HK1180239B - Microencapsulated compositions and methods for tissue mineralization - Google Patents

Description

Microencapsulated compositions and methods for tissue mineralization

RELATED APPLICATIONSCross reference to

This application claims priority to U.S. provisional application No. 61/172,939, filed on 27/4/2009, which is incorporated herein by reference.

Statement regarding federally sponsored research or development

The present invention was developed independently by the inventors without the use of any federal fund.

Technical Field

The present invention relates to compositions, mixtures and methods for the mineralization of various body tissues, primarily bone and teeth.

Background

Mineralized connective tissue includes teeth, bone and various connective tissues of mammals, including humans, such as collagen, cartilage, tendons, ligaments and other dense connective tissues and reticular fibers comprising type iii collagen. For purposes of definition in this specification, "mineralized tissue" shall specifically refer to bone and teeth. The terms "mineralization", "tissue mineralization" are used interchangeably herein and refer to a process wherein crystals of calcium phosphate are produced by osteoblasts or odontoblasts and placed in precise amounts within the fibrous matrix or bone of the mineralized tissue as defined herein above.

Calcium phosphates are a class of minerals including, but not limited to, calcium ions and orthophosphates, metaphosphates and/or pyrophosphates that may or may not contain hydrogen ions or hydroxide ions.

For purposes of definition in this specification, "remineralization" is the process of restoring minerals to the lattice structure of hydroxyapatite of teeth in the form of mineral ions. As used herein, the term "remineralization" includes mineralization, calcification, recalcification, and fluoridation, as well as other processes in which a variety of specific ions are mineralized to the tooth. The term "tooth" as used herein includes dentin, enamel, pulp and cementum of a tooth within the oral cavity of an animal (including a human).

In some embodiments, the present invention provides methods of bleaching the surface of a dental material by using the compositions of the present invention. For the purposes defined in this specification, "dental material" as referred to herein refers to natural teeth, dentures, dental plates, fillings, crowns (caps), crowns (crowns), bridges, dental implants, and the like, and any other hard-surfaced dental prosthesis that is permanently or temporarily fixed to teeth in the oral cavity of an animal, including a human. As used herein, the terms "bleaching" and "tooth bleaching" are used interchangeably to refer to the alteration of the visual surface of a tooth as defined herein, preferably such that the tooth has a brighter shade or luster.

Condition of bone

Currently applied treatment strategies do not involve methods or compositions that adequately stimulate or enhance the growth of new bone mass. The present invention provides compositions, products and methods that increase bone mineralization at a localized site or directly increase tooth remineralization in the oral cavity, and thus can be utilized in conjunction with the treatment of a wide variety of situations where it is desirable to increase bone or tissue mass as a result of any situation that may be enhanced by the bioavailability of physiological salts, particularly calcium and phosphate.

Some variation in bone mass occurs throughout the life of an individual. After about age 40 and continuing to the final stages of life, men and women experience slow bone loss. Loss of bone mineral content can be caused by a variety of conditions and can lead to significant medical problems. Without proper regulation of the process of tissue mineralization, the result may be too little or too much mineral — either of which may compromise bone health, stiffness and strength. A number of bone growth disorders are known which cause an imbalance in the bone remodeling cycle. The major of these are diseases of bone metabolism, such as osteoporosis, hyperosteogeny (osteomalacia), chronic renal failure and hyperparathyroidism, resulting in abnormal or excessive loss of bone mass, known as osteopenia. Other bone diseases, such as Paget's disease, also cause excessive loss of bone mass at a local site.

Osteoporosis is the structural deterioration of the skeleton caused by loss of bone mass resulting from an imbalance in bone formation, bone resorption or both. Bone resorption is the process by which osteoclasts destroy bone and release minerals, resulting in the transfer of calcium from the bone secretions to the blood. Bone resorption dictates the bone formation phase, thereby reducing the load bearing capacity of the affected bone. In healthy adults, the rates of bone formation and resorption are closely related, such that skeletal bone turnover is maintained. However, imbalances in these bone remodeling cycles are manifested in osteoporotic individuals, leading to loss of bone mass and the formation of microarchitectural defects in the continuum of bone. These bone problems resulting from confusion in the reconstruction sequence accumulate and eventually reach a point where the structural integrity of the bone is severely compromised and a fracture may occur. Although this imbalance occurs gradually with age in most individuals, it occurs more acutely and rapidly in postmenopausal women. In addition, osteoporosis can also result from nutritional and endocrine imbalances, genetic abnormalities, and a variety of malignant transformations.

Osteoporosis in humans has been preceded by clinical osteopenia (bone mineral density greater than 1 standard deviation, but less than 2.5 standard deviations, less than the average for young adult bones), a condition found in approximately two thousand five million people in the united states. In the united states, another 7-8 million patients are diagnosed with clinical osteoporosis (defined as bone mineral content greater than 2.5 standard deviations, below mature young adult bone). Osteoporosis is one of the most costly diseases in the health care system, costing billions of dollars each year in the united states. In addition to health care related costs, the long term home care and lost workdays increase the financial and social costs of the disease. There are approximately seven thousand five million people worldwide at risk for osteoporosis.

The frequency of osteoporosis in the population increases with age, and in caucasians, predominantly women, comprise approximately 80% of american osteoporosis patients. In addition, in women, another phase of bone loss may occur due to postmenopausal estrogen deficiency. In this stage of bone loss, women may lose an additional 10% in cortical bone and 25% from the trabecular compartment (trabecular patent). In this population, the increased risk of accidental falls exacerbates the increased fragility and sensitivity of skeletal bone fractures in elderly people. More than one hundred and fifty thousand osteoporosis-related fractures are reported annually in the united states. Fractured hips, wrists and vertebrae are the most common osteoporosis-related injuries. Hip fractures are particularly uncomfortable and costly for the patient, and for women, it is associated with a high rate of mortality and morbidity.

Patients suffering from chronic kidney (renal) failure suffer almost universally from a loss of skeletal bone mass, known as renal bone disease. Although renal dysfunction is known to cause an imbalance of calcium and phosphate in the blood, regular supplementation of calcium and phosphate by dialysis is not effective in inhibiting osteodystrophy in patients suffering from chronic renal failure. In adults, osteodystrophy is often a significant cause of illness. In children, renal failure often leads to growth arrest due to the inability to maintain and/or increase bone mass.

Hyperosteogeny, also known as osteomalacia ("cartilage"), is a defect in bone mineralization (e.g., incomplete mineralization) and is typically associated with vitamin D (1, 25-dihydroxyvitamin D3) deficiency. This defect can cause compression fracture of the bone, reduction in bone mass and overgrowth and proliferative cartilage replacing an enlarged area of bone tissue. The deficiency may be caused by a deficiency in nutrition (e.g., rickets in children), malabsorption of vitamin D or calcium, and/or impaired vitamin metabolism.

Hyperparathyroidism (overproduction of parathyroid hormone) is known to cause malabsorption of calcium, leading to abnormal bone loss. In children, hyperparathyroidism may inhibit growth; in adults, the integrity of the bone is compromised and typically the ribs and vertebrae are fractured. The imbalance of parathyroid hormone is typically caused by thyroid tumors or gland hyperplasia, or may be caused by prolonged pharmacological application of steroids. Secondary hyperparathyroidism may also be caused by renal osteodystrophy. In the early stages of the disease, osteoclasts are stimulated to resorb bone in response to the presence of excess hormones. As the disease progresses, the trabecular bone is eventually resorbed and, as a result of microfracture, the bone marrow is replaced by fibrosis, macrophages and bleeding surfaces, a condition clinically recognized as fibroosteitis.

Paget's disease (osteitis deformans) is generally recognized as a disorder of viral etiology characterized by excessive bone resorption at a localized site, with sudden outbreaks and healing, but ultimately chronic and progressive and possibly leading to malignant transformation. The disease typically affects adults over 25 years of age.

Although osteoporosis has been defined as an increase in the risk of bone fracture due to reduced bone mass, none of the currently available treatments for skeletal disorders adequately increase bone density in adults. There is a strong feeling among doctors: drugs are necessary that can increase bone density in adults, particularly bones of the wrist, spine and hip, which are at risk for osteopenia and osteoporosis.

Current strategies for preventing osteoporosis may provide some advantages to an individual, but do not warrant resolution of the disease. These strategies include reducing the severity of physical activities, particularly weight-bearing activities, adding appropriate calcium to the diet at the time of aging, and avoiding consumption of alcohol-containing products or smoking. For patients exhibiting clinical osteopenia or osteoporosis, all current therapeutic drugs and strategies involve reducing more bone mass loss by inhibiting bone-resorbing spurs, a natural component of the rapidly occurring bone remodeling process.

For example, estrogens are now used to delay bone loss. However, there is some debate as to whether there is any long-term benefit to the patient and whether there is any effect on patients over age 75. Furthermore, the use of estrogens is believed to increase the risk of breast and endometrial cancer. High doses of dietary calcium with or without vitamin D have been recommended for postmenopausal women. However, ingestion of high doses of calcium often has unpleasant gastrointestinal side effects and the serum and urine calcium levels must be constantly monitored.

Other therapies that have been proposed include calcitonin, bisphosphonates, anabolic cholesterol, and sodium fluoride. However, such therapies have undesirable side effects which may prevent their use, for example, calcitonin and steroids may cause regurgitation and cause immune reactions although bone density is increased appropriately, bisphosphonates and sodium fluoride may inhibit repair of bone fractures.

The above disorders are examples of situations that may lead to fractures, fractures or splits in bones in individuals who suffer from a particular disorder. Current treatment methods are insufficient to treat the disorder when they occur in the individual, requiring improved treatment of the fracture. The present invention provides improved compositions, products and methods for the topical treatment of fractures, fissures and similar bone fractures, or for strengthening broken down bone tissue by mechanisms that increase bone mineralization. It is envisaged that the invention will also cause mineralization of surrounding connective tissue such as collagen, cartilage, tendons, ligaments and other dense connective tissue and reticular fibres.

Oral cavity

With respect to tissue breakdown in the oral cavity, it is generally known in the dental field that some kind of dental breakdown and tooth decay that occurs over time in the mouth begins with acid etching of the enamel, where the acid source is a metabolite produced by the action of bacteria and enzymes in the oral cavity on food particles. It is generally understood that plaque, a soft deposit on the tooth surface, consisting of the organic structure of microorganisms, proteinaceous and carbohydrates, epithelial cells and food debris, is a factor that plays a role in the development of a variety of pathological conditions of the teeth and soft tissues of the oral cavity. The sugar decomposing organisms of the oral cavity associated with plaque cause demineralization or decalcification of teeth beneath the plaque site through metabolic activity that leads to accumulation and local concentration of organic acids. Erosion and demineralization of tooth enamel can continue until they cause the formation of dental caries and periodontal disease in the oral cavity.

The teeth cycle through loss and repair of minerals, also as a result of pH fluctuations in the oral cavity. The total loss or gain of mineral in a given tooth area determines whether the carious process will revert, stabilize or enter an irreversible state. Most relevant patient factors influence the balance of the remineralizing or demineralizing part of this cycle and include oral hygiene, diet, and the quantity and quality of saliva. At the most extreme point of this process, a restoration will be required to repair the tooth.

Methods for preventing and reducing plaque and tooth decay in the oral cavity generally include brushing the teeth with toothpaste, mechanically flossing the plaque, treating and washing the oral cavity with mouth rinses, tooth powders, and disinfectants, remineralizing and bleaching the teeth with fluoridating agents, calcium agents, and bleaching agents, and a variety of other applications to the oral cavity. Still missing in the art are delivery systems for tooth remineralization that can address the problem of tooth demineralization that is constantly facing in the oral cavity.

Teeth that have reached a deep carious state often require the installation of dental restorations in the mouth. Of all dental restorations, half lose their function within 10 years, while replacing them takes 60% of the average dentist's working time. Current dental materials are challenged by the harsh mechanical and chemical environment of the oral cavity, making secondary tooth decay a major cause of failure. There remains a need to develop stronger and longer lasting biocompatible dental restorations by designing new dental materials or new resin systems, strengthening existing materials and incorporating bioactive agents in the materials to combat microbial destruction and withstand the harsh mechanical and chemical environment of the oral cavity.

Despite a variety of prophylactic oral health strategies, dental caries remains an important oral health problem. More than 50% of children 6-8 years old suffer from dental caries; over 17 years of age, more than 80% will have experienced the disease. Caries is also seen in adults as a primary disease and as a recurrent disease in treated teeth. Advances in diagnosis and treatment have led to non-invasive remineralization techniques for the treatment of dental caries. However, the repair and replacement of mechanically removed diseased, intolerable tissues and enamel and dentin remains the most widely used clinical strategy for treating primary caries, restoring tooth function, and preventing further tooth decay. In addition, nearly 50% of newly placed prostheses are replacements for non-functioning prostheses. Clearly, repair materials are a key element in the treatment of such widely distributed diseases.

The choice of repair materials has changed significantly in the last few years. Although silver amalgam is still considered the most cost effective material, there is a growing demand for a choice of tooth color that can provide the same clinical life as silver amalgam. The use of composite resins has grown dramatically internationally as a material of choice as a restorative material for posterior dental restorations in place of amalgams. This need is driven in part by consumer concerns about aesthetic material preferences and amalgam mercury content. It is also motivated by dentists who acknowledge that resin-based bonding materials are promising in retaining and even supporting tooth structures. Many studies have shown that incorporating restorations into the retained tooth structure reduces breakage of the multi-sided permanent molar article. Unfortunately, posterior teeth that are directly repaired with resin restorative materials have a higher secondary caries rate. This has led to shorter clinical service and narrower clinical signs for composite resin materials compared to amalgams.

The most frequently cited reason for prosthesis replacement is the recurrent tooth decay around or near existing prostheses. Possibly, due to shrinkage of the polymerization, the fracture at the edge may lead to the appearance of a clinical environment at the border of the restoration and the tooth, which collects dental plaque and thus initiates tooth decay. Therefore, the development of dental materials having anticaries ability is a very important point for extending the life of the restoration.

Tooth remineralisation

Although natural remineralization often occurs in the mouth, the level of this behavior varies depending on the situation in the mouth as discussed. Incorporation of fluoride during remineralization has been the rationale for caries prevention. The efficacy of fluoride released from a variety of delivery platforms, including some dental restorative materials, has been widely demonstrated. It is generally believed that fluoride prevents dental caries from incorporation of it into fluorapatite or fluorine fortified hydroxyapatite in tooth minerals, thereby reducing the solubility of tooth enamel. More recently, anticaries activity has been demonstrated using methods that increase the calcium and phosphate content of solubility to levels exceeding ambient concentrations of oral fluid. In order for fluoride to be effective in the remineralization of previously demineralized tooth enamel, sufficient calcium and phosphate ions must be used. For every two (2) fluoride ions, ten (10) calcium ions and six (6) phosphate ions are required to form a unit of fluorapatite (Ca)₁₀(PO₄)₆F₂). Thus, a limiting factor in the remineralization of reticular enamel is the utilization of calcium and fluoride in saliva.

The low solubility of calcium phosphates has limited their use in clinical delivery platforms, particularly when fluoride ions are present. These insoluble phosphates are only able to generate available ions that diffuse into the enamel in an acidic environment. They do not effectively settle on the surface of the teeth and are difficult to apply in clinically useful forms. Due to their inherent solubility, soluble calcium and phosphate ions can only be used at very low concentrations. They do not produce a concentration gradient that diffuses into the enamel below the tooth surface. This solubility problem is exacerbated by the lower solubility of calcium phosphate fluoride.

There are several commercially available methods of using calcium and phosphate products that have been commercialized into various models of dental delivery. These limited organisms of calcium and phosphate ions that have been mixed to overcome the remineralization process are said to beAnd (4) utilization degree. The first technique uses casein phosphopeptide (CCP) (RECALDENT) stabilized with Amorphous Calcium Phosphate (ACP)CCP-ACP of cadburyenterprise sp. It is hypothesized that casein phosphopeptides may promote stability of calcium and phosphate available at high concentrations of ions even when fluoride is present. The formulation binds to pellicle and plaque, and while the casein phosphopeptide prevents calculus formation, the ions are able to diffuse down the concentration gradient to the subsurface enamel lesions, promoting remineralization. In contrast to CCP-ACP, bioavailable ions are available in the compositions of the invention because the salt is already a solvate in the microcapsules of the invention. Amorphous calcium phosphate is insoluble in water or saliva. Although the manufacturer claims to release bioavailable ions from amorphous calcium phosphate, it is not as a result of decomposition of the complex. Second technique (ENMELON)) An unstabilized amorphous calcium phosphate is used. Calcium ions and phosphate ions are introduced into the dual chamber apparatus separately to form amorphous calcium phosphate as dentifrice in situ. It has been proposed that the formation of the amorphous complex promotes remineralization. The third method uses so-called bioactive glass containing calcium sodium phosphosilicate (NOVAMIN, NOVAMIN technology inc). It has been proposed that the glass releases calcium and phosphate ions which promote remineralisation. More recently, dental composite formulations have been mixed using zirconia-hybrid ACP, which has the potential to promote clinical remineralization.

Although Recaldent as describedAnd enamolonThe formulations have in situ and in vivo evidence of enhanced remineralization, which are applied topically and do not specifically target the most dangerous areas of recurrent caries at the interface of dental restorations. While the bioactive glass and zirconia hybrid ACP filler technologies have potential, they are relatively rigid depending on the range of formulations in which they may be used due to the challenges of handling fragile fillers and some limitations in controlling filler particle size.

Another approach taken to reduce dental caries in the oral cavity is to limit demineralization of enamel and bone by drinking water fluorination. Fluoride contained in drinking water has been shown to combine to some extent into hydroxyapatite, the main inorganic component of enamel and bone. Fluorinated hydroxyapatite is less susceptible to acid-induced demineralization and is therefore believed to resist the deteriorating forces of acidic dental plaque and small metabolites. Furthermore, the fluoride ion content in saliva is increased by consumption of fluorinated drinking water. Saliva thus acts as an additional store of fluoride ions and, in combination with the buffer salts naturally found in saliva, fluoride ions are actively exchanged at the enamel surface, further counteracting the effect of demineralizing acid metabolites.

Although fluoride treatment of teeth has definite benefits, fluoride ion treatment can result in irregular spots or stains on teeth, whether by drinking water treatment or by topical application of fluoride treatment, depending on the individual. The effect is known to be concentration-related and patient-specific. In addition, its toxicology has been studied with respect to the long-term effects of fluoride on human health. A targeted approach to fluorination in the oral cavity is desired.

Another method of limiting the proliferation of microbial communities in the oral environment is through the topical or systemic application of broad spectrum antibacterial compounds. Reducing the number of oral microflora in the mouth results in a direct reduction or elimination of dental plaque and small accumulations and their destructive acidic metabolites. The main disadvantage of this particular method is that a wide variety of benign or beneficial bacterial strains are found in the oral environment, which can be killed by the same antibacterial compounds in the same way as harmful strains. Furthermore, the treatment with antibacterial compounds allows the selection of certain bacteria and fungi, which may later develop resistance to the antibacterial compounds used and therefore proliferation spreads, not limited by the symbiotic power of the totally balanced microbial communities. Thus, it is not advisable to use a broad spectrum antibiotic alone or in combination with a broad spectrum for the treatment of dental caries, and a more specific, targeted approach is needed.

Tooth bleaching

Cosmetic tooth bleaching or whitening is highly desired by the general public. Many people desire "bright" smiles and white teeth and consider dull and stained teeth cosmetically unattractive. Unfortunately, without preventive or remedial measures, stained teeth are inevitable due to the absorptive properties of the tooth material. Everyday activities such as eating, chewing or drinking certain foods and beverages (especially coffee, tea and red wine) and smoking or other oral use of tobacco products cause undesirable staining of tooth surfaces. The apparent staining of the acquired film results from the mixture, such as tannins and polyphenolic compounds, being captured by and tightly bound to the protein layer of the tooth surface. This type of staining can often be removed by mechanical methods of tooth cleaning. In contrast, internal staining occurs when staining compounds penetrate the enamel and even the dentin or from an intra-dental source. The chromogens or color-contributing substances in these materials become part of the biofilm layer and can penetrate the enamel layer. Even with conventional brushing and flossing, the aged accumulation of chromogens can impart significant tooth discoloration. Intrinsic staining can also result from microbial activity including that associated with dental plaque. This type of staining is not responsive to mechanical methods of tooth cleaning and requires chemical methods.

Without specifically defining the mechanism of action of the present invention, the compositions, products and methods of the present invention are capable of precipitating salts onto tooth surfaces in the oral cavity and making the salts available for adhesion to tooth surfaces and remineralization of teeth. The mineralized salts precipitate in the interstitial spaces of the teeth, making the teeth flatter, increasing the light reflection at the tooth surface and thus giving the teeth a brighter, glossier surface and whiter visual effect.

Dental bleaching compositions generally fall into two categories: (1) gels, pastes, paints or liquids, including toothpastes that mechanically agitate the stained tooth surfaces to stain the teeth by abrading the stained acquired film; and (2) a gel, paste, paint or liquid which accomplishes the tooth bleaching effect by a chemical process in which the gel, paste, paint or liquid is contacted with the stained tooth surface for a specified time, after which the preparation is removed. In some instances, the mechanical process is supplemented by a chemical process that may be oxidative or enzyme assisted. Initially, tooth bleaching was performed in the dentist's office. There are already few expensive home dental bleaching kits, such as bleaching strips and discs in single or dual chamber systems.

Tooth bleaching in the office and at home typically involves the application of peroxide-containing compositions to the tooth surface to achieve the desired bleaching effect. Most office and home dental bleaching compositions act by oxidation. These compositions are used by the patient directly in the dental bleaching tray, keeping the contact in place in the mouth a number of times, sometimes several times a day, half an hour each; or more than 60 minutes per day for periods as long as 8-12 hours. In large part, the slow rate of bleaching is a result of formulations developed to maintain the stability of the oxidizing composition. Aqueous tooth whitening gels have proven worthwhile due to hydration of the tooth structure, reducing the likelihood of tooth sensitivity.

The most commonly used oxidizing compositions comprise the hydrogen peroxide precursor carbamide peroxide in admixture with an anhydrous or low water content hygroscopic viscous carrier comprising glycerol and/or propylene glycol and/or polyethylene glycol. Upon contact with water, carbamide peroxide decomposes into urea and hydrogen peroxide. Hydrogen peroxide has become the tooth bleaching material of choice because its bleaching power is faster than higher concentrations of urea peroxide.

An alternative source of hydrogen peroxide is sodium percarbonate and this has been used in silicone polymer products which are applied to teeth to form a durable film for overnight bleaching processes. The peroxide was slowly released for up to 4 hours.

The slow rate of bleaching, combined in a hygroscopic carrier, causes tooth sensitivity in more than 50% of patients. Tooth sensitivity is thought to result from the movement of fluid through the dentinal canal to the nerve endings of the tooth. This movement is enhanced by the carrier of carbamide peroxide. It has been determined that glycerin, propylene glycol and polyethylene glycol all alter tooth sensitivity after the tooth has been subjected to heat, cold, excessively sweet substances and other pathogens.

In addition to tooth sensitivity, hydrogen peroxide tooth bleaching formulations have limitations. Until recently, stable aqueous hydrogen peroxide tooth bleaching gels have virtually not existed. Hydrogen peroxide is a strong oxidizing agent and an unstable compound that readily decomposes over time into water and oxygen. Some chemical and physical effects in the mouth can promote the rate of decomposition, and for a stable tooth bleaching gel, control is required to be present. Temperature, pH and variable metal ions all have profound effects on the decomposition of hydrogen peroxide, particularly in aqueous formulations.

One advantage of the compositions of the present invention is that the sensitivity of the patient's teeth is reduced or eliminated. When used in conjunction with current dental bleaching products, the microcapsules of the present invention release salt ions that precipitate in the oral cavity to form salts and mineralize the open dentinal tubules of the teeth, thereby reducing the sensitivity of the teeth to dental bleaching products having oxidizing properties.

The bleaching systems on the market include two-part systems that require mixing of the ingredients at the time of use and faster and easier to use and often dentists bleach the preferred single part composition in the office. Two-part systems include products such as dual syringes, liquid hydrogen peroxide/powder systems, and bleaching strips. The single component dental bleaching compositions are preferably stored at room temperature to eliminate costly and inconvenient storage problems. The pH of the aqueous hydrogen peroxide tooth bleaching composition is also important in relation to the stability of the formulation. The two-part system demonstrated better shelf life stability. Formulations containing hydrogen peroxide solutions are strongly acidic and maintain their stability in acidic pH formulations. The stable aqueous hydrogen peroxide tooth bleaching gels can be formulated at acidic pH ranges. However, bleaching compositions in the acidic pH range (pH 2.0-5.5) tend to demineralize tooth enamel by dissolving calcium ions from the tooth surface. The reduction of surface enamel results in sensitivity and discomfort to the patient's teeth. By mixing the compositions of the present invention into a dental bleaching product or using them with a dental bleaching product, the microcapsules of the present invention can modify the pH level in the oral cavity to accelerate the bleaching process.

Many available products are time consuming and limited in their effectiveness and subject the user to a variety of physical discomfort. More importantly, it has been shown that, as currently practiced, prolonged contact of teeth with bleaching compositions has a number of side effects in addition to tooth sensitivity. Over time, any peroxide known in the art to achieve the desired tooth bleaching effect will act as a calcium chelator. Other examples of chelating agents often found in dental bleaching products include EDTA and salts thereof, citric acid and salts thereof, gluconic acid and salts thereof, alkali metal pyrophosphates, and alkali metal polyphosphates. Dissolution of calcium from the enamel layer may occur at pH values less than 5.5 with associated demineralization. The chelating agent will penetrate intact enamel and dentin so as to reach the pulp chamber of a living pulp tooth, thereby risking pulpal tissue destruction. Other side effects include dilution of the bleaching composition with saliva in the oral cavity, resulting in leaching out of the dental tray and subsequent digestion by the user.

It has been shown that the rate of bleaching can be increased by increasing the temperature of the hydrogen peroxide system, wherein an increase of 10 ℃ can double the reaction rate. Thus, there are a number of methods of increasing the temperature of hydrogen peroxide using high intensity light to accelerate the rate of tooth bleaching. Other methods of heating hydrogen peroxide have been described, such as dental appliance heating. Current methods and work have focused on facilitating peroxide bleaching while illuminating the anterior teeth with a variety of sources having a range of wavelengths and spectral powers, including halogen curing lights, plasma arc lamps, lasers, and light emitting diodes. Some products used in light activated bleaching processes contain ingredients that act as photosensitizers to aid the transfer of energy from the light to the peroxide gel and often coloured materials such as carotene and manganese sulphate. However, excessive heating can cause irreversible damage to the pulp. In addition, in vitro and clinical studies literature and actual results demonstrate: the practical effects of light on tooth bleaching are limited, contradictory and controversial.

There is therefore a need for improved compositions, methods and products that overcome the deficiencies of the prior art. The challenge remains to create a platform for tooth bleaching and remineralization technologies for mixing stable and efficient tissue remineralization ions that can be mixed into myriad tooth materials and a variety of products. Such a delivery platform would facilitate the formulation of dental products capable of remineralizing teeth. The compositions, products, and methods of the present invention described herein meet these and other needs. The net effect is to reduce recurring caries-the most common reason for restoration replacement, bleaching teeth and resulting in improved overall strength and health of teeth in the mouth.

Disclosure of Invention

In accordance with the description and desires herein to provide products for improved tissue and bone mineralization and tooth remineralization, the present invention provides compositions and methods for increasing tissue mineral content and tissue mineral density. Methods of using these compositions in the treatment and prevention of a wide variety of conditions resulting from tissue breakdown are also presented. The invention also provides dental compositions and products for remineralisation and bleaching of teeth. More specifically, the present invention provides compositions comprising a salt solution encapsulated within a semi-permeable polymeric shell capable of releasing bioavailable ions that are delivered to mineralized tissue. The microcapsules may be mixed into various bone restorations and dental products. The microcapsules may be prepared by any commonly known microencapsulation process, but are preferably prepared by surfactant-free inverse emulsions. More specifically, the present invention is a composition comprising an aqueous solution of polymeric microencapsulated calcium, phosphate, fluoride salts and combinations and mixtures thereof. Furthermore, the release rate of salt ions from microcapsules can be tailored in a single type of microcapsule and in products containing many different types of microcapsules, such that the application is delivered over a controlled time release of ions, resulting in a tissue remineralization effect occurring over an extended period of time.

Drawings

FIG. 1 is an optical micrograph of microcapsules of the present invention comprising 0.1MCa (NO) suspended in methyl benzoate₃)₂An aqueous solution.

Detailed Description

Microencapsulation

In a preferred embodiment, the composition of the present invention is formed by combining water, salt, an oil-soluble emulsifier, and at least one type of combined polymer, and upon mixing or agitation, to form the microcapsules of the present invention. For purposes of definition, the term "microcapsule" as used herein refers to a small particle or droplet surrounded by a coating to provide a small capsule with beneficial properties. Microcapsules are sometimes referred to as microspheres, although the microcapsules of the invention need not be spherical. The material inside the microcapsules should be referred to herein as the "core" or "internal phase", while the material surrounding the core means the "shell", "wall", "coating", "film" or "external phase". The shell need not completely or uniformly coat the core of the microcapsule, so long as a substantial majority of the core is coated with a polymeric shell as will be further described herein.

Preferably, the diameter of the microcapsules of the invention ranges between 100 nanometers and 3 millimeters. More preferably, the microcapsules have a size of between 1 micron and 1 mm. In general, the preferred size of the microcapsules will be determined by the desired end use. One parameter used to control the microcapsule size is the amount and force with which the emulsion is mixed or agitated. Other parameters for controlling the microcapsule size and microcapsule composition are discussed further below. The size of the microcapsules of the invention can be optimized so that sufficient microcapsules can be applied to the solid phase surface of the matrix, in interfacial contact with tissue, bone or dental material to affect mineralization.

Various encapsulation methods are known for producing microencapsulated microparticles, although none have so far been applied to the formation of tissue or bone mineralizing or tooth remineralizing compositions as contemplated by the present invention. The method of constructing the microcapsules may be physical or chemical. Physical manufacturing methods include pan coating, air suspension coating, centrifugal extrusion, vibrating nozzle, and spray drying. Chemical fabrication methods include polymerization, such as interfacial polymerization, in situ polymerization, and templated polymerization. In interfacial polymerization, at least two monomers are separately dissolved in immiscible liquids. At the interface of the liquids, a rapid reaction occurs to produce a thin shell or wall of microcapsules. In situ polymerization is the direct polymerization of a single monomer that occurs on the surface of the microparticles. In templated polymerization, the core material is implanted during the formation of the microcapsules. Microcapsules can also be constructed by using sol-gel techniques, by aqueous or organic solution precipitation synthesis methods, complex coacervation, and by other methods known in the art.

The preferred method of preparing microcapsules of the present invention is the synthesis developed herein to produce microcapsules containing aqueous solutions of salts, specifically, salts including water soluble calcium, phosphate salts, and fluoride ion containing salts. For encapsulating the ionic aqueous solution in microcapsules, it is preferred to use water-in-oil surfactant-free inverse emulsions. Any continuous oil phase may be used in the process of the present invention. Application to dental materialIn this way, a hydrophobic oil is used as the continuous oil phase in the process, and an emulsifier is used to sterically stabilise the dispersed phase. One preferred oil phase of the present invention is methyl benzoate. FIG. 1 is an optical micrograph of microcapsules of the present invention comprising 0.1MCa (NO) suspended in methyl benzoate₃)₂An aqueous solution.

Stabilizing the dispersed droplets using a surfactant on a standard emulsion format; however, the preferred process of the present invention uses an emulsifier in the continuous oil phase to sterically stabilise the dispersed water droplets so that interfacial polymerisation occurs. This results in an efficient synthesis of a polymeric shell around the ionic aqueous solution in the dispersed phase. The amphiphilicity of the surfactant causes interference with the polymerization that must occur at the interface of the dispersed and continuous phases necessary to produce the capsules. Surfactants also suffer from their affinity for ions. The polar hydrophilic head groups will be attracted to the ions contained in the capsules for remineralization. The presence of the surfactant reduces the percentage of truly bioavailable ions, effectively acting as a chelator that prevents the release of ions from the capsule. Therefore, surfactant-free inverse emulsion interfacial polymerization is the first choice for the method of forming the dental microcapsules of the present invention.

Emulsifier

The preferred emulsifiers in the dental microcapsules of the present invention are different from surfactants in that the emulsifiers are exclusively divided into oil phases and are not surface active. The inherent idea of using surfactant-free inverse emulsions is that the water droplets can be divided into droplets whose size and size distribution depend on the form and amount of energy input, and the droplets formed are present briefly due to the slow rate of formation. Although surfactant-free emulsions have been frequently used in solvent extraction, emulsion polymerization, food production such as oil and vinegar flavor production, little attention has been paid to the basic properties of their use in microencapsulation of aqueous bioactive systems. The emulsifier sterically stabilizes the droplets without interfering with interfacial polymerization. The sequestration of remineralizing ions is thus minimized.

Polymer and method of making same

The microcapsules of the present invention comprise a shell composed of at least one polymer, preferably the shell is semi-permeable to an aqueous solution of a particular salt. As used herein, the term "polymer" means a precursor polymer molecule, preferably in the size range of 1,000-50,000 g/mole, more preferably 1,500-20,000 g/mole; and more preferably, 1,500-8,000 g/mole. Larger polymers, as well as smaller oligomers or prepolymers, can be used, but the molecular weight of the polymer is controlled by the actual use of the desired dental product application. It is contemplated that monomers may be used in the process of the present invention. Many polymers can be incorporated into one microcapsule to produce an end use product having the specific desired release characteristics of the core component.

In one embodiment of the invention, the microcapsule shell is designed to have limited or substantially no permeability, depending on the desired application. The impermeable shell is formed during synthesis by selecting a particular polymer that is known to be impermeable to a particular ion in the desired end use application. For example, such microcapsules may be synthesized for "blasting" applications as discussed below.

Many types of polymers may be used within the scope of the present invention, and the selection depends on the specific desired properties. Examples include, but are not limited to: acrylic polymers, alkyd resins, aminoplasts, coumarone indene resins, epoxy resins, fluoropolymers, phenolic resins, polyacetals, polyacetylenes, polyacrylic resins, polyalkylene resins, polyalkenylene groups, polyalkynylene groups, polyamic acids, polyamides, polyamines, polyanhydrides, polyarylene alkenylene groups, polyarylene alkylene groups, polyarylene, polymethines, polybenzimidazole, polybenzthiazole, polybenzoxazinones, polybenzoxazole, polyphenylmethyls, polycarbodiimides, polycarbonates, polycarboboranes, polycarbosilanes, polycyanurates, polydienes, polyester-polyurethanes, polyesters, polyetheretherketones, polyether-polyurethanes, polyethers, polyhydrazides, polyimidazoles, polyimides, polyimines, polyisocyanurates, polyketones, polyolefins, polyoxadiazoles, polyoxaalkylenes, polyoxyalkylenes, polyoxyarylenes, polyoxymethylenes, phenolics, polyacetals, polyacetylenes, polyacet, Polyphenylene, polyphosphazene, polypyrrole, polypyrrolone, polyquinoline, polyquinoxaline, polysilane, polysilazane, polysiloxane, polysilsesquioxane, polysulfide, polysulfonamide, polysulfone, polythiothiazole, polythioalkylene, polythioarylene, polythioether, polymercaptomethylene, polyphenylene sulfide, polyurea, polyurethane, polyvinyl acetal, polyvinyl butyral, polyvinyl formal. One skilled in the art will further appreciate that the selection of the particular type of polymer will affect the composition and permeation characteristics of the microcapsules of the present invention.

Salt (salt)

Fluoride, calcium and phosphate salts are preferred in the compositions of the present invention for application to tissue and particularly to teeth, although other salts may also be used depending on the desired application. Examples of calcium salts include, but are not limited to: calcium acetate, calcium aluminosilicate, calcium benzoate, calcium bromide, calcium butyrate, aragonite calcium, calcite, calcium chloride, calcium aluminate, calcium silicofluoride chloride orthophosphate (calcium chlorofluoride ortho phosphate), calcium thiosulfate, calcium valerate, calcium cinnamate, calcium citrate, calcium fluorosilicate, calcium fluoride, calcium formate, calcium fumarate, calcium gluconate, calcium glycerophosphate, calcium iodate, calcium iodide, calcium isobutyrate, calcium lactate, calcium lysinate, calcium malate, calcium malonate, calcium nitrate, calcium 1-phenol-4-sulfonate, calcium orthophosphate, calcium pyrophosphate, calcium propionate, calcium salicylate, calcium quiniate, calcium orthosilicate, calcium tartrate, calcium sulfate, and calcium thiocyanate. Sodium salts, fluorine donating salts include, but are not limited to: sodium fluoride, fluorosilicic acid, sodium fluorosilicate, sodium monofluorophosphate, sodium fluorosilicate, potassium fluoride, cuprous fluoride, tin fluorides such as stannous fluoride or tin chlorofluoride, ammonium fluorosilicate, aluminum monofluorophosphate and aluminum difluorophosphate. Examples of phosphates include, but are not limited to: potassium phosphate, sodium phosphate and magnesium phosphate.

In a preferred embodiment of the surfactant-free inverse emulsion polymerization process of the present invention, the very low molecular weight polyurethane is pre-mixed into the continuous oil phase. Preferably, the molecular weight of the polyurethane is 1,500 to 20,000 g/mole; more preferably, 1,500 to 8,000 g/mole. Due to the amphiphilic nature of low molecular weight polyurethanes, the polyurethane is most of the time at the boundary between the dispersed and continuous phases.

In the described embodiment, a diol is added to the system to increase the molecular weight of the isocyanate as a polyurethane shell. The preferred diol is ethylene glycol. The diol ultimately results in an ethylene oxide linker unit in the microcapsule chemical structure. In industrial applications it has been shown that ethylene oxide does not inhibit the ionic current between the electrodes. This method helps to understand the structural performance relationship of the polyurethane with respect to the permeability of the microcapsules, since its chemical structure can be easily changed in the synthesis of the microcapsules by simply changing the characteristics of the diol used in the polyurethane wall of the microcapsules. In this embodiment, the ion permeability of the microcapsule shell of the composition is based on the chemical composition of the diol as the spacer monomer used in the synthesis of the microcapsule. The following figure shows the reactions for synthesizing the microcapsule shells of the present embodiments.

Wherein n is 1, 2, 3 or 4.

The length of the ethylene oxide spacer in the microcapsule wall can be varied to control the ion permeability of the membrane shell. A preferred embodiment includes the use of microcapsules of ethylene glycol (n ═ 1) and from 1, 4-butanediol (n ═ 2). Preferred embodiments include microcapsules from diols where n ═ 3(1, 6-hexanediol) or 4(1, 8-octanediol).

A second property that affects the ion permeability of the microcapsule membrane is the shell or wall thickness, which can be varied by varying the ratio of the amount of material from which the shell is synthesized to the volume of the dispersed ionic salt aqueous solution. At a constant agitation rate, adding more material relative to the ionic water phase will result in the formation of a thicker microcapsule wall. In a preferred embodiment, the invention comprises an aqueous solution in a ratio of 1 gram of polyurethane to 15 to 40 mL.

Microencapsulation of specific remineralizing ions allows mixing all elements into a single phase without the need to separate multiple reactive ions by physical barriers such as double syringes, double capsule tubes or two separate container systems for the dental bleaching product. The process of the present invention allows mixing of the reactive remineralizing ions of discrete and isolated microcapsules into the water system. The single phase aqueous dental composition eliminates the need for a specific design of a binary container and extends the stability of the finished dental product until needed. Preferred embodiments of such dental compositions include products for direct application to the oral cavity such as single phase dentifrices, mouthwashes, bleaching creams, gels, liquids and paints, and bleaching strips. The combined use of these specific remineralizing ions in a single phase of an aqueous system is not currently feasible.

Embodiments of the dental material of the present invention may be formulated such that only one type of mineralized ion is contained in the core of the microcapsules, or alternatively, multiple different types of salts and salt ions may be mixed into one microcapsule.

In other embodiments, multiple microcapsules containing one type of ion may be mixed with microcapsules containing other ions into one product. For example, calcium salt-containing microcapsules can be incorporated into a mouthwash product that also contains phosphate-containing microcapsules. The calcium and phosphate ions will be released into the oral cavity by permeation through the shell membrane of the microcapsules or by bursting of the microcapsules in the mouth. Upon release, the calcium and phosphate ions will form amorphous calcium phosphate, which will precipitate from saliva and cause remineralization of teeth. Another example product may be a mouthwash comprising a calcium salt, a phosphate salt, and a fluoride salt, each in separate microcapsules, which may be semi-permeable or impermeable. By rinsing, the microcapsules will burst open to release salt ions which combine in the mouth to form calcium fluoride and amorphous calcium fluoride phosphate and precipitate on the teeth.

Controlled release

The microcapsules and products of the present invention can be designed to have different time-release properties in such a way as to allow release of specific ions or elements at controlled times, also known as sustained or extended release to achieve different desired results. Thus, multiple salt ions or ingredients of the present invention can be released from each microcapsule at different time periods.

Furthermore, the ratio of release times of the different types of microcapsules can be fused into the design of a single product to optimize the permeability and concentration of specific ions or elements of each type of microcapsule in the product relative to each other and relative to the environment in which they are needed. Such a design enables the mineralized product to deliver multiple active ingredients to specific sites of tissue decay over a controlled period of time, without the need for multiple applications of the product to the patient, thereby minimizing the patient's treatment regimen.

For example, the dental product can remineralize areas of the dental material that are in contact with the dental composition to prevent dental caries, bleach teeth, and/or provide antimicrobial treatment to a target tooth surface in the oral cavity. For example, fillers, sealants and cements can be designed to contain the controlled release microcapsules of the present invention and release salt ions over time to the area contacting the teeth or tooth material. A sustained release dosage form of a dental product will avoid frequent application of the active, but at the same time achieve the desired level of remineralization or bleaching in the oral cavity.

One way in which controlled release design can be achieved is to specifically select and synthesize a shell polymer having a desired permeability in the shell. Another way to control permeability and release properties is to control the thickness of the shell layer during microcapsule synthesis as described herein.

The ion concentration in the microcapsules can also be varied to affect permeability. In a preferred embodiment, the biologically active Ca is²⁺、PO₄ ^-And F^-Ions and combinations thereof may be mixed in the microcapsules. Each microcapsule is synthesized with an aqueous solution of a salt containing a range of concentrations of the particular target ion. Salts with high water solubility are preferred, but not required. Preferred embodiments include Ca (NO)₃)₂、K₂HPO₄And NaF. Preferred embodiments include microcapsules having a range of molar concentrations, reflecting the percentage of saturation state of a given ion, from 5-95%; more preferably, from 25-95%; and more preferably from 70-90%. Table 1 lists several preferred embodiments.

TABLE 1

For example, tablets may be produced comprising microcapsules of the invention wherein the active ingredient is not completely absorbed, but the active ingredient may be released gradually and continuously over the time of administration.

In the oral cavity, direct release or "burst" release of the microcapsules may be generated based on mechanical agitation of the teeth, such as by using a toothbrush or dental floss in the oral cavity; by conventional chewing, grinding, biting, compressing or gripping teeth or gums; by tongue movement or tongue compression; or by swishing or gargling by movement of the mandibular muscles and other muscles of the mouth. As described above, the semipermeable microcapsules and impermeable microcapsules of the present invention may be incorporated into products designed for burst release effects.

Filling of microcapsules

The microcapsules of the present invention comprise a semipermeable polymeric shell wherein the semipermeable effect is to release salt ions from the microcapsule and allow salt ions from the surrounding environment into the microcapsule as a result of the concentration gradient. Accordingly, embodiments are contemplated in which: microcapsules that have been formed with no or less than the maximum possible amount of aqueous salt solution in the core may be filled with additional salt solution or salt ions, designated herein as "loading". Loading also includes "refilling" of empty microcapsules in the presence of reactive ions and appropriate concentration gradients. By immersing the microcapsules in a highly mineralized filled salt solution, new ions can be introduced into the core of the partially filled microcapsules or reintroduced into the core of the empty microcapsules, wherein the salt ion concentration in the salt solution is greater than the salt ion concentration within the core of the microcapsules.

Embodiments of the refill application of the present invention include products that can be retained in the oral cavity for a relatively long period of time, such as dental resins and binders, and can therefore be used to remineralize, fluorize or bleach teeth. The refill rate of the microcapsules will depend on the concentration gradient of the salt ions and the release properties of the particular polymer of the product.

Bone repair material

The compositions of the present invention are useful in a variety of bone repair or regeneration products. There is a need for new materials that can stimulate the body's own regenerative matrix and heal tissue. A porous plate as a scaffold is considered necessary for three-dimensional bone tissue growth. It has recently been found that bioactive glasses are a high potential scaffold material because they stimulate osteoblasts to produce new bone, they are degradable in the body and they bind to bone.

In one example, a study evaluated the use of a stereo polycaprolactone tricalcium phosphate bone composite scaffold in bone engineering. The bone scaffolds were immersed in simulated body fluids at 37 ℃ and monitored for weight loss and water absorption. Biochemical tests and microscopy showed that calcium was precipitated on the surface of the scaffold and caused crystallization of the hydroxyapatite layer of the scaffold. The microcapsules of the present invention may be mixed with such and similar bioactive bone scaffolds to initiate or augment bone formation and induce bone regeneration (see YLei, b.rai, k.h.ho and s.h.teoh, invitrogenaton novel bioactive polycaprolactone-20% tricopeptide phosphatecospongscaffolds for bone engineering, national university of site, 2006).

Applications of bone regeneration products in the dental field include the accumulation of bone tissue around implants placed in the alveoli after tooth extraction or in preparation for future implantation of a denture or denture prosthesis. Another useful application is to fill bone defects after removal of the root, resection or removal of impacted teeth. Another application is to repair bone defects after re-opening the wound in the mouth.

Dental product

Specific dental products comprising the microcapsules of the present invention include dental gels, pastes, mouthwashes, dentifrices, bleaching products, breath fresheners, artificial saliva systems, paints, desensitizers, and other dental products known in the dental art. Dental restorative materials include composites and other solid phase filling materials, adhesives and cements, temporary restorative materials, coatings on implants for inducing bone growth. Various embodiments of the present invention include use other than by physician's prescription, such as toothpastes, bleaches, paints, sealants, sealers, resin restorative materials, glass ionomers (including resin modified glass ionomers), bioactive glasses, composite (compomer) restorative materials, glass composite (giomer) restorative materials, mouthwashes, any topical prophylactic or remineralizing agent (liquid, gel foam, paste), any mouthwashes containing antibacterial agents, "coated" liquid gels for professional use and other than by physician's prescription, paints, sealers, indirect laboratory materials including laboratory resins, dentures, denture base materials, dental cements, root canal fillers and sealers, materials for bone implants, bone cements, dental implant tissue growth materials, endodontic root canal filling materials (i.e., apical excision materials sometimes referred to as back-filling materials), Pulp capping material, temporary prosthetic filling material, toothpaste (propyphase), periodontal clearing gel, air abrasion powder for prophylaxis, orthodontic cement, dental surgery extraction socket dressing, cadaver bone and other bone substitutes.

Embodiments of the dental product also include products that can dissolve in the oral cavity upon contact with saliva as a result of enzymatic activity in the oral cavity, such as a dissolvable bleaching strip. Other products that may affect remineralization of teeth that incorporate microcapsules include chewing gum, candy, lozenges, capsules, tablets, and various foods.

In one embodiment, the dental composition of the invention in which the specific remineralizing ions are microencapsulated allows the salt ions to be fused into the matrix of the polymeric composition and other solid filled dental restorative materials such as glass ionomer cements, the fusion of the microencapsulated ions providing a source of bioactive filler material and binder. The use of semi-permeable microcapsules allows the material to release these remineralizing compounds at the interface of the tooth structure and the restorative filling material or adhesive. This interface is particularly susceptible to bacterial entry, attack and subsequent secondary caries development. The presence of liquid within this interface may signal possible microleakage at the repair interface, but also allow activation of the material to release the required ions for the remineralization process to take place. Embodiments of the microcapsules of the present invention may be designed to release salt ions under mechanical stress at the mouth of the tooth/filler interface space.

Dental composition embodiments of the present invention can also be designed to include a solid phase, such as a composite, which provides a variety of advantages. Currently, the activity of adding remineralizing ions to resin compositions and providing ions is unknown because the ions may be fused or embedded in the resin or plastic insoluble matrix.

In a preferred practice of the invention, an oral dental product, such as a toothpaste, mouthwash or tooth powder, comprising the microcapsule composition of the invention is preferably applied to the oral cavity regularly, such as daily or every two days or every three days or several times a day, although regular application is not required.

According to various embodiments of the present invention, a dental bleaching composition is provided for providing a natural white appearance to a tooth surface. The tooth surface is generally composed of enamel, dentin, and an acquired pellicle, and the bleaching composition contacts and preferably adheres to the tooth surface to impart a directly discernible bleaching effect, thus rapidly changing the color of the tooth surface. In some embodiments, the present invention provides methods of bleaching tooth surfaces by using the compositions of the present invention. The dental product acts as a delivery system that operates to disperse and adsorb the salt ions as bleaching particles for the tooth surface to provide a natural white appearance. The bleaching compositions of the present invention may be applied to the teeth by any suitable means known in the art of dental bleaching. Examples include the use of toothpaste, mouth washes, gels, extruded forms such as strips, including dissolvable bleaching strips, coating liquids and paints, single and dual compartment products.

The increase in whiteness of the tooth surface can be observed visually, for example, by means of a colorimetric chart or standard, or by colorimetric measurement using any suitable instrument, such as a minolta chromameter, e.g., model CR-400(minolta corp., Ramsey, n.j.). For example, the instrument can be operated to measure the HunterLab value or L according to standards established by the International Commission on illumination (CIE)^*a^*b^*The value is obtained. Although there is no standard in the dental field to measure and determine tooth color, a very common method is VITATooth selecting color plate (Vita)Zahnfarbik, BadSackingen, germany). VITAThe range of shade of the tooth selection plate can vary from very bright (B1) to very dark (C4). A total of 16 tooth shades constitute the range of colors between these two endpoints with respect to intensity level. Patient satisfaction with tooth bleaching procedures and products increases with the number of tooth shade changes achieved.

Other additives

In some embodiments, a sweetener is used in the product, which is mixed in the microcapsule composition of the present invention. Sweeteners useful herein include orally acceptable natural or artificial, nutritive or non-nutritive sweeteners. Such sweeteners include dextrose, polydextrose, sucrose, maltose, dextrin, dried invert sugar, mannose, xylose, ribose, fructose, levulose, galactose, corn syrup (high fructose corn syrup and corn syrup solids), partially hydrolyzed starch, hydrogenated starch hydrolysate, sorbitol, mannitol, xylitol, maltitol, isomalt, aspartame, neotame, saccharin and salts thereof, sucralose, dipeptide-based high potency sweeteners, cyclamates, dihydrochalcones and mixtures thereof. Depending strongly on the particular sweetener selected, one or more sweeteners may be present in a total amount.

The product incorporating the composition of the present invention optionally includes a flavoring agent in various embodiments. Flavoring agents useful herein include any material or mixture of materials operable to increase the taste of the composition. Any orally acceptable natural or synthetic flavorant can be used, such as flavoring oils, flavoring aldehydes, esters, alcohols, similar materials, and combinations thereof. Flavoring agents include vanillin, sage, oregano, parsley oil, spearmint oil, cinnamon oil, oil of wintergreen (methyl salicylate), peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, citrus oils, fruit oils and essences including those from lemon, orange, lime, grapefruit, apricot, banana, grape, apple, strawberry, cherry, pineapple, etc., spices from beans and nuts such as coffee, cocoa, cola, peanut, almond, etc., adsorbed and encapsulated spices, and mixtures thereof. Ingredients that provide aroma and/or other sensory effects in the mouth, including cooling or heating effects, are also included in the flavoring agents. Such ingredients include menthol, menthyl acetate, menthyl lactate, camphor, eucalyptus oil, eucalyptol, anethole, eugenol, cassia oil, raspberry ketone, a-ionone, propylene o-ethoxyphenol, thymol, linalool, benzaldehyde, cinnamaldehyde, N-ethyl-p-menthane-3-carboxamide, N, 2, 3 trimethyl-2-isopropylbutanamide, 3-1 menthoxy-1, 2-propanediol, Cinnamaldehyde Glycerol Acetal (CGA), aldehyde reagent glycerol acetal (MGA), and mixtures thereof. One or more flavoring agents may optionally be present in the compositions of the present invention.

In various embodiments, products comprising the compositions of the present invention comprise an active ingredient. In some embodiments, the optional active ingredient is a "systemic active ingredient" operable to treat or prevent a disorder that is not, in whole or in part, an oral disorder. In various embodiments, the active ingredient is an "oral care active ingredient" operable to treat or prevent disorders in the oral cavity or to provide cosmetic benefits (e.g., to the teeth, gums, or other hard or soft tissues of the oral cavity). Oral care actives useful in the dental compositions herein include anticaries agents, tartar control agents, periodontal actives, abrasives, breath freshening agents, odor control agents, tooth desensitizers, salivary stimulants, and combinations thereof. It will be appreciated that while the general characteristics of each of the above categories of active ingredients may differ, they share common characteristics and any given material may be suitable for multiple purposes in two or more of such categories of active ingredients.

Products comprising the composition of the invention may optionally comprise an antioxidant. Any orally acceptable antioxidant can be used, including Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), vitamin a, carotenoids, vitamin E, flavonoids, polyphenols, ascorbic acid, herbal antioxidants, chlorophyll, melatonin, and mixtures thereof.

Products comprising the compositions of the invention optionally include an orally acceptable source of zinc ions for use as, for example, an antibacterial, anticalculus or breath freshening agent. One or more such sources may be present. Suitable sources of zinc ions include, but are not limited to: zinc acetate, zinc citrate, zinc gluconate, zinc glycinate, zinc oxide, zinc sulfate, sodium zinc citrate, etc. The products of the present invention may optionally include suitable pH adjusting agents, including but not limited to sodium hydroxide, potassium hydroxide, and ammonium, for controlling the stability and shelf life of the dental product.

The dental products of the present invention optionally include an antiplaque (e.g., plaque-disrupting) agent. One or more such agents may be present in an antiplaque effective total amount. Suitable antiplaque agents include, but are not limited to: tin, copper, magnesium and strontium salts, dimethicone copolyols such as cetyl dimethicone copolyol, papain, glucoamylase, glucose oxidase, urea, calcium lactate, calcium glycerophosphate, strontium polyacrylates and chelating agents such as citric acid, tartaric acid and alkali metal salts thereof.

Dental products and pharmaceutical mixtures comprising the compositions of the present invention optionally include an anti-inflammatory agent. One or more such agents may be present in an anti-inflammatorily effective total amount. Suitable anti-inflammatory agents include, but are not limited to: steroidal agents such as fluocinolone and hydrocortisone, and non-steroidal agents (NSAIDs) such as ketorolac, flurbiprofen, ibuprofen, naproxen, indomethacin, diclofenac, etodolac, indomethacin, sulindac, tolmetin, ketoprofen, fenoprofen, piroxicam, nabumetone, aspirin, diflunisal, meclofenamic acid, mefenamic acid, oxyphenbutazone, and phenylbutazone.

The dental composition into which the composition of the present invention is incorporated optionally includes a desensitizing agent or a tooth sensitivity protecting agent. One or more such agents may be present. Suitable desensitizing agents include, but are not limited to: potassium salts such as potassium citrate, potassium tartrate, potassium chloride, potassium sulfate and potassium nitrate. Another suitable desensitizing agent is sodium nitrate. Alternatively or additionally, a topical or systemic analgesic such as aspirin, codeine, acetaminophen, sodium salicylate or triethanolamine salicylate may be used.

The product, such as a food material, into which the composition of the present invention is mixed optionally includes a nutrient. Suitable nutrients include vitamins, minerals, amino acids and mixtures thereof. Vitamins include vitamins C and D, thiamine, riboflavin, calcium pantothenate, niacin, folic acid, nicotine, pyridoxine, cyanocobalamin, p-aminobenzoic acid, bioflavonoids, and mixtures thereof. Nutritional supplements include amino acids (e.g., L-tryptophan, L-lysine, methionine, threonine, levocarnitine, and L-carnitine), lipotropics (e.g., choline, inositol, betaine, and linoleic acid), fish oil (including ingredients such as omega-3 (N-3) polyunsaturated fatty acids, eicosapentaenoic acid, and docosahexaenoic acid), coenzyme Q10, and mixtures thereof.

In another embodiment of the present invention, the product comprising the microcapsules may further comprise an antibacterial agent released on the surface of the bone tissue or teeth. A wide variety of antibacterial active compounds may be used. These actives can be generally classified as halogenated hydrocarbons, quaternary ammonium salts, and sulfur compounds. Halogenated hydrocarbons include halogenated derivatives of: salicylanilide, carbanilide, bisphenol, diphenyl ether, thiophenecarbonanilide, and chlorhexidine. Quaternary ammonium compounds include alkylamines, pyridinium salts, and isoquinolinium salts. Sulfur-active compounds include thiuram sulfides and dithiocarbamates.

Other suitable examples include, but are not limited to, copper (ii) compounds such as copper (ii) chloride, copper (ii) fluoride, copper (ii) sulfate, and copper (ii) hydroxide; zinc ion sources such as zinc acetate, zinc citrate, zinc gluconate, zinc glycinate, zinc oxide, zinc sulfate and sodium zinc citrate; phthalic acid and its salts such as monopotassium magnesium phthalate, hexetidine, octenidine, sanguinarine, benzalkonium chloride, domiphen bromide, alkylpyridines such as cetylpyridinium chloride (CPC) (CPC combination including zinc and/or enzymes), tetradecylpyridines and N-tetradecyl-4-ethylpyridinium chloride, iodine, sulfa drugs, biguanides such as alexidine, chlorhexidine and chlorhexidine gluconate, piperidine derivatives such as delmopinol and octapinol, magnolia extract, grape seed extract, menthol, geraniol, citral, eucalyptol, antibiotics such as augmentin, amoxicillin, tetracycline, doxycycline, minocycline, metronidazole, neomycin, kanamycin and clindamycin, and the like.

Other suitable antimicrobial agents include nonionic and anionic antimicrobial agents known to those skilled in the art. Examples of nonionic antibacterial agents include substantially water-insoluble, noncationic antibacterial agents such as alkylphenoxyphenol, cycloalkylphenoxyphenol, 9, 10-dihydrophenanthrenol, alkylphenols, cycloalkylphenols, phenolic compounds, halocarbonyls, halogenated salicylanilides, benzoin esters, halogenated diphenyl ethers, and mixtures thereof. Particularly suitable nonionic antibacterial agents are diphenyl ethers such as 2, 4, 4 '-trichloro-2' -hydroxylated diphenyl ether (Triclosan) and 2, 2 '-dihydroxy-5, 5' -dibromodiphenyl ether. One or more antibacterial agents are optionally present in an antibacterial effective total amount.

In various embodiments of the dental products of the present invention, the dental products include an adhesive or an adhesion enhancer that provides multiple functions, including enhancing the adhesion of the composition to the tooth surface to be remineralized or bleached. The adhesive is optimized for bonding to teeth, adhesion against non-dental oral surfaces such as lips, gums or other mucosal surfaces, and remains adhered to teeth for an extended period of time. Optimization of these aspects can be accomplished by varying the physical and chemical properties of a single binder or combining different binders. In some embodiments of the invention, the binder polymers in the product are those in which the dental particles can be dispersed and are well known in the art.

The compositions of the present invention may also be incorporated into confections, lozenges, chewing gums, tablets, capsules or other products. Mixing of the microcapsules in the product can be accomplished, for example, by stirring to a warm gum base or coating the outer surface of the gum base, which can be exemplified by gelatin, latex, synthetic resins and similar compounds desirably with conventional plasticizers or softeners, sugar, glucose, sorbitol or other sweeteners. It is also contemplated herein that the microcapsule compositions of the present invention may be mixed into a variety of foods.

It should be clearly understood that although the present description is directed specifically to use in humans, the invention may also be used for veterinary purposes. Thus, in all aspects, the methods and compositions of the present invention are used in livestock, such as cattle, sheep, horses and poultry; and pets such as cats and dogs; and other animals.

It will be appreciated by persons skilled in the art that the present invention is not limited to the specific embodiments specifically shown and described herein above. The more appropriate scope of the invention includes both combinations of features described and modifications and variations thereof which would occur to persons skilled in the art upon reading the foregoing description and which are not in the prior art.

Examples

The following examples illustrate the compositions and methods of synthesis of the present invention. These experiments demonstrate the feasibility of using interfacial polymerization of surfactant-free inverse emulsions to successfully encapsulate ionic solutions of salts to produce effective tissue-mineralizing compositions.

Example 1

Synthesizing data

Three microcapsule compositions of the invention were prepared: the first one contains Ca (NO)₃)₂An aqueous solution; the second one contains K₂HPO₄An aqueous solution; the third is an aqueous solution of NaF by interfacial polymerization in a saline solution of a stable inverse emulsion in a continuous phase of methyl benzoate. 6 g of polyglycerol-3-polyricinoleate (P3P) are used as emulsifier. The emulsifier and 4 grams of the polyurethane polymer were mixed together. After mixing, the aqueous salt solution (100mL of 1 molar dipotassium hydrogen phosphate) was added to 210mL of the continuous benzoate oil phase. 0.2 grams of ethylene glycol was then added to the inverse emulsion to complete the interfacial polymerization of the polyurethane polymer at the interface of the droplets of the aqueous solution of dispersed salt. The average size of the microcapsules is controlled by the rate of agitation. Using the process of the invention, the following salt solutions were thus prepared: (1) ca (NO)₃)₂[5 mols of]；(2)K₂HPO₄[5 mols of]And (3) NaF [0.1 mol ]]。

Example 2

The following preparation of the composition of the invention having remineralisation capability as a cavity paint. A common cavity paint (97 wt%) containing rosin, ethanol and thymol was received to obtain the following remineralizing agent (3 wt%) in combination with 1.5 wt% microcapsules containing 1M aqueous solution of dipotassium hydrogen phosphate and 1.5 wt% microcapsules containing 1M solution of calcium nitrate.

Example 3

Compositions having remineralizing potential as toothpastes are prepared comprising a gel cement, humectant, preservative, flavoring agent, abrasive and detergent. 2 wt% of microcapsules containing 2M aqueous solution of dipotassium hydrogenphosphate and 2 wt% of microcapsules containing 1M aqueous solution of calcium nitrate were mixed. In addition, microcapsules containing 0.25M NaF solution were mixed into toothpaste as therapeutic agents for fluorination. When applied to the oral cavity, the microcapsules will burst in the mouth by the movement and pressure of the toothbrush against the teeth. The calcium ions will be released from the calcium nitrate solution and cause mineralization and bleaching of the teeth.

Example 4

Compositions having remineralizing and therapeutic fluoridating capabilities as dental resin compositions are prepared as follows. A resin mixture (total of 16 wt%) was first prepared by combining the urethane dimethacrylate resin and triethylene glycol dimethacrylate (TEGDMA) in a proportion of 4/1. Photosensitizer (camphorquinone) was added in an amount of 0.7 wt% of the total composition. An accelerator (ethyl 4-dimethylaminobenzoate) was added at 3 wt% of the total composition. Inhibitor (4-methoxyphenol) was added in an amount of 0.05 wt% of the total composition. The resin, photosensitizer, accelerator and inhibitor were combined and mixed in a flask at 50 ℃. When homogenized, the resin mixture described above will be mixed with the following fillers (total 84 wt%): 71 wt% strontium silicide glass, 10 wt% fumed silica, 1.25 wt% microcapsules containing a 2.5M calcium nitrate solution, 1.25 wt% microcapsules containing a 1.0M dipotassium hydrogen phosphate solution, and 0.5 wt% microcapsules containing a 0.25M naf solution.

Claims (36)

1. A composition for topical use, wherein said composition comprises a microcapsule composition comprising at least one polymer substantially as a semipermeable shell surrounding and in direct contact with an aqueous solution of at least one salt comprising at least one salt ion, wherein said salt ion permeates through said shell, and said composition is suitable for delivery to a mammal, and wherein (i) said aqueous solution is selected from Ca (NO), and₃)₂solution, K₂HPO₄Solutions, NaF solutions, and mixtures thereof,(ii) the polymer is an amphiphilic polyurethane.

2. The composition of claim 1, wherein the polymer has a molecular weight of 1,000 g/mole to 50,000 g/mole.

3. The composition according to claim 1, wherein the diameter of the microcapsules is from 1 μm to 3 mm.

4. The composition of claim 1, wherein the salt ions prevent tooth demineralization or cause tooth remineralization of teeth in the oral cavity of the mammal.

5. The composition of claim 1, wherein the salt ions cause tooth bleaching in the oral cavity of the mammal.

6. The composition of claim 1, wherein the salt ions cause a reduction in tissue sensitivity in the oral cavity of the mammal.

7. The composition of claim 1, wherein the composition comprises a plurality of microcapsules having different and distinct salt ion release properties, thereby allowing for controlled release of salt ions.

8. A product for tissue mineralization comprising the composition of claim 1.

9. A bone mineralization product comprising the composition of claim 1 which causes an increase in bone mass in a mammal.

10. The bone mineralization product of claim 9 in the form of a bone cement or bioactive glass.

11. A dental product comprising the composition of claim 1, the dental product selected from the following forms: pastes, gels, foams, mouthwashes, dentifrices, tooth bleaching products, breath fresheners, artificial saliva systems, paints, desensitizers, dental restoratives, composites, adhesives, bioactive glasses, glass ionomers, dentures, denture bases, and sealants.

12. The dental product of claim 11, selected from the following forms: cements, composites, resins, pulp capping materials, and filler restorations.

13. The dental product of claim 11, selected from the following forms: root canal filling material, tooth transplantation tissue regeneration material and glass composite body.

14. The dental product of any one of claims 11-13, further comprising an additive selected from the group consisting of preservatives, antiplaque agents, antitartar agents, antibacterial agents, flavoring agents, sweeteners, and dyes.

15. A tissue mineralization product comprising a plurality of the compositions of claim 1, wherein the microcapsules comprise different aqueous salt solutions.

16. A product comprising as an active ingredient the composition of claim 1, said product being selected from the group consisting of tablets, capsules, candies, antitussives and gums.

17. A food material incorporating the composition of claim 1.

18. A pharmaceutical mixture comprising the composition of claim 1.

19. A dental product comprising microcapsules for reducing or preventing dental caries, said microcapsules comprising an amphiphilic polyurethane and comprising a material selected from Ca (NO)₃)₂、K₂HPO₄And NaF, and wherein said microcapsules are prepared by interfacial polymerization of a reverse phase emulsion, said amphiphilic polyurethane forming a shell around said aqueous solution.

20. A method of forming microcapsules suitable for delivery to a mammal for tissue mineralization, comprising combining at least an amphiphilic polyurethane and at least one Ca (NO) selected from the group consisting of₃)₂Solution, K₂HPO₄An aqueous salt solution of a solution, a NaF solution, and mixtures thereof, wherein the amphiphilic polyurethane forms a shell around the salt solution.

21. A method of forming microcapsules by surfactant-free inverse emulsion interfacial polymerization, said microcapsules suitable for delivery to a mammal for tissue mineralization, said method comprising contacting (a) a surfactant selected from Ca (NO)₃)₂Solution, K₂HPO₄An aqueous solution of a salt of a solution, a NaF solution, and mixtures thereof, (b) an oil phase, (c) an amphiphilic polyurethane, and (d) an emulsifier, wherein the amphiphilic polyurethane forms a shell around the aqueous solution of the salt.

22. The method of claim 20 or 21, wherein the shell is semi-permeable or impermeable.

23. The method of claim 20 or 21, wherein the tissue is bone or tooth.

24. The method of claim 20 or 21, wherein the mammal is a human.

25. The method of claim 21, further comprising adding a diol, an isocyanate, or both.

26. The method of claim 21, wherein the oil phase is methyl benzoate.

27. The method of claim 21, wherein the emulsifier is polyglycerol-3-polyricinoleate.

28. A method of forming semi-permeable polymeric microcapsules by surfactant-free inverse emulsion interfacial polymerization, the microcapsules adapted for delivery to a mammal for tissue mineralization, comprising contacting (a) an aqueous solution selected from Ca (NO) for forming a semi-permeable shell around the aqueous solution, (b) an oil phase, (c) an amphiphilic polyurethane, and (d) an emulsifier, wherein the amphiphilic polyurethane forms a semi-permeable shell around the aqueous solution₃)₂Solution, K₂HPO₄A solution, a NaF solution, and mixtures thereof, and wherein the tissue is bone or tooth.

29. Use of a composition according to claim 1 for the preparation of a medicament for subsequent remineralization of teeth.

30. Use according to claim 29, wherein the medicament is selected from the group consisting of a paste, a gel, a foam, a mouthwash, a dentifrice, an artificial saliva system, a paint or an adhesive.

31. Use of a microcapsule composition comprising microcapsules comprising an aqueous solution of a salt encapsulated by a semi-permeable amphiphilic polyurethane polymer shell, said aqueous solution being selected from Ca (NO) for the preparation of a medicament for increasing bone mass or preventing bone mass loss₃)₂Solution, solution,K₂HPO₄Solutions, NaF solutions, and mixtures thereof, which release salt ions that permeate out of the microcapsules through the semi-permeable shell.

32. Use of a microcapsule composition comprising microcapsules containing an aqueous solution of a salt selected from Ca (NO) encapsulated by a semi-permeable polymeric shell for the preparation of a medicament for remineralisation of teeth₃)₂Solution, K₂HPO₄Solutions, NaF solutions, and mixtures thereof, wherein the polymer is an amphiphilic polyurethane and wherein the aqueous solution of salt releases salt ions that permeate out of the microcapsules through the semi-permeable shell.

33. The use of claim 32, wherein the salt ions cause bleaching of teeth.

34. Use according to claim 32, characterized in that the medicament is selected from the group consisting of pastes, gels, foams, mouthwashes, dentifrices, bleaching products, breath fresheners, artificial saliva systems, paints, desensitizers, dental restoratives, composites, adhesives, bioactive glasses, glass ionomers, dentures, denture base materials and sealants.

35. The use according to claim 32, wherein the medicament is selected from the group consisting of cements, composites, resins, pulp capping materials and filler restorations.

36. The use according to claim 32, wherein said medicament is selected from root canal filling materials and dental implant tissue regeneration materials.