CA2116115C - Sustained-release matrices for dental application - Google Patents

Sustained-release matrices for dental application Download PDF

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Publication number
CA2116115C
CA2116115C CA002116115A CA2116115A CA2116115C CA 2116115 C CA2116115 C CA 2116115C CA 002116115 A CA002116115 A CA 002116115A CA 2116115 A CA2116115 A CA 2116115A CA 2116115 C CA2116115 C CA 2116115C
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Canada
Prior art keywords
water
matrix
wear
layer
indicating
Prior art date
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Expired - Fee Related
Application number
CA002116115A
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French (fr)
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CA2116115A1 (en
Inventor
Mingchih M. Tseng
Carl M. Philbrook
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Gillette Co LLC
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Gillette Co LLC
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Priority claimed from US07/898,471 external-priority patent/US5340581A/en
Application filed by Gillette Co LLC filed Critical Gillette Co LLC
Publication of CA2116115A1 publication Critical patent/CA2116115A1/en
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Publication of CA2116115C publication Critical patent/CA2116115C/en
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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • AHUMAN NECESSITIES
    • A46BRUSHWARE
    • A46BBRUSHES
    • A46B11/00Brushes with reservoir or other means for applying substances, e.g. paints, pastes, water
    • AHUMAN NECESSITIES
    • A46BRUSHWARE
    • A46BBRUSHES
    • A46B15/00Other brushes; Brushes with additional arrangements
    • A46B15/0002Arrangements for enhancing monitoring or controlling the brushing process
    • A46B15/0004Arrangements for enhancing monitoring or controlling the brushing process with a controlling means
    • A46B15/001Arrangements for enhancing monitoring or controlling the brushing process with a controlling means with means indicating the remaining useful life of brush
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/43Guanidines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/81Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
    • A61K8/8135Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an acyloxy radical of a saturated carboxylic acid, of carbonic acid or of a haloformic acid; Compositions of derivatives of such polymers, e.g. vinyl esters (polyvinylacetate)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/86Polyethers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/42Colour properties
    • A61K2800/43Pigments; Dyes

Abstract

A sustained-release matrix (20) for dental application includes either an anti-microbial agent or a colorant that is released from the matrix (20) when the matrix (20) contacts water. The preferred matrices (20) include a water-soluble polymer and a water-insoluble support resin.

Description

WO 93/03649 PCI~/US92/06770 2~

SUSTAINED-RELEASE MATRICES FOR DEN~AL APPLICATION
The invention relates to sust~i~e~
release matrices.
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.
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. Patent 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 21i~1iS
W093/03~9 PCT/US92/067,~

exposed to water the sodium carbonate dissolves, forming an alkaline solution that in turn dissolves ~ome sulfur, which k~lls bacteria.
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 lo of the toothbrush.
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.
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 ~Yroce~ 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.
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.
An oral brush, as used herein, is any brush that includes a handle and a head attached to W093/0~9 PCT/US92/06770 211611~
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., USSN
07/724,129, which was filed on July 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.
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 EmhoAiments section. Preferably, the polymer used as the su~oLL resin should have a low processing temperature (less than 130-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.
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-C. and 35-C., respectively.
A water-soluble substance, as used herein, is a substance that is sufficiently soluble W093/0~9 2 I 1611 ~ PCT/US92/067, in water that it will dissolve out of the matrix during contact with water to form ch~nnels in the matrix through which the anti-microbial agent wil~
leach into the water. A further description of what constitutes a water-soluble substance is provided in the Other Embodiments section.
The preferred water-soluble subst~nces 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.
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.
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 O.01 in2, more preferably at least about 0.1 in2. Most preferably, the template has the same surface area as the toothbrush head (minus the bristles). In this position the template is eY~ose~ 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 W093/03~9 2 1 1 6 1~ ~ PCT/US92/06770 handle), provided that the part of the brush it is attached to is suffi~iently close to the head end tha~ it typica;ly is inserted into the mouth during use.
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 reGQn~
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.
The invention features, in another aspect, an oral brush that includes a template including a water-soluble polymer and an anti-microbial agent.
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, Ch~p~, 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).
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 2116II~
W093/03~9 ~ PCT/US92/067;~

bristles of the brush. The matrices are easy to manufact~re, and their ccmposition, shape and tnickness 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.
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 br~ching~ 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., TiO2) 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 secon~ layer, and also can include an anti-microbial agent.
The oral brushes having a matrixincluding 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 W093/03~9 21 1 B 1 I ~ PCT/US92/06770 is not water-leachable and thus is not released from the matrix, typically the portion of the template including a water-leachable s~bstance dissolves away through repeated use of the brush to 5 ~YpQ~q 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.
Other features and advantages of the invention will be apparent from the description of the preferred embodiment thereof, and from the claims.
Figure 1 is a perspective view of the preferred toothbrush.
Figures 2a-2e provide perspective views of some alternative two-layer templates. Figure 2f is a cross-sectional view of the template of Figure 2e, taken along line A-A. In these figures the holes through which the bristles would be inserted are not shown.
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.
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.

W093/0~9 2 1 ~ ~6 11~ PCT/US92/067,~

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 longit~ n~l lengths of between 0.3 and 6 cm, and substantially uniform cross-sectional dimensions between about 110 to about 350 microns.
There are three types of preferred templates.
1. Single-laYer tem~late includinq chlorhexidine The single-layer template consists of a resin, ethylene vinyl acetate; a water-soluble polymer, Polyox; and an anti-microbial agent, chlorhexidine digluconate.
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.
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 W093/03~9 21 1 6 I 1 ~ PCT/US92/06770 g acetate by weight.
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.
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.
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.
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.
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 W093/03~9 21 1 6 I 1 S PCT/US92/06, the level of the desired dosage and amount of Polyox; preferably, the matrix includes between 1 percent and 30 pe~cent of chlorhexidine digluconzte by weight. If too high a level of chlorhexidine is included, the matrix may become brittle. Of course, a ~ufficient amount of the agent should be included so that enough is released during use to be effective.
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 O.5 mm thick to ensure adequate mech~nical strength, and can be up to at least 4 mm thick.
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.
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 W093/03~9 21 1 6 1 1 ~ PCT/US92/06770 of water-soluble polymer and agent included in the matrix. Also, to increase the released dosage, a more water-solu~le .orm of Polyox ~an be employed.
The lifetime of a given matrix can be increased by increasing the thic~nec~ of the template.
Examples of preferred matrices were made by the following procedure.
Materials a. Chlorhexidine di~luconate 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:
1. Measure 500 ml of chlorhexidine digluconate in a graduated cylinder and transfer it to a 1 liter flask.
2. Adjust volume to 1 liter with double distilled filtered water and mix together.
3. Transfer 300 ml. portions of mixture to glass evaporating ~icheC (8 inch diameter).
4. Place all evaporating ~ s in the freeze-drying apparatus until all water is removed.
5. Transfer the chlorhexidine freeze-dried powder to a 1 liter glass bottle and cap.
6. Store the bottle in a refrigerator or a dark room at approximately 4-C.
b. EthYlene Vinyl Acetate 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-C.
(ASTM D638); an elongation of 800 percent at 23 C.
(ASTM D638); a softening temperature~of 53 C. (ASTM
D1525); and a flexural modulus of 26 Mpa at 23 C.
(ASTM D790). ELVAX 360 contains 500 ppm BHT as an anti-oxidant.
In order to mix with chlorhexidine and W093/03~9 2 1 1 6 1i~ PCT/US92/067;~

Polyox powders, ELVAX 360 pellets are ground into powders with particle sizes of less than 250 mi~rons with a Glen Mill Granulator (Model #CS
150/lOQ-2) installed with a screen plate having 1 mm screen holes. A suction system is added to the grin~ng chamber to facilitate the removal of powders from the chamber to a container. During grind ing, the material is recycled through the grinder as many times as n~C~cc~ry (usually two or three pAss~s) to meet the size requirement. A
sieve ch~ker manufactured by the W.S. Tyler Co. is used to control the sizes as nee~e~.
C. PolYOX
Polyox WSR N-750 is available from union Carbide, and has a melting point of-62-67 C. and a molecular weight of 300,000. The Polyox is used as received and mixed with other components to form the template.
d. Blendinq of Materials 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.
e. Processing 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 W093/0~9 2 1 1 6 1 1 ~ PCT/US92/06770 pressure and temperature. Pulling speed are adjusted to produce a 1" wide strip with a thicknesc of 0.020" Gr 0.040". The strip can then be fabricated into templates.
Samples were made with both a twin-screw and single-screw extruder. The Werner & Pfleiderer 3Omm twin-screw extruder is based on a corotating and inter~-~h;ng 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 conveyinq 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 T20).
Alternatively, a ~aake 3/4 inches single-screw extruder equipped with a SHP 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-C., and a die temperature of 113-C.
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.
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.

W093/0~9 2 I ~ PCT/US92/06;

Toothbrush PreDaration Toothbrushes including the ~ust~i n~A-release matrix were prepared according to the following procedure:
1. Toothbrush handles with undercuts on the toothbrush head for placing templates were molded.
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 stretch~ng.
3. Sets of holes correspon~ing to the desired bristle pattern to be used with the brush were punched with a Dake arbor press.
4. Templates of the desired size were cut from the strips, and glued to the head of the toothbrush body.
5. The bristles were attached to the head by stA~AArd procG~l~res.
Testin~ for Sustained-Release Properties The sustAine~-release matrices of the invention can be tested for their long-term release profiles according to the following procedure.
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 proce~llre is summarized below:
1. Samples (1/2" x 1") were cut from the strip by random sampling.
2. The samples were placed in 250 ml beakers, which were then set into a ~hAking water bath (37 C., 80 rpm).
3. 5 ml of distilled water were pipetted to each beaker.
4. After 5 minutes, the samples were removed from beakers and assayed for chlorhexidine W093/0~9 2 1 1 fi 11~ PCT/US92/06770 - lS -content in release solution by uv-spectrophoto-metric analysis.
5. This procedure was repaated fcr too release periods.
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 ~ i ~C-l~r~~ above the Polyox is either the more preferred WSR N-750, or a 60:40 blend (60% Polyox coagulant grade, 40% WSR N-7S0 from Union Carbide);
CHG is chlorhexidine digluconate; "S" means the template was prepared by single-screw extrusion, "T" by twin-screw extrusion; tCHG] (ppm) is the ronc~ntration of CHG in ppm in the release solution at 100 releases and 60m (60 mesh) or 18m (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 2mm thick and includes 60% EVA, 2S lS% Polyox WSR N-750, and 25% chlorhexidine digluconate.

21~511~
WO 93/03649 P~/US92/067, ~h;~TYx:c Cocpo6ition (%) tCHG]
(~) (E~) ~ Pol~ ~.
1.0 70 15 (60:40' 15 ICI S 5.51 5 1.0 65 15 (60:40 20 ICI S 6.49 1.0 70 15 (~ - 750 15 IC_ S 20.98 0.5 ~0 15 '60: ' 0 15 ICI S 1.32 0.5 70 15 ~-750 15 IC S 1.57 0.5 ~0 15 ~-7~ 0 15 IC S 2.19 10 0.5 7Q 15 N--' 0 15 IC S 2.53 1.0 65 20 N-750 15 ICI S 8.63 1.0 ~ o 2c N-750 15 ICr S 12.41 1.0 ro 3~ tN--50 1~ ICI S 7.04 1.0 .0 1 (N-750 1~ ICI T 7.84 15 1.0 70 1c (~--750 lc Icr T 23.15 1.0 70 5 (N-750 1' ICI T 2.73 1.0 70 ~ C !N-7C O 20 ICI T 21.38 2.0 65 ~ (~-7'0 20 '60m IC~) S 17.59 2.0 70 lc (N-7'0 15 Pliva) S 12.43 20 2.0 65 20 (N-750 15 60m IC~ S 7.62 2.0 70 15 (N-750 15 60m ICI S 11.20 2.0 70 15 (N-750 15 18m ICI S 6.78 2.0 70 15 rN-750 ~ 5 Om ICI T 9.10 2.0 65 20 (N-,50 _5 'Om ICL T 9.08 25 2.0 70 15 lN-750 5 ~ ~1iva~ T 1.53 2.0 60 1~ (N-750 25 (60~ ICI) T 50.76 2.0 65 lr (N-750' 20 (60m I__) T 7.67 2.0 60 1~ (N-750 25 (60m ~_ va) T 9.83 2.0 55 1' (N--50 30 (60m ~_ va) T 7.10 30 2.0 60 15 (N-750 25 (60m~Cn S 63.00 2.0 55 10 (N-750 35 (60m Pliva) T 15.78 2.0 60 15 (N-750 25 '18m ICL) S 62.34 2.0 60 15 (N-750' 25 6 ~n (Pliva) 47.22 2.0 60 15 (N-750 25 P_ va) S 72.63 35 2.0 60 15 (N-750 25 ~ P__va) T 29.72 2.0 60 15 (N-750 25 (ICI) S 54.56 2.0 60 15 (N-750' 25 (ICL~ T 31.37 2.0 60 15 (N-750 25 (60m P va S 61.24 2.0 60 15 (N-750 25 (60m P va S 60.03 40 2.0 60 15 (N-750 25 (60m P_ va S 60.43 W093/0~9 2 1 ~ 6 1 1 ~ PCT/US92/06770 2. Two-laYer template including chlorhexidine The preferred single-layer template generally includes over 50% support resin (E~A) by weight to achieve good mechAnical properties an~
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.
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.
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.

W093/03~9 2 1 1 6 1 1 5 PCT/US92/06~

An alternative two-layer emhoAiment has an outer layer consisting only of the support resin and the anti-microbial agent. The preferred anti-microbial agent, chlorhexidine 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, eno~gh 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.
3. Template includinq a colorant 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 QeCQn~ 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.
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 ~isrl~Qsed above.
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.
Alternative two-layer template embodiments are illustrated in Figs. 2b-2f. In W093/0~9 2 1 1 ~ PCT/US92/06770 these emho~iments, 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 awayduring use the colorant in the second layer becomes visible, or more visible, providing an indication of the degree of wear of the brush.
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.
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.
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.
Although not illustrated, other alternative matrices include those in which the inner layer(s) is simply two narrow strips, like W093/03~9 2 ~ PCT/US92/067 elements 30; and those in which the inner layer include~ cylindrical elements that extend upwards from the inner layer into the outer layer. Tn the latter embodiment, as the outer layer dissolves away the inner layer becomes visible as colored dots.
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.
~am~le A
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 o.s% of a dark blue pigment (FD&C Blue No. 2, Aluminum Lube 35-42%, available from Warner JDnkin~on 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
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.
Exam~le C
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.
Other Embodiments Other embodiments are within the claims.

W093/0~9 2 1 1 61 ~ ~ PCT/US92/067 ~

For example, other water-ir.soluble polymers can be used as the support resin. To d~termine whether a polymer can be used a~ a -upport 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" x 1") having a thicknesR of 2 mm are placed in 250 ml beakers which are then set into a ~hAk;ng water bath (37-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 Mnns~to Chemical). Prolytropes and Rraton G-7680 are more preferred because of their relatively low processing temperatures, 29-C. and 57 C., respectively. Examples of other general classes of polymers that can be used as support resins include polyurethanes, polycarbonates, polyesters, polyethylenes, polypropylenes, poly~-y.anes, and polyvinyl chloride; polyurethanes, polyethylenes, and polystryenes are more preferred because forms of these polymers with relatively low processing temperatures are available.
Additionally, other water-soluble subst~nces can be used in place of Polyox in the W093/0~9 PCT/US92/06-~- ~tl~illS

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" x 1") having a thickness of 2mm are placed in 250 ml beakers which are then set into a eh~ki~g water bath (37 C., 80 rpm) for 8 hours. After that time, the matrix is removed, and photomi~Loy.aphs (magnification of 350X) of the matrix after the proce~l~re are compared to photomi~Lo~aphs (350X) 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 that 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 that 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, Na2CO3 and KCl) and fillers may also be used.
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, W093/0~9 PCT/US92/06770 rancemycin, gramicidin, saramycin, and polymyxin B;
as well as antiplaque enzymes such as muc;n~es, pancreatin, fungal enzymes, protease-amylase, dextranase, moimnase, ~endium, amyloglucosidase, and glucose oxidase. Other conventional anti-microbials that can be used include phenolic com~o~,ds (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 chlorh~ ine digluconate.
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.
Templates can be designed that are sustained-release but that do not release over l ppm chlorhexidine after 100 uses by the test previously designed. For example, a disposable W093/0~9 2 1 1 6 1 1 ~5 PCT/US92/067 toothbrush, which would be ~cArded after only a few uses, does not require such ext~n~ release lifetime. For the purposes of this invention, sus~inP~-release means that the matrix still releases at least 1 ppm of the anti-microbial agent after lO uses (more preferably after 50 uses) when tested according to the procedure described in the Preferred Embodiment section.
Any of the two-layer templates shown in Figure 2 can be used to provide the sustained-release of an anti-microbial agent.
Further, other well-known, conventional additives such as fillers, binders, lubricants, and ch~nneling agents can be included in the matrix, although care should be taken that these additives do not adversely affect the agent release rate.

Claims (47)

-25-
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 attached to said body, said matrix comprising a water-insoluble support resin, a water-soluble polymer, and an anti-microbial agent.
2. The oral brush of claim 1, wherein said resin comprises ethylene vinyl acetate.
3. The oral brush of claim 1, wherein said polymer comprises polyethylene oxide.
4. The oral brush of claim 1, wherein said anti-microbial agent comprises chlorhexidine.
5. 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.
6. The oral brush of claim 1, wherein said matrix comprises a flat template no greater than 4mm thick.
7. 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.
8. The oral brush of claim 1, wherein said matrix comprises a. a first layer including said water-soluble polymer and said anti-microbial agent, and b. a second layer joined with said first layer and comprising said support resin.
9. The oral brush of claim 8, wherein said water-soluble polymer is polyethylene oxide.
10. The oral brush of claim 8, wherein said support resin is ethylene vinyl acetate.
11. The oral brush of claim 1, wherein said matrix comprises a. a first layer comprising said anti-microbial agent and said support resin, and b. a second layer joined with said first layer and comprising said support resin.
12. The oral brush of claim 11, wherein said support resin comprises ethylene vinyl acetate.
13. The oral brush of claim 1, wherein said brush comprises a plurality of bristles and said matrix is in the form of a flat template disposed at the base of said bristles.
14. 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 attached to said body, said matrix comprising a water-insoluble support resin, a water-soluble polymer, and an anti-microbial agent; and contacting the portion of said brush to which said matrix is attached with water, causing said water-soluble polymer in said matrix to dissolve, thereby releasing said anti-microbial agent into said water.
15. The method of claim 14, 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.
16. The method of claim 14, wherein said anti-microbial agent is chlorhexidine.
17. The method of claim 14, wherein said resin comprises ethylene vinyl acetate.
18. The method of claim 14, wherein said water-soluble polymer comprises polyethylene oxide.
19. The method of claim 14, wherein said brush comprises a plurality of bristles and said matrix is in the form of a flat template disposed at the base of said bristles.
20. A wear-indicating matrix comprising a water-insoluble support resin, a colorant and a water-leachable substance that leaches into water during use to cause the matrix to change color after repeated uses.
21. The wear-indicating matrix of claim 20 wherein the water-leachable substance comprises a water-soluble polymer.
22. The wear-indicating matrix of claim 21 wherein the water-soluble polymer is selected from polyethylene oxide, polyethylene glycol and polyvinyl alcohol.
23. The wear-indicating matrix of claim 22 wherein the support resin is selected from polystyrene, polyurethane, ethylene vinyl acetate, polyethylene, styrene/rubber and ethylene/propylene.
24. The wear-indicating matrix of claim 20 wherein the matrix comprises:
a first layer comprising the water-leachable substance;
and a second layer comprising the water-insoluble support resin.
25. The wear-indicating matrix of claim 24 wherein the second layer comprises the colorant.
26. The wear-indicating matrix of claim 24 wherein the first layer comprises the colorant.
27. The wear-indicating matrix of claim 24 wherein the first layer comprises a first colorant and the second layer comprises a second colorant which is a different color than the first colorant.
28. The wear-indicating matrix of claim 25, 26 or 27 wherein the water-leachable substance comprises a water-soluble polymer.
29. The wear-indicating matrix of claim 28 wherein the water-soluble polymer comprises polyethylene oxide.
30. The wear-indicating matrix of claim 29 wherein the first layer further comprises a water-insoluble support resin.
31. The wear-indicating matrix of claim 30 wherein the support resin is selected from polystyrene, polyurethane, ethylene vinyl acetate, polyethylene, styrene/rubber and ethylene/propylene.
32. The wear-indicating matrix of claim 27 wherein the first layer dissolves away through repeated use to expose the second layer, thereby revealing a color change.
33. A wear-indicating matrix comprising two joined layers, an outer layer comprising a water-soluble polymer, a water-insoluble polymer and a first colorant, and an inner layer comprising a water-insoluble polymer and a second colorant different from the first colorant.
34. The wear-indicating matrix of claim 33 wherein the water-soluble polymer comprises polyethylene oxide.
35. The wear-indicating matrix of claim 34 wherein the polyethylene oxide has a molecular weight of 100,000 to 5,000,000.
36. The wear-indicating matrix of claim 35 wherein the polyethylene oxide is a blend comprising 60 parts of coagulant grade polyethylene oxide and 40 parts of polyethylene oxide of molecular weight 300,000.
37. The wear-indicating matrix of claim 34, 35 or 36 wherein the water-insoluble polymer in each layer is selected from the group consisting of polystyrene, polyurethane, ethylene vinyl acetate, polyethylene, styrene/rubber and ethylene/propylene.
38. The wear-indicating matrix of claim 33 wherein the inner layer additionally comprises a water-soluble polymer.
39. The wear-indicating matrix of claim 38 wherein the water-soluble polymer in each layer comprises polyethylene oxide.
40. The wear-indicating matrix of claim 39 wherein the water-insoluble polymer in each layer is selected from the group consisting of polystyrene, polyurethane, ethylene vinyl acetate, polyethylene, styrene/rubber and ethylene/propylene.
41. The wear-indicating matrix of claim 33, 35, 38 or 40 wherein said two joined layers are coextruded.
42. The wear-indicating matrix of claim 33, 35, 38 or 40 wherein said outer layer is adapted to dissolve away through repeated contact with water to expose said inner layer.
43. A wear-indicating matrix comprising a water-insoluble polymer, a water-soluble polymer, and a water-leachable colorant, wherein said matrix is adapted to change color after repeated uses.
44. The wear-indicating matrix of claim 43 wherein the water-soluble polymer comprises polyethylene oxide.
45. The wear-indicating matrix of claim 44 wherein the water-insoluble resin is selected from the group consisting of polystyrene, polyurethane, ethylene vinyl acetate, polyethylene, styrene/rubber and ethylene/propylene.
46. The wear-indicating matrix of any of claims 20 to 45 additionally comprising an antimicrobial agent.
47. The wear-indicating matrix of claim 46 adapted to change color corresponding with the depletion of said antimicrobial agent.
CA002116115A 1991-08-23 1992-08-13 Sustained-release matrices for dental application Expired - Fee Related CA2116115C (en)

Applications Claiming Priority (5)

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US749,137 1976-12-09
US74913791A 1991-08-23 1991-08-23
US07/898,471 US5340581A (en) 1991-08-23 1992-06-15 Sustained-release matrices for dental application
US898,471 1992-06-15
PCT/US1992/006770 WO1993003649A1 (en) 1991-08-23 1992-08-13 Sustained-release martrices for dental application

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