Title:  Antibiotic toothpaste

United States Patent:  6,123,925

Inventors:  Barry; John E. (Derry, NH); Trogolo; Jeffrey A. (Boston, MA)

Appl. No.:  123755

An antibiotic toothpaste is formulated with an inorganic antibiotic metal containing composition that is present in an amount effective to impart substantial antimicrobial activity within the normal time for brushing teeth.

DETAILED DESCRIPTION OF THE INVENTION

All patent applications, patents, patent publications, and literature references cited in this specification are hereby incorporated by reference in their entirety. In the case of inconsistencies, the present description, including definitions, is intended to control.

According to the present invention, an inorganic antibiotic metal containing composition is incorporated in a toothpaste formulation to provide quick, non-toxic antimicrobial action without the possibility, associated with organic compounds of the prior art, of development of antibiotic resistance or irritation. The use of a silver containing composition in particular allows an exceptionally safe, non-toxic and effective toothpaste to be formulated.

In the preferred embodiment, antibiotic ceramic particles are formulated in the toothpaste to provide antimicrobial activity. The toothpaste formulation provides antibiotic action that is at least as long lasting as presently used agents, such as triclosan, but avoids use of an organic antibiotic. Development of resistant bacterial strains is avoided. Furthermore, it has been determined that such a toothpaste formulation is able to adequately kill microorganisms during the time required for a normal toothbrushing.

This has been found to be true even when the particles are separated by a barrier layer from the portion of the toothpaste containing inactivating ingredients. For example, it has been found that silver containing zeolite that is incorporated in a polymer to separate the silver from phosphates and sulfates, releases silver upon normal brushing at a sufficient rate to quickly impart substantial antimicrobial action to the toothpaste.

It has also been found that a residue of antibiotic silver is retained on the surface of commonly used antibiotic zeolites that is especially effective at imparting quick antimicrobial action. At the same time, particles retained on the teeth and on or in the gums following brushing continue to slowly release non-exchanged antibiotic metal for an extended period.

In one embodiment of the invention, the inorganic antibiotic metal containing composition is an antibiotic metal salt. Such salts include silver acetate, silver benzoate, silver carbonate, silver iodate, silver iodide, silver lactate, silver laurate, silver nitrate, silver oxide, silver palmitate, silver protein, and silver sulfadiazine. Silver nitrate is preferred. These salts are particularly quick acting, as no release from ceramic particles is necessary for the toothpaste to function antimicrobially.

The toothpaste formulation allows the inorganic antibiotic metal containing composition to be incorporated without deactivating the antibiotic properties of the antibiotic metals as a result of contact with conventional agents employed in toothpaste formulations, such as sodium lauryl sulfate and trisodium phosphate. This is accomplished by isolating the inorganic antibiotic metal containing composition from these agents using a barrier composition, such as polymer compositions that are described in further detail below. Alternately, the antibiotic metal containing composition is isolated from other ingredients using packaging wherein the packaging provides a physical barrier between the metal containing composition and the portion of the formulation containing agents that have the potential to deactivate the antibiotic metals.

The ceramics employed in the antibiotic ceramic particles of the present invention include zeolites, hydroxyapatite, zirconium phosphates or other ion-exchange ceramics. Zeolites are preferred, and are described in the preferred embodiments referred to below. Hydroxyapatite particles containing antimicrobial metals are described, e.g., in U.S. Pat. No. 5,009,898. Zirconium phosphates containing antimicrobial metals are described, e.g., in U.S. Pat. Nos. 5,296,238; 5,441,717; and 5,405,644.

Toothpaste containing non-antibiotic zeolites, wherein the zeolites are conventionally used for abrasive purposes, is described, for example, in U.S. Pat. No. 4,349,533. The formulation described therein is suitable for preparing the antibiotic toothpaste formulation of the invention, however, the conventional zeolites described in the '533 patent (used only for their abrasive properties) can be substituted for by the inorganic antibiotic metal containing composition. The inorganic antibiotic metal containing composition is separated from other inactivating ingredients by a barrier layer.

Other conventional toothpaste formulations can be employed to make the formulation of the invention, adding the antimicrobial composition in an effective amount. Toothpaste formulations employed to make the formulation of the invention can include conventional ingredients such as chalk, dicalcium phosphate dihydrate, sorbitol, water, hydrated aluminum oxide, precipitated silica, sodium lauryl sulfate, sodium carboxymethyl cellulose, flavoring, sorbitan monooleate, sodium saccharin, tetrasodium pyrophosphate, methyl paraben, propyl paraben. One or more coloring agents, e.g. FD&C Blue, can be employed if desired. Other suitable toothpaste formulations are described, for example, in U.S. Pat. No. 5,560,517.

As stated above, in the preferred toothpaste formulation of the present invention, antibiotic zeolite particles are separated from the deactivating ingredients of the formulation by a barrier composition. The barrier prevents contact of the zeolite particles with the deactivating agents, but is adapted to allow mixing of the particles with the rest of the formulation during brushing. Examples of barrier compositions that can be used include polyacrylic acid, sorbitol, polysorbate, starch, agar, carboxymethyl cellulose, PEG, and any suitable material, including polymeric materials, or in particular thermoplastic and thermosetting polymers.

Preferably, a gelling polymer is employed as a barrier layer. Carbopol is an appropriate gelling polymer that is commonly commercially available.

It is possible to employ barrier layers in several ways. For example, the barrier layer may be employed to microencapsulate individual particles of antimicrobial zeolite. Alternately, several particles of antimicrobial zeolite may be distributed within each "drop" of a barrier material. For example, assemblages of several antibiotic zeolite particles can be coated with Carbopol. The coated particles are released from the coating upon brushing, the coatings being of a thickness to allow easy release of the particles, but to protect the silver in the particles from deactivating ingredients. It has been determined that such compositions are capable of exhibiting a long shelf life. It is also possible to microencapsulate individual antibiotic particles, e.g., in starch or agar, and to then incorporate the microencapsulated particles into another barrier layer, e.g., Carbopol. Where the inorganic antibiotic metal containing composition is a silver salt, the barrier layer can isolate the silver salt from inactivating ingredients.

Where antibiotic zeolite particles are microencapsulated, conventional microencapsulation compositions and techniques are employed. For example, it is possible to coat individual particles with starch, agar, or polymer using conventional methods such as spray drying, fluidized bed coating, electrostatic deposition, centrifugal extrusion, rotational suspension separation, polymerization at a phase boundary, pressure extrusion, or spraying into a solvent bath. Chemical processes of microencapsulation as also possible, such as complex coacervation, polymer-polymer incompatibility methods, interfacial polymerization, in-situ polymerization, in-liquid drying, thermal or ionic gelation, and desolvation in liquid media. Microencapsulation techniques usable to coat the antibiotic zeolites are well-known in the pharmaceutical industry, and include, for example, methods described in U.S. Pat. Nos. 5,503,851 and 5,393,533 among many other known methods.

It is preferable to physically separate all of the antibiotic zeolite from the deactivating parts of the formulation in the toothpaste dispensing device, e.g., to have the antibiotic portion of the formulation entirely separated from the deactivating parts in one continuous stripe. In this embodiment, the toothpaste can be formulated to administer at least two stripes containing separate ingredients per dose. Technology for manufacturing toothpastes containing such stripes is well known in this art, and described, e.g., in U.S. Pat. Nos. 5,324,505, 5,035,349, and 3,881,529.

The toothpaste of the invention has the capability of effecting substantial anti-microbial action during the time required for a normal toothbrushing. Ion release rate experiments show that the initial release rate of antibiotic zeolites in a typical concentration in toothpaste of, e.g., about 1%, can reach 25 parts per billion (ppb) per minute. At this rate, the minimum inhibitory concentration (MIC) for bacteria of about 2 ppb is reached in less than 5 seconds. This high rate of release generally occurs for about one minute following contact with water, after which a slower rate of release is exhibited.

Furthermore, it has been determined that ion release begins substantially at the time the toothpaste formulation is prepared. Therefore, at the time the toothpaste is applied to oral surfaces, significant amounts of antibiotic metal ion are available in the formulation to effect antimicrobial action, i.e., the concentration of antimicrobial metal ion is at or above the MIC.

One or more surfactants can be added to the toothpaste composition, in particular to aqueous slurries of antibiotic zeolite employed, to prevent aggregation. Suitable surfactants are well-known, and include, for example a mixture of sodium polyacrylate (e.g., 0.5 wt. %) and polysaccaride (e.g., 0.3 wt. %).

The coated zeolite particles employed in the aqueous formulations of the invention preferably have a particle diameter size of between 1 and 500, more preferably between about 1 and 300, most preferably between about 20 and 100 .mu.m.

The uncoated zeolite particles preferably have a particle diameter size of from about 0.2 to 40 .mu.m, more preferably between about 0.5 to 5 .mu.m.

Antibiotic zeolites are well-known and can be prepared for use in the present invention using known methods. These include the antibiotic zeolites disclosed, for example, in U.S. Pat. Nos. 4,938,958 and 4,911,898.

Either natural zeolites or synthetic zeolites can be used to make the antibiotic zeolites used in the present invention. "Zeolite" is an aluminosilicate having a three dimensional skeletal structure that is represented by the formula: XM2/nOAl₂ O₃ --YSiO₂ --ZH₂ O. M represents an ion-exchangeable ion, generally a monovalent or divalent metal ion, n represents the atomic valency of the (metal) ion, X and Y represent coefficients of metal oxide and silica respectively, and Z represents the number of water of crystallization. Examples of such zeolites include A-type zeolites, X-type zeolites, Y-type zeolites, T-type zeolites, high-silica zeolites, sodalite, mordenite, analcite, clinoptilolite, chabazite and erionite. The present invention is not restricted to use of these specific zeolites.

The ion-exchange capacities of these zeolites are as follows: A-type zeolite=7 meq/g; X-type zeolite=6.4 meq/g; Y-type zeolite=5 meq/g; T-type zeolite=3.4 meq/g; sodalite=11.5 meq/g; mordenite=2.6 meq/g; analcite=5 meq/g; clinoptilolite=2.6 meq/g; chabazite=5 meq/g; and erionite=3.8 meq/g. These ion-exchange capacities are sufficient for the zeolites to undergo ion-exchange with ammonium and antibiotic metal ions.

The specific surface area of preferred zeolite particles is preferably at least 150 m² /g (anhydrous zeolite as standard) and the SiO₂ Al₂ O₃ mol ratio in the zeolite composition is preferably less than 14, more preferably less than 11.

The antibiotic metal ions used in the antibiotic zeolites should be retained on the zeolite particles through an ion-exchange reaction. Antibiotic metal ions which are adsorbed or attached without an ion-exchange reaction exhibit a decreased bacteriocidal effect and their antibiotic effect is not long-lasting. Nevertheless, it is advantageous for imparting quick antimicrobial action to maintain a sufficient amount of surface adsorbed metal ion.

In the ion-exchange process, the antibiotic metal ions tend to be converted into their oxides, hydroxides, basic salts etc. either in the micropores or on the surfaces of the zeolite and also tend to deposit there, particularly when the concentration of metal ions in the vicinity of the zeolite surface is high. Such deposition tends to adversely affect the bacteriocidal properties of ion-exchanged zeolite.

In an embodiment of the antibiotic zeolites, a relatively low degree of ion exchange is employed to obtain superior bacteriocidal properties. It is believed to be required that at least a portion of the zeolite particles retain metal ions having bacteriocidal properties at ion-exchangeable sites of the zeolite in an amount less than the ion-exchange saturation capacity of the zeolite. In one embodiment, the zeolite employed in the present invention retains antimicrobial metal ions in an amount up to 41% of the theoretical ion-exchange capacity of the zeolite. Such ion-exchanged zeolite with a relatively low degree of ion-exchange may be prepared by performing ion-exchange using a metal ion solution having a low concentration as compared with solutions conventionally used for ion exchange.

In antibiotic zeolite particles used in the present invention, ion-exchangeable ions present in zeolite, such as sodium ions, calcium ions, potassium ions and iron ions are preferably partially replaced with ammonium and antibiotic metal ions. Such ions may co-exist in the antibiotic zeolite particle since they do not prevent the bacteriocidal effect. While antibiotic metal ions include ions of silver, copper, zinc, mercury, tin, lead, bismuth, cadmium, chromium and thallium, edible antibiotic zeolites to be formulated into compositions to be used in the toothpaste of the invention include silver, gold, copper and zinc ions. These antibiotic metal ions can be used by themselves or in a mixture.

The antibiotic metal ion is preferably present in the range of from about 0.1 to 15wt. % of the zeolite. In one embodiment, the zeolite contain from 0.1 to 15wt. % of silver ions and from 0.1 to 8wt. % of copper or zinc ions. Although ammonium ion can be contained in the zeolite at a concentration of about 20 wt. % or less of the zeolite, it is desirable to limit the content of ammonium ions to from 0.5 to 15 wt. %, preferably 1.5 to 5 wt. %. Weight % described herein is determined for materials dried at 110^oC., as this is the temperature employed for the preferred post-manufacturing drying process.

A preferred antibiotic zeolite for use in a toothpaste formulation is type A zeolite containing either a combination of ion-exchanged silver, zinc, and ammonium or silver and ammonium. One such zeolite is manufactured by Shinegawa, Inc. under the product number AW-10N and consists of 0.6% by weight of silver ion-exchanged in Type A zeolite particles having a diameter of about 2.5.mu.. Another formulation, AJ-10N, consists of about 2% by weight silver ion-exchanged in Type A zeolite particles having a diameter of about 2.5.mu.. Another formulation, AW-80, contains 0.6% by weight of silver ion-exchanged in Type A zeolite particles having a diameter of about 1.0.mu.. Another formulation, AJ-80N, consists of about 2% by weight silver ion-exchanged in Type A zeolite particles having a diameter of about 1.0.mu.. These zeolites preferably contain about between 0.5% and 2.5% by weight of ion-exchanged ammonium. The zeolites are often obtained in master batches of low density polyethylene, polypropylene, or polystyrene, containing 20 wt. % of the zeolite.

The antibiotic particles are preferably present in a concentration by weight in the toothpaste formulation of from 0.05 to 10%, more preferably from 0.1 to 5% by weight, and most preferably from 0.1 to 1%.

The antibiotic properties of the aqueous formulations of antibiotic zeolite particles of the invention may be assayed using conventional assay techniques, including for example determining the minimum growth inhibitory concentration (MIC) with respect to a variety of bacteria, eumycetes and yeast. In such a test, the bacteria listed below may be employed:

Bacillus cereus var mycoides,

Escherichia coli,

Pseudomonas aeruginosa,

Staphylococcus aureus,

Streptococcus faecalis,

Aspergillus niger,

Aureobasiduim pullulans,

Chaetomium globosum,

Gliocladium virens,

Penicillum funiculosum,

Candida albicans,

Saccharomyces cerevisiae,

The assay for determining MIC can be carried out by smearing a solution containing bacteria for inoculation onto a plate culture medium to which a test sample of the encapsulated antibiotic zeolite particles is added in a particular concentration, followed by incubation and culturing of the plate. The MIC is defined as a minimum concentration thereof required for inhibiting the growth of each bacteria.

Claim 1 of 18 Claims

What is claimed is:

1. A toothpaste formulation having antimicrobial properties comprising:

an antimicrobial agent comprising ceramic particles comprising antimicrobial metal ions;

at least one ingredient capable of inactivating said antimicrobial metal ions;

said antimicrobial agent being disposed within an aqueous based paste or gel forming a barrier layer separating said metal ions from said at least one ingredient, said metal ions being released imparting substantial antimicrobial action to an oral surface upon contact with said oral surface during normal toothbrushing.

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