PHARMACEUTICAL FORMULATIONS

Abstract

Disclosed herein is glutathione in conjunction with an isoselenazol or isothiazol derivative, e.g., ebselen or ebsulfur derivative, to treat diabetes, lupus, or other chronic inflammatory disease. The glutathione is preferably provided in a rapid release oral formulation that presents the glutathione for absorption in the first part of the ileum. The isoselenazol or isothiazol derivative is preferably provided in a delayed release formulation to avoid overlapping high enteric concentration. These may be provided within the same unit dosage form.

Claims

1. A method, comprising coadminstering to a mammal: (a) a glutathione component, comprising glutathione, or a pharmaceutically acceptable salt thereof; and (b) an azol component, comprising at least one of: an isoselenazol, an isoselenazol derivative, an isothiazol, an isothiazol derivative, and a pharmaceutically acceptable salt of the isoelenazol, the isoselenazol derivative, the isothazol, or the isothiazol derivative, each of the glutathione component and the azol component being present in a therapeutically effective amount.

2. The method according to claim 1, wherein the mammal is a human having a chronic inflammatory disorder, and the glutathione component and the azol component are each individually present in a therapeutically effective amount to treat the chronic inflammatory disorder or to ameliorate a symptom associated with the chronic inflammatory disorder.

3. The method according to claim 2, wherein the chronic inflammatory disorder is selectively associated with one or more of the group consisting of systemic lupus erythematosus, diabetes mellitus type II, acne vulgaris, asthma, an autoimmune disease, an autoinflammatory disease, a celiac disease, chronic prostatitis, diverticulitis, glomerulonephritis, hidradenitis suppurativa, a hypersensitivity, an inflammatory bowel disease, interstitial cystitis, otitis, a pelvic inflammatory disease, a reperfusion injury, rheumatic fever, rheumatoid arthritis, sarcoidosis, a transplant rejection, and vasculitis.

4. (canceled)

5. The method according to claim 1, wherein the azol component comprises at least one compound according to Formula I or a pharmaceutically acceptable salt thereof: ##STR00023## wherein X is selenium or sulfur; wherein each R is individually selected from the group consisting of: H; alkyl having a carbon chain of 1 to 14 carbon atoms, wherein the carbon chain is branched or unbranched, and which is optionally substituted with one or more of: bensisoselenazol-3(2H)-one-2-yl, bensisotiazol-3(2H)-one-2-yl, OH, alkoxyl, SH, NH.sub.2, N-alkylamino, N,N-dialkylamino wherein the alkyl groups are identical or different, COOH, aryl which is optionally substituted with one or more of: C.sub.1-C.sub.5 alkyl, OH, alkoxyl, SH, NH.sub.2, N-alkylamino, N,N-dialkylamino wherein the alkyl groups are identical or different, COOH, CHO, NO.sub.2, F, Cl, Br, I, or heteroaryl which is optionally substituted with one or more of: C.sub.1-C.sub.5 alkyl, OH, alkoxyl, SH, NH.sub.2, N-alkylamino, N,N-dialkylamino, COOH, CHO, NO.sub.2, F, Cl, Br, or I; aryl which is optionally substituted with one or more of: C.sub.1-C.sub.5 alkyl, OH, alkoxyl, SH, NH.sub.2, N-alkylamino, N,N-dialkylamino wherein the alkyl groups are identical or different, COOH, CHO, NO.sub.2, F, Cl, Br, or I; and heteroaryl which is optionally substituted with one or more of: C.sub.1-C.sub.5 alkyl, OH, alkoxyl, SH, NH.sub.2, N-alkylamino, N,N-dialkylamino wherein the alkyl groups are identical or different, COOH, CHO, NO.sub.2, F, Cl, Br, or I; wherein A represents a saturated, unsaturated or polyunsaturated 3 to 6 member carbon chain, which is optionally substituted with one or more of: OR.sup.2, SR.sup.2, and alkylamino, C.sub.1-C.sub.5 alkyl, OH, alkoxyl, SH, NH.sub.2, N-alkylamino, N,N-dialkylamino wherein the alkyl groups are identical or different, COOH, CHO, NO.sub.2, F, Cl, Br, and I, wherein NR.sup.1 may optionally substitute for one or more carbons; wherein each R.sup.1 individually is an electron pair, H, an alkyl chain of 1-14 carbon atoms, aryl, or heteroaryl; and wherein R.sup.2 is selected from the group consisting of: alkyl having a carbon chain of 1 to 14 carbon atoms, wherein the carbon chain is branched or unbranched, and which is optionally substituted with one or more of: bensisoselenazol-3(2H)-one-2-yl, bensisotiazol-3(2H)-one-2-yl, OH, alkoxyl, SH, NH2, N-alkylamino, N,N-dialkylamino wherein the alkyl groups are identical or different, COOH, aryl which is optionally substituted with one or more of: C1-C5 alkyl, OH, alkoxyl, SH, NH.sub.2, N-alkylamino, N,N-dialkylamino wherein the alkyl groups are identical or different, COOH, CHO, NO.sub.2, F, Cl, Br, I, or heteroaryl which is optionally substituted with one or more of: C.sub.1-C.sub.5 alkyl, OH, alkoxyl, SH, NH.sub.2, N-alkylamino, N,N-dialkylamino, COOH, CHO, NO.sub.2, F, Cl, Br, or I; aryl or heteroaryl which is optionally substituted with one or more of: C.sub.1-C.sub.5 alkyl, OH, alkoxyl, SH, NH.sub.2, N-alkylamino, N,N-dialkylamino wherein the alkyl groups are identical or different, COOH, CHO, NO.sub.2, F, Cl, Br, or I; and heteroaryl which is optionally substituted with one or more of: C.sub.1-C.sub.5 alkyl, OH, alkoxyl, SH, NH.sub.2, N-alkylamino, N,N-dialkylamino wherein the alkyl groups are identical or different, COOH, CHO, NO.sub.2, F, Cl, Br, or I.

6-16. (canceled)

17. The method of claim 16, wherein after oral administration of the integral capsule to the mammal, the glutathione component in the immediate release portion is solubilized in a stomach of the mammal and the azol component in the delayed release granule is not solubilized in the stomach of the mammal.

18. The method according to claim 1, wherein the azol component is provided within a delayed release portion comprising a surfactant and an outer coating which dissolves after passage through the stomach after oral administration, which is physically isolated from the glutathione component within a common unit dosage form.

19. (canceled)

20. The method according to claim 1, wherein the azol component is dispersed within a slowly dissolving matrix separated from the glutathione component.

21. The method according to claim 12, wherein the unit dosage form further comprises a pharmaceutically acceptable antibiotic in an amount effective to treat a bacterial infection of the mammal.

22-24. (canceled)

25. The method according to claim 5, wherein the azol component comprises the compound of Formula I in an amount of 3 M to about 1 mM per dosage form.

26-27. (canceled)

28. A pharmaceutically acceptable unit dosage form, comprising: glutathione in an amount of at least 250 mg, in a charge transfer complex with a sacrificial antioxidant; and an azol comprising an isoselenazol, an isothiazol, or a pharmaceutically acceptable salt thereof, each individually in a therapeutically effective amount of at least 10 mg to treat at least one chronic inflammatory disorder of a human.

29-30. (canceled)

31. The pharmaceutically acceptable unit dosage form of claim 28, wherein the glutathione is provided within an immediate release formulation; the azol is provided within a delayed release formulation; and the glutathione within the immediate release formulation is chemically separated from the azol within the delayed release formulation.

32. The pharmaceutically acceptable unit dosage form of claim 28, wherein the azol comprises a compound according to Formula I or a pharmaceutically acceptable salt thereof: ##STR00024## wherein X is selenium or sulfur; wherein each R is individually selected from the group consisting of: H; alkyl having a carbon chain of 1 to 14 carbon atoms, wherein the carbon chain is branched or unbranched, and which is optionally substituted with one or more of: bensisoselenazol-3(2H)-one-2-yl, bensisotiazol-3(2H)-one-2-yl, OH, alkoxyl, SH, NH.sub.2, N-alkylamino, N,N-dialkylamino wherein the alkyl groups are identical or different, COOH, aryl which is optionally substituted with one or more of: C.sub.1-C.sub.5 alkyl, OH, alkoxyl, SH, NH.sub.2, N-alkylamino, N,N-dialkylamino wherein the alkyl groups are identical or different, COOH, CHO, NO.sub.2, F, Cl, Br, I, or heteroaryl which is optionally substituted with one or more of: C.sub.1-C.sub.5 alkyl, OH, alkoxyl, SH, NH.sub.2, N-alkylamino, N,N-dialkylamino, COOH, CHO, NO.sub.2, F, Cl, Br, or I; aryl which is optionally substituted with one or more of: C.sub.1-C.sub.5 alkyl, OH, alkoxyl, SH, NH.sub.2, N-alkylamino, N,N-dialkylamino wherein the alkyl groups are identical or different, COOH, CHO, NO.sub.2, F, Cl, Br, or I; and heteroaryl which is optionally substituted with one or more of: C.sub.1-C.sub.5 alkyl, OH, alkoxyl, SH, NH.sub.2, N-alkylamino, N,N-dialkylamino wherein the alkyl groups are identical or different, COOH, CHO, NO.sub.2, F, Cl, Br, or I; wherein A represents a saturated, unsaturated or polyunsaturated 3 to 6 member carbon chain, which is optionally substituted with one or more of: OR.sup.2, SR.sup.2, and alkylamino, C.sub.1-C.sub.5 alkyl, OH, alkoxyl, SH, NH.sub.2, N-alkylamino, N,N-dialkylamino wherein the alkyl groups are identical or different, COOH, CHO, NO.sub.2, F, Cl, Br, and I, wherein NR.sup.1 may optionally substitute for one or more carbons; wherein each R.sup.1 individually is an electron pair, H, an alkyl chain of 1-14 carbon atoms, aryl, or heteroaryl; and wherein R.sup.2 is selected from the group consisting of: alkyl having a carbon chain of 1 to 14 carbon atoms, wherein the carbon chain is branched or unbranched, and which is optionally substituted with one or more of: bensisoselenazol-3(2H)-one-2-yl, bensisotiazol-3(2H)-one-2-yl, OH, alkoxyl, SH, NH.sub.2, N-alkylamino, N,N-dialkylamino wherein the alkyl groups are identical or different, COOH, aryl which is optionally substituted with one or more of: C1-C5 alkyl, OH, alkoxyl, SH, NH.sub.2, N-alkylamino, N,N-dialkylamino wherein the alkyl groups are identical or different, COOH, CHO, NO.sub.2, F, Cl, Br, I, or heteroaryl which is optionally substituted with one or more of: C.sub.1-C.sub.5 alkyl, OH, alkoxyl, SH, NH.sub.2, N-alkylamino, N,N-dialkylamino, COOH, CHO, NO.sub.2, F, Cl, Br, or I; aryl or heteroaryl which is optionally substituted with one or more of: C.sub.1-C.sub.5 alkyl, OH, alkoxyl, SH, NH.sub.2, N-alkylamino, N,N-dialkylamino wherein the alkyl groups are identical or different, COOH, CHO, NO.sub.2, F, Cl, Br, or I; and heteroaryl which is optionally substituted with one or more of: C.sub.1-C.sub.5 alkyl, OH, alkoxyl, SH, NH.sub.2, N-alkylamino, N,N-dialkylamino wherein the alkyl groups are identical or different, COOH, CHO, NO.sub.2, F, Cl, Br, or I.

33. The pharmaceutically acceptable unit dosage form of claim 32, wherein in the compound of Formula I is ##STR00025##

34-36. (canceled)

37. The pharmaceutically acceptable unit dosage form of claim 21, wherein the glutathione comprises reduced L-glutathione which is pharmaceutically stabilized with a charge transfer complex forming agent that serves as a sacrificial antioxidant, the glutathione being separated within the pharmaceutically acceptable unit dosage form from the azol.

38-40. (canceled)

41. The pharmaceutically acceptable unit dosage form of claim 37, wherein the dosage form is packed in a multidose pack under an inert gas.

42-47. (canceled)

48. The pharmaceutically acceptable unit dosage form of claim 28, wherein azol is provided within a delayed release portion which is physically isolated from the glutathione, the delayed release form comprising an outer coating which is configured to dissolve after passage through a stomach of a mammal after oral administration, and a surfactant to facilitate dissolution of the azol, after the outer coating is dissolved within a common unit dosage form.

49. (canceled)

50. The pharmaceutically acceptable unit dosage form of claim 28, wherein the azol is dispersed within a slowly dissolving matrix.

51. The pharmaceutically acceptable unit dosage form of claim 28, wherein the dosage form further comprises a pharmaceutically acceptable antibiotic.

52-56. (canceled)

57. A pharmaceutically acceptable unit dosage form, comprising: at least 250 mg reduced L-glutathione; an agent which forms a charge transfer complex with the reduced L-glutathione to substantially cancel a mixing-induced triboelectric charge on the glutathione and acts as a sacrificial antioxidant; and at least 25 mg of an isoselenazol, or an isothiazol, which is a mammalian glutathione peroxidase mimic, and a bacterial thioredoxin reductase inhibitor.

58. The pharmaceutically acceptable unit dosage form of claim 57, wherein the unit dosage form has an immediate release portion comprising the reduced L-glutathione and the agent, and a delayed release portion comprising the isoselenazol, or the isothiazol, wherein the reduced L-glutathione of the immediate release portion is physically separated within the unit dose form from the isoselenazol or the isothiazol of the delayed release portion, wherein the pharmaceutically acceptable unit dosage form is configured after administration by a human to: (a) substantially release the reduced L-glutathione in solution in the stomach, and (b) substantially release the isoselenazol or the isothiazol after the ligament of Treitz, to provide non-overlapping physiological release profiles.

59-88. (canceled)

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0168] Compounds Synthesis:

[0169] Benzisoselenazol-3(2H)-one (1-11) and bisbenzisoselenazol-3(2H)-one (12-14) derivatives were synthesized by the treatment of 2-(chloroseleno)benzoyl chloride, which was obtained from anthranilic acid [30], with corresponding amines or diamines using the reported procedure with minor modifications (Scheme 1). Disodium diselenide used in this procedure was prepared by the reaction of sodium borohydride with selenium in water, instead of the reaction between sodium and selenium in THF. This method is safer, as the unreacted sodium, if there is any, may cause an explosion in the next step of the reaction, which has to be carried out in water. Synthesis of 7-azabenzisoselenazol-3(2H)-ones were reported. However, when the synthesis of 2-(5-chloro-2-pyridyl)-7-azabenzisoselenazol-3(2H)-one (17) was repeated, and formation of different organoselenium compounds were observed depending on amount of thionyl chloride, nature of solvent and reaction time. Formation of selenamide (20) and diethyl 2, 2-diselenobisnicotinate (21) was observed when dichloromethane used as received to extract the 2-(chloroseleno)nicotinoyl chloride (16) and for further cyclization with 5-chloro-2-aminopyridine. The products were easily separated by column chromatography using dichloromethane as eluent. This reaction was reproducible. Expected product 17 was obtained as major product along with bis(2-carbamoyl)phenyl diselenide (18) when the dry dichloromethane or acetonitrile used as solvent and refluxed for 36 hrs. When the reflux time is reduced to 16 hr or less with same amount of thionyl chloride compound 18 was obtained as major product. The reactions are shown in Scheme 2. Formation of 20 may be explained via the formation ethyl 2-(chloroseleno)nicotinate (19) due to the reaction of ethyl alcohol present in dichloromethane as impurity with the hard electrophilic center of chloride (16) localized on the carbonyl carbon atom. o-Acylation is expected to proceed faster than o-selenenylation as reported. Acyclic selenamides are very unstable and so far only few reports about acyclic selenamides are known in the literature. The stability of selenamide (20) may be due to the presence of Se . . . O intramolecular interaction between the carbonyl oxygen of carboxyl ethyl group and selenium. The stabilization organoselenium compounds by such type of Se . . . O intramolecular interactions have been extensively studied in the literature. All reactions were performed under inert atmosphere using Schlenk techniques. All solvents were purified by the standard procedures.sup.[37] and were freshly distilled prior to use. All chemicals were purchased from Sigma-Aldrich or Lancaster and used as received. .sup.1H NMR spectra were recorded in CDCl.sub.3 or DMSO-d.sub.6 on a Varian VXR spectrometer operating at 400 MHz and chemical shifts are reported in ppm relative to TMS. Benzisoselenazol-3(2H)-one (1-11) and bisbenzisoselenazol-3(2H)-one (12-14) were prepared from 2-(chloroseleno)benzoyl chloride using the synthetic procedure described in the literature with slight modifications. Diselenide of nicotinic acid (17) were also synthesized by reported method.

##STR00022##

Synthesis of 2-(5-chloro-2-pyridyl)-7-azabenzisoselenazol-3(2H)-one (17)

[0170] 1 g of 15 is suspended in 50 ml of thionyl chloride and one drop of dimethylformamide was added, and the reaction mixture was refluxed for 36 hr. The excess thionyl chloride was removed under reduced vacuum and dichloride 16 was occurred as yellow crystalline solid. Due to its low stability dichloride 16 (2 mmole) was dissolved in 50 ml dry dichloromethane or acetonitrile and the solution of 5-chloro-2-aminopyridine (6 mmole) dissolved in dichloromethane or acetonitrile was added dropwise at ice/salt temperature. After 24 hr the solvent was evaporated. The residue was purified by column chromatography using dichloromethane as eluent. Yield (40%). .sup.1H NMR (400 MHz, DMSO-d.sub.6, ppm): 67.54 (dd, 1H), 8.04 (dd, 1H), 8.24 (d, 1H), 8.50 (s, 1H), 8.61 (d, 1H), 8.87 (d, 1H).

Synthesis of Ethyl 2-(5-chloro-2-pyridylamidoseleno)nicotinate (20) and diethyl 2, 2-diselenobisnicotinate (21)

[0171] A suspension of 15 (1 g) in thionyl chloride (7 ml) and one drop of dimethylformamide were refluxed for 8 h. After this period further 7 ml of thionyl chloride and one drop of dimethyl formamide was added and refluxed for further 12 h. The excess thionyl chloride was evaporated under reduced pressure and the residue was dissolved in dichloromethane and filtered under inert conditions. From the filtrate the dichloromethane was evaporated to obtain the dichloride (19) as yellow crystalline solid. To the ice/salt bath solution of dichloride (2.5 mmole) dissolved in dichloromethane was added dropwise the solution of 5-chloro-2-aminopyridine (7.5 mmole), and the reaction was continued for 3 h. After this period the reaction mixture was washed with water thrice (320 ml) and the organic layer was separated and dried in anhydrous sodium sulfate. The solvent was removed under reduced pressure and product was further purified by column chromatography using dichloromethane as eluent to get 20 and 21. Compound 20 is white crystalline substance and compound 21 is pale yellow color. Compound 20: Yield, 35%. .sup.1H NMR (400 MHZ, DMSO-d.sub.6, ppm): 1.38 (t, CH.sub.3), 4.40 (q, CH.sub.2), 6.85 (d, ArH), 7.35 (dd, ArH), 7.5 (dd, ArH), 7.98 (s, NH), 8.02 (s, ArH), 8.25 (dd, ArH), 8.6 (dd, ArH). Compound 21: Yield, 20%. .sup.1H NMR (400 MHz, CDCl.sub.3, ppm): 61.4 (t, CH.sub.3), 4.4 (q, CH.sub.2), 7.10 (dd ArH), 8.2 (dd, ArH), 8.45 (dd, ArH)

[0172] Glutathione Peroxidase (GPx) Activity Assay:

[0173] GPx activity of ebselen derivatives was performed in the potassium phosphate buffer, pH 7.4 containing 240 M NADPH, 0.5 mM GSH, and 0.5 unit of glutathione reductase with 30 M compound in the presence of 0.5 mM of H.sub.2O.sub.2. The absorbance at 340 nm was followed for 10 min, and GPx activity was calculated in terms of NADPH consumption per minute. The sample in the absence of H.sub.2O.sub.2 was used as the control.

[0174] Measurement of IC50 of Ebselen Derivatives for Mammalian TrxR:

[0175] The inhibition of ebselen derivatives on mammalian TrxR was performed in the 50 mM Tris-HCl, pH 7.5 buffer containing 100 nM recombinant rat TrxR, 200 M NADPH. The compounds of different concentration (0.02-10 M) were incubated for 10 minute and then 1 mM DTNB was added to assay TrxR activity by following the initial linear increase at A412 for 2 minutes. The sample incubated with DMSO was used as the control.

[0176] Cell Viability Experiment:

[0177] Human embryonic kidney cells (HEK 293T) were cultured in RPMI 1640 (GIBCO) supplemented with 2 mM L-glutamine, 10% FCS, 100 units/ml penicillin, and 100 g/ml streptomycin at 37 C. in a 5% CO.sub.2 incubator. HEK 293T cells were plated at a density of 110.sup.4 cells/well in 96 micro-well plates and allowed to grow in the growth medium for 24 h. Then different concentrations of ebselen derivatives were added in the medium, and incubation was conducted for another 24 h. Cell proliferation and viability were determined using an XTT kit (Roche). After XTT agents were added, the cells were grown for another 3 hours. The data are the means of three experiments and at least repeated twice.

Example 1

[0178] Reduced L-glutathione, a naturally-occurring water-soluble tripeptide (gamma-glutamyl-cysteinyl-glycine) is the most prevalent intracellular thiol in most biological systems. A preferred formulation of glutathione according to the present invention provides capsules for oral use containing 500 mg reduced L-glutathione, 250 mg USP grade crystalline ascorbic acid, and not more than 0.9 mg magnesium stearate, NF grade in an OO-type gelatin capsule.

[0179] Also within the capsule is provided enteric release ebselen, 100-500 mg, as granules of ebselin in a binder/solubilizer coated with an enteric release film. The formulation may administered 1-4 capsules by mouth, two to four times daily, preferably on a empty stomach. For example, a capsule may contain 100, 200, 250, 300, 330, 400 or 500 mg of ebselin or another isoselenazol or isothiazol derivative which is effective as a mammalian glutathione peroxidase mimic. The granules preferably are designed to release the ebselen or other isoselenazol or isothiazol derivative after the ligament of Treitz, and for example, may have a solubility that is insoluble in acid and increases in solibility neutral or basic solutions, i.e., in the presence of pacrteatic secretions, or includes a shell which is hydrolyzed by bile acids or pancreatic enzymes.

[0180] As noted in the literature, ebselen doses in the range of 10-30 mg/kg i.p.or i.v or p.o. have been found particularly effective for treatment of diseases. Lindenblatt, Nicole, et al. Anti-oxidant ebselen delays microvascular thrombus formation in the rat cremaster muscle by inhibiting platelet P-selectin expression. Thrombosis and haemostasis 90.5 (2003): 882-892; Lapchak, Paul A., and Justin A. Zivin. Ebselen, a seleno-organic antioxidant, is neuroprotective after embolic strokes in rabbits synergism with low-dose tissue plasminogen activator. Stroke 34.8 (2003): 2013-2018; Dawson, D. A., et al. The neuroprotective efficacy of ebselen (a glutathione peroxidase mimic) on brain damage induced by transient focal cerebral ischaemia in the rat. Neuroscience letters 185.1 (1995): 65-69.

[0181] The capsule is preferably a standard two-part hard gelatin capsule of double-0 (00) size, which may be obtained from a number of sources. After filling, the capsules are preferably stored under nitrogen, to reduce oxidation during storage. The capsules are preferably filled according to the method of U.S. Pat. No. 5,204,114, using crystalline ascorbic acid as both an antistatic agent and stabilizer. Further, each capsule preferably contains 500 mg of glutathione and 250 mg of crystalline ascorbic acid. A preferred composition includes no other excipients or fillers; however, other compatible fillers or excipients may be added. While differing amounts and ratios of glutathione and stabilizer may be used, these amounts are preferable because they fill a standard double-O capsule, and provide an effective stabilization and high dose. Further, the addition of calcium carbonate, a component of known high dose glutathione capsules, is avoided as there may be impurities in this component. Further, calcium carbonate acts as a base, neutralizing stomach acid, which accelerates degradation of glutathione in the small intestine.

[0182] Because the glutathione and ascorbic acid are administered in relatively high doses, it is preferred that these components be highly purified, to eliminate impurities, toxins or other chemicals, which may destabilize the formulation or produce toxic effects or side effects. As stated above, the formulation may also include other pharmaceutical agents, of various classes.

Example 2

[0183] The preferred regimen for treatment of humans with glutathione according to the present invention is the administration of between 1 and 10 grams per day, in two divided doses, between meals (on an empty stomach), of encapsulated, stabilized glutathione and ebselen according to Example 1.

Example 3

[0184] A formulation disclosed herein is administered to a human at a dosage disclosed herein, which results in a pharmacokinetic parameter disclosed herein.

[0185] The foregoing disclosure of embodiments and exemplary applications of the present invention has been presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise forms disclosed.