FIELD OF DISCLOSURE

[0001] The present disclosure relates to improved taurolidine compositions having improved purity profiles, including pharmaceutical compositions, methods of making and using the same, taurolidine polymorphs, and the synthesis of such taurolidine polymorphs.

BACKGROUND

[0002] Hemodialysis access systems for access to a patient's vascular system for exchange of blood between the vascular system and an external processing apparatus are well known in the art. The simplest such system is a catheter alone placed directly in the patient's right jugular vein with the distal end extending into the central venous system, typically into the superior vena cava. Other more complicated systems, for example ports, usually involve indwelling catheters as well. The exchange of blood for hemodialysis treatment typically involves high blood flow rates under conditions designed not to induce shear stress beyond a certain level so as to not cause red cell damage or the activation of platelets.

[0003] As with any implanted device, placement of an obiect that must remain in the patient over a protracted period of time gives rise to the likelihood of blood stream infection promoted by the indwelling device. Infection risk is seriously aggravated by the fact that such devices are frequently handled and manipulated by medical workers, leading to microbial colonization of the catheter's internal surfaces, that is, formation of a biofilrn in the lumen. Infection from a bi oft Im reservoir is much more serious than a simple infection since it is often impossible to eradicate with conventional means. In refractory’ cases the device must be explanted to treat the patient effectively. As a result, the literature, both scientific and patent, is replete with hopeful but not definitive suggestions as to how to defeat, or at least hold at bay, catheter related infections.

[0004] Antibiotics have been used to treat devices such as catheters to prevent infection, but chronic use of antibiotics as a prophylactic accelerates emergence of antibiotic-resistant bacterial strains. .Advances in catheter locks described in the scientific literature and other patent documents have involved the use of a substance generally referred to as taurolidine and/or taurinamide and taurinamide derivatives for routine antimicrobial use, in particular in catheters, taurolidine and related compounds are biocidal but are known not to induce development of resistant bacterial strains. For example, Sodemann, U.S. Pat. No. 6, 166,007, issued Dec. 26, 2000 and Sodemann, U.S. Pat. No. 6,423,706, issued Jul. 23, 2002, among others, disclosed use of taurolidine and other taurinamide-related compounds as part of a catheter lock solution.

[0005] Coagulation of the blood inside catheters in or connected to the vascular system has also proven troublesome and many methods have been tried for its prevention, particularly for inhibiting the dogging of the catheter, which can diminish or destroy the catheters usefulness. It is standard procedure to flush blood from the catheters and then lock them with a heavy-duty anticoagulant, heparin locking solution being the standard. Unfortunately, heparin alone lacks biocidal capability, but this deficiency is often ignored.

[0006] A formulation of taurolidine with citrate and citric acid described in U.S. Pat. Nos. 6,166,007 and 6,423,706, the contents of which are hereby incorporated by reference in their entirety, has worked well in minimizing catheter-caused infections in hemodialysis patients.

[0007] However, catheter lock solutions including taurolidine prepared using conventional techniques may include potential impurities remnant from the synthesis of such taurolidine. What is needed is an improved synthesis of taurolidine presenting an improved purity profde and useful compositions including the same.

SUMMARY

[0008] The present disclosure provides a method of synthesizing taurolidine. The method may comprise the following steps:

[0009] The present disclosure provides a composition or formulation comprising taurolidine, wherein the taurolidine may be substantially free of impurities. The composition or formulation may comprise Low-Molecular- Weight Heparin (LMWH). Tn another embodiment, the composition or formulation may comprise unfractionated heparin (UFH). In another embodiment, the composition or formulation may exclude heparin. A method for reducing an amount of impurities in taurolidine is provided. The method may comprise synthesizing the taurolidine according to the above synthesis.

[00010] The taurolidine may be substantially free of impurities. The taurolidine may be a polymorph, for example, Polymorph A as demonstrated by an X-ray powder diffraction (XRPD) in Figure 2 and/or Polymorph B as demonstrated by an XRPD in Figure 3. The polymorphs A or B may also be crystalized and/or otherwise isolated. Compositions, including pharmaceutical compositions, can then be made, including one or both of Polymorphs A or B.

BRIEF DESCRIPTION OF DRAWINGS

[00011] This application/patent contains at least one drawing executed in color. [00012] The foregoing summary and the following detailed description are better understood when read in conjunction with the appended drawings. Example embodiments are shown in the drawings; however, it is understood that the embodiments are not limited to the specific structures depicted herein. In the drawings:

[00013] Figure 1 is a chart showing the role of temperature in various polymorph forms of a taurolidine compound, according to an example embodiment of the present disclosure.

[00014] Figure 2 is an X-Ray Powder Diffraction (XRPD) output of a taurolidine Polymorph

A, according to an example embodiment of the present disclosure.

[00015] Figure 3 is an X-Ray Powder Diffraction (XRPD) output of a taurolidine Polymorph

B, according to an example embodiment of the present disclosure.

[00016] Figures 4 A and 4B are X-Ray Powder Diffraction (XRPD) outputs comparing taurolidine Polymorphs A and B, according to an example embodiment of the present disclosure. [00017] Figure 5 is a graph showing the effect of Perlman’s catalyst on the yield and speed of reaction, according to an example embodiment of the present disclosure.

DETAILED DESCRIPTION

[00018] The terminology used in the present disclosure is for the purpose of describing particular example embodiments only and is not intended to be limiting. As used in the description of the embodiments of the disclosure and the appended claims, the singular forms “a,” “an,” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[00019] The term “and/or,” as used herein, refers to and encompasses any and all possible combinations of one or more of the associated listed items. [00020] The term “about,” as used herein when referring to a measurable value such as an amount of a component, time, temperature, and the like, is meant to encompass variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount. Unless otherwise defined, all terms, including technical and scientific terms used in the description, have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

Improved Synthesis of Taurolidine

[00021] Taurolidine can be synthesized according to the following (the “Conventional

Synthesis”):

[00022] Step A of the Conventional Synthesis includes catalytic hydrogenation (Step A) of Cbz- taurinamide using palladium on carbon and succinic acid. Step B comprises condensation of the taurinamide-acid material to form taurolidine using toluene and dimethyl sulfoxi de (DMSO), both classified as Class 2 solvents. The use of a Class 2 solvent, such as toluene in the Conventional Synthesis, can result in high or undesirable levels of impurities. The Conventional Synthesis can also result in a high or undesirable level of taurultam and/or taurinamide.

[00023] In an embodiment, the disclosure provides a synthesis of, or method of manufacturing, taurolidine. The synthesis of, or method of manufacturing, taurolidine includes the following steps: Improved Purity Profile

[00024] The synthesis of this disclosure includes catalytic hydrogenation (Step A) of Cbz- taurinamide using Pearlman’s catalyst (i.e., Pd(OH)2) and Hydrochloric acid. Step B includes condensation of the taurinamide-acid material to form taurolidine using acetone (a Class 3 solvent) and water. The effect or improvement of using Pearlman’s catalyst and Hydrochloric acid in Step A instead of Palladium on carbon and succinic acid in the Conventional Synthesis may be demonstrated via efficiency or rate of removal of the N-carboxybenzyl (Cbz) group to form a taurinamide-acid intermediate. The synthesis of this disclosure provides a cleaner reaction using a Class 3 solvent, e.g., acetone, in the purification process.

[00025] A traditional catalytic hydrogenation approach used is Pd/C, H2 (high pressure). The present disclosure provides the discovery that Perlman’s catalyst accelerates the speed of the reaction and increases the yield of the reaction. (See Figure 5). In the synthesis of the present disclosure, HC1 is used because the starting material for Taurolidine is the hydrochloric acid salt of Taurinamide. Traditional synthesis of Taurolidine uses Pd/C when very stable protection groups are inserted to a molecular structure to further synthesis and prevent unwanted side reactions at the protected site. Hydrogenation reactions involving Pd/C to remove the protection group may proceed at slower rates than those using Pearlman’s catalyst and with lower yields. Also, side reactions may produce by-products and impurities. In the case of the carboxybenzyl carbamate (Cbz-N) protecting group, hydrogenolysis could result in the formation of benzyl alcohol and toluene as by-products in addition to Taurinamide succinate. Hydrogenolysis with Pd/C may be strongly affected by the nature of the solvent, with this ascending order of efficiency: Toluene < Methanol < Ethanol < Tetrahydrofuran. The synthesis of the present disclosure can use Hydrochloric acid, which is stronger than succinic acid used in the Conventional Synthesis, facilitating debenzylation process via protonation of the oxygen atom of the O-benzyl ether protection group.

Residual Organic Solvents: USP (c467) and ICH R8) Classification

[00026] Residual organic solvents can be Class 1, Class 2 or Class 3, as set forth below:

[00027] Class 1 (USP c467) solvents should not be employed in the manufacture of drug substances, excipients, and drug products because of the unacceptable toxicities or deleterious environmental effects of these residual solvents. According to the ICH Q3C guidelines, Class 1 solvents may comprise known human carcinogens, strongly suspected human carcinogens, and environmental hazards.

[00028] Class 2 (USP c467) Class 2 solvents should be limited in drug substances, excipients, and drug products because of the inherent toxicities of the residual solvents. According to the ICH Q3C guidelines, Class 2 solvents may be suspected of other significant toxicities.

[00029] Class 3 (USP c4367) May be regarded as less toxic and of lower risk to human health. According to the ICH Q3C guidelines, Class 3 solvents may comprise solvents with low toxic potential to man; no health-based exposure limit is needed. Class 3 solvents may have PDEs of 50 mg or more per day.

[00030] Table 1 below compares various residual solvents used in, or carried over from a precursor in, the Conventional Synthesis and the Present Synthesis based on class.

Table 1: | | Methanol | Yes | No |

[000311 I ⁿ an embodiment, the taurolidine synthesized according to the Present Synthesis can be free of, substantially free of, or can have low levels of impurities. The taurolidine synthesized according to the Present Synthesis can have a better purity profile and/or have lower levels of related impurities (e.g., Taurine and Taurultam) than the taurolidine synthesized according to the Conventional Synthesis. In an embodiment, taurolidine synthesized according to the Present Synthesis can have a better purity profile than taurolidine synthesized according to the Conventional Synthesis. Taurolidine synthesized according to the Conventional Synthesis may have higher levels of Taurultam and may contain taurinamide while taurolidine synthesized according to the Present Synthesis may not contain taurinamide Taurolidine synthesized according to the Conventional Synthesis may use Class 2 solvents in the active pharmaceutical ingredient (API) formulation step and may exhibit additional carry-over residual solvents, while taurolidine synthesized according to the Present Synthesis may use a Class 3 solvent (e.g., acetone), which has a lower toxicity and poses a lower risk to human health than the Class 2 solvents (e.g., toluene and hexane).

[00032] Table 2 below sets forth a comparison of certain impurities and residual solvents of a taurolidine API synthesized according to Conventional Synthesis and a taurolidine API synthesized according to Present Synthesis.

Table 2:

[00033] Although USP classifies Dimethyl sulfoxide (DMSO) as a Class 3 solvent, it is possible that DMSO could have an organotropic action of the solvent directing the carcinogenic effect of nitrosamines. If patients are receiving certain class of medications for hypertension, nitrosamines may be of concern to the FDA and DMSO may enhance the carcinogenic effect.

[00034] The present disclosure also provides an advantageous analytical method applied for detecting impurities in the Taurolidine according to the present disclosure. A traditional analytical technique for testing APIs is HPLC coupled with UV/Visible detector, which has limitation detecting impurities whenever their chemical structures do not have chromophores (i.e., UV/Vis light absorbing chemical structural moiety). The confirmation of reduced, limited, or zero impurities for the Present Synthesis can be performed through HPLC-CAD (Charged Aerosol Detection) which is independent of chromophores because it is based the detection of particles charged with an ion-jet and detects impurities at the nanogram level.

Polymorphs

[00035] In an embodiment, one or more polymorphs of taurolidine synthesized according to the Present Synthesis is provided, for example, Polymorph A and/or Polymorph B. Differential Scanning Calorimetry (DSC) and XRPD were used to characterize two polymorphic crystalline structures of taurolidine synthesized according to the Present Synthesis. In view of the present synthesis of taurolidine detailed above, the polymorphs, when purified, crystallized or otherwise isolated for later use, are free of, substantially free of, or have low levels of at least Class 2 impurities such as hexane and toluene. In an embodiment, one or more polymorphs of taurolidine synthesized according to the Present Synthesis is provided, for example, Polymorph A and/or Polymorph B, which are free of Class 2 impurities such as hexane and toluene.

[00036] Figure 1 is a chart showing the role of temperature in various polymorph forms of a taurolidine compound, according to an example embodiment of the present disclosure. Control of the temperature of the reaction mixture during the addition of reagents may be important for controlling the polymorphic content (see Figure 1). In an embodiment, control of the temperature of the reaction mixture during the addition of reagents is important for controlling the polymorphic content. In an embodiment, a lower temperature of the reaction mixture can produce Polymorph B. In an embodiment, a higher temperature of the reaction mixture can produce Polymorph A.

[00037] Figure 2 is an X-Ray Powder Diffraction (XRPD) output of a taurolidine Polymorph A, according to an example embodiment of the present disclosure. Lower temperature (e.g., -1.5°C to -0.5°C) may favor the kinetic Polymorph B (see Figure 2, an XRPD for pure Polymorph B). [00038] Figure 3 is an X-Ray Powder Diffraction (XRPD) output of a taurolidine Polymorph B, according to an example embodiment of the present disclosure. Higher temperatures (e.g., 0°C - 5°C) may favor the thermodynamic Polymorph A (see Figure 3, an XRPD for pure Polymorph A).

[00039] Figures 4 A and 4B are X-Ray Powder Diffraction (XRPD) outputs comparing taurolidine Polymorphs A and B synthesized according to the Present Synthesis, according to an example embodiment of the present disclosure. A study (Alcami Report SS19-032-RHL-190128) confirmed taurolidine Polymorph B (see Figure 4).

[00040] It is understood that the X-Ray Powder Diffraction (XRPD) output/plots shown in Figures 2, 3, 4A and 4B characterize Polymorphs A and/or B (as applicable). It is further understood that, based on the XRPD outputs/plots shown in Figures 2, 3, 4A and 4B, one or more peaks can characterize Polymorphs A and/or B (as applicable). For example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks or substantially all of the peaks shown in Figures 2, 3, 4A and 4B can characterize Polymorphs A and/or B (as applicable). The present disclosure incorporates by reference each peak of the XRPD outputs/plots shown in Figures 2, 3, 4A and 4B. Each peak of the XRPD outputs/plots shown in Figures 2, 3, 4A and 4B is understood to characterize Polymorphs A and/or B (as applicable), precisely or ± 5%.

[00041] Taurolidine Polymorphs A and B synthesized according to the Present Synthesis may both be soluble in 26.1 mg/mL aqueous citric acid, at T=25°C.

Formulations

U.S. Patent No. 7,696,182 titled “Antimicrobial Locking Solutions Comprising taurinamide

Derivatives and Biologically Acceptable Salts and Acids, with the Addition of Small Concentrations of Heparin” is incorporated herein by reference in the entirety, except to the extent that the incorporated material is inconsistent with the express disclosure herein, in which case the language in this disclosure controls.

[00042] The following disclosure may relate to taurolidine synthesized according to the Present Disclosure. The taurolidine may be free of impurities, substantially free of impurities or may have low levels of impurities. The taurolidine may be in the form of Polymorph A and/or Polymorph B as disclosed herein. In an embodiment, taurolidine based antimicrobial and anti -coagulant lock solutions may be made with the polymorphs described herein, which reduce catheter patency complications brought on by taurolidine reacting with red cells and the characteristics of the clot formed in the distal portion of a catheter.

[00043] The concentration of taurolidine in such solutions is preferably in the range of from about 0.4 to about 5% by weight, depending upon the solubility of the compound. The addition of citrates and citric acid in combination, or alternatively the addition of citric acid and adjustment of the pH with sodium hydroxide, such that the pH of the end solution is in the vicinity of 5.2 to 6.5, substantially increases the biocidal effectiveness of taurolidine solution. The approach creates a buffer system of citric acid/sodium citrate by adjustment of pH using sodium hydroxide.

[00044] Thus, the use of citric acid and sodium citrate in this combination thus increases the stability and solubility of taurolidine in solution and prevents or severely slows down the precipitation out of solid taurolidine and reaction products frequently seen in taurolidine solution prepared with polyvinylpyrrolidone (PVP). Long term stability tests have verified this result. The composition employed in the practice of the present invention preferably also contains a pharmacologically acceptable carrier solution, such as, water for injection.

[00045] Other biologically acceptable acids and biologically acceptable salts thereof are possible for combination with taurolidine. Other possible such acids are acetic acid, dihydroacetic acid, benzoic acid, citric acid, sorbic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, hydrochloric acid, malic acid, phosphoric acid, sulfurous acid, vanillic acid, tartaric acid, ascorbic acid, boric acid, lactic acid, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis-{P- aminoethyl ether} -N,N,N',N'-tetraacetic acid, and di ethylenetriamine pentaacetic acid, esters of p- hydroxybenzoic acid (Parabens), and the like, and biologically acceptable salts of the foregoing, such as, ammonium phosphate, potassium citrate, potassium metaphosphate, sodium acetate, sodium citrate, sodium lactate, sodium phosphate, and the like. A blood anticoagulating amount of an acid selected from the group consisting of citric acid, phosphoric acid, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis-{P-aminoethyl ether} -N,N,N',N'- tetraacetic acid, and diethylenetriamine pentaacetic acid and biologically acceptable salts thereof is preferred. It is preferred that the acid employed in the practice of the present invention be an organic acid, especially one having at least one carboxyl group, particularly citric acid or EDTA. It is more preferred that the acid be citric acid and most preferred that it be used in combination with a citrate salt, e g., sodium citrate, since, in addition to its pH lowering and anti coagulation capabilities, it is also known to be an antiseptic at the 3% level.

[00046] Since calcium is one factor that is known to have a role in the coagulation of blood, it is believed possible that at least part of EDTA's efficacy in anticoagulant activity may be brought about by this means. Sodium citrate is also believed to have anti coagulation properties by virtue of its ability to generate insoluble calcium citrate.

[00047] In an embodiment, the present disclosure provides a formulation that includes taurolidine synthesized according to the Present Disclosure. The taurolidine may be free of impurities, substantially free of impurities or may have low levels of impurities. The taurolidine may be in the form of Polymorph A and/or Polymorph B as disclosed herein. Table 3 below sets forth a formulation, according to an embodiment of the present disclosure. NaOH may be used at early stage raise pH to between 5.9-6.1. Final pH range of the citrate buffered system may be 5.5 - 6.5.

[00048] Table 3:

Low Molecular Weight Heparin (LMWH)

[00049] In an example embodiment, the formulation can further comprise low molecular weight heparin (LMWH). The following may be advantages of using LMWH in such formulation: the formulation may require only once or twice daily dosing, may not require monitoring activated partial thromboplastin time (aPTT), lower risk of bleeding Heparin-induced thrombocytopenia (low platelet counts may cause bleeding), lower risk of osteoporosis, and/or anticoagulant effect of UH can be reverted with protamine sulfate, but its effect on LMWH may be limited.

Unfractionated Heparin (UFH)

[00050] In an example embodiment, the formulation of the present disclosure can comprise unfractionated heparin (UFH). In an embodiment, the UFH may be heparin that has not been fractionated to sequester the fraction of molecules with low molecular weight. The UFH may be used as an effective anticoagulant.

Exclusion of Heparin

[00051] In an example embodiment, formulations of the present disclosure may exclude heparin, including unfractionated heparin (UFH) or low molecular weight heparin (LMWH). Certain advantages may be obtained with the exclusion of heparin, including UFH or LMWH from formulations of the present disclosure.

[00052] In an embodiment, the present disclosure provides a locking solution composition for treating and reducing infection and flow reduction in blood catheters, wherein the composition comprises a solution of taurolidine and a biologically acceptable acid in sufficient concentration to bring the pH of the composition into a range that enhances the antimicrobial activity of the taurolidine, wherein the composition does not include heparin. The composition may also exclude urokinase. The composition may be substantially free of hexane and toluene. In an embodiment, the taurolidine may be a polymorph, and may be Polymorph A as demonstrated by an XRPD in Figure 2 or may be Polymorph B as demonstrated by an XRPD in Figure 3. In an embodiment, the composition may comprise taurolidine in the form of one or both of Polymorph A and Polymorph B. In an embodiment, the biologically acceptable acid may be chosen from the group consisting of citric acid and lactic acid.

Urokinase

[00053] In an example embodiment, formulations of the present disclosure may include urokinase. Certain advantages may be obtained with the inclusion of urokinase from formulations of the present disclosure. In an embodiment, formulations of the present disclosure may include urokinase in an amount of about 5000 units/vial to about 250000 units/vial. In an embodiment, formulations of the present disclosure may include urokinase in an amount of about 5000 International Unites (TU) to about 25000 TU.

[00054] In an embodiment, the present disclosure provides a locking solution composition for treating and reducing infection and flow reduction in blood catheters, wherein the composition comprises a solution of taurolidine and a biologically acceptable acid in sufficient concentration to bring the pH of the composition into a range that enhances the antimicrobial activity of the taurolidine, and urokinase, wherein the composition does not include heparin. The composition may be substantially free of hexane and toluene. In an embodiment, the taurolidine may be a polymorph, and may be Polymorph A as demonstrated by an XRPD in Figure 2 or may be Polymorph B as demonstrated by an XRPD in Figure 3. In an embodiment, the composition may comprise taurolidine in the form of one or both of Polymorph A and Polymorph B. In an embodiment, the biologically acceptable acid may be chosen from the group consisting of citric acid and lactic acid.

Method of Preparing Formulations

[00055] The present disclosure provides a method of preparing a locking solution formulation or composition suitable for treating and reducing infection and flow reduction in blood catheters. In an embodiment, the method may comprise providing a polymorph of taurolidine, wherein the polymorph is characterized by an X-ray powder diffraction (XRPD) plot as shown in Figure 2, and a biologically acceptable acid in sufficient concentration to bring the pH of the composition into a range that enhances the antimicrobial activity of the taurolidine. In an embodiment, the method may comprise providing a polymorph of taurolidine, wherein the polymorph is characterized by an X-ray powder diffraction (XRPD) plot as shown in Figure 3, and a biologically acceptable acid in sufficient concentration to bring the pH of the composition into a range that enhances the antimicrobial activity of the taurolidine. In an embodiment, the method may comprise providing one or more polymorphs of taurolidine, wherein the one or more polymorphs are characterized by X-ray powder diffraction (XRPD) plots as shown in Figure 2 and/or Figure 3, and a biologically acceptable acid in sufficient concentration to bring the pH of the composition into a range that enhances the antimicrobial activity of the taurolidine. [00056] Tn an embodiment, the method may further comprise providing urokinase. Tn an embodiment, the method may further comprise excluding heparin from the composition. In an embodiment, the composition is substantially free of hexane and toluene The biologically acceptable acid may be chosen from the group consisting of citric acid and lactic acid. The composition may be substantially free of hexane and toluene.

Impurities

[00057] In an embodiment, the formulations and compositions of the present disclosure may be substantially free of impurities, for example, hexane and/or toluene. The methods of preparing formulations and compositions of the present disclosure may result in a formulation or composition that is substantially free of impurities, for example, hexane and/or toluene.

Buffering system

[00058] In an embodiment, formulations of the present disclosure can comprise alternative buffering systems with pH capacity that offer better and/or comparable taurolidine solubility profde as well as safety profde as existing formulations. Existing buffers in parenteral products can be citrate (Neutrolin, for example), phosphate and acetate, which are already approved by the FDA. Other buffering systems are listed in Table 4 below.

Table 4:

.Conclusion

[00059] While the present disclosure has been discussed in terms of certain embodiments, it should be appreciated that the present disclosure is not so limited. The embodiments are explained herein by way of example, and there are numerous modifications, variations and other embodiments that may be employed that would still be within the scope of the present disclosure. [00060] It is to be understood that the disclosed subject matter is not limited in its application to the details of construction and to the arrangements of the components set forth in the following description or illustrated in the drawings. The disclosed subject matter is capable of other embodiments and of being practiced and carried out in various ways. The examples set forth in this document are for illustrative purposes and all elements of the example may not be required or exhaustive. Accordingly, other implementations are within the scope of the following claims. Also, it is to be understood that the phraseology and terminology employed herein are for the purpose of description and should not be regarded as limiting. As such, those skilled in the art will appreciate that the conception, upon which this disclosure is based, may readily be utilized as a basis for the designing of other structures, methods, and systems for carrying out the several purposes of the disclosed subject matter. It is important, therefore, that the claims be regarded as including such equivalent constructions insofar as they do not depart from the spirit and scope of the disclosed subject matter.

[00061] Although the disclosed subject matter has been described and illustrated in the foregoing exemplary embodiments, it is understood that the present disclosure has been made only by way of example, and that numerous changes in the details of implementation of the disclosed subject matter may be made without departing from the spirit and scope of the disclosed subject matter. For example, the steps and/or limitations in the specification, drawings, and/or claims may be performed in an order other than the order set forth in the specification, drawings, and/or claims. [00062] In addition, it should be understood that any figures which highlight the functionality and advantages are presented for example purposes only. The disclosed methodology and system are each sufficiently flexible and configurable such that they may be utilized in ways other than that shown. For example, other steps may be provided, or steps may be eliminated, from the described flows, and other components may be added to, or removed from, the described systems. [00063] Although the term “at least one” may often be used in the specification, claims and drawings, the terms “a”, “an”, “the”, “said”, etc. also signify “at least one” or “the at least one” in the specification, claims and drawings.

[00064] Finally, it is the applicant's intent that only claims that include the express language

"means for" or "step for" be interpreted under 35 U.S.C. 112(f). Claims that do not expressly include the phrase "means for" or "step for" are not to be interpreted under 35 U.S.C. 112(f).