HIGHLY STABLE OXIDIZING COMPOSITIONS

Field of the Invention

[001] The present invention relates to compositions used to whiten teeth, and more particularly to highly stable oxidizing compositions comprising hydrogen peroxide and an oxidation-resistant thickened carrier comprising a 2-acrylamido-2-methylpropane sulfonic acid (AMPS) polymer or copolymer. The inventive compositions thickened with an AMPS polymer or copolymer are found to be unexpectedly stable, particularly with respect to viscosity and hydrogen peroxide concentration over time, such that highly effective tooth whitening gels may be formulated and stored at room temperature for extended periods of time without the need for refrigeration.

Background of the Invention

[002] As the connections between healthy teeth and gums, and general overall health, have become increasingly evident in the past 100 years, oral care has become an important part of people's daily health maintenance regimens. In the process, a healthy looking smile has become representative of one's level of personal grooming and even social status, with straight, white and well shaped teeth being promoted in advertising and by cosmetic dentists as an integral part of one's self-image. Over the past 20 years, the availability of tooth whitening products and services has exploded in the marketplace, ranging from low-priced over-the-counter (OTC) self-applied trays, strips, pens, mouthwashes and toothpastes, to expensive professionally applied or monitored products and procedures capable of effectively whitening teeth in as little as 45 minutes. In general, professionally applied products and services administered to a patient in a dental office or other clinical setting are seen to achieve the best teeth whitening results in the shortest amount of time. This is primarily due to the concentration of active ingredient, usually hydrogen peroxide or a hydrogen peroxide precursor, found in professionally applied whitening compositions. Such high concentrations, typically above 15% hydrogen peroxide by weight and often as high as 50% hydrogen peroxide by weight, can only be safely administered in a controlled setting where a professionally trained individual can isolate soft tissues from contact with these highly oxidative compositions. Frequent monitoring of a patient's progress over, for instance, a one-hour period is also critical in maintaining a high degree of safety when working with such high hydrogen peroxide concentrations. Optionally, light or heat energy may be applied in conjunction with these strong oxidizing compositions, in order to accelerate the process beyond that which is possible using just the compositions on their own. In general, these

professionally- monitored products and services applied in a dental office or clinic will be referred to collectively as in-office or chairside whitening procedures.

[003] In order to safely and effectively apply hydrogen peroxide in an active form to the teeth surfaces during a chairside whitening procedure, a certain degree of flow control must be maintained in order to allow for precise placement of the hydrogen peroxide on the tooth surfaces in need of whitening. In general, hydrogen peroxide is formulated into gel or paste compositions that have sufficient "body" (or in other words, a high enough level of viscosity and/or thixotropy) in order to adhere, cling or otherwise remain in contact with the tooth surfaces without risk of migrating to adjacent soft tissue surfaces such as the crevicular spaces, the lingual and buccal mucosa, and other soft tissue surfaces in the oral cavity. Whitening compositions with sufficient body are also easier to apply using standard clinical applicators such as brushes, syringes, swabs and other similar devices.

[004] While a wide variety of bodying or thickening agents are available, there are very few that are capable of providing increased viscosity in compositions where oxidizing agents are present. This is most often due to instability of the thickening agent in the presence of hydrogen peroxide, and as most thickening agents are polymers or copolymers they are susceptible to oxidation reactions that can reduce molecular weight and their ability to maintain a consistent viscosity over time. A number of polymers and copolymers have been successfully employed in hydrogen peroxide teeth whitening compositions to provide sufficient viscosity to form thickened gels and pastes. Polymers and copolymers (hereinafter referred to simply as "polymers" or "polymer") such as carboxypolymethylene (Carbopol®), acrylic acid / C10-C30 alkyl acrylate copolymers (Pemulen®), polyoxyethylene / polyoxypropylene block copolymers (Pluronic®), and hydroxypropylcellulose (Klucel®), amongst others, have been used with varying degrees of success, but generally exhibiting a time- and temperature- dependent decrease in viscosity in the presence of hydrogen peroxide and even when composition stabilizers are present.

[005] The relative lack of success in identifying and employing thickening polymers and copolymers is most likely related to a long-standing common wisdom within the dental materials research community that ingredients not previously employed or approved for oral care or food applications may not be suitable in tooth whitening compositions. However, the polymers and copolymers of the present invention possess the relatively low order of toxicity required for tooth whitening applications and, despite conventional wisdom, were not discounted out of hand by the present inventor. In fact, the unpredicted results shown by the inventive use of the polymer or copolymer with the exceptional stability profile that is so important to tooth whitening gel performance is expected to reduce the possibility of patient harm (such as tissue damage and ingestion). This is expected to be due, in part, to the consistency of rheological properties observed over time and the reduced likelihood of undesirable liquefaction that has been observed in prior art tooth whitening gel compositions. In addition, polymers and copolymers utilized in the present inventive compositions may be employed for their particularly unique properties, such as reduced water solubility for those circumstances in which long term gel contact could lead to "leaching" of a typical water-soluble gel from a delivery device such as a dental tray. Such leaching can lead to composition ingestion and contact with sensitive soft tissues in the oral cavity and digestive tract. Limiting this result of viscosity degradation is a significant and unexpected improvement over the water-soluble prior art compositions.

[006] Depending upon the rate of viscosity decrease observed in stability studies

(conducted typically at 25 degrees C. and 60% relative humidity to represent room temperature storage conditions and at 40 degrees C. and 75% relative humidity to represent accelerated or stressed storage conditions), limitations are placed on the expiration dating of a particular composition. The expiration date represents that date beyond which the performance-related properties (such as remaining concentration of hydrogen peroxide and, in particular, viscosity) are observed or predicted to fall below a suitable established range. In order to extend expiration dates, manufacturers often have no choice but to recommend storage of tooth whitening compositions at refrigerated temperatures, which is inconvenient and time-consuming, but allows for the longer product shelf life demanded by dentists and dental distributors who cannot precisely predict when a product in inventory may be used or sold.

[007] A number of thickened hydrogen peroxide gels are commercially available for whitening teeth. In order to preserve hydrogen peroxide potency over a reasonable shelf life (e.g., 12 to 18 months), it is necessary to store these commercial products in a refrigerated state, typically between 2 degrees C and 8 degrees C (36 degrees Fahrenheit to 46 degrees Fahrenheit). Opalescence Boost Gel (Ultradent, South Jordan, UT) is a 45% hydrogen peroxide gel that despite its low pH of approximately 3.0 (which is more favorable for hydrogen peroxide stability than higher pH levels), the product must still be refrigerated to avoid loss of hydrogen peroxide potency and gel viscosity, both of which would lead to poor performance of the product as a tooth whitener. Colgate Visible White Chairside gel (Colgate-Oral Pharmaceuticals, New York, NY), according to information on its MSDS, is a 40 - 50% hydrogen peroxide gel with a pH between 1.8 and 2.8, and thickened with silicon dioxide. Refrigerated storage is also recommended for this product to avoid premature degradation of gel potency and rheological properties. Both of these commercial products require refrigerated storage, which is often inconvenient in the limited space available in a typical dentist's office, and both products require a waiting period for the gels to equilibrate to room temperature before use, which is often not possible or is inconvenient due to tight patient scheduling windows.

[008] For the reasons stated above, there is a need for thickened tooth whitening compositions that have a stable viscosity and stable concentration of active hydrogen peroxide content over an extended period of time when stored at typical room

temperatures or non-refrigerated conditions. The present invention addresses that need.

Summary of the Invention

[009] The present invention is directed to highly storage- stable oxidizing compositions for general bleaching or whitening purposes, but in particular for whitening teeth, comprising (1) hydrogen peroxide and (2) a thickening polymer or copolymer comprising a pendant sulfonic acid group contributed by building block monomers such as 2-acrylamido-2-methylpropane sulfonic acid (AMPS). While not being bound to any particular theory, it is speculated that the pendant sulfonic acid moiety on the thickener polymer or copolymer contributes to the stability of the hydrogen peroxide. This is in stark contrast to prior art thickening polymers or copolymers which are not observed to possess such stabilizing abilities and in fact may contribute to more rapid degradation of the hydrogen peroxide in the composition.

[0010] The present invention is further directed to tooth whitening compositions comprising (1) hydrogen peroxide at a concentration between about 3 and 50% by weight, (2) a hydrogen peroxide stabilizer, and (3) a thickening polymer or copolymer comprising a pendant sulfonic acid group, said compositions being stable for extended periods of time when stored at room temperature.

[0011] The present invention is further directed to a method of using these compositions.

These and other features, aspects and advantages of the invention will become evident to those skilled in the art from a reading of the present disclosure.

Detailed Description of the Invention

[0012] While the specification concludes with claims particularly pointing out and distinctly claiming the invention, it is believed that the present invention will be better understood from the following description.

[0013] All percentages and ratios used hereinafter are by weight of total composition, unless otherwise indicated.

[0014] All measurements referred to herein are made at 25° C. unless otherwise specified.

[0015] All percentages, ratios, and levels of ingredients referred to herein are based on the actual amount of the ingredient, and do not include solvents, fillers, or other materials with which the ingredient may be combined as a commercially available product, unless otherwise indicated.

[0016] All publications, patent applications, and issued patents mentioned herein are hereby incorporated in their entirety by reference. Citation of any reference is not an admission regarding any determination as to its availability as prior art to the claimed invention. Herein, "comprising" means that other steps and other components which do not affect the end result can be added. This term encompasses the terms "consisting of and "consisting essentially of."

[0017] The highly stable oxidizing compositions of the present invention are comprised of an oxidizing compound and a thickening polymer containing a pendant sulfonic acid moiety. In addition to these essential components, the inventive

compositions may also contain optional components. Both the essential and optional components will be described more fully in the following paragraphs.

[0018] Oxidizing Compounds

[0019] Oxidizing compounds contemplated to have utility in the formulation of the inventive compositions include hydrogen peroxide, carbamide peroxide, sodium percarbonate, calcium peroxide, PVP-hydrogen peroxide complexes, allyl methacrylate crosspolymer / hydrogen peroxide complexes, and other similar compounds that yield or generate hydrogen peroxide in the presence of water.

[0020] Thickening Polymer

[0021] Thickening polymers containing a pendant sulfonic acid moiety that are contemplated to have utility in the formulation of the inventive compositions include 2- acrylamido-2-methylpropane sulfonic acid (AMPS) polymers and copolymers. The molecular structure of AMPS is shown below

O H CH-,

H ₂ C = CH— C N C CH ₂ — S0 ₃ H

[0022] Polymers, copolymers and crosspolymers synthesized from AMPS include hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer (Sepinov EMT-10 from Seppic S.A., a division of Air Liquide), ammonium acryloyldimethyl taurate / vinyl pyrrolidone copolymer (Aristoflex AVC, Clariant International LTD), ammonium acryloyldimethyltaurate / beheneth-25 methacrylate crosspolymer (Aristoflex HMB, Clariant International LTD), sodium acrylate / sodium acryloyldimethyltaurate copolymer (a component of Sepigel EG and Simulgel SMS 88, Seppic S.A.),

acrylamide / sodium acryloyldimethyltaurate copolymer (a component of Simulgel 600 and Simulgel 600 PHA, Seppic S.A.).

[0023] Optional Components

[0024] Optional components may be added or included in the inventive compositions in order to modify, preserve or enhance the performance or organoleptic characteristics. Optional components include hydrogen peroxide stabilizers, humectants, secondary active ingredients, surface active agents, photoactive compounds, colorants, flavors, and sweeteners.

[0025] Methods of Use

[0026] The inventive compositions can be employed in a number of different methods of whitening teeth, including those intended for application to the teeth of a patient or subject by a dentist or other dental professional, and those intended for application by a patient or subject to his or her own teeth. Tooth whitening methods involving application by a dentist or dental professional are referred to as "chairside" or "in-office" whitening procedures, and typically involve the placement of a tooth whitening gel directly onto the tooth surfaces or a subject while the subject is seated in a dental chair at a dental office, medspa, or other such setting. Tooth whitening methods involving self-application of a tooth whitening composition by a subject are typically referred to as "take-home" or "over-the-counter" whitening procedures. Take-home products may involve the fabrication of a custom-molded tray by a dentist or other dental professional, into which the tooth whitening gel is placed at home by the subject using a syringe, tube or other such container to dispense the gel. Pre-molded or "one-size-fits-all" dental trays may be provided that are "pre-dosed" with a tooth whitening gel for subject or patient convenience. Strips of material can be fashioned from various materials including deformable and non-deformable polymers and waxes, coated with a thin layer of tooth whitening gel and applied directly to the tooth surfaces in order to effect whitening. Dispensing devices with integrated brushes, swabs or dauber applicators to allow for direct application of tooth whitening gels to the teeth surfaces may also be used effectively by a patient or subject. While not intended to impose any limitations to any particular method of use, it is contemplated that the present inventive compositions, due to their exceptional stability profiles, will be useful in all of the application modes and tooth whitening methods mentioned above, in particular when extended storage periods at room temperature are either desired or required.

[0027] Examples

[0028] The following examples further describe and demonstrate embodiments within the scope of the present invention. The examples below are presented solely for the purpose of illustration and are not to be construed as limitations of the invention, as many variations hereof are possible without departing from the scope and spirit of the invention.

[0029] EXAMPLE 1

Wt % Wt %

Ingredient

(added) (net)

Water (Aqua)

Glycerin 99.7%

Etidronic acid (60% solution)

Potassium Stannate

Hydrogen Peroxide (35% solution)

Hydroxyethyl Acrylate / Sodium acryloyldimethyltaurate

3.750 3.750 copolymer

Ammonium Hydroxide (29% solution) (to pH 5.0)

100.000 100.000

[0030] The composition above was manufactured by combining the water, glycerin, hydrogen peroxide, etidronic acid and potassium stannate in a Kynar-coated 2- gallon Ross mixing vessel and mixing with moderate to high shear agitation until the components were well blended. While continuing to mix, the hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer was quickly added and the mixture agitated until the polymer powder was well dispersed and wetted out. The resulting mixture was then transferred to the Ross vacuum agitator, and slow agitation was begun under vacuum to defoam and deaerate the mixture. The agitation was increased and continued under vacuum until the mixture became smooth, relatively clear and free from entrapped bubbles and/or air. The mixture was then adjusted to a pH of about 5.0 with the ammonium hydroxide solution while continuing to mix under a vacuum. The finished mixture, a transparent to translucent gel, was then filled into plastic syringes for further testing.

[0031] The finished composition above was tested for viscosity, pH and hydrogen peroxide content as follows:

[0032] Viscosity determination - The viscosity of the gel of Example 1, as well as all of the other examples in the present invention, was determined by cone-plate viscometry using a Brookfield DVII+ Pro Viscometer (Brookfield Engineering) with cone-plate attachment. Cone-plate spindle 51Z was used and the conditions were 1 rpm spindle speed and temperature was held constant at 25 deg C using a circulating water bath. The viscosity 24 hours after manufacture was 39,353 centipoise.

[0033] pH Determination— The pH of the gel of Example 1, as well as all of the other examples in the present invention, was determined using an Accumet AR15 pH/ISE meter (Fisher Scientific) and a standardized (two-point standardization at pH 4 and pH 7) combination pH probe. All samples were determined in neat form. The pH 24 hours after manufacture was 4.9.

[0034] Hydro en peroxide determination - The hydrogen peroxide content, expressed as weight percent of the total composition weight, was determined using a standard iodometric titration (FMC Product Technical Guide: Hydrogen Peroxide Quantitative Test - Iodometric). The hydrogen peroxide concentration 24 hours after manufacture was 31.7% by weight of the entire composition.

[0035] Stability Studies

[0036] Syringes of the gel from Example 1 were placed in a controlled environment storage chamber at 40 degrees C. and 75% relative humidity. For the first 12 weeks, samples were drawn from the stored syringes and allowed to equilibrate to room temperature overnight. Thereafter, test samples were drawn on a monthly basis.

Viscosity, pH and hydrogen peroxide determination tests were performed as described above and the values are reported in Table 1 below.

[0037] TABLE 1

[0038] Testing results for Example 1 gel stored at 40 degrees C. and 75% relative humidity. Hydrogen

Time Viscosity (cps) pH peroxide (wt %)

Initial 39,353 4.9 31.7

1 wk 41,424 4.9 33.4

2 wk 40,181 4.9 31.6

3 wk 40,181 5.0 30.8

4 wk 38,524 4.9 31.5

5 wk 37,696 5.0 31.5

6 wk 38,939 4.8 31.3

7 wk 39,353 4.8 31.8

8 wk 39,767 4.9 31.2

9 wk 36,867 4.9 31.8

10 wk 32,725 4.8 31.3

11 wk 39,353 4.9 31.3

12 wk 37,282 4.8 31.0

16 wk 37,696 4.8 30.7

20 wk 35,625 4.5 31.8

24 wk 29,411 4.4 30.6

[0039] As is clearly evident from the data above, the gel of Example 1 possesses a high degree of stability with respect to viscosity, pH and hydrogen peroxide content. Regression analysis of the above data indicates that all of the physical properties tested will remain within +/-10% range of the initially reported numbers for pH and hydrogen peroxide concentration and within +/20 of the initially reported numbers for viscosity for at least 24 weeks, which is a high standard of control for performance specifications. Accelerated product aging is typically used to justify expiration dating for new products when room temperature stability testing would delay the introduction of a product to market. Typically, a product stored at 40 degrees C. for 12 weeks can be reliably projected to be stable at room temperature (25 degrees C.) for at least 18 months, and if stored for 24 weeks under the same conditions will be stable at room temperature for at least 24 months. Regression analyses for the change hydrogen peroxide concentration, pH and viscosity in the Example 1 syringe samples stored at 40 degrees C. and 75% relative humidity are shown in Charts 1, 2 and 3 below, respectively. [0040] CHART 1

[0041] CHART 2

[0042] CHART 3

[0043] Clinical Studies

[0044] A small pilot clinical study was conducted to determine the tooth whitening efficacy of the gel in Example 1. Five patients were enrolled in the pilot study, all of whom were of good general dental health and had average starting tooth shades between CI and B3 (arranged according to brightness) on the VITA Classical Shade Guide (Vident Inc., Brea, CA). Shades were expressed in terms of numerical values, as follows:

[0045] Patients were treated as follows:

[0046] 1. A cheek retractor was placed in the subject's mouth and soft tissues adjacent to the buccal tooth enamel were isolated using a light-cured resin dam

[0047] 2. The Example 1 gel was dispensed from a syringe directly onto and brushed evenly over the buccal tooth surfaces to be whitened, three of which (teeth #6 -

#8) were treated with an alkaline pre-treatment whitening accelerator and three of which

(teeth #9 - #11) were not treated with an alkaline pre-treatment accelerator.

[0048] 3. A contact time of 15 minutes elapsed, at which point the gel was suctioned off the tooth surfaces and gel placement repeated as in (2) above.

[0049] 4. A second contact time of 15 minutes elapsed, at which point the gel was again suctioned off the tooth surfaces and gel placement repeated as in (2) above.

[0050] 5. After a final 15 minute gel contact time, the gel was suctioned from the tooth surfaces and all isolation materials were removed.

[0051] 6. The patient was instructed to rinse with water to remove any residual gel or isolation materials.

[0052] 7. Final VITA shades were taken and compared to those taken prior to the whitening procedure.

[0053] The average VITA shade change for the pre-treatment teeth (#6 - #8) for all of the patients was 5.93, while the average VITA shade change for the non-pre- treatment teeth (#9 - #11) for all of the patients was 5.67. The Example 1 gel was thus observed to whiten teeth effectively with and without an alkaline pre-treatment accelerator.

[0054] EXAMPLE 2

Wt % Wt %

Ingredient

(added) (net)

Water (Aqua) 5.360 45.629

Glycerin 99.7% 5.000 5.000

Etidronic acid (60% solution) 0.500 0.300

Potassium Stannate 0.260 0.260

Hydrogen Peroxide (50% solution) 90.000 45.000

Hydroxyethyl Acrylate / Sodium acryloyldimethyltaurate

3.750 3.750 copolymer

Ammonium Hydroxide (29% solution) (to pH 5.0) 0.140 0.041

100.000 100.000

[0055] The composition of Example 2 was manufactured in the same manner as in Example 1, resulting in a translucent gel that was packaged into polypropylene syringes. The Example 2 gel syringes were subjected to a high temperature stress test to determine the gel's ability to maintain functional properties under extremes of

temperature. After 24 hours at 85 degrees C, the gel syringe was observed to contain a small number of large bubbles, but viscosity and hydrogen peroxide testing showed little change even after being subjected to the harsh storage conditions.

[0056] EXAMPLE 3

[0057] The comparative stability of the hydrogen peroxide gel of Example 2 was compared to that of a commercially available hydrogen peroxide gel used for tooth whitening in a chairside setting (Opalescence Boost, Ultradent Products, South Jordan, UT). The hydrogen peroxide concentration of the Boost gel was determined to be 46% using the method previously described, and which is similar to the concentration of hydrogen peroxide in the gel of Example 2 (45%). Three samples of both gels (in syringes) were placed in a constant temperature oven set to 85 degrees C for a period of 6 hours, during which the syringes were observed for any movement of the plunger (an indication of poor hydrogen peroxide stability). After 6 hours, all of the plungers of the Boost syringes had been dispelled from the barrels, but the plungers of the Example 2 syringes were all still intact. Hydrogen peroxide concentrations were not retested for either product, as the loss of the plungers in the Boost samples would have resulted in moisture loss and therefore would have distorted the concentrations. However, viscosity measurements for both aged accelerated Boost and Example 2 gels were made using the previously described method. The Boost sample showed a loss of viscosity of 46%

(404,000 cps at t = 0 and 219,000 at t = 6 hours), while the Example 2 gel showed a loss of viscosity of only 15% (42,000 cps at t = 0 to 36,000 cps at t = 6 hours), demonstrating the superior rheological stability of the inventive composition.

[0058] EXAMPLE 4

[0059] The following composition is designed to be utilized in a patient- or subject- applied tooth whitening method involving a dental tray fabricated by a dentist or dental professional.

Wt % Wt %

Ingredient

(added) (net)

Water (Aqua)

Glycerin 99.7%

Etidronic acid (60% solution)

Potassium Stannate

Hydrogen Peroxide (35% solution)

Hydroxyethyl Acrylate / Sodium acryloyldimethyltaurate

5.000 5.000 copolymer

Ammonium Hydroxide (29% solution) (to pH 7.0)

100.000 100.000

[0060] The following Table 2 contains a summary of the approximate ranges of concentrations (on a weight percent basis) for various components that may be present in the inventive compositions.

[0061] TABLE 2

Water (or other carrier) 40-98

Hydrogen peroxide (or precursor) 1-50

Sulfonic acid polymer / copolymer 0.1 - 10

Stabilizer 0.01-5.0

Secondary active ingredients 0-20

Humectants 0-50

Surfactants 0-10

Photoactive compounds 0-5

Colorants 0-5

Flavorants 0-3

Sweeteners 0-20