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1. WO2013191763 - COMPOSITIONS CONTAINING THEOBROMINE AND THEIR USE IN TREATING TOOTH HYPERSENSITIVITY

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COMPOSITIONS CONTAINING THEOBROMINE AND THEIR USE IN TREATING TOOTH HYPERSENSITIVITY TO RELATED APPLICATIONS 0001 This application is the international stage of Provisional Patent Application filed on 20 June which is hereby incorporated by reference in its BACKGROUND Field The present disclosure relates to dental sensitivity treatment compositions that contain theobromine the principal alkaloid in Theobroma and the uses Uses include the treatment of dentine sensitivity or and effective occlusion of dental Description of Related Art Dental decay is the most widespread and prevalent disease plaguing Erosion of tooth enamel is the primary cause of painful dentine Gum recession is also a contributing factor to exposed Erosion of the enamel can occur from the acidic foods such as citrus fruits or wine that can significantly damage the outer enamel and cause the exposure of open dentinal Hypersensitive teeth are also sensitive to and along with and is one of the four major components of It is a calcified tissue and is usually covered by enamel the and cementum the and completely surrounds the Dentin radially striated in due to the large number of microtubules that radiate outward through the dentin from the center pulp cavity to the periphery of the dentin exterior cementum or enamel The tubules are roughly two microns in diameter at the base the and become more narrow at the periphery the and contained fluid and cellular structures extensions of odontoblasts that once formed the and maintain the odontoblast cell bodies are aligned along the inner aspect of dentine against a layer of where they also form the peripheral boundary of the dental Due to the dentinal dentin has some which can elevate the sensation of pain and the rate of tooth In a healthy oral these tubules are covered by enamel and cementum is in turn covered by the gingival In the United dental hypersensitivity affects roughly 40 million among which roughly are chronically affected Clin North Most incidences of tooth hypersensitivity begin in the age range of and worsen with Exposed dentinal tubules allow increased hydrodynamic flow and a direct pressure gradient that is able to excite nerve endings in the dental The hydrodynamic flow can be increased by various environmental factors but not limited air sour or acidic or mechanical forces acting on the In brushing with abrasive toothpaste may abrade the dentin surface and open dentinal tubules if combined with corrosive Excitation of exposed nerve endings in the dentinal pulp can be incredibly and is the root cause of dentinal Compositions known in the art use potassium bioactive glass strontium strontium or amorphous calcium phosphates as yet doubts regarding their effectiveness these compounds promote the deposition of minerals within the lumen of dentinal tubules and on the exposed thereby preventing transmission of noxious According to at least one there is no strong evidence to support the efficacy of potassium salts for dental Poulsen et Potassium nitrate toothpaste for dentine Orchardson Gillam The efficacy of potassium salts as agents for treating dentin J Orofac None of the compositions known in the art have used or suggested using theobromine as a catalyst for nearly instant and complete dentinal tubule The solution to this technical problem is provided by the embodiments characterized in the BRIEF SUMMARY The present disclosure relates to compositions and methods for treating reducing dentine as well as methods and compositions for treating preventing 001 More the present disclosure relates to the use of theobromine additive to commercially available dental products and as a natural treatment that is able to fully occlude dentinal tubules in a treatment period significantly shorter than currently available dentinal hypersensitivity treatment Due to the safety profile of the this makes theobromine a particularly useful additive to a variety of and beverage related 001 1 Compositions according to the instant disclosure that contain theobromine for treating reducing dentinal hypersensitivity include but are not limited dental over the counter coated orthodontic and pediatric dental cements or tooth bleaching cavity filling materials and resins UV and and endodontic materials including gutta 001 Foods of particular interest for the reduction of dentinal hypersensitivity but are not limited ready to eat sports and isotonic energy meal replacement beverages and milk vitamin or enhanced bottled soy yogurt fruit powdered or liquid flavored and calcium 001 In one embodiment is provided an oral care composition isolated or a salt or double salt a source of calcium selected from the group consisting of calcium calcium calcium calcium calcium and combinations a source of phosphate selected from the group consisting of potassium dihydrogen dipotassium hydrogen tripotassium sodium dihydrogen disodium hydrogen trisodium and combinations 001 In one embodiment is provided a method of reducing oral sensitivity comprising applying to the surface of a mammalian tooth an oral care composition isolated or a salt or double salt a source of calcium selected from the group consisting of calcium calcium calcium calcium calcium and combinations a source of phosphate selected from the group consisting of potassium dihydrogen dipotassium hydrogen tripotassium sodium dihydrogen disodium hydrogen trisodium and combinations 001 In one embodiment is provided a method of maintaining or increasing the systemic health of a mammal comprising applying a composition to an oral surface of a mammal at least once a day for a duration of wherein the composition isolated or a salt or double salt or a comprising a source of calcium selected from the group consisting of calcium calcium calcium calcium calcium and combinations a source of phosphate selected from the group consisting of potassium dihydrogen dipotassium hydrogen tripotassium sodium dihydrogen disodium hydrogen trisodium and combinations 001 In one embodiment is provided a method of occluding a dentinal tubule within the surface of a mammalian tooth comprising applying to the tooth surface a composition isolated or a salt or double salt or a comprising a source of calcium selected from the group consisting of calcium calcium calcium calcium calcium and combinations a source of phosphate selected from the group consisting of potassium dihydrogen dipotassium hydrogen tripotassium sodium dihydrogen disodium hydrogen trisodium and combinations 001 In one embodiment is provided a method of depositing a precipitate on the surface of a mammalian tooth comprising applying to the tooth surface a composition isolated or a salt or double salt or a comprising a source of calcium selected from the group consisting of calcium calcium calcium calcium calcium and combinations a source of phosphate selected from the group consisting of potassium dihydrogen dipotassium hydrogen tripotassium sodium dihydrogen disodium hydrogen trisodium and combinations 001 The composition may have a pH of from about 3 to about from about 4 to about from about 5 to about from about 6 to about from about 6 to about from about to about about from about 7 to about from about 8 to about from about 8 to about from about to about about from about 3 to about from about 3 to about from about 3 to about preferably from about 4 to about more preferably from about to about and even more preferably about 001 The composition may further comprise at least one isotonic The isotonic agent may be a polyhydric The polyhydric alcohol may be selected from the group consisting of and combinations The composition of said method may further comprise at least one The thickener may be selected from the group consisting of methyl carboxymethyl ethyl hydroxypropyl and combinations The composition may further comprise an antibacterial an antimicrobial or combinations The antibacterial agent may be selected from the group consisting of hydrogen clove and combinations BRIEF DESCRIPTION OF THE DRAWINGS For a further understanding of the and advantages of the present reference should be had to the following detailed read in conjunction with the following wherein like reference numerals denote like 0021 1 shows patent dentinal tubules from a control tooth 2 shows occluded dentinal tubules from a test tooth specimen treated with a 3 shows CLINICAL TRIAL patent dentinal tubules from a control tooth 4 shows CLINICAL TRIAL occluded dentinal tubules from a test tooth specimen treated with a 5 shows a representative human and the inset box indicates the dentin area used for dentin block preparations for the studies described 6 shows CLINICAL TRIAL the percentage of completely occluded tubules after and 7 use and 14 of the four toothpastes and For each group of columns is the followed as the 7 shows CLINICAL TRIAL the percentage of tubules after and 7 use and 14 of the four toothpastes and For each group of columns is the followed as the 8 shows CLINICAL TRIAL the percentage of tubules after and 7 use and 14 of the four toothpastes and For each group of columns is the followed as the 9 shows CLINICAL TRIAL the percentage of surface area covered by deposited smear layer after and 7 use and 14 of the four toothpastes and For each group of columns is the followed as the 10 shows CLINICAL TRIAL typical SEM images of the surfaces of dentin blocks with tubules before treatment and after using the four toothpastes and 2 times 4 times 6 times or 14 times at and DETAILED DESCRIPTION 0031 Before the subject disclosure is further it is to be understood that the disclosure is not limited to the particular embodiments of the disclosure described as variations of the particular embodiments may be made and still fall within the scope of the appended It is also to be understood that the terminology employed is for the purpose of describing particular and is not intended to be the scope of the present disclosure will be established by the appended In this specification and the appended the singular include plural reference unless the context clearly dictates Unless defined all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure Current methods for assessing dental tubule occlusion rely on the preparation of dentin block samples that are treated with a composition for a period of time to the number of dental tubules the number of partially occluded dental and the number of completely occluded dental Preliminary data of samples shows that the formulation of the instant claims is significantly and surprisingly more effective than former proposed dentinal tubule occlusion The results presented herein show that after one directed use of the instant formulation over of all dentinal tubules are partially or completely occluded 1 and 3 2 and The compositions and formulations may contain from about to about to about to about to about to about to about to about or to about by preferably from about to about to about to about to about to about to about or to about by and more preferably from about to about to about to about to about to about to about to about of isolated depending on the The compositions and formulations may contain conventional excipients such as binding agents syrups such as corn polyethylene glycols waxes and other cocoa cocoa butter hydrogenated hydrogenated vegetable hydrogenated cotton seed palm kernel soybean stannol glycerol polyalcohol polyoxyethylene esters of hydrophilic and hydrophobic balances from to above 20 and polyethylene oligosaccharides dextrose and derivatives and mixtures gum hydrogenated starch and mixtures fillers silicon stearic magnesium dicalcium microcrystalline and mixtures lubricants magnesium calcium silicon and mixtures disintegrants sodium starch microcrystalline and mixtures bonding agents polyethylene glycols in solid monoglycerides glycerides of vegetable or animal acetylated hydrocolloidal other emulsifiers or fats and mixtures or pharmaceutically acceptable wetting agents sodium lauryl compositions and formulations useful for the instant methods have been disclosed in International Publication WO which claims priority to Provisional Application the disclosures of which are hereby incorporated by reference herein their MATERIALS METHODS Selection of root dentin and dentin block preparation Freshly extracted human molar teeth stored in or disinfectant were cleaned of and examined for smooth dentin area A diamond wire saw Diamond Wire Norcross was used to cut dentin blocks measuring approximately mm x Blocks having a height of about mm and a smooth working surface were obtained by polishing the samples using diamond lapping films in a MultiPrep precision polishing machine High Tech initially with 30 μm diamond grit and finishing with 1 μm grit to obtain a smooth The resulting blocks are referred to Final sample size was mm length x mm width x mm The surface area was marked with an indelible pencil to distinguish it from the working At least one or two vertical or horizontal dentin blocks were obtained from the root of each Bifurcations and the junction were 0041 Creating control and test specimens Each sample mm length x mm width x mm was sectioned into two halves using a diamond wire saw to produce two blocks measuring mm length x mm width x mm one serving as the test sample and the other as control matching control and test samples were In other each test sample has a corresponding control The cutting edge of both specimens was also marked with Removal of smear layer Acid etching and sonication was performed to remove smear layer and debris formed during sample preparation and to obtain patent dentin Both halves and of each samples were sonicated simultaneously Sonifier for no longer than 2 minutes setting in a 200 ml beaker containing citric pH citric acid added to distilled After etching with citric the specimens were sonicated for 2 minutes setting in distilled pH Following the samples were carefully dried as The samples were initially dried with Kimwipes and then placed in a clean petri dish with working surfaces facing upward from the bottom of the petri The petri dish was covered with Parafilm to avoid contamination by and then overnight longer than 16 in a laminar flow SEM examination of control dentin block Prior to the control samples were examined via scanning electron microscopy to ensure quality of specimen preparation and patent dentinal Upon establishment of uniformity and integrity of specimen scanning electron micrographs of three randomly selected areas from each specimen were Samples with surface artifacts and occluded dentinal tubules were The SEM images of the selected samples were recorded and saved for future comparative Etched test dentin blocks that corresponded to control dentin blocks with uniform open dentinal tubules throughout the sample were chosen for PRELIMINARY IN VITRO STUDY Prior to the clinical study described two test samples were brushed for one minute using a toothbrush and a toothpaste The toothpaste was allowed to remain on the test samples for one additional after which they were rinsed with 10 mL of water for 10 The test samples were then immersed in artificial as were the two matching control the two test and two control samples were removed from the artificial saliva containing sources of calcium and phosphate for International Publication WO which claims priority to Provisional Application the disclosures of which are hereby incorporated by reference herein their and allowed to in a petri dish for 24 After the samples were with The samples were then visualized and analyzed via SEM USA Model A defined area on the surface of each dentin block was examined using Scanning Electron Microscopy at a magnification of CLINICAL STUDY Scanning Electron Microscope examination of control dentin block 0051 Prior to clinical the control samples were examined with SEM to ensure quality of specimen preparation and patent dentinal Upon establishment of uniformity and integrity of specimen scanning electron micrographs of three randomly selected areas were Samples with surface artifacts and occluded dentinal tubules were The SEM images reading of the selected samples were recorded and saved for future blocks corresponding to dentin with dentinal tubules throughout the were chosen for Storage of samples construction of in situ appliances Prior to and following test samples an in situ were stored dry in a petri dish with their working surface facing upwards from the bottom of the petri Care was taken not to touch the working surfaces during further Insertion of the blocks into in situ appliances was performed no earlier than two days prior to clinical The appliances were constructed for each human subject so that dentin blocks could be attached to a healthy molar Each appliance was based on the design of brackets used in orthodontic Each appliance consisted of an orthodontic molar pad with retentive mesh backing having a ring of mm orthodontic wire welded to it so that the ring closely encircled each dentin The dentin blocks were retained within the bracket using Intermediate Restorative Material temporary restoration exposing only one surface of the block to the oral the appliances were sterilized using ethylene Selection of study subjects The study was an parallel single controlled clinical Approximately 80 generally healthy adults meeting the necessary inclusion exclusion criteria were enrolled per treatment Screening visits occurred days prior to collection of baseline At the screening each subject completed a history and read and signed an informed consent Following each subject began a washout period and was instructed to start brushing with the assigned test toothpaste and bristled toothbrush twice in their usual The following eligibility criteria were designed to select subjects for whom protocol treatment was considered General Inclusion Criteria Subjects were required to meet all of the following inclusion criteria to be eligible for enrollment into the Male or female at least 18 years of age in good general and oral health without any known allergy to commercial dental products or Evidence of a personally signed and dated informed consent document indicating the subject legally acceptable had been informed of all pertinent aspects of the and Willingness to use the assigned products according to availability for and likelihood of completing the clinical Oral Exam Inclusion Criteria A minimum of 18 healthy teeth exposed to the oral Crowned or extensively restored teeth were not included in the tooth Unrestored and sound enamel on the buccal surface of both lower first permanent mandibular molars 19 and which had been chosen as the teeth to carry the two in situ Absence of significant oral soft tissue based on a visual examination and at the discretion of the Absence of removable partial Adequate oral hygiene daily and no obvious signs of oral and Absence of extensive supragingival General Exclusion Criteria Subjects presenting with any of the following were excluded from the History or presence of kidney disorders or kidney Disease or other malabsorption History of significant adverse effects following use of oral hygiene products such as toothpastes and Physical limitations or restrictions that could preclude use of normal oral hygiene procedures Currently taking any antibiotics or medication that could adversely affect the salivary flow Reported allergy to drugs or chemicals used in the Use of antimicrobial whether prescribed or within four weeks prior to screening Receiving or planning to receive dental treatment which could affect such as oral prophylaxis was Requirement for premedication prior to dental Participation in a dental clinical trial involving oral care products within the past 30 nursing or planning to become pregnant during the course of the study and Other or chronic medical or psychiatric condition or laboratory abnormality that could possibly increase the risk associated with trial participation or could possibly interfere with the interpretation of trial results in the judgment of the could make the subject inappropriate for entry into the If the subject reported taking a history of a chronic disease in the opinion of the would not affect the clinical being assessed in the study or the safety of the the subject was enrolled in the study and it was noted on the source 0061 Oral Exam Exclusion Criteria Teeth that were grossly orthodontically abutment teeth for fixed or removable prostheses or third molars were not be included in the Periodontal surgery and orthodontic treatment within previous 3 History or current evidence of significant oral soft tissue pathology based on the dental visual and at the discretion of the Presence of severe marginal gingivitis based on a clinical examination and discretion of the and Visual evidence of Periodontitis Type Removal of Subjects from the Study An investigator could terminate a subject from investigational treatment in the event Adverse Compliance Serious eligibility or violations of the decision to Withdrawal of and Trial Treatments Subjects were randomly assigned to one of four treatment Theodent toothpaste Theocorp Holding antisensitivity toothpaste 5000 DENTSPLY Standard fluoride toothpaste Colgate New or Theodent toothpaste with Theocorp Holding The efficacy of the four Colgate and were compared at 1 days 2 days 3 days and 7 days time The efficacy of each product after 6 and 14 were also compared to determine longitudinal Clinical Procedures All subjects received a soft bristled manual toothbrush and their respective toothpaste for use throughout the duration of the They started a washout period and were instructed to brush two times morning and just before in their usual On each subjects brushed for one minute using at least a strip of their respective toothpaste and then wait for another one minute before rinsing with 10 ml of water for 10 The first brushing occasion occurred at the research facility and was supervised by the Study Subjects were asked not to take any drink for at least 30 minutes after A diary was provided to each subject to keep a record of the number of times brushed each All subjects were asked to maintain their normal dietary The use of any other oral hygiene such as prescription was After the washout the in situ made out of dentin blocks originating from extracted human teeth of samples construction of in situ were assigned and fitted to each subject at the Baseline Visit Each subject wore four dentin specimens to permit efficacy assessments after 1 day product 2 days product 6 days product and 7 days product The appliances were fitted by a qualified who was different from the Laboratory Assistant who later processed and analyzed the samples to produce the final The buccal surfaces of each mandibular first and second permanent molar teeth chosen to carry the appliances were carefully acid etched for 30 in accordance with current principles of dental washed and dried for a further 30 and then isolated using cotton The bottom of the appliance was carefully positioned to avoid causing occlusal interference and to avoid soft tissue Subjects were instructed to brush their teeth twice in the and just before Subjects were instructed to brush on each occasion for one minute and then wait for an additional one minute before rinsing with 10 ml of water for 10 Subjects were instructed to avoid drinking anything for at least 30 minutes after A diary was provided to each subject to keep a record of the number of times brushed each All subjects were asked to maintain their normal dietary The use of any other oral hygiene such as prescription was 0071 Immediately after attachment of the appliance day each subject made the first use of their product under the supervision of the Study Each subject was instructed to arrive at the clinic on the morning of day 2 prior to using the assigned whereupon one of the four appliances was detached and sent to the laboratory for Immediately after detachment of the the subject was allowed to use the product supervised by the Study This process was repeated on day 3 2 days of product day 4 3 days of product and day 8 7 days of product when the remaining appliances were detached after 14 product The detached dentin blocks were sent to the lab for analysis immediately after Any bonding agent left on the tooth surface was carefully and completely removed with SEM examination of control dentin block After detachment of the test dentin blocks from their the test dentin blocks were placed in a petri dish for air drying as described After 24 hours the blocks were with gold then visualized and analyzed via SEM USA Assessment of tubule occlusion To determine the numbers of and dentin the image of each control block was examined with that of the treated The center of the surface of each dentin block was examined using SEM and the image acquired at a magnification of 10B Each acquired SEM image was assessed by two calibrated blinded examiners for the extent of tubule occlusion based the numbers of and dentin tubules as well as the percentage of the dentin surface covered by smear layer on each of The examiners were calibrated against a standard set of 20 Agreement to the standard set was quantified by Kappa The Kappa scores were and score was considered to be acceptable as adequate The average of the two assessments was calculated for each Smear layer assessment In addition to counting the numbers of and the counting technicians also examined the image of each treated block for deposition of smear layer The percentage of area covered by smear layer was estimated in each image and Safety Assessment Safety was assessed through observation and query of each subject at each visit during the study for any new or continuing symptoms since the previous visit and through the tabulation of adverse No adverse incidents were Statistical Methods 0081 Statistical analysis of the data was conducted using statistical software Statistics with α set as the level of The numbers of partially and completely closed tubules in each block were counted and expressed as a percentage of the number of tubules on the corresponding control The mean of the percentages of partially and completely closed tubules were calculated for the individual Also the mean of the percentage of the surface area covered by deposited smear layer were calculated for each With repeated followed by post hoc comparisons using HSD the efficacy of the four toothpastes in occluding dentin tubules were compared based on the percentage of and surface covered by smear EXAMPLE 1 Preliminary in vitro data Preliminary data from samples derived from the preliminary in vitro study demonstrates that formulations containing theobromine are unexpectedly and surprisingly more effective than dentinal tubule occlusion The results herein demonstrate that after one directed use of a formulation containing theobromine over or all dentinal tubules are partially or completely occluded 1 and 3 with a precipitate deposited on the surfaces exposed to the 1 and 3 are SEM micrographs showing control samples that were not treated with a Patent dentinal tubules are clearly evident over the entirety of each 2 and 4 are SEM micrographs showing matched test samples from the same block as the control samples of 1 and that were treated with a dentifrice as explained As shown by 2 and all dentinal tubules are either mostly or completely occluded after only one treatment with the containing 2 and 4 also show a mineral layer deposited on the tooth surfaces exposed to a EXAMPLE 2 Results of Clinical Study The 80 subjects recruited for clinical trial completed the study without As stated the efficacies of the toothpastes were compared based on four the percentage of and surface area covered by smear 6 shows the percentage of completely occluded tubules after and 7 use and 14 of the four toothpastes and Letters compared the efficacy of the four toothpastes at each usage time point 3 7 Different letters denotes statistically significant difference in the percentage of completely occluded while same letters denotes not significantly Symbols compared the efficacy of the same toothpaste after different lengths 3 7 of Different symbols between columns denotes statistically significant difference in the percentage of completely occluded while same symbols means not significantly 7 shows the percentage of tubules after and 7 use and 14 of the four toothpastes and Letters compared the efficacy of the four toothpastes at each usage time point 3 7 Different letters between columns denotes statistically significant difference in the percentage of while same letters denotes not significantly Symbols compared the efficacy of the same toothpaste after different lengths 3 7 of Different symbols between columns denotes statistically significant difference in the percentage of while same symbols denotes not significantly 0091 8 shows the percentage of tubules after and 7 use and 14 of the four toothpastes and Letters compared the efficacy of the four toothpastes at each usage time point 3 7 Different letters between columns denotes statistically significant difference in while same letters denotes not significantly Symbols compared the efficacy of the same toothpaste after different lengths 3 7 of Different symbols between columns denotes statistically significantly difference in while same symbols denotes not significantly 9 shows the percentage of surface area covered by deposited smear layer after and 7 use and 14 of the four toothpastes and Letters compared the efficacy of the four toothpastes at each usage time point 3 7 Different letters between columns denotes statistically significant difference in completely occluded while same letters denotes not significantly Symbols compared the efficacy of the same toothpaste after different lengths 3 7 of Different symbols between columns denotes statistically significantly difference in completely occluded while same symbols denotes not significantly and 10D show typical SEM images of the surface of the dentin blocks with tubules before treatment and after use of the four toothpastes and 10A shows the results obtained after 2 uses 10B shows the results obtained after 4 uses 10C shows the results obtained after 6 uses and 10D shows the results obtained after 14 uses The images demonstrate the increasing occlusion of the dentinal tubules and deposition of smear layers with increased usage of the toothpastes Sensodyne and but not Colgate Regular Toothpaste deposited a negligible amount of smear layer after 14 The result of this clinical study demonstrated that toothpastes Theodent and Sensodyne Nupro are efficacious in occluding dentin tubules as well as depositing smear layers on the dentin with both Theodent Classic and toothpastes being equally All references cited in this specification are herein incorporated by reference as though each reference was specifically and individually indicated to be incorporated by The citation of any reference is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such reference by virtue of prior It will be understood that each of the elements described or two or more together may also find a useful application in other types of methods differing from the type described Without further the foregoing will so fully reveal the gist of the present disclosure that others by applying current readily adapt it for various applications without omitting features from the standpoint of prior fairly constitute essential characteristics of the generic or specific aspects of this disclosure set forth in the appended The foregoing embodiments are presented by way of example the scope of the present disclosure is to be limited only by the following insufficientOCRQuality