WO2025122687A1 - Polymeric ion releasing fillers - Google Patents

Abstract

A method of manufacture of a micron-sized polymeric ion releasing filler (micro PIRF) comprising: forming a divalent ion salt solution; admixing an effective amount of an emulsifying agent into the divalent ion salt solution, the emulsifying agent comprising a polysaccharide component; adding an alginate solution dropwise into the divalent ion salt solution and emulsifying agent wherein the divalent ion salt solution and emulsifying agent are under a shear rate; and collecting formed micro PIRFs from the divalent ion salt solution.

Description

POLYMERIC ION RELEASING FILLERS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of US Provisional Patent Application

No. 63/606,380 filed on December 5, 2023, with the United States Patent and Trademark Office, the contents of which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

[0002] The present invention is related to methods of manufacture and compositions related to crosslinked alginate ion releasing fillers.

BACKGROUND OF THE INVENTION

[0003] Alginate is a well-known and understood compound that can be utilized to form materials that may be generally considered to be capsules, which encapsulate a material therein. Alginate is typically sourced from alginic acid, or algin, and is a naturally occurring edible polysaccharide that is commonly found in brown algae. It is hydrophilic and forms a viscous gum when hydrated. The acid form normally forms salts, such as with sodium, potassium, or calcium, which is then known as an alginate. Typically, these are sodium alginate (NaCekhOe) or potassium alginate (KCeHvOe), which are soluble in water. The use of alginate, as well as pectin, which may be combined, and are frequently filled with fruit juices, purees, or flavor adding agents. These are then added into beverages for human consumption.

[0004] These flavor filled capsules are often a few millimeters in size and sometimes even larger. Some of the smaller capsules are found in products such as chewing gum, or in other products, where they are intended to burst or slowly release the material contained therein. Typically, these release sweet or minty flavors in edible products. [0005] Additional types of micro and macro capsules are well-known in the art. These are often formed of nonbiodegradable materials and allow for their insertion into materials for modifying chemistry, or in some cases, to modify structural integrity. Some of these nonbiodegradable, or partially degradable materials may also release therapeutic materials, whether in burst or slow-release format.

[0006] Furthermore, the prior art teaches the manufacture of liposomes and other structures for delivery of agents to the body. However, these have certain limitations which limit their use in dental materials.

[0007] The prior art is silent as to teaching of the unique properties of high concentration therapeutic salts into crosslinked alginate structure, which provides a unique opportunity for capturing divalent ions in high concentrations. Primary divalent ions, such as calcium²⁺ and zinc²⁺ as nonlimiting examples. Applicant details methods of manufacture of micron-sized polymeric ion releasing fillers (PIRFs), the micron-sized PIRFs themselves, as well as compositions comprising the same. In preferred embodiments, the methods and compositions are directed toward alginate-based micro PIRFs made by dropping alginate into high molarity solutions of divalent salts that may or may not contain a buffer.

SUMMARY OF THE INVENTION

[0008] The embodiments herein detail the formation of micron-sized polymeric ion releasing fillers (micro PIRFs) comprising therein divalent ions.

[0009] In a preferred embodiment, a method of manufacture of a micro PIRF : (a) forming a high molarity solution of a divalent ion salt solution; (b) admixing an effective amount of an emulsifying agent, said emulsifying agent comprising a polysaccharide or a glycopeptide, or both into the salt solution; (c) adding a solution of alginate dropwise into the salt solution and emulsifying agent wherein the salt solution and emulsifying agent are under a shear rate wherein the alginate is preferably one sodium alginate (NaCeHvOe) or potassium alginate (KCeHvOe) and (d) collecting formed micro PIRFs from the salt solution.

[0010] In a further embodiment, the method wherein the high molarity solution is a divalent ion salt solution having a molarity greater than about 2.5M, 3.0M, 3.5M, 4.0M, 4.5M, and preferably about 5.0M. In preferred embodiments, the salt solution is a 5M calcium chloride solution. In a further embodiment, the method wherein the salt solution is a 3M zinc chloride solution. In a further preferred embodiment, the method wherein the divalent salt solution is a calcium² solution. In a further preferred embodiment, the method wherein the divalent salt solution is a zinc² solution. In a further preferred embodiment, the method wherein the calcium²⁴ solution or zinc²⁴ solution is formed from calcium chloride or zinc chloride.

[0011] In a further embodiment, the method wherein the emulsifying agent is selected from the group consisting of: gum arabic, locust bean gum, xanthan gum, guar gum, and combinations thereof.

[0012] In a further embodiment, the method wherein the shear rate is at least 1,884 s

[0013] In a further embodiment, the method wherein the components are in a ratio of between 1 mL and 1 L of 5M CaCh:between 125 mL and 240 mL of an alginate solutiombetween 0.5 g and 12.5 g of the emulsifying agent.

[0014] In a further embodiment, the method wherein the pH of the final supernatant is between 4.0 and 6.5. [0015] In a further embodiment, the method wherein the alginate formed from either a potassium alginate, or most preferably a sodium alginate.

[0016] In a preferred embodiment, a micro PIRF made by any preceding method.

[0017] In a further embodiment, the micro PIRF wherein the PIRF has a crosslinked alginate structure, comprising therein divalent ions.

[0018] In a further embodiment, the micro PIRF comprises a concentration of divalent ions, preferably wherein the concentration of divalent ions is a value defined by the dilution of the original divalent ion solution. Thus, when a 5M solution is diluted by the addition of alginate, the 5M solution will be reduced by the total volume of the alginate addition.

[0019] In a preferred embodiment, a micro PIRF made by the method wherein the ion within the PIRF is a calcium ion present at at least 3.0M.

[0020] In a further embodiment, the micro PIRF made by a process comprising the method wherein the components are in a ratio of between 1 mL and 1 L of 3M ZnC12:between 125 mL and 240 mL of an alginate solutiombetween 0.5 g and 12.5 g of an emulsifying agent.

[0021] In a further embodiment, the micro PIRF is isolated for subsequent use in a composition.

[0022] In a preferred embodiment, the micro PIRFs are isolated by centrifugation.

[0023] In a preferred embodiment, a dental composite comprising a micro PIRF made by the method of any one of the preceding embodiments. [0024] In a preferred embodiment, a dental brushing gel comprising a micro PIRF made by the method of any one of the preceding embodiments.

[0025] In a preferred embodiment, a dental prophy paste comprising a micro PIRF made by the method of any one of the preceding embodiments. In a further embodiment, the micro PIRF when provided in a dental material, including but not limited to a: dental composite, an orthodontic sealer, a base layer, a dental material used for sealing, filling, lining, luting, cementing, or/and as a lining material used within a tray or a dental appliance.

[0026] In a preferred embodiment, use of a micro PIRF by the method of any one of the preceding embodiments to treat or improve a disease of the mouth by loading a PIRF with a therapeutic divalent ion, and wherein the therapeutic divalent ion permeates from the PIRF in an aqueous environment.

[0027] In a preferred embodiment, a method of forming micron-sized polymeric ion releasing fillers (micro PIRF), the method comprising: (a) forming a high molarity divalent salt solution; (b) admixing an emulsifying agent into the high molarity divalent salt solution wherein the emulsifying agent comprises a polysaccharide component, a glycopeptide, or both; (c) adding an alginate solution dropwise into the high molarity divalent salt solution and the emulsifying agent under a shear rate; and (d) collecting formed micro PIRF from the high molarity divalent salt solution.

[0028] In a preferred embodiment, a method of treating or improving a disease of the mouth, the method comprising: (a) loading a therapeutic ion into a micro PIRF of any preceding claim; and (b) applying the micro PIRF to the mouth wherein the therapeutic ion permeates from the micro PIRF in an aqueous environment to treat or improve the disease of the mouth. [0029] In a preferred embodiment, a method of manufacturing a micro PIRF, the method comprising: (a) forming an aqueous divalent ion salt solution; (b) admixing an emulsifying agent comprising polysaccharide into the aqueous divalent ion salt solution; (c) adding an aqueous alginate solution dropwise into the aqueous divalent ion salt solution containing the emulsifying agent under shear to form the micro PIRF; and (d) collecting the micro PIRF from the divalent ion aqueous salt solution.

[0030] In a preferred embodiment, a method of delivering a biologically active divalent ion for therapeutic action, the method comprising: (a) loading a biologically active divalent ion into a micro PIRF; (b) incorporating the micro PIRF into a dental composition; and (c) allowing the biologically active divalent ion to be released from the micro PIRF in an aqueous environment.

[0031] In a preferred embodiment, a method for producing micro PIRF comprising therapeutic divalent ions, the method comprising: (a) preparing a high molarity salt solution comprising a divalent cation; (b) adding a emulsifying agent having a polysaccharide component to the high molarity salt solution; (c) adding an alginate solution dropwise into the high molarity salt solution under a sufficient shear rate; (d) allowing the alginate solution to crosslink with the high molarity salt solution to form micro PIRFs; and (e) wherein the micro PIRFs comprise a semipermeable component allowing the divalent cationic ions to diffuse from the semipermeable component in an aqueous environment.

[0032] In a preferred embodiment, a micron-sized polymeric ion releasing filler (micro PIRF) produced by any preceding method method wherein the micro PIRF wherein the semipermeable component allows bidirectional movement of ions from the micro PIRF. [0033] In a preferred embodiment, a method of manufacturing micron-sized polymeric ion releasing filler (micro PIRFs), the method comprising: (a) adding an alginate solution dropwise into a salt solution containing a gum arabic emulsifier; (b) applying a high shear mixing rate of at least 1,884 s ¹ to the salt solution; and (c) wherein the high shear mixing selectively forms the micro PIRF.

[0034] In a preferred embodiment, a method of manufacturing micron-sized polymeric ion releasing fillers, the method comprising: (a) forming a divalent ion salt solution having a molarity of greater than about 3M; (b) admixing an effective amount of an emulsifying agent comprising a polysaccharide component into the divalent ion salt solution; (c) adding an alginate solution dropwise into the divalent ion salt solution containing the emulsifying agent wherein the divalent ion salt solution and emulsifying agent are under a shear rate of at least 1,884 s '; and (d) collecting formed micro PIRFs from the divalent ion salt solution wherein the formed micro PIRFs comprise a crosslinked component comprising alginate and the divalent ion.

[0035] In a preferred embodiment, a method of manufacture of a micron-sized polymeric ion releasing filler (micro PIRF), the method comprising: (a) forming a divalent salt solution of greater than 3M and an effective amount of an emulsifying agent comprising a polysaccharide component; (b) adding an alginate solution dropwise into the divalent salt solution and emulsifying agent wherein the divalent salt solution and emulsifying agent are under a shear rate; and (c) collecting formed micro PIRFs from the divalent salt solution.

[0036] In a further embodiment, the method wherein the divalent salt solution is a calcium²⁺ solution. In a further embodiment, the method wherein the divalent salt solution is a zinc²⁺ solution. In a further embodiment, the method wherein the calcium²⁺ solution or zinc²¹ solution is formed from calcium chloride or zinc chloride.

[0037] In a further embodiment, the method wherein the emulsifying agent is selected from the group consisting of: gum arabic, locust bean gum, xanthan gum, guar gum, and combinations thereof.

[0038] In a further embodiment, the method wherein the shear rate is at least 1,884 s f

[0039] In a further embodiment, the method wherein the components are in a ratio of between 1 mb and 1 L of 5M CaCh:between 125 mL and 240 mL of the alginate solutiombetween 0.5 g and 12.5 g of the emulsifying agent.

[0040] In a further embodiment, the method wherein the pH of the final supernatant is between 4 and 6.4.

[0041] In a further embodiment, the method wherein the alginate solution is formed from a potassium alginate or a sodium alginate.

[0042] In a further embodiment, the method wherein the alginate solution is a

1 w/v% alginate solution.

[0043] In a preferred embodiment, a micron-sized polymeric ion releasing filler (micro PIRF) made by the method.

[0044] In a further embodiment, the micro PIRF wherein the micro PIRF has a crosslinked alginate component comprising alginate and a divalent ion, the crosslinked alginate component comprising a portion of the divalent ion. In a further embodiment, the micro PIRF wherein the divalent ion is in a concentration of greater than about 3M.

[0045] In a preferred embodiment, a micron-sized polymeric ion releasing filler (micro PIRF) made by any preceding method wherein a calcium ion is present within the micro PIRF at least at about 3M.

[0046] In a further embodiment, the micro PIRF made by a process comprising the method wherein the components are in a ratio of between 1 mL and 1 L of 5M of CaCh or ZnCb:between 125 mL and 240 mL of an alginate solution: between 0.5 g and 12.5 g of an emulsifying agent.

[0047] In a further embodiment, the micro PIRF wherein the micro PIRF is isolated for subsequent use in a composition by centrifugation of the micro PIRF.

[0048] In a preferred embodiment, a dental composite comprising the micro PIRF.

[0049] In a preferred embodiment, a dental brushing gel comprising the micro PIRF.

[0050] In a preferred embodiment, a dental prophy paste comprising the micro PIRF.

[0051] In a preferred embodiment, a dental brushing paste comprising the micro PIRF.

[0052] In a preferred embodiment, use of a micron-sized polymeric ion releasing filler (micro PIRF) to treat or improve a disease of the mouth by loading a micro PIRF made by the method with a therapeutic divalent ion wherein the therapeutic divalent ion permeates from the micro PIRF in an aqueous environment. [0053] In a preferred embodiment, a method of forming micron-sized polymeric ion releasing fillers (micro PIRFs), the method comprising: (a) forming a high molarity divalent salt solution; (b) admixing an emulsifying agent into the high molarity divalent salt solution wherein the emulsifying agent comprises a polysaccharide component, a glycopeptide, or both; (c) adding an alginate solution dropwise into the high molarity divalent salt solution and the emulsifying agent under a shear rate; and (d) collecting formed micro PIRFs from the high molarity divalent salt solution.

[0054] In a preferred embodiment, a method of treating or improving a disease of the mouth, the method comprising: (a) loading a therapeutic ion into a micron-sized polymeric ion releasing filler (micro PIRF); and (b) applying the micro PIRF to the mouth wherein the therapeutic ion permeates from the micro PIRF in an aqueous environment to treat or improve the disease of the mouth.

[0055] In a preferred embodiment, a method of manufacturing a micron-sized polymeric ion releasing filler (micro PIRF), the method comprising: (a) forming an aqueous divalent ion salt solution; (b) admixing an emulsifying agent comprising polysaccharide into the aqueous divalent ion salt solution; (c) adding an aqueous alginate solution dropwise into the aqueous divalent ion salt solution containing the emulsifying agent under shear to form the micro PIRF; and (d) collecting the micro PIRF from the divalent ion aqueous salt solution.

[0056] In a preferred embodiment, a method of delivering a biologically active divalent ion for therapeutic action, the method comprising: (a) loading a biologically active divalent ion into a micron-sized polymeric ion releasing filler (micro PIRF); (b) incorporating the micro PIRF into a dental composition; and (c) allowing the biologically active divalent ion to be released from the micro PIRF in an aqueous environment.

[0057] In a preferred embodiment, a method for producing micron-sized polymeric ion releasing fillers (micro PIRFs) comprising therapeutic divalent ions, the method comprising: (a) preparing a high molarity salt solution comprising a divalent cation; (b) adding an emulsifying agent having a polysaccharide component to the high molarity salt solution;

(c) adding an alginate solution dropwise into the high molarity salt solution under a sufficient shear rate; (d) allowing the alginate solution to crosslink with the high molarity salt solution to form micro PIRFs; and (e) wherein the micro PIRFs comprise a semipermeable component allowing the divalent cation to diffuse from the semipermeable component in an aqueous environment.

[0058] In a preferred embodiment, a micron-sized polymeric ion releasing filler (micro PIRF) produced by the method wherein the semipermeable component allows bidirectional movement of ions from the micro PIRF.

[0059] In a preferred embodiment, a method of manufacturing micron-sized polymeric ion releasing fillers (micro PIRFs), the method comprising: (a) adding an alginate solution dropwise into a salt solution containing a gum arabic emulsifier; (b) applying a high shear mixing rate of at least 1,884 s ' to the salt solution; and (c) wherein the high shear mixing selectively forms the micro PIRF.

[0060] In a preferred embodiment, a method of manufacturing micron-sized polymeric ion releasing fillers (micro PIRFs), the method comprising: (a) forming a divalent ion salt solution having a molarity of greater than about 3M; (b) admixing an effective amount of an emulsifying agent comprising a polysaccharide component into the divalent ion salt solution; (c) adding an alginate solution dropwise into the divalent ion salt solution containing the emulsifying agent wherein the divalent ion salt solution and emulsifying agent are under a shear rate of at least 1,884 and (d) collecting formed micro PIRFs from the divalent ion salt solution wherein the formed micro PIRFs comprise a crosslinked component comprising alginate and divalent ions.

BRIEF DESCRIPTION OF THE FIGURES

[0061] FIG. 1 depicts the release profile of a 5 wt.% micro PIRF in a topical gel.

[0062] FIG. 2 depicts the release profile of a 15 wt.% micro PIRF in a topical gel.

[0063] FIG. 3 depicts the release profile of a 5 w/w% micro PIRF in a composite.

[0064] FIG. 4 depicts two images of micro PIRF of the present disclosure at different magnification within a dental composite.

DETAILED DESCRIPTION OF THE INVENTION

[0065] As used herein, the term “about” means plus or minus 5% of the numerical value of the number with which it is being used. Therefore, about 50% means in the range of 47.5%-52.5%, about 20 mg means the range including 19 mg and 21 mg, and the like.

[0066] In certain of the products made using the micro PIRFs, such micro PIRFs are incorporated into a product, such as a dental gel, paste, prophy paste, or a composite. The additional components used in such products include those which are “pharmaceutically acceptable,” meaning they are the components including, but not limited to the carrier, diluent, adjuvant, or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0067] As used here, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term in relation to “pharmaceutical composition” is intended to encompass a product comprising the active ingredient(s) and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation, or aggregation of any two or more of the ingredients or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing the micro PIRFs, which comprising a divalent ion and wherein the ion permeates from the crosslinked alginate structure for release into the environment. Thus, the composition may be any of a dental material or other material intended to allow for the release of the ions from the filler materials, such as a gel, paste, prophy paste, composites, or similar materials.

[0068] Synthesis of alginate-based materials is well established, immaterial of whether the alginate is a sodium alginate (NaCeHvOe) or potassium alginate (KCTHvOe) salt. The use of calcium salts to produce gel-based materials is also well-known in the food industry in the production of boba. Boba are typically created with very low concentrations of a salt ion, to crosslink into alginate, forming the well-known balls, which comprise various flavors. These gel-based boba materials are often several millimeters in diameter, if not larger, and are intended to be ruptured easily when consumed. The low concentration of salt is necessary, as a higher salt concentration would make the material wholly unpalatable.

[0069] However, the ability of making micro PIRFs from alginate that are capable of releasing therapeutically relevant concentrations of calcium ions for prolonged periods of time that are subsequently stable and capable to withstand the stresses from isolation from synthesis that are able to be mixed into composites without rupture in a scalable manufacturing process is unique. Applicant discloses embodiments for a method for manufacturing micro PIRFs and compositions and products that contain these aforementioned PIRFs.

[0070] A hallmark of the embodiments is the creation of a new micro PIRFs that allows for specific release of high concentrations of divalent therapeutic ions for use within the medical industry. One particular ion of interest is a calcium ion (Ca²⁺), which has specific therapeutic possibilities in the dental industry. Additional divalent ions are readily understood by those of ordinary skill in the art, such as zinc (Zn²⁺) and magnesium (Mg²⁺) as nonlimiting examples. In the embodiments herein, we specifically report the use of about 5M calcium salt solutions in the micro PIRFs. By dripping an alginate solution into a concentration of calcium salt, micro PIRFs are formed. The alginate, when it hits the surface of the calcium salt is crosslinked with the calcium, and rapidly forms micro PIRFs. The divalent ions combined with the alginate to crosslink the alginate material to form the insoluble micro PIRFs. In practice, the formation of the micro PIRFs is nearly instantaneous as the alginate is dripped into the divalent ion salt solution. While lower or higher molarity salt solutions are possible, the higher molarity salts are desired for their ability to release the divalent ions from the micro PIRFs. [0071] As used herein, the terms “agent,” “active agent,” “therapeutic agent,” or

“therapeutic” mean a compound or composition utilized to treat, combat, ameliorate, prevent, or improve an unwanted condition or disease of a patient. Furthermore, the terms “agent,” “active agent,” “therapeutic agent,” or “therapeutic” encompass a divalent ion that can be released from the micro PIRF as described in the present disclosure.

[0072] Classically, very dilute solutions of calcium are used to accomplish the formation of millimeter-sized boba. However, the compositions herein would be intolerable in the food industry as the taste would be overwhelmingly too salty. However, the use of 5M divalent salt enables a significant improvement in dentistry. The significant excess of calcium or zinc or other divalent ions become entrapped in the micro PIRF. Therefore, the divalent ion is not only the crosslinking agent but becomes a source of bioavailable ions for use in remineralization contained therein. Additionally, filler used in dental material requires a significantly higher strength than “boba” as used in food. The combination of materials, including the 5M salt solution, the emulsifying agent having a polysaccharide component, and the alginate solution, when combined under a minimum shear rate creates high yields of micro PIRFs that are significantly stronger than those for food due to the high crosslink density generated by the unique combination, while being selective for a desired size.

[0073] In addition to the high salt concentrations, a second change to the classic boba recipe is the use of an emulsifying agent that comprises a polysaccharide component. In the food industry, no emulsifying agents are needed to produce boba due to their large sizes, and there is no reason to make a stable colloid of boba. In our experiments, without the emulsifying agent, alginate added dropwise into a high molarity divalent salt solution will form milli PIRF, such as those having an average diameter of 1 mm, 2 mm, or 3 mm or larger. This is because the entire drop of alginate is utilized to form the large, milli PIRFs. Even upon the addition of certain common emulsifying agents, no improvement was made to the selectivity of PIRF size.

[0074] However, for therapeutic fillers in dentistry, the production of micro PIRFs is necessary. The simple answer is that a filler in the dental space must meet certain size limitations. The larger sized classical boba would be as large or larger than a dental filling itself, and thus would simply be incompatible with use therein.

[0075] Applicant began by experimenting with known materials in an effort to manufacture stable micro PIRFs. Table 1 reports the initial synthetic conditions, including reactant solution volumes, emulsifying agent, and shear rate for the desired production of micro PIRFs (polymeric ion releasing fillers). Micro PIRFs are defined as those having an average particle size of between 0.5 micron and 10 microns with an ordinary dispersion of particles above and below this number. By comparison, the milli PIRFs created in some experiments had an average size of more than 1 mm. The synthesis is characterized by yield and particle size.

[0076] In all tests, the volume of the alginate is a sodium salt alginate at

1 g/100 mL (1 w/v%). A lower w/v% is acceptable but will decrease yield. A higher w/v% can also be utilized, such as 2 w/v%, 5 w/v%, and 10 w/v%, and such solutions may be plausibly higher, to modify possible yield. The 1 w/v% was utilized for ease of dissolving the material into water for the testing solutions. Accordingly, the concentration of the 125 mL and 240 mL examples merely changes the total amount of the alginate added to the solution. All experiments were performed at room temperature (defined herein as about 20°C), unless otherwise specified. [0077] Applicant first tried to create micro PIRFs without the use of an emulsifying agent. Adding a 1 w/v% alginate solution dropwise into a 5M CaCh solution created no stable micro PIRFs as detailed in Table 1, Experiments 1-3. Indeed, even modifying the amount of alginate solution had no impact on the formation of stable micro PIRF of any size as detailed in Experiments 1 and 2. Furthermore, modifying the shear rate of the salt solution did not appreciably change the result, when comparing Experiments 1 and 3. This did not mean that zero PIRFs were formed, but merely contemplates that the process was unable to create stable micro PIRFs that could be isolated and utilized in a further dental product.

[0078] TABLE 1:

[0079] Stable PIRF yield refers to micro PIRFs being isolated by centrifugation and subsequently being able to withstand the forces of shear mixing into a dental composition. Some unstable synthesis products may have initially formed a PIRF but either formed a macroscopic gel upon filtering or a macroscopic gel in a centrifuge tube during isolation or, ruptured on mixing into a dental formulation after isolation.

[0080] Because no stable micro PIRFs were formed and able to be separated, further modification of the reaction conditions to form any stable micro PIRFs at the desired micron size was necessary. Applicant tried several emulsifying agents, with the requirement that the emulsifying agent allowed the formation of substantially all micro PIRFs, and wherein the micro PIRFs could be separated after formation, such as isolated by centrifugation or filtration maintaining the micro PIRFs as discrete particles, the latter being necessary to capture and place the micro PIRFs into downstream products and would maintain their continuity in such processing.

[0081] Applicant already confirmed that the absence of an emulsifying agent present in the mixture yielded no stable micro PIRFs. However, the selection of the emulsifying agent proved to be critical. IMWITOR was tested in Experiments 4 and 5 and lecithin was tested in Experiments 6 and 7 as both are suitable for human consumption. However, as detailed in Table 1, these failed to yield stable micro PIRFs in any appreciable numbers. Indeed, in some of the experiments, larger sized milli PIRFs were formed, while in others, a combination of micro and milli PIRFs were formed. Finally, even when micro or milli PIRFs were formed, upon trying to separate the formed PIRFs, such as in Experiments 4-7, the PIRFs failed upon separating. In some cases, the PIRFs essentially coagulated into a gel-like mass, and thus could not be individually separated. In other cases, the PIRFs ruptured upon basic handling, thus showing that the PIRFs were not of sufficient strength for the desired purposes. Other emulsifying agents could not prevent the gelation of the discrete particles formed during synthesis from forming a paste like gelatinous structure upon filtration or centrifugation or storage. Accordingly, these emulsifying agents were unable to create sufficient numbers of PIRFs for use.

[0082] A different class of emulsifying agent was then utilized to try to control and solve the problem with stable formation of the micro PIRFs. Unexpectedly, by using gum arabic (CAS No. 9000-01-5), an emulsifying agent that is primarily polysaccharides with a mixture of glycoproteins, as the emulsifying agent, the stability problem was solved. The inclusion of gum arabic provided the necessary stability for isolation, storage, and subsequent mixing of the micro PIRFs into the desired dental product examples. The selective inclusion of this class of emulsifying agents was unexpectedly superior to the other well-known emulsifying agents that precluded stable formation of the micro PIRFs desired for the particular applications.

[0083] Table 2 details different tests using two different volumes of alginate, with three different concentrations of gum arabic as the emulsifying agent in Experiments 8-11. Gum arabic was tested first at a concentration of 6.25 g and then tested with 125 mL of alginate and then 240 mL of alginate in Experiments 8 and 9. Then, the amount of the emulsifying agent was reduced to 3.12 g of gum arabic in Experiment 10, and finally, the amount of the emulsifying agent was increased to 12.5 g of gum arabic in Experiment 11. The results show that stable micro PIRFs were formed, at between 2.4 pm and 3.2 pm (differences in size were not statistically significant). However, yield was significantly impacted, with yield for the 3.12 g and the 6.25 g being nearly double that of the 12.5 g gum arabic emulsifying agent. [0084] TABLE 2:

[0085] Interestingly, the results show that a minimal amount of the emulsifying agent is needed in order to create the stable micro PIRFs. However, control of the emulsifying agent is also necessary to maximize yield. For example, once the emulsifying agent was added beyond a certain limit, additional emulsifying agent significantly decreased yield. This is evidenced in the differences between Experiments 9 and 10, juxtaposed with Experiment 11, which has a significantly reduced yield in comparison to Experiments 9 and 10.

[0086] When a lower amount of gum arabic was utilized in Experiment 10, the highest yield was obtained. By comparison, using 6.25 g of gum arabic and varying the amount of alginate in Experiments 8 and 9 provided a yield of 34.7 g in Experiment 8 (which used a lower amount of the alginate) and a yield of 92.7 g in Experiment 9.

[0087] Thus, varying the concentration of the gum arabic emulsifying agent, Applicant is able to sustain the micro PIRF formation, at the 1,884 s ¹ shear rate. However, modifications of the emulsifying agent did vary the yield slightly. The amount of the gum arabic needed is likely below the 3.12 g:240 m alginate (sodium):375 L of 5M CaCh ratio, but we know that amounts at above 12.5 g in said ratio will also decrease the yield of micro PIRFs. Therefore, Applicant requires greater than zero of the emulsifying agent, but no more than the above ratio with

12.5 g of the emulsifying agent to maintain the highest yield for gum arabic. Preferably, the emulsifying agent is present at above 0.25g. However, as noted herein, different emulsifying agents may have different optimal concentration, which can be modified based on the concentration of the other components of the system, when seeking to maximize yield.

[0088] In varying the amount of alginate, one would expect there to be a linear yield gradient. The results show that the ramp and yield is slightly lower for the 125 mb of alginate compared to the use of 240 mL of alginate. Additional testing may reveal that a small sample size yielded such differences, or that yield may be optimized by varying some of the components to create a theoretical maximum yield. [0089] Finally, after a stable operating parameter was confirmed, Applicant verified that a similar divalent ion solution would function within the same general parameters. In Experiment 15, zinc chloride was used in place of calcium chloride from all prior experiments. Notably, the divalent ion of the salt is a critical component to successfully crosslink with the alginate to form the stable insoluble micro PIRFs.

[0090] Experiments 16, 17, and 18 from Table 2 further detail the addition of emulsifying agents that have a polysaccharide component. Each of the locust bean gum (galactomannan polysaccharide, CAS No. 9000-42-2, EC No. 232-541-5), xanthan gum (CAS No. 11138-66-2), and guar gum (CAS No. 9000-30-0) contain a saccharide or polysaccharide component.

However, each of these components, as compared to gum arabic has some appreciable impact on the viscosity of the ion solution at room temperature. Therefore, based upon the particular agent, it may be impossible to add larger amounts, or quantities as high as gum arabica, for example, because of the increase in viscosity of the resulting ion solution. Notably, at least xanthan gum solutions have shear thinning, meaning when under higher shear rates the viscosity decreases. Thus, the high shear rates of the present disclosure aid in the use of such a material.

[0091] Some of Experiments 16-18 also obtained slightly smaller average particle size. It may be possible to further select for particle size by inclusion of one or more additional emulsifying agents. Therefore, it is further contemplated that a combination of two or more emulsifying agents, at least one of which is a may be used to increase or decrease size selectivity of the formed micro PIRFs.

[0092] Once the micro PIRFs were formed, the issue of forming only micro PIRFs was addressed. The challenge of rupturing the alginate solution prior to the seemingly instantaneous crosslinking reaction of the alginate into milli PIRFs was challenging. However, the control of the size distribution of formed particles is achieved by the use of the combination of the emulsifying agent within the salt solution, and addition of the alginate into said salt and emulsifying agent solution at a shear rate of 1,884 s ' . Below this shear rate (Experiments 12-14 in Table 2), a bimodal distribution of PIRF sizes formed. One population was millimeter in size (milli PIRFs), the other population was micronic in size (micro PIRFs). However, Applicant desires a maximum yield of micro PIRFs, preferably having a mean size of between 0.5 pm and 10 pm (largest cross-sectional length, e.g., a diameter if a perfect sphere), inclusive of all ranges in between, with an ordinary distribution of particles from that mean size. Most preferably, the micro PIRFs are about 0.5 pm-5 pm in size, with an ordinary distribution above and below that optimal size.

[0093] Most notably, the lower shear rate, keeping all other variables stable, decreases the quantity of micro PIRFs, while increasing the quantity of milli PIRFs. Only at the lowest end does this also begin to decrease the total yield rate as well, as seen in Experiment 12. Thus, use of a higher shear rate, such as in Experiment 9, both creates the relative highest yield and selectively generates a higher yield, with virtually 100% of the yield being micro PIRFs, than the same reaction performed with lower shear forces. As Applicant desires the formation of micro PIRFs, higher shear rates greater than 1,400 s ' are desired. While the 1,884 s ' shear rate is used as an example, Applicant does not require such a limited number and recognizes that values slightly below 1,884 s ' but also above 1,884 s ' will create the desired product and optimize the yield. However, it is preferable that the shear rate is at least about 1,884 s ¹ to optimize the formation of the micro PIRFs. It is postulated that in the experiments using a calcium salt, the calcium replaces the sodium in the alginate in a fraction of a second. Therefore, if there is a low shear rate, or even no shear rate, the entire or most of a single drop of alginate solution will be incorporated into the PIRF. Therefore, in order to create the desired micro PIRF, a single drop of alginate will need to virtually explode, faster than the calcium can replace the sodium, to create the tiny droplets that will crosslink with the calcium to form the desired micro PIRF.

[0094] In summary, when all other variables are stable, addition of fluid movement, within the salt solution, when adding, dropwise, the alginate solution dramatically modifies the selectivity of particle size formation. When no stirring occurred, the majority of the PIRFs that formed were larger structures, typically on the size of 1-2 mm or larger in diameter (depending on the volume of alginate). These milli PIRFs are too large to be utilized in many dental and medical applications, specifically, when the PIRFs are being utilized for composite materials, larger-sized PIRFs would make the composites fail.

[0095] One option for modifying the shear rate within the reaction chamber and thus modifying the energy within the salt solution is to use a high energy immersion mixer. This provides for mixing of the salt solution prior to and/or during the dropwise addition of alginate solution. By increasing the energy in such a manner, the alginate drop virtually explodes at the surface of the salt solution from the shear forces it encounters, forming a plurality of micro PIRFs instead of one individual milli PIRF from a single droplet of alginate solution.

[0096] Taking a single milli PIRF as a nonlimiting example, the drop size of alginate solution, which expressed from an 18-gauge needle, dropwise into the salt solution is on the order of 1-3 mm. Instead, when the same volume of alginate solution is dropped into the 5M calcium chloride solution with gum arabic as the emulsifying agent and, when sufficient shear rate is present, the drop explodes into thousands to millions of micro PIRFs yielding the desired product. Each of the micro PIRFs then incorporates some of the calcium ion into the micro PIRF and forms an alginate structure that is crosslinked with the calcium. The reaction is virtually instantaneous as it hits the surface. It is hypothesized that by imparting energy into the calcium solution, the single droplet of alginate is exploded into a plurality of alginate droplets, allowing for the rapid formation of the micro PIRFs. When there is insufficient or no energy input to the salt solution in the reaction vessel, there is not enough energy to shear and rupture the initial droplet thereby resulting in milli PIRFs which are unsuitable for use in the dental space.

[0097] Accordingly, selective preparation of micro PIRFs can be obtained by the processes as detailed in the embodiments herein. Notably, the calcium salt may be exchanged for other salts, as a nonlimiting example, in Table 2, Experiment 15 identifies the use of zinc chloride, which is also a divalent ion, such as Zn²⁺. Furthermore, other suitable anions may be used, with the limiting factor related to the suitability of the materials for human consumption, and a desire for higher yields, thus necessitating a high molarity, suggested to be at least 2.5, if not at least 3.0 molar.

[0098] Several examples of manufacture are described herein that yield the micro PIRFs, whether with a calcium ion, or a zinc ion and using one of several different emulsifying agents. The following example uses gum arabic as the emulsifying agent, calcium chloride, to create a Ca²⁺ ion, and sodium alginate. As detailed herein, additional materials may be exchanged for either the emulsifying agent, the ion, or the alginate material, and remain with the scope of the embodiments. A preferred example thus is between about 0.5 g to 12.5 g of gum arabic, which is provided in a solution of a divalent ion, such as 375 mL of a 5M calcium chloride, and which an alginate solution of about 0.25-10 g/100 mL of sodium alginate is added in a dropwise manner, typically at between 0.1 x of the volume of the salt solution to 10* of the volume of the salt solution. Those of skill in the art will recognize that modifying from lab scale to commercial scale often times results in optimization of these ratios.

[0099] Thus, in the embodiments detailed herein, a micro PIRF is formed that is crosslinked with the salt ion it is dripped into. The use of the 5M calcium²⁺ with a premixed emulsifying agent having a polysaccharide component generated a filler that withstood the high stresses of high shear mixing to form the desired micro PIRF. These micro PIRFs could be collected and then utilized as a filler, to disperse the micro PIRFs in a variety of dental formulations (e g., prophy pastes, composites).

[0100] Gum arabic is a high molecular weight polysaccharide, that often contains certain glycoproteins and is used for deriving ribose and arabinose sugars. In some cases, gum arabic is defined as a branched chain, multifunctional hydrocolloid with a complex of magnesium, calcium and potassium salts, and arabinogalactan proteins. There are additional structures which utilize a similar high-molecular-weight polysaccharide and which can suitably function as the emulsifying agent instead of the gum arabic. In some embodiments, it may be suitable to add into the reaction a suitable protein structure, as is found in gum arabic, or to add in another suitable ion, such as a nitrogen, which may take part in the crosslinking of the alginate, which in some embodiments, may increase the integrity of the alginate structure. In some embodiments, therefore, an emulsifying agent comprises a glycoprotein or a glycopeptide. [0101] Preferably, the pH of the supernatant when manufacturing is between about a pH of 4-6.5 and more preferably between about 4.5 and 6.

[0102] Furthermore, the viscosity of the emulsifying agent and ion solution is frequently modified by the selection of the emulsifying agent. Certain emulsifying agents also act as a thickener, yielding a more viscous solution than others, when both are compared at room temperature. Gum arabic, as one example, does not alter viscosity as much as xanthan gum or guar gum. Thus, to maintain the viscosity of the emulsifying agent and ion solution within a suitable range to make the micro PIRFs, smaller amounts of the xanthan gum or guar gum, as nonlimiting examples, can be added, as compared to the gum arabic.

[0103] Upon manufacture of the micro PIRFs, the micro PIRFs were added as a 5 wt.% or 15 wt.% filler in a topical gel, and the rate of release of the Ca²⁺ ion was measured as a function of time, in order to determine the rate of release of the ions. FIGS. 1 and 2 show topical gels formulated with calcium containing micro PIRFs were placed in dialysis tubing soaked in water. The release of calcium ions from the gels was measured as a function of time, with the 5 wt.% in FIG. 1 and the 15 wt.% in FIG. 2. In each case, the rate of release from the topical gel is quite rapid, with virtually all of the material permeating from the micro PIRF in less than 1,800 minutes. This may be due to the aqueous environment surrounding the micro PIRF to release some of the ions through the semipermeable structure.

[0104] A further use of the material is to include it within dental composite materials. Dental composites are materials that are utilized to fill and seal a cavity within a tooth, typically after removal of the diseased tissue. Many of these are photopolymerized in the mouth in order to accelerate the cure rate. However, the composite may be improved by allowing for the permeation of selective ions out of the composite to aid in treatment of the tooth, such as to aid in remineralization. Here, an example with and without the micro PIRF added at 5 w/w% was tested for flexural strength. This test is important because we do not want the strength of the composite to be materially altered by the presence of the micro PIRFs. The inclusion of the novel fillers did not diminish the mechanical properties of the composite, as is depicted below in Table 3:

[0105] TABLE 3:

[0106] FIG. 3 shows the release profile of a composite formulated with calcium containing micro PIRFs soaked in water. Calcium ion release was measured as a function of time. Thus, when the material is utilized in a composite, the release of the calcium ions from the micro PIRFs remains and shows a nearly linear release of the ions over the course of about 90 days. This allows for a slow release of the calcium ions within the composite and allows for the calcium ions to be utilized for remineralization. To the extent that a different ion is utilized, the release rate would be analogous to the release rate of the calcium as defined above.

[0107] FIG. 4 shows scanning electron micrographs of the micro PIRF formulated into a dental composite. The fillers are intact and withstood the forces from isolation by centrifugation and dispersion during high shear mixing. Thus, the addition of the ions and the emulsifying agent significantly impacts the strength of the micro PIRFs, thus enabling their manufacture at the desired sizes. [0108] Several examples of manufacture of the micro PIRFs are detailed below, as well as examples of products using the same.

EXAMPLES

[0109] In performing the various experiments, a solution of 5M calcium chloride was created for Experiments 1-14 as detailed in Tables 1 and 2, and a further solution of zinc chloride was used for a further Experiment 15. The amount of calcium or zinc chloride was measured out and added to water to dissolve. A second solution of sodium alginate was created by dissolving approximately 1 g of sodium alginate into 100 mL of water to create a 1 w/v% solution.

Additional amounts were created to provide the necessary volume for testing. The sodium alginate may be lightly warmed to encourage dissolution and allowed to cool to room temperature (about 20°C) before proceeding.

[0110] Testing in the experiments revealed that specific elements were required. These were: (1) a high molarity divalent salt solution, (2) a specific class of emulsifying agent, and (3) a sufficient shear rate. Each of these differed significantly from the classic boba formation protocols.

[0U1] It was only after the inclusion of a polysaccharide backboned emulsifying agent, gum arabic, that an unexpected control and yield were obtained. Indeed, the selection of an emulsifying agent having a polysaccharide component was necessary at a minimal concentration. However, the addition of excess amounts of the emulsifying agent did not further increase yield, and instead actually decreased yield with additional concentrations of the emulsifying agent.

Therefore, the reaction is optimized for yield in a specific range, requiring a concentration of a divalent ion, for example, the Ca²⁺ from calcium chloride, that is provided at 5M within a given volume, e.g., 375 mL in the test experiments. Added into this high molarity divalent salt solution is at least a minimal amount of the polysaccharide emulsifying agent, for example, gum arabic. Preferably this is added at a concentration of at least 0.5 g to the 375 mL of 5M CaCh, with an optimized amount including 3.12 g and 6.25 g for such volume. A sodium alginate at a concentration of about 1 g/mL is added dropwise into the salt solution from a needle dropper or other suitable dropping component, and the salt solution is imparted with energy forming a shear rate sufficient to selectively form the micro PIRFs.

[0112] As provided in the examples above, further emulsifying agents that contain a polysaccharide component, such as locust bean gun, xanthan gum, and guar gum may replace, or be used in combination with the gum arabic. Fine tuning of the quantities of each component to maximize yields can be achieved by the skilled artisan, notably as some of the materials increase viscosity of the resulting salt solution.

[0113] In preferred embodiments, the volume of alginate solution added into the salt solution is in a ratio of 1 : 100 to about 10: 1. That is, by addition of the entirety of the alginate solution, the concentration of the salt solution is reduced, that is, a 5M solution would be diluted based on the total volume of the alginate solution.

[0114] In a preferred embodiment, the mixture is a salt solution of between 3M and 8M, and preferably between 4M and 7M, with an addition of about 0.5 g to 12.5 g of an emulsifying agent per 375 mL of an exemplar 5M calcium chloride solution. This recognizes that some ions cannot reach higher molarity in water. Finally, added dropwise to this mixture is the quantity of the alginate, which is provided at about 1 g/100 mL of water, with the dropwise addition occurring in the presence of a shear rate of 1,884 s ¹ within the reaction chamber. The reaction is preferably performed at room temperature, e.g., about 20°C.

[0115] Preferably, the reaction is performed at a slightly acidic pH, such that the final supernatant has a pH of between about 3.5 and 6.5, and preferably between about 4.5 and about 6, which can be modified by the addition of an acid, such as HC1. However, a combination of an acid and a base may be utilized to create a buffer solution which can still be buffered to this acidic pH range. Indeed, in Tables 1 and 2, the resulting supernatant pH is shown in each of the reactions. Control of the pH can be modified by the addition of acids or bases as is known to those of ordinary skill in the art, and wherein buffers can be formulated by addition of conjugate acids and bases in suitable concentrations. The particular control of and resulting pH may be useful for control of strength, yield, and/or particle sizes.

[0116] It is possible, after making the micro PIRFs to add additional concentration of the desired ion into the reaction chamber wherein the addition of the higher concentration solution will diffuse through the formed structure of the micro PIRF and increase the ionic concentration within the micro PIRF. Such actions allow the formation of the micro PIRF, and subsequent further loading of the desired ions into the structure.

RELEASE OF THE IONS FROM THE MICRO PIRFS

[0117] The resulting structure formed from the process is semipermeable. Thus, in an aqueous environment, the ions will permeate out of the micro PIRF into the less concentrated environment, or ions will permeate into the micro PIRF when the exterior solution is higher than the concentration inside the micro PIRF. [0118] Applicant has described embodiments of making unique micro PIRFs. Such micro PIRFs are highly desirable for use in the dental industry, where the release of ions with an aqueous medium can increase the relative abundance of selected ions for therapeutic purposes. Applicant has detailed the unexpected process that utilizes an emulsifying agent comprising a polysaccharide component, such as gum arabic, to selectively form stable micro PIRFs comprising high concentrations of divalent ions. Specific embodiments detail the specific ratio of components and the requirement for a minim threshold of the emulsifying agent and a shear rate in selective control and formation of the micro PIRFs.

[0119] The embodiment now being described, those of ordinary skill in the art will recognize that modifications may be made to the various processes to make the micro PIRFs of the present disclosure, and to optimize yield and ease of manufacture at scale, without diverging from the scope of the embodiments detailed herein.

Claims

What is claimed is:

1. A method of manufacture of a micron-sized polymeric ion releasing filler (micro PIRF), the method comprising: a. forming a divalent salt solution of greater than 3M and an effective amount of an emulsifying agent comprising a polysaccharide component; b. adding an alginate solution dropwise into the divalent salt solution and emulsifying agent wherein the divalent salt solution and emulsifying agent are under a shear rate; and c. collecting formed micro PIRFs from the divalent salt solution.

2. The method of claim 1 wherein the divalent salt solution is a calcium²⁴ solution.

3. The method of claim 1 wherein the divalent salt solution is a zinc²⁴ solution.

4. The method of claim 2 or 3 wherein the calcium² solution or zinc²⁴ solution is formed from calcium chloride or zinc chloride.

5. The method of claim 1 wherein the emulsifying agent is selected from the group consisting of: gum arabic, locust bean gum, xanthan gum, guar gum, and combinations thereof.

6. The method of claim 1 wherein the shear rate is at least 1,884 s ' .

7. The method of claim 1 wherein the components are in a ratio of between 1 mL and

1 L of 5M CaCh:between 125 mL and 240 mL of the alginate solution: between 0.5 g and 12.5 g of the emulsifying agent.

8. The method of claim 1 wherein the pH of the final supernatant is between 4 and 6.4.

9. The method of claim 1 wherein the alginate solution is formed from a potassium alginate or a sodium alginate.

10. The method of claim 1 wherein the alginate solution is a 1 w/v% alginate solution.

11. A micron-sized polymeric ion releasing filler (micro PIRF) made by the method of any one of claims 1 to 10.

12. The micro PIRF of claim 11 wherein the micro PIRF has a crosslinked alginate component comprising alginate and a divalent ion, the crosslinked alginate component comprising a portion of the divalent ion.

13. The micro PIRF of claim 12 wherein the divalent ion is in a concentration of greater than about 3M.

14. A micron-sized polymeric ion releasing filler (micro PIRF) made by any preceding claim wherein a calcium ion is present within the micro PIRF at least at about 3M.

15. The micro PIRF of claim 14 made by a process comprising the method of claim 1 wherein the components are in a ratio of between 1 mL and 1 L of 5M of CaCk or ZnCh:between 125 mL and 240 mL of an alginate solution: between 0.5 g and

16. The micro PIRF of any one of claims 11 to 15 wherein the micro PIRF is isolated for subsequent use in a composition by centrifugation of the micro PIRF.

17. A dental composite comprising the micro PIRF of any one of claims 11 to 16.

18. A dental brushing gel comprising the micro PIRF of any one of claims 11 to 16.

19. A dental prophy paste comprising the micro PIRF of any one of claims 11 to 16.

20. A dental brushing paste comprising the micro PIRF of any one of claims 11 to 16.

21. Use of a micron-sized polymeric ion releasing filler (micro PIRF) to treat or improve a disease of the mouth by loading a micro PIRF made by the method of any one of claims 1 to 10 with a therapeutic divalent ion wherein the therapeutic divalent ion permeates from the micro PIRF in an aqueous environment.

22. A method of forming micron-sized polymeric ion releasing fillers (micro PIRFs), the method comprising: a. forming a high molarity divalent salt solution; b. admixing an emulsifying agent into the high molarity divalent salt solution wherein the emulsifying agent comprises a polysaccharide component, a glycopeptide, or both; c. adding an alginate solution dropwise into the high molarity divalent salt solution and the emulsifying agent under a shear rate; and d. collecting formed micro PIRFs from the high molarity divalent salt solution.

23. A method of treating or improving a disease of the mouth, the method comprising: a. loading a therapeutic ion into a micron-sized polymeric ion releasing fdler (micro PIRF) of any preceding claim; and b. applying the micro PIRF to the mouth wherein the therapeutic ion permeates from the micro PIRF in an aqueous environment to treat or improve the disease of the mouth.

24. A method of manufacturing a micron-sized polymeric ion releasing filler (micro PIRF), the method comprising: a. forming an aqueous divalent ion salt solution; b. admixing an emulsifying agent comprising polysaccharide into the aqueous divalent ion salt solution; c. adding an aqueous alginate solution dropwise into the aqueous divalent ion salt solution containing the emulsifying agent under shear to form the micro PIRF; and d. collecting the micro PIRF from the divalent ion aqueous salt solution.

25. A method of delivering a biologically active divalent ion for therapeutic action, the method comprising: a. loading a biologically active divalent ion into a micron-sized polymeric ion releasing filler (micro PIRF); b. incorporating the micro PIRF into a dental composition; and c. allowing the biologically active divalent ion to be released from the micro PIRF in an aqueous environment.

26. A method for producing micron-sized polymeric ion releasing fillers (micro PIRFs) comprising therapeutic divalent ions, the method comprising: a. preparing a high molarity salt solution comprising a divalent cation; b. adding an emulsifying agent having a polysaccharide component to the high molarity salt solution; c. adding an alginate solution dropwise into the high molarity salt solution under a sufficient shear rate; d. allowing the alginate solution to crosslink with the high molarity salt solution to form micro PIRFs; and e. wherein the micro PIRFs comprise a semipermeable component allowing the divalent cation to diffuse from the semipermeable component in an aqueous environment.

27. A micron-sized polymeric ion releasing filler (micro PIRF) produced by the method of claim 26 wherein the semipermeable component allows bidirectional movement of ions from the micro PIRF.

28. A method of manufacturing micron-sized polymeric ion releasing fillers (micro PIRFs), the method comprising: a. adding an alginate solution dropwise into a salt solution containing a gum arabic emulsifier; b. applying a high shear mixing rate of at least 1,884 s ' to the salt solution; and c. wherein the high shear mixing selectively forms the micro PIRF.

29. A method of manufacturing micron-sized polymeric ion releasing fillers (micro PIRFs), the method comprising: a. forming a divalent ion salt solution having a molarity of greater than about 3M; b. admixing an effective amount of an emulsifying agent comprising a polysaccharide component into the divalent ion salt solution; c. adding an alginate solution dropwise into the divalent ion salt solution containing the emulsifying agent wherein the divalent ion salt solution and emulsifying agent are under a shear rate of at least 1,884 s '; and d. collecting formed micro PIRFs from the divalent ion salt solution wherein the formed micro PIRFs comprise a crosslinked component comprising alginate and divalent ions.