DESC:FIELD OF THE INVENTION:
The present invention relates to stable, solid dosage forms for co-administration of two or more, incompatible, active agents wherein one active agent is a polyphenol such as resveratrol and the other active agent is a transition metal ion such as copper. The present invention also provides a process for the preparation of the said solid dosage forms.

BACKGROUND OF THE INVENTION:
Polyphenols have demonstrated to be effective in the prevention and treatment of various diseases and disorders. The efficacy of polyphenols is largely attributed to their potent antioxidant and anti-inflammatory properties. Polyphenols have demonstrated to modulate molecular targets and signaling pathways that are associated with cell survival, proliferation, differentiation, migration, angiogenesis, hormone activities, detoxification enzymes, and immune responses.

Transition metal ions such as Copper (Cu) and Iron (Fe) are essential micronutrient and act as co-factors, playing a central role in the formation of reactive oxygen species (ROS), oxygen and hydroxyl radicals.

Cell-free fragments of chromatin, DNA and RNA (released from dying cells) circulating in the blood can readily enter into healthy cells of the body to integrate into their genomes and trigger DNA damage, apoptotic and inflammatory response in healthy cells. Thus, increased levels of circulating chromatin, DNA and RNA contribute to various diseases and conditions like cancers, tumors, ageing, viral infections, reactions to transfusions of blood/blood products, autoimmune diseases, inflammations, athero-vascular diseases, and other infections.

In the presence of transition metal ions such as copper, polyphenols act as pro-oxidants, catalyzing DNA degradation and causing oxidative DNA cleavage in plasmids. When administered with a transition metal ion such as copper (II), polyphenols form a complex with copper (II), leading to its reduction to copper (I), with concomitant production of ROS. ROS is responsible for DNA scission. Thus, polyphenols and copper ions, in combination, are capable of degrading, preventing the formation of, and/or reducing circulating fragments of chromatin, DNA and RNA.

Co-administration of polyphenols and transition metal ions are capable of having beneficial effects in conditions like cancers, tumors, ageing, viral infections, reactions to transfusions of blood/blood products, autoimmune diseases, inflammations, atherovascular diseases, other infections and many other diseases/disorders.

PCT Publication no. WO/2015/011732 discloses a combination comprising a plant polyphenol like resveratrol, and copper ions, in a molar ratio of about 1:1 to 1:10-10 to provide therapeutic treatment for conditions associated with raised levels of chromatin fragments including cancer and HIV. The said compositions are administered intraperitoneally at a dose level of 10 mg to 100 mg polyphenol per kg weight of the subject, and contains a solvent selected from acetonitrile, aqueous ethanol, weak alkaline solution and water. For resveratrol to be given orally, a dose that is around 100 times greater than an intraperitoneal dose would be required to compensate for the lower gastrointestinal absorption of resveratrol.

Poor solubility of polyphenols and low doses of copper ions, pose challenge to co-administer two incompatible active agents, in terms of dose volume, dose uniformity, dissolution and storage stability of active agents. Use of solvents such as acetonitrile and ethanol are also not desirable.

Further it is known that polyphenols such as resveratrol react with transition metal ions such as copper to form complexes. Therefore for co-administration of such incompatible active agents, they need to be administered separately, as separate dosage forms, to achieve desired stability and dissolution.

It has surprisingly been found that the present invention enables polyphenols such as resveratrol and transition metal ion such as copper, that are incompatible with each other, to be co-administered through single, stable, solid dosage forms, with the desired characteristics of stability and dissolution.

OBJECTS OF THE INVENTION
The principal object of the present invention is to provide stable, solid dosage forms for co-administration of incompatible active agents wherein one active agent is a polyphenol and the other active agent is a transition metal ion.

Another object of the present invention is to provide stable, solid dosage forms for co-administration of incompatible active agents - polyphenols and transition metal ions, wherein the said solid dosage forms are in the form of powder, granules, tablets and/or capsules.

Yet another object of the present invention is to provide stable, solid dosage forms for co-administration, the said dosage forms comprising granules of polyphenol, and granules of transition metal ions.

Yet another object of the present invention is to provide stable, solid dosage forms for co-administration, comprising polyphenol and transition metal ions, wherein the said solid dosage forms are in the form of a multi-layered tablet.

Yet another object of the invention is to provide a process for preparation of such stable, solid dosage forms for co-administration of two or more incompatible active agents.

SUMMARY OF THE INVENTION
The present invention relates to stable, solid dosage forms, for co-administration of two or more, incompatible active agents wherein one active agent is a polyphenol such as resveratrol and the other active agent is a transition metal ion such as copper. The present invention also provides a process for the preparation of such solid dosage forms.

DETAILED DESCRIPTION OF THE INVENTION
Experiments conducted in the course of the present invention has demonstrated the incompatibility of resveratrol (polyphenol) and copper glycinate (transition metal ion) in a weight ratio of 1:1 when exposed to accelerated storage conditions of 400C and 75% relative humidity (RH), wherein the resveratrol content drops by about 15% after 1 month of storage.

It has surprisingly been found that it is possible to provide stable, solid dosage forms in which polyphenol and transition metal ion can be formulated for co-administration without loss of activity of the active agent. The said dosage form also demonstrates the desired stability and dissolution.

It has further been found that the stable, solid oral, dosage forms of the present invention, containing such actives, are capable of being used in the treatment, retardation, mitigation, and prevention of diseases, disorders and conditions, like cancers, tumors, ageing, viral infections, transfusions of blood/blood products, autoimmune diseases, inflammations, atherovascular diseases, and other infections.
Another aspect is that the solid dosage forms are in the form of powder, granules, tablets and/or capsules.

Yet another aspect is that tablet dosage forms maybe in the form of orally disintegrating, chewable, dispersible, buccal, sublingual, effervescent, and/or lozenge tablets. The tablets may be in the form of single layered, multi-layered tablets (such as bi-layered, tri-layered), press-coated, or molded tablets. The tablets may be further coated with film-coating, sugar coating, enteric coating or extended-release coating. The tablets may provide immediate, controlled, timed and/or delayed release of the active agents.

Yet another aspect is that the solid dosage forms maybe in the form of granules wherein a first granule composition comprises polyphenol, and a second granule composition comprises the transition metal ion.

In an embodiment, granules of polyphenol, and granules of transition metal ion can further be compressed into tablets, or filled into capsules.

Yet another aspect is that the solid dosage forms maybe in the form of multi-layered tablets, wherein a first layer comprises polyphenol, a second layer comprises transition metal ion, and optionally the third and subsequent layers comprise other active agents.

Yet another aspect is that the solid dosage forms maybe in the form of multi-layered tablets, wherein a first layer comprises polyphenol, a second layer comprises transition metal ion, and optionally the third and subsequent layers act as inert layers.

‘Polyphenol’ as used herein refers to polyhydroxyphenol class of natural, synthetic or semisynthetic, organic chemicals characterized by the presence of large multiples of phenol structural units in them. Resveratrol, beta-carotene and curcuminoids (such as curcumin) are examples of such polyphenols.

‘Transition metal ion’ as used herein include but are not limited to ions such as copper and iron, and their salts, derivatives, chelates and analogues.

‘Resveratrol’ as used herein includes salts, derivatives and analogues of resveratrol.

‘Copper ion’ as used herein may be derived from copper salts such as copper sulfate, copper carbonate, and copper derivatives/chelates such as copper oxides, copper glutamate, copper aspartate, copper bisglutamate, copper bisaspartate and copper glycinate.

The molar ratios of resveratrol: copper, in the said solid dosage forms may range from about 1:1 to about 1:10-9, preferably in the range about 1:1 to about 1:10-7, more preferably in the range of about 1:1 to about 1:10-5, and most preferably in the range of about 1:10-2 to about 1:10-4.

Polyphenol, in the solid dosage forms, may range from about 0.5% to about 50% by weight of the solid dosage form.

In an embodiment, polyphenol, such as resveratrol, in the solid dosage forms, may range from about 0.5% to about 12% by weight of the solid dosage form.

It has surprisingly been found that when solid dosage forms of the present invention, comprise at least one diluent, in a concentration of not less than about 50% of the solid dosage form, they exhibit the desired stability and dissolution.

Solid dosage forms comprising resveratrol as the polyphenol, copper ion in the form of copper glycinate as the transition metal ion, and a diluent in a concentration of not less than about 50% of the solid dosage form, when subjected to accelerated storage conditions of 400C and 75% relative humidity (RH), exhibited the desired stability, wherein the content of resveratrol at the end of storage was within ± 5% of the initial content and the total impurities was not more than 2%.

Solid dosage forms of the present invention, comprise at least one diluent in concentrations of about 50% to about 99.5%, preferably from about 60% to about 99% and most preferably from about 70% to about 99%, by weight of the solid dosage forms.

Diluents are selected from those known in the art such as microcrystalline cellulose, carboxymethylcellulose sodium, carboxymethylcellulose calcium, starch, modified starch, pregelatinized starch, maltodextrin, calcium phosphate, calcium sulfate, cyclodextrins (e.g. ß-cyclodextrin, hydroxylpropyl ß-cyclodextrin, gamma-cyclodextrin, sulfobutylether ß-cyclodextrin), glucose, lactose, mannitol, sucrose, dextrose, and sorbitol.

In an aspect of the invention, the solid dosage forms comprise granules of polyphenol, wherein the granules of polyphenol comprise at least one diluent, and the diluent(s) is present in concentrations of not less than 50% by weight of the said granules.

In another aspect of the invention, the solid dosage forms comprise granules of transition metal ion, wherein the granules of transition metal ion comprise at least one diluent, and the diluent(s) is present in concentrations of not less than 50% by weight of the said granules.

In yet another aspect, the solid dosage forms of the present invention comprise granules of polyphenol, and granules of transition metal ion, wherein each of the granules comprise at least one diluent, and wherein the diluent in granules of polyphenol is not less than 50% by weight of the said granules, and wherein the diluent in granules of transition metal ion is not less than 50% by weight of the said granules.

In an embodiment, the stable, solid dosage forms of the present invention comprise granules of polyphenol and granules of transition metal ion,
• wherein each of the granules comprise at least one diluent,
• wherein the molar ratio of polyphenol and transition metal ion in the dosage form is 1:1 to 1:10-9,
• wherein the diluent in granules of polyphenol is not less than 50% by weight of the said granules, and
• wherein the diluent in granules of transition metal ion is not less than 50% by weight of the said granules.

Granules of polyphenol, and granules of transition metal ion can further be compressed into tablets, or filled into capsules.

Polyphenol in the said embodiment can be selected from resveratrol, beta-carotene or curcuminoids, and transition metal ion in the said embodiment can be selected from copper or iron.

Solid dosage forms of the present invention further comprise at least one excipient selected from the group of binders, disintegrants, antioxidants, surfactants, lubricants, glidants, coating materials, plasticizers, colorants, and pigments.

Binders may be present in concentrations from about 0.1% to about 40%, preferably from about 0.1% to about 30%, and more preferably from about 0.1% to about 20% by weight of the solid dosage form, and are selected from those known in the art such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl cellulose, starch, polyvinylpyrrolidone (PVP), polyvinyl alcohol, waxes, fatty alcohols, polyethylene glycol, carbomer, gums, alginates, and polymethacrylates. Binders can be used in their dry form, or can be dissolved in a suitable solvent to give a granulating liquid which is used to prepare granules.

Disintegrants may be present in concentrations from about 1% to about 25% by weight of the composition, and are selected from those known in the art such as sodium starch glycolate, crospovidone, low-substituted hydroxypropylcellulose, croscarmellose sodium, and croscarmellose calcium.

Antioxidants may be present in concentrations from about 0.05% to about 3% by weight of the composition, and are selected from those known in the art such as butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, sodium metabisulfite, sodium sulfite, sodium bisulfite, citric acid, and ascorbic acid.

Surfactants may be present in concentrations from about 0.05% to about 5% by weight of the solid dosage form, and are selected from those known in the art such as sodium lauryl sulphate, poloxamers, lecithins, esters of sorbitan and fatty acids (e.g. Span®), esters of polyoxyethylenesorbitan and fatty acids (e.g. Tween®), polyoxyethylated hydrogenated castor oil (e.g. Cremophor®), and polyoxyethylene stearates (e.g. Brij®).

Lubricants may be present in concentrations from about 0.25% to about 5% by weight of the solid dosage form, and are selected from those known in the art such as magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, sodium benzoate, palmitic acid, talc, and glyceryl behenate.

Glidants may be present in concentrations from about 0.1% to about 10% by weight of the solid dosage form, and are selected from those known in the art such as colloidal silicon dioxide, hydrated silicon dioxide, light anhydrous silicic acid, aluminium silicate, titanium oxide, stearic acid, and talc.

Solid dosage forms of the present invention may optionally be coated with a coating layer comprising one or more coating materials, and optionally one or more excipients selected from plasticizers, colorants, pigments, glidants, and lubricants.

Coating materials are selected from those known in the art such as hydroxypropyl methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, polyacrylic acid, polymethacrylates, polyvinyl alcohol, polyvinyl acetate, and polyvinyl acetate phthalate.

Plasticizers are selected from those known in the art such as triacetin, triethyl citrate, tributyl citrate, diethyl phthalate, dibutyl sebacate, diethyl phthalate, polyethylene glycol, propylene glycol, glycerol monocaprylocaprate, and acetylated mono- and di-glycerides.

Solvents used in granulation and coating, are selected from aqueous, alcoholic, hydro-alcoholic, and organic solvents such as water, methanol, ethanol, isopropanol, acetone, dichloromethane, or mixtures thereof. Water is the preferred solvent. Solvent alone, without binder, can be used as a granulating liquid.

Dissolution and storage stability of the solid dosage forms have been investigated.

The percent cumulative dissolution of polyphenol, from the solid dosage forms of the present invention, ranges from about 20% to about 70%, in 1 hour of dissolution.

In another embodiment, the percent cumulative dissolution of polyphenol, from the solid dosage forms of the present invention, may range from about 40% to about 85%, in 2 hours of dissolution.

In yet another embodiment, the percent cumulative dissolution of polyphenol, from the solid dosage forms of the present invention, is not less than 85%, in 3 hours of dissolution.

In yet another embodiment, the percent cumulative dissolution of polyphenol, from the solid dosage forms of the present invention, is not less than 90%, in 4 hours of dissolution.

The process for preparing solid dosage forms of the present invention comprise steps selected from sifting, blending, dissolving, dispersing, granulating (wet granulating, dry granulating, roll compaction, slugging, spray-drying, fluid-bed granulating, melt granulating, melt-extruding, co-milling or co-precipitating), drying, milling, screening, filling into capsules, compressing, and coating.

In an embodiment granules of polyphenol are prepared by a process that uses steps selected from:
a. blending polyphenol with at least one diluent, and optionally at least one excipient selected from binders, disintegrants, antioxidants, and surfactants;
b. granulating the blend of step ‘a’ with a granulating liquid;
c. dry granulating the blend of step ‘a’ by roll compaction, slugging, melt method or co-milling;
d. drying the granules of step ‘b’ or step ‘c’, and optionally blending the granules with at least one excipient selected from diluents, disintegrants, antioxidants, surfactants, lubricants and glidants.

In an embodiment granules of transition metal ion are prepared by a process that uses steps selected from:
a. blending transition metal ion with at least one diluent, and optionally at least one excipient selected from binders, disintegrants, antioxidants, and surfactants;
b. granulating the blend of step ‘a’ with a granulating liquid;
c. dry granulating the blend of step ‘a’ by roll compaction, slugging, melt method or co-milling;
d. drying the granules of step ‘b’ or step ‘c’, and optionally blending the granules with at least one excipient selected from diluents, disintegrants, antioxidants, surfactants, lubricants and glidants.

Granules of polyphenol and granules of transition metal ion, can further be:
• compressed into tablets, and the tablets optionally coated; or
• compressed into tablets, the tablets optionally coated, and said tablets filled into capsules; or
• filled into capsules.

The invention is illustrated with non – limiting examples.

Example 1
Resveratrol granules: Resveratrol 5.6 g, microcrystalline cellulose 60.4 g and hypromellose (6cps) 25.0 g were sifted through 40 mesh ASTM and blended for 10 minutes to give a resveratrol-diluent mixture. The resveratrol-diluent mixture was granulated with a granulating liquid of hypromellose (6cps) 3.0 g in water to give granules. The granules were dried, and co-milled. The dried granules were sifted through 30 mesh ASTM. Microcrystalline Cellulose (PH 102) 5.0 g was sifted through 40 mesh ASTM, and mixed with the dried granules for 10 minutes. Magnesium stearate 1.0 g was sifted through 60 mesh ASTM, and blended with the dried granules to give a resveratrol granules.

Copper granules: Microcrystalline cellulose 24.7 g, croscarmellose sodium 0.8 g and Lake of indigo carmine 0.1 g were sifted through 40 mesh ASTM, and blended for 10 minutes to give a diluent mixture. Hypromellose (E5) 1.2 g was added to purified water and stirred till dissolved. Copper glycinate 0.00056 g was added to the hypromellose solution, and stirred till dissolved, to give the granulating liquid. The diluent mixture was granulated with the granulating liquid to give granules. The granules were dried, and co-milled. The dried granules were sifted through 30 mesh ASTM. Microcrystalline Cellulose (PH 102) 12.0 g, and croscarmellose sodium 0.8 g were sifted through 40 mesh ASTM, and mixed with the dried granules for 10 minutes. Magnesium stearate 1.0 g was sifted through 60 mesh ASTM and blended with the dried granules. Colloidal Silicon dioxide was sifted through 60 mesh ASTM and blended with the dried granules to give copper granules.

Resveratrol granules and copper granules were compressed as bi-layered tablets using 6.00 mm round punches.

Example 2
Resveratrol granules: Resveratrol 5.6 g, microcrystalline cellulose 60.4 g and hypromellose (4000 cps) 25.0 g were sifted through 40 mesh ASTM, and blended for 10 minutes to give a resveratrol-diluent mixture. The resveratrol-diluent mixture was granulated with a granulating liquid of hypromellose (6cps) 3.0 g in water to give granules. The granules were dried, and co-milled. The dried granules were sifted through 30 mesh ASTM. Microcrystalline Cellulose (PH 102) 5.0 g was sifted through 40 mesh ASTM and mixed with the dried granules for 10 minutes. Magnesium stearate 1.0 g was sifted through 60 mesh ASTM and blended with the dried granules to give a resveratrol granules.

Copper glycinate granules: Microcrystalline cellulose 24.7 g, croscarmellose sodium 0.8 g and Lake of indigo carmine 0.1 g were sifted through 40 mesh ASTM, and blended for 10 minutes to give a diluent mixture. Hypromellose (E5) 1.2 g was added to purified water and stirred till dissolved. Copper glycinate 0.00056 g was added to the hypromellose solution, and stirred till dissolved, to give the granulating liquid. The diluent mixture was granulated with the granulating liquid to give granules. The granules were dried, and co-milled. The dried granules were sifted through 30 mesh ASTM. Microcrystalline Cellulose (PH 102) 12.0 g, and croscarmellose sodium 0.8 g were sifted through 40 mesh ASTM, and mixed with the dried granules for 10 minutes. Magnesium stearate 1.0 g was sifted through 60 mesh ASTM, and blended with the dried granules. Colloidal Silicon dioxide was sifted through 60 mesh ASTM, and blended with the dried granules to give copper glycinate granules.

Resveratrol granules and copper glycinate granules were compressed as bi-layered tablets using 6.00 mm round punches. The bi-layered tablets were film-coated with polyvinyl alcohol based film-coating solution (4% coating).

Example 3
Resveratrol granules and copper glycinate granules, from Example 1 were mixed, and compressed as a single layered tablet using 6.00 mm round punches.

Example 4
Resveratrol granules and copper glycinate granules, from Example 1 were mixed, and filled in hard gelatin capsules of size 2.

Dissolution
Dissolution of resveratrol from the solid dosage forms of examples 1-4 was evaluated in 750ml of 0.1M hydrochloric acid for the first 2 hours and subsequently in 1000ml of phosphate buffer pH 6.5 containing 0.25% Tween 80. The results of the dissolution are given in Table 1.

Table 1: Cumulative dissolution of tablets of Examples 1, 2, 3 and 4
Example
% Cumulative Dissolution of Example 1
1 h 2 h 3 h 4 h
1 30.0 48.0 95.0 102.0
2 62.0 84.0 ND 94.0
3 42.0 63.0 94.0 99.0
4 57.0 69.0 88.0 90.0
*ND = Not done

Solid dosage forms of examples 1-4, exhibited the desired dissolution for resveratrol. The percent cumulative dissolution of the polyphenol - resveratrol, for examples 1-4, ranged from about 20% to about 70%, in 1 hour of dissolution.

Storage Stability
The multi-layered tablets of Examples 1 and 2 were stored at accelerated storage conditions of 400C and 75% relative humidity (RH), and evaluated for dissolution, resveratrol content, and total impurities, after specific storage periods.

Dissolution of resveratrol from the multi-layered tablets of Examples 1 and 2, was evaluated in 750ml of 0.1M hydrochloric acid for the first 2 hours and subsequently in 1000ml of phosphate buffer pH 6.5 containing 0.25% Tween 80. The results of the dissolution are given in Table 2.

Table 2: Cumulative dissolution of tablets of Examples 1 and 2 on storage at 400C and 75% RH
Time (hour)
% Cumulative Dissolution of Example 1
on storage at 400C and 75% RH
Initial 1 month 2 months 3 months
1 30.0 23.0 28.0 37.0
2 48.0 43.0 46.0 56.0
3 95.0 89.0 85.0 93.0
4 102.0 94.0 92.0 97.0
Time (hour)
% Cumulative Dissolution of Example 2
on storage at 400C and 75% RH
Initial 1 month 3 months 6 months
1 62.0 66.0 66.0 66.0
2 84.0 85.0 87.0 79.0
4 94.0 96.0 96.0 101.0

Solid dosage forms of examples 1 and 2, exhibited the desired dissolution for resveratrol, after 3 months / 6 months of storage at accelerated storage conditions of 400C and 75% RH. The percent cumulative dissolution of polyphenol ranged from about 20% to about 70%, in 1 hour of dissolution.

Resveratrol content and total impurities were determined by high performance liquid chromatography (HPLC). Table 3 provides the content of resveratrol, and total impurities in the tablets of example 1, at specific storage periods after storage at accelerated storage conditions of 400C and 75% RH.

Table 3: Content and Impurities of tablets of Examples 1 and 2 on storage at 400C and 75% RH
Example 1
Storage at 400C and 75% RH
Initial 1 month 2 months 3 months
Resveratrol Content 108.5 117.3 112.4 111.5
Total impurities 0.50 0.50 0.48 0.60
Example 2
Storage at 400C and 75% RH
Initial 1 month 3 months 6 months
Resveratrol Content 104.3 106.2 104.3 104.5
Total impurities 0.40 0.47 0.42 0.51

Solid dosage form of examples 1 and 2 showed the desired storage stability at the end of 3 months / 6 months of storage at 400C and 75% RH. The content of resveratrol was within ± 5% of the initial content, and the total impurities was not more than 2%.

Thus, it has surprisingly been found that polyphenols such as resveratrol and transition metal ions such as copper, although incompatible with each other, can be co-administered through solid dosage forms of the present invention, with the desired stability and dissolution.
,CLAIMS:1. Stable, solid dosage forms comprising granules of polyphenol, and granules of transition metal ion, each of the granules comprising at least one diluent,
wherein the molar ratio of polyphenol and transition metal ion, in the dosage form, is 1:1 to 1:10-9;
wherein the diluent in the granules of polyphenol is not less than 50% by weight of the said granules, and
wherein the diluent in the granules of transition metal ion is not less than 50% by weight of the said granules.

2. Stable, solid dosage forms of claim 1, wherein the percent cumulative dissolution of polyphenol, from the said dosage form, ranges from 20% to 70%, in 1 hour of dissolution.

3. Stable, solid dosage forms of any of the preceding claims, wherein the polyphenol is selected from resveratrol, beta-carotene or curcuminoids.

4. Stable, solid dosage forms of any of the preceding claims, wherein the transition metal ion is selected from copper or iron.

5. Stable, solid dosage forms of any of the preceding claims, wherein the molar ratio of polyphenol and transition metal ion, in the dosage form, is 1:1 to 1:10-5.

6. Stable, solid dosage forms of any of the preceding claims, wherein the solid dosage form further comprises at least one excipient selected from binders, disintegrants, antioxidants, surfactants, lubricants, glidants, coating materials, plasticizers, colorants, and pigments.

7. Stable, solid dosage forms of any of the preceding claims, wherein the solid dosage form is in the form of tablets, capsules or a combination thereof.

8. A process for preparing the stable, solid dosage forms of claim 1, comprising steps selected from:
a. blending polyphenol with at least one diluent, and optionally at least one excipient selected from binders, disintegrants, antioxidants, and surfactants;
b. granulating the blend of step ‘a’ with a granulating liquid, or dry-granulating the blend of step ‘a’ by roll compaction, slugging, melt method or co-milling;
c. drying the granules of step ‘b’, and optionally blending the granules with at least one excipient selected from diluents, disintegrants, antioxidants, surfactants, lubricants and glidants;
d. blending transition metal ion with at least one diluent, and optionally at least one excipient selected from binders, disintegrants, antioxidants, and surfactants;
e. granulating the blend of step ‘d’ with a granulating liquid, or dry-granulating the blend of step ‘d’ by roll compaction, slugging, melt method or co-milling;
f. drying the granules of step ‘e’, and optionally blending the granules with at least one excipient selected from diluents, disintegrants, antioxidants, surfactants, lubricants and glidants;
g. compressing the granules of step ‘c’ and granules of step ‘f’ into tablets, and optionally coating the tablets;
h. filling the tablets of step ‘g’ into capsules; and
i. filling the granules of step ‘c’ and the granules of step ‘f’, into capsules.