantially
uniform cross-sectional dimensions between about 110 to about 350
microns.
[0027] There are three types of preferred templates.
[0028] 1. Single-Layer Template Including Chlorhexidine
[0029] The single-layer template consists of a resin, ethylene
vinyl acetate; a water-soluble polymer, Polyox; and an
anti-microbial agent, chlorhexidine digluconate.
[0030] Ethylene vinyl acetate is the backbone of the matrix and has
negligible solubility in water. It provides the matrix with its
structural integrity when the other components of the matrix leach
out during use. Ethylene vinyl acetate has low toxicity and grades
are available that have low processing temperatures. Importantly,
ethylene vinyl acetate maintains the integrity of the matrix
without becoming stiff and brittle.
[0031] A sufficient amount, preferably greater than 50 percent by
weight, of ethylene vinyl acetate should be included in the matrix
so that when the other components leach out there is still enough
resin present to maintain the structure of the matrix. Of course,
not so much should be included that the matrix cannot be loaded
with a sufficient amount of the water-soluble polymer and
anti-microbial agent; preferably, the matrix should include less
than 90 percent of the ethylene vinyl acetate by weight.
[0032] The ethylene vinyl acetate polymer used in the matrix
preferably should contain between 5 percent and 50 percent by
weight vinyl acetate. If the polymer includes too little vinyl
acetate, the matrix may be too stiff and require higher processing
temperatures. If the polymer includes too much vinyl acetate, the
matrix may be rubber-like and too soft to process.
[0033] Polyox water-soluble resins are non-ionic ethylene oxide
homopolymers that range in molecular weight from about 100,000 and
5,000,000. Polyox has a very low degree of toxicity, and grades are
available that have a low processing temperature, and are
completely water soluble in cold and warm water.
[0034] The preferred Polyox, available from DuPont, is WSR N-750,
which has a molecular weight of 300,000. WSR N-750 has a water
solubility that is sufficient to provide a controlled-release of
the anti-microbial agent from the matrix at bactericidal levels,
but the solubility in the matrix is low enough that it dissolves
out slowly, over a period of many uses.
[0035] The matrix preferably contains between 5 percent and 40
percent Polyox WSR N-750 by weight. If too much Polyox is included,
the anti-microbial agent may leach out too quickly, and the
structural integrity of the matrix once most of the Polyox has
leached out may be adversely affected. If too little Polyox is
included, too low a quantity of the anti-microbial agent may be
released from the matrix during use.
[0036] The preferred anti-microbial agent is chlorhexidine
digluconate, which is well-known for its gingivitis-prevention
properties. The amount of chlorhexidine included in the matrix
depends on the level of the desired dosage and amount of Polyox;
preferably, the matrix includes between 1 percent and 30 percent of
chlorhexidine digluconate by weight. If too high a level of
chlorhexidine is included, the matrix may become brittle. Of
course, a sufficient amount of the agent should be included so that
enough is released during use to be effective.
[0037] The template should be formed to fit to the shape of the
head at the base of the bristles, and should be as thick as
possible to allow for many uses before all of the anti-microbial
agent is leached out. Preferably, the template is at least 0.5 mm
thick to ensure adequate mechanical strength, and can be up to at
least 4 mm thick.
[0038] In use, the toothbrush is rinsed with water, toothpaste
applied, and then the head of the brush is inserted into the mouth
to brush the teeth with the bristles. Upon contact with water some
of the anti-microbial agent diffuses out of the matrix, onto and
down the bristles, and eventually into the saliva of the mouth,
killing bacteria on contact. As the Polyox slowly dissolves with
repeated uses of the brush, water is allowed to penetrate into the
matrix, making more of the anti-microbial agent accessible by
diffusion from the matrix core. Eventually, all of the Polyox and
agent have left the matrix, and the toothbrush is discarded.
[0039] The matrix is designed to incorporate the desired criteria
of release rate, dosage, and effective template lifetime by
adjusting the thickness of the template included on the brush, the
quantity of anti-microbial agent contained in the matrix, and the
quantity of Polyox, or other water-soluble polymer, included in the
matrix. The higher the desired dosage, the greater the quantity of
water-soluble polymer and agent included in the matrix. Also, to
increase the released dosage, a more water-soluble form of Polyox
can be employed. The lifetime of a given matrix can be increased by
increasing the thickness of the template.
[0040] Examples of preferred matrices were made by the following
procedure.
[0041] Materials
[0042] a. Chlorhexidine digluconate
[0043] A 20 percent solution of chlorhexidine digluconate,
available from Pliva Pharmaceutical, Chemical, Food, and Cosmetic
Industry of Zagreb, Yugoslavia, or ICI, was freeze-dried as
follows:
[0044] 1. Measure 500 ml of chlorhexidine digluconate in a
graduated cylinder and transfer it to a 1 liter flask.
[0045] 2. Adjust volume to 1 liter with double distilled filtered
water and mix together.
[0046] 3. Transfer 300 ml. portions of mixture to glass evaporating
dishes (8 inch diameter).
[0047] 4. Place all evaporating dishes in the freeze-drying
apparatus until all water is removed.
[0048] 5. Transfer the chlorhexidine freeze-dried powder to a 1
liter glass bottle and cap.
[0049] 6. Store the bottle in a refrigerator or a dark room at
approximately 4.degree. C.
[0050] b. Ethylene Vinyl Acetate
[0051] The most preferred ethylene vinyl acetate is sold by DuPont
under the tradename ELVAX 360, and has a vinyl acetate content of
25 percent by weight; a tensile strength of 18.0 Mpa at 23.degree.
C. (ASTM D638); an elongation of 800 percent at 23.degree. C. (ASTM
D638); a softening temperature of 53.degree. C. (ASTM D1525); and a
flexural modulus of 26 Mpa at 23.degree. C. (ASTM D790). ELVAX 360
contains 500 ppm BHT as an anti-oxidant.
[0052] In order to mix with chlorhexidine and Polyox powders, ELVAX
360 pellets are ground into powders with particle sizes of less
than 250 microns with a Glen Mill Granulator (Model #CS 150/100-2)
installed with a screen plate having 1 mm screen holes. A suction
system is added to the grinding chamber to facilitate the removal
of powders from the chamber to a container. During grinding, the
material is recycled through the grinder as many times as necessary
(usually two or three passes) to meet the size requirement. A sieve
shaker manufactured by the W. S. Tyler Co. is used to control the
sizes as needed.
[0053] C. Polvox
[0054] Polyox WSR N-750 is available from Union Carbide, and has a
melting point of 62-67.degree. C. and a molecular weight of
300,000. The Polyox is used as received and mixed with other
components to form the template.
[0055] d. Blending of Materials
[0056] The ELVAX 360, Polyox, and chlorhexidine digluconate are
mixed in a blender. Each component is first weighed and then poured
into a glass jar with a capacity of 0.5 kilograms. The jar is then
placed on a ball-mill rotator and mixed for approximately 1/2 hour.
For a quantity greater than 0.5 kilograms, a V-blender manufactured
by Patterson-Kelly Co. Inc. is used. The blended material should be
stored in a dry, cool room.
[0057] e. Processing
[0058] The conventional equipment used to produce the matrix
includes an extruder, a cooling plate, and a puller. An extrusion
die with an opening of 2" wide is used. To control the thickness of
the template, the die utilizes a flexible lip design which enables
the die lip to be adjusted anywhere from 0.15" to 0.45". Each die
is supplied with a sensor for the recording of melt pressure and
temperature. Pulling speed are adjusted to produce a 1" wide strip
with a thickness of 0.020" or 0.040". The strip can then be
fabricated into templates.
[0059] Samples were made with both a twin-screw and single-screw
extruder. The Werner & Pfleiderer 30 mm twin-screw extruder is
based on a corotating and intermeshing twin-screw system. To
minimize Polyox and chlorhexidine degradation during processing,
the twin screws consists of only two high-shear kneading elements
and the rest being low-shear conveying screw elements; the screw
speed and processing temperatures are reduced to a minimum. The
mixture is fed using a K-Tron twin-screw feeder (Model T-20).
[0060] Alternatively, a Haake 3/4 inches single-screw extruder
equipped with a 5HP drive motor is employed. When making the most
preferred matrix, the extruder was operated with a screw speed of
35 rpm, a barrel pressure of 70 psi, a die pressure of 80 psi,
barrel temperature of 113.degree. C., and a die temperature of
113.degree. C.
[0061] The blend of materials is fed to either extruder and the
strip produced is pulled onto a plate by a Farris puller at a speed
of between three or four feet per minute with minimum tension on
the strip. The strip is cooled on a plate placed inside a PVC tube
by blowing dry compressed air into the tube at approximately 10
CFM. The finished product should be kept in a cool, dry room.
[0062] The matrices can also be made by other conventional
processes, such as by injection molding, casting foam dispensing
machines, and reaction injection molding. In addition, two color
injection molding can be used to make the toothbrush/matrix
combination.
[0063] Toothbrush Preparation
[0064] Toothbrushes including the sustained-release matrix were
prepared according to the following procedure:
[0065] 1. Toothbrush handles with undercuts on the toothbrush head
for placing templates were molded.
[0066] 2. The strips prepared above were cut into two strips having
maximum width of 39/64". Tape was used to hold the material to
prevent stretching.
[0067] 3. Sets of holes corresponding to the desired bristle
pattern to be used with the brush were punched with a Dake arbor
press.
[0068] 4. Templates of the desired size were cut from the strips,
and glued to the head of the toothbrush body.
[0069] 5. The bristles were attached to the head by standard
procedures.
[0070] Testing for Sustained-Release Properties
[0071] The sustained-release matrices of the invention can be
tested for their long-term release profiles according to the
following procedure.
[0072] First, a calibration plot of chlorhexidine digluconate in
distilled water was prepared over concentration range of 2 to 40
mcg/ml. Release studies were performed in triplicate; the procedure
is summarized below:
[0073] 1. Samples (1/2".times.1") were cut from the strip by random
sampling.
[0074] 2. The samples were placed in 250 ml beakers, which were
then set into a shaking water bath (37.degree. C., 80 rpm).
[0075] 3. 5 ml of distilled water were pipetted to each beaker.
[0076] 4. After 5 minutes, the samples were removed from beakers
and assayed for chlorhexidine content in release solution by
uv-spectrophotometric analysis.
[0077] 5. This procedure was repeated for 100 release periods.
[0078] The preferred strips showed excellent chlorhexidine release
characteristics over extended periods of use. The composition of
the preferred strips, and their release properties after 100 uses,
are summarized in the Table below. In the Table, EVA is the
preferred ethylene vinyl acetate discussed above; the Polyox is
either the more preferred WSR N-750, or a 60:40 blend (60% Polyox
coagulant grade, 40% WSR N-750 from Union Carbide); CHG is
chlorhexidine digluconate; "S" means the template was prepared by
single-screw extrusion, "T" by twin-screw extrusion; [CHG] (ppm) is
the concentration of CHG in ppm in the release solution at 100
releases and 60 m (60 mesh) or 18 m (18 mesh) is the particle size
of chlorhexidine digluconate employed (no particle size listing
indicates that the chlorhexidine was not sieved following
freeze-drying). All of the templates were still releasing over 1
ppm chlorhexidine after 100 uses. The most preferred matrix is 2 mm
thick and includes 60% EVA, 15% Polyox WSR N-750, and 25%
chlorhexidine digluconate.
1 Thickness Composition (%) [CHG] (mm) EVA Polyox CHG (ppm) 1.0 70
15 (60:40) 15 ICI S 5.51 1.0 65 15 (60:40) 20 ICI S 6.49 1.0 70 15
(N-750) 15 ICI S 20.98 0.5 70 15 (60:40) 15 ICI S 1.32 0.5 70 15
(N-750) 15 ICI S 1.57 0.5 70 15 (N-750) 15 ICI S 2.19 0.5 70 15
(N-750) 15 ICI S 2.53 1.0 65 20 (N-750) 15 ICI S 8.63 1.0 60 25
(N-750) 15 ICI S 12.41 1.0 50 35 (N-750) 15 ICI S 7.04 1.0 70 15
(N-750) 15 ICI T 7.84 1.0 70 15 (N-750) 15 ICI T 23.15 1.0 70 15
(N-750) 15 ICI T 2.73 1.0 70 10 (N-750) 20 ICI T 21.38 2.0 65 15
(N-750) 20 (60 m ICI) S 17.59 2.0 70 15 (N-750) 15 (Pliva) S 12.43
2.0 65 20 (N-750) 15 (60 m ICI) S 7.62 2.0 70 15 (N-750) 15 (60 m
ICI) S 11.20 2.0 70 15 (N-750) 15 (18 m ICI) S 6.78 2.0 70 15
(N-750) 15 (60 m ICI) T 9.10 2.0 65 20 (N-750) 15 (60 m ICI) T 9.08
2.0 70 15 (N-750) 15 (Pliva) T 1.53 2.0 60 15 (N-750) 25 (60 m ICI)
T 50.76 2.0 65 15 (N-750) 20 (60 m ICI) T 7.67 2.0 60 15 (N-750) 25
(60 m Pliva) T 9.83 2.0 55 15 (N-750) 30 (60 m Pliva) T 7.10 2.0 60
15 (N-750) 25 (60 m ICI) S 63.00 2.0 55 10 (N-750) 35 (60 m Pliva)
T 15.78 2.0 60 15 (N-750) 25 (18 m ICI) S 62.34 2.0 60 15 (N-750)
25 (60 m Pliva) 47.22 2.0 60 15 (N-750) 25 (Pliva) S 72.63 2.0 60
15 (N-750) 25 (Pliva) T 29.72 2.0 60 15 (N-750) 25 (ICI) S 54.56
2.0 60 15 (N-750) 25 (ICI) T 31.37 2.0 60 15 (N-750) 25 (60 m
Pliva) S 61.24 2.0 60 15 (N-750) 25 (60 m Pliva) S 60.03 2.0 60 15
(N-750) 25 (60 m Pliva) S 60.43
[0079] 2. Two-Layer Template Including Chlorhexidine
[0080] The preferred single-layer template generally includes over
50% support resin (EVA) by weight to achieve good mechanical
properties and processibility. This, to some extent, limits the
quantity of chlorhexidine that can be included in the matrix. An
alternative two-layer template provides a higher quantity of
chlorhexidine in the portion of the template that primarily
contacts water and saliva. The first, outer layer contains less
ethylene vinyl acetate and more polyethylene oxide and
chlorhexidine. The second, inner layer has the composition of the
preferred single-layer embodiment, although the second layer could
consist entirely of ethylene vinyl acetate. A preferred two-layer
matrix includes 65% ethylene vinyl acetate, 15% Polyox, and 20%
chlorhexidine digluconate in the inner layer, and 30% ethylene
vinyl acetate, 25% Polyox, and 45% chlorhexidine digluconate in the
outer layer. The inner layer should include at least 60% of the
support resin; the outer layer can include upwards of 50%
chlorhexidine.
[0081] The outer layer releases a higher dosage of chlorhexidine
when contacted with water, yet has good strength and processibility
because the second layer provides the necessary support. As the
outer layer wears away, the anti-microbial agent in the inner layer
also is released. The outer layer preferably is 0.25 to 3 mm thick,
while the inner layer preferably is 0.1 to 0.5 mm thick.
[0082] The two-layer templates can be produced either by
conventional co-extrusion or co-injection molding techniques, from
two different mixtures. Alternatively one layer can be extruded and
then the other layer can be thermoformed/compression molded or
laminated onto the extruded layer.
[0083] An alternative two-layer embodiment has an outer layer
consisting only of the support resin and the anti-microbial agent.
The preferred anti-microbial agent, chlorhexidene digluconate, is
water-soluble, although not to the same degree as the water-soluble
polyethylene oxide. Because the outer layer includes a high
quantity of the anti-microbial agent, enough of the agent can
dissolve out of the matrix to provide a sufficient dosage of the
agent without the assistance of a water-soluble polymer.
[0084] 3. Template Including a Colorant
[0085] The wear-indicator template preferably includes two layers,
each with a different colorant. The outer layer includes a
water-soluble polymer (preferably polyethylene oxide, polyethylene
glycol, or polyvinyl alcohol) and a colorant, preferably a
water-leachable colorant; a support resin is optional. The inner
layer includes a support resin and a second colorant, like titanium
dioxide, which provides a solid white appearance. The different
colorants should be selected to provide a clear contrast so that a
user can plainly discern the color change as the colorant in the
outer layer leaches out over time.
[0086] The two-layer templates including a colorant can be produced
by the same techniques used to produce the two-layer templates
including an anti-microbial agent discussed above.
[0087] The preferred wear-indicating template is illustrated in
FIG. 2a and consists of an outer layer 22, which includes the
colorant that is released during use, and an inner layer 24, which
is adjacent the toothbrush during use. Inner layer 24 includes
titanium dioxide.
[0088] Alternative two-layer template embodiments are illustrated
in FIGS. 2b-2f. In these embodiments, no colorant is included in
the outer layer 26 and a non-white colorant is included in the
inner layer 28. The outer layer in these embodiments preferably
consists only of water-soluble polymer; as the outer layer
dissolves away during use the colorant in the second layer becomes
visible, or more visible, providing an indication of the degree of
wear of the brush.
[0089] Referring to FIG. 2b, a template has a flat outer layer 26
and a flat inner layer 28 that are approximately the same size. As
outer layer 26 dissolves away with repeated use, a colorant in
inner layer 28 becomes visible to a user looking straight down at
the surface of the bristles that contact the teeth.
[0090] Referring to FIG. 2c, inner layer 28 of a template has
elements 30 that extend into grooves in outer layer 26. As outer
layer 26 dissolves away, elements 30, which include colorant,
become visible to the user as stripes at the base of the bristles.
A similar embodiment is illustrated in FIG. 2d, except that
elements 32 extend along the exterior of outer layer 26. In this
embodiment, as outer layer 26 dissolves away a colored strip along
the edge of the template becomes visible to a user looking straight
down at the surface of the bristles that contact the teeth.
[0091] Referring to FIGS. 2e and 2f, an alternative template
includes an inner layer 28 that is fully surrounded by the outer
layer 26 except at surface 34, where the template is attached to
the head of the brush. As outer layer 26 dissolves, inner layer 28
becomes visible from the sides and from the top.
[0092] Although not illustrated, other alternative matrices include
those in which the inner layer(s) is simply two narrow strips, like
elements 30; and those in which the inner layer includes
cyclindrical elements that extend upwards from the inner layer into
the outer layer. In the latter embodiment, as the outer layer
dissolves away the inner layer becomes visible as colored dots.
[0093] The following examples were made from two 3/4 inch extruders
with a co-extrusion die to produce two-layer templates having the
design shown in FIG. 2a and having a thickness of about 10 mm.
Example A
[0094] The first layer of the template consisted of 44.6% ethylene
vinyl acetate (Elvax 360), 44.5% Polyox N-750, 10% polyethylene
glycol (Dow-E4500), and 0.9% of a dark blue pigment (FD&C Blue
No. 2, Aluminum Lube 35-42%, available from Warner Jenkinson of St.
Louis, Mo.). The second layer consisted of 99.5% Elvax 360 and 0.5%
titanium dioxide. When the template was submerged in water for
24-hours, the initial dark blue color changed to a light blue.
Example B
[0095] The first layer of the template includes 49.5% Elvax 360,
49.5% Polyox N-750, and 1% dark blue pigment. The second layer was
the same as in Example A. The results of a 24-hour water-submerge
test also were the same.
Example C
[0096] The first layer of the template consists of 99% polyvinyl
alcohol and 1% of the dark blue pigment, and no support resin. The
second layer was the same as for the other two examples. When this
template was subjected to a 24-hour water-submerge test, the
initial dark blue color of the template turned to white.
[0097] Other Embodiments
[0098] Other embodiments are within the claims. For example, other
water-insoluble polymers can be used as the support resin. To
determine whether a polymer can be used as a support resin within
the meaning of this application, a template should be prepared
containing 60% of the polymer, 15% Polyox WSR N-750, and 25%
chlorhexidine digluconate. Matrix samples (1/2".times.1") having a
thickness of 2 mm are placed in 250 ml beakers which are then set
into a shaking water bath (37.degree. C., 80 rpm) for 8 hours. If
the matrix has maintained its structural integrity in the bath and
does not fall apart, the polymer is a support resin. Examples of
the specific polymers that can be used in place of EVA as the
support resins include Hytrel G-4074 (a polyester available from
DuPont); Hytrel 4056 (a polyester elastomer also available from
DuPont); Vestenamer 8012 (TPE, available from Huls America);
Rimplast PSW 2159 (a silicone, available from Petrarch Systems);
Prolytropes (an ethylene/propylene alloy available from A.
Schulman, Inc.); Millathanes (a polyester urethane available from
Millathane); Kraton G-7680 (a styrene/rubber available from Shell
Chemical); and Santoprene 101-55 (a polyolefin alloy available from
Monsanto Chemical). Prolytropes and Kraton G-7680 are more
preferred because of their relatively low processing temperatures,
29.degree. C. and 57.degree. C., respectively. Examples of other
general classes of polymers that can be used as support resins
include polyurethanes, polycarbonates, polyesters, polyethylenes,
polypropylenes, polystyrenes, and polyvinyl chloride;
polyurethanes, polyethylenes, and polystyrenes are more preferred
because forms of these polymers with relatively low processing
temperatures are available.
[0099] Additionally, other water-soluble substances can be used in
place of Polyox in the matrix. To determine whether something is a
water-soluble substance within the meaning of this application, a
template should be prepared containing 80% EVA and 20% of the
substance. Matrix samples (1/2".times.1") having a thickness of 2
mm are placed in 250 ml beakers which are then set into a shaking
water bath (37.degree. C., 80 rpm) for 8 hours. After that time,
the matrix is removed, and photomicrographs (magnification of
350.times.) of the matrix after the procedure are compared to
photomicrographs (350.times.) of the matrix prior to the procedure.
If after the procedure channels and pores have formed into the
matrix, the substance is a water-soluble substance. Other
water-soluble natural polymers than can be used include agar;
carrageenan; corn starch; guar gum; gum arabic; gum karaya; gum
tragacanth; locust bean gum; potato, wheat and rice starches;
tapioca; casein; pectin; and sodium alginate. Modified natural
polymers then can be used include cationic starch; dextran;
hydroxyalkyl starches; hydroxyethyl and hydroxypropyl cellulose;
methyl cellulose; sodium carboxymethyl cellulose; xanthan gum;
gelatin; and sodium carboxymethyl starch. Synthetic polymers
suitable for use include polyvinyl alcohol; cationic resins and
quaternary ammonium compounds; poly (N-vinyl-2-pyrrolidinone);
vinyl ether polymers; styrene-maleic anhydride copolymers;
ethylene-maleic anhydride copolymer; hydrophilic gels; and
polymeric surface-active agents. Inorganic salts, (e.g., EDTA,
NaCl, Na.sub.2CO.sub.3, and KCl) and fillers may also be used.
[0100] Anti-microbial agents that can be used in place of
chlorhexidine digluconate include antibiotics such as actinobolin,
chlortetracycline, tetracycline, streptomycin, kanamycin, neomycin,
niddamycin, bacitracin, erythromycin, penicillin, rancemycin,
gramicidin, saramycin, and polymyxin B; as well as antiplaque
enzymes such as mucinases, pancreatin, fungal enzymes,
protease-amylase, dextranase, moimnase, zendium, amyloglucosidase,
and glucose oxidase. Other conventional antimicrobials that can be
used include phenolic compounds (e.g., phenol, thymol,
2-phenylphenol, hexylresorcinol), and listerine (thymol,
eucalyptol, menthol, methylsalicylate); bi-pyridines (e.g.,
octenidene); pyrimidines (e.g., hexetidine); halogens (e.g.,
iodine, iodophores, fluorides); quaternary ammonium salts (e.g.,
cetylpyridinium chloride, benzethonium chloride, domiphen bromide);
oxygenating agents (e.g., peroxides; perborate); herbal extracts
(e.g., sangnimarine); heavy metal salts (e.g., silver, mercury,
zinc, copper, tin); and other bis-biguanidines besides
chlorhexidine (e.g., alexidine). Of course, other chlorhexidine
salts like the diacetate and dihydrochloride can be used in place
of chlorhexidine digluconate.
[0101] Moreover, the matrices can be used in other ways, for
example by impregnating the bristles of a toothbrush with small
matrix particles, by inserting the matrices into the holes the
toothbrush head into which bristles are then inserted, or by
coating the matrix on dental floss. The matrix also can be attached
to the side of the head of the toothbrush opposite the side to
which the bristles are attached. Alternatively, a matrix can be
designed to be inserted and left in the mouth for an extended
period of time, for example as a small ring that fits around a
tooth.
[0102] Templates can be designed that are sustained-release but
that do not release over 1 ppm chlorhexidine after 100 uses by the
test previously designed. For example, a disposable toothbrush,
which would be discarded after only a few uses, does not require
such extended release lifetime. For the purposes of this invention,
sustained-release means that the matrix still releases at least 1
ppm of the anti-microbial agent after 10 uses (more preferably
after 50 uses) when tested according to the procedure described in
the Preferred Embodiment section.
[0103] Any of the two-layer templates shown in FIG. 2 can be used
to provide the sustained-release of an anti-microbial agent.
[0104] Further, other well-known, conventional additives such as
fillers, binders, lubricants, and channeling agents can be included
in the matrix, although care should be taken that these additives
do not adversely affect the agent release rate.
* * * * *