Drug – bio-affecting and body treating compositions – Dentifrices – Ammonia – amine – or derivative thereof
Reexamination Certificate
1998-06-04
2002-10-01
Rose, Shep K. (Department: 1614)
Drug, bio-affecting and body treating compositions
Dentifrices
Ammonia, amine, or derivative thereof
C132S075600, C132S321000
Reexamination Certificate
active
06458341
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to stable coatings for delivering chlorhexidine gluconate.
BACKGROUND
Chlorhexidine digluconate (commonly known as “chlorhexidine gluconate”) is an antimicrobial that is useful for various applications, particularly in the oral environment. Specifically, chlorhexidine gluconate in dental rinses has been clinically proven to reduce gingival inflammation and bleeding. The disadvantages to delivering chlorhexidine gluconate in a rinse are bad taste and staining. Chlorhexidine gluconate is known to decompose to form para-chloroaniline, which is highly toxic.
Hill (U.S. Pat. No. 5,098,711; WO 95/30404; U.S. Pat. No. 5,165,913; U.S. Pat. No. 4,911,927) describes floss coating compositions with chlorhexidine gluconate. The compositions of Hill contain a surfactant and a coating substance that is insoluble in the surfactant. Optionally, the compositions may contain a humectant like glycerin or polyethylene glycol. In Hill's examples, chlorhexidine gluconate is formed in situ by heating gluconic acid and chlorhexidine free base at high temperature.
Simionato et al (AU 9,464,534) describes putting chemotherapeutic agents in a floss coating composition that contains an emulsifiable wax.
Bowen (U.S. Pat. No. 5,603,921) describes dental floss coating compositions that contain chlorhexidine gluconate and a 2/1 ratio of polyethylene glycol (PEG) 3350/PEG 1000, which are solids at room temperature.
SUMMARY OF THE INVENTION
Devices, coating compositions and methods for preparing coating compositions are provided whereby stable chlorhexidine gluconate may be delivered to the oral environment from an essentially non-aqueous system. The coating comprises chlorhexidine gluconate and a Solubilizing Glycol. The coating additionally comprises a modulus-enhancing component to give proper handling properties. The coating does not contain more than 200 ppm of para-chloroaniline after four weeks at 45° C.
DETAILED DESCRIPTION OF THE INVENTION
As noted above, it is desirable to deliver chlorhexidine gluconate (“CHG”) to the oral environment. To date, however, systems have not been adequate to deliver CHG in a format other than in an aqueous rinse in a manner that would also provide stability. CHG degrades to toxic byproducts in a non-aqueous environment, including para-chloroaniline (“PCA”) a suspected carcinogen. It is therefore surprising to find that a non-aqueous composition (i.e. having less than about 2% water by weight) may be formulated for stable delivery of CHG to the oral environment.
Non-aqueous coatings of the present invention provide significant advantages in the delivery of CHG. Because the coating does not contain water, it is more shelf-stable for longer term storage since there is no water loss or requirement for special packaging to retain water in the coating.
Coated CHG delivery devices of the present invention, as compared to aqueous rinses, are useful particularly for delivering chlorhexidine gluconate interproximally and subgingivally, where it is needed to treat gingivitis. Site specific delivery of chlorhexidine gluconate from a device, as in the present invention, minimizes the discomfort associated with the bad taste of chlorhexidine gluconate and reduces tooth staining by reducing contact of the chlorhexidine gluconate with the facial tooth surfaces.
The device of the present invention is any device suitable for physical delivery of CHG to the oral environment, and most preferably a device suitable for delivery to interproximal and subgingival surfaces of the oral environment. Such devices include dental floss, dental picks, and dental tape. Additionally, the device may be a dental packing material, such as a fiber. Other embodiments include periodontal membranes.
Dental floss coated with the compositions of the present invention is highly advantageous, because it slips easily between the teeth and yet is easy to hold in the user's hands.
The coating of the present invention comprises chlorhexidine gluconate. CHG may be commercially obtained from many manufacturers, but typically only in an aqueous format. It is important to properly handle aqueous CHG, particularly as to exposure to high temperatures, to retain stability when formulating the non-aqueous compositions of the present invention, as will be described in more detail below.
Preferably, the coating of the present invention comprises between about 0.1% and 15% of CHG by weight. More preferably, the coating comprises 0.5-10%, and most preferably, the coating comprises 1-5% of CHG by weight.
For purposes of the present invention, a “Solubilizing Glycol” is a glycol that provides a clear solution when mixed with CHG in the glycol/CHG ratio to be used in the ultimate coating composition. This evaluation of solution clarity is made to a mixture containing only CHG, glycol and any residual water, after water has been removed to a level less than about 10% and the solution is at room temperature (about 21° C.). It is understood that mechanical mixing under heat as high as 100° C. may be employed to mix the CHG with the glycol, but that the evaluation will be made after the solution has cooled and allowed to stand for 60 minutes.
Examples of glycols capable of dissolving and stabilizing chlorhexidine gluconate are glycerin, sorbitol, polyethylene glycol (preferably of molecular weight between about 200 and 600), polyglycerols (e.g. triglycerol, hexaglycerol and decaglycerol), and propylene glycol. These glycols may be used separately or in combination. It will be recognized that while individual glycols may not provide the desired clear liquid, mixtures of glycols may be suitable to be collectively used as the Solubilizing Glycol.
Solubilizing Glycol is preferably present in the coating in an amount such that the ratio of Solubilizing Glycol to chlorhexidine gluconate by weight is 0.2-200. More preferably the ratio of Solubilizing Glycol to chlorhexidine gluconate by weight is 0.5-7, and most preferably, the ratio is 1-5.
The modulus-enhancing component is any material that provides the desired final modulus properties for the coating, such that it will have the proper tackiness and material delivery properties of a coating. Thus, the coefficient of dynamic friction (ASTM D3247) is preferably less than 2.0 and more preferably less than 1.0. The elastic modulus, G′, should be greater than 10,000 and preferably greater than 100,000 dynes/cm
2
at a frequency of 1 rad/sec and at room temperature. The ratio of the viscous modulus, G″, to G′ (or tan delta) should be less than 0.8 and preferably less than 0.5 at a frequency of 1 rad/sec and at room temperature.
Examples of modulus enhancing components include surfactants that contain both (a) hydrophilic group(s) capable of dispersing chlorhexidine gluconate and a glycol, and (b) an alkyl group(s). Preferably the alkyl group makes up 3 to 75% by weight of the modulus-enhancing component, and more preferably 5 to 60 wt. %. Examples of such preferred surfactants include polyglyceryl alkyl esters and ethers, ethoxylated polyhydric alcohol alkyl esters, and polyoxyethylene alkyl ethers or esters. These surfactants may act to bind individual fibers of a dental floss together, or may help in the formulation process to assist in making certain ingredients compatible in the overall coating formulation. Surfactants may be particularly beneficial in assisting wax to be compatible with the rest of the coating composition.
Alternative modulus enhancing components include waxes, poly-n-vinyl pyrrolidone, crystalline fatty alcohols, paraffins, polyethylene oxides having molecular weight greater than about 900, hydroxypropyl cellulose and cellulose derivatives. Preferably, these materials are soluble in or emulsifiable with glycerin.
Wax is particularly preferred in the tooth floss embodiment when it may be desirable to help bind the floss fibers together and to improve the floss handling characteristics. Examples of waxes are microcrystalline wax and beeswax. Alternatively, floss coatings may be formulated such th
Asmus Robert A.
Morrison Brian R.
Rozzi Sharon M.
3M Innovative Properties Company
Rose Shep K.
Skolnick Steven E.
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