EP2265253A2

EP2265253A2 - Oral dosage form containing a pyridinol derivative

Info

Publication number: EP2265253A2
Application number: EP09722113A
Authority: EP
Inventors: Ashok Vasantray Vyas; Ravindra Tukaram Jadhav; Subhash Trimbak Phad
Original assignee: Marvel Lifesciences Ltd
Current assignee: Marvel Lifesciences Ltd
Priority date: 2008-02-19
Filing date: 2009-02-19
Publication date: 2010-12-29
Also published as: EA201001328A1; WO2009116078A2; WO2009116078A3

Abstract

An oral pharmaceutical composition comprising 3-hydroxy 2,4,6 trimethylpyridine, pharmaceutically acceptable salts, esters, derivatives and polymorphs thereof for the treatment of ischemia, intraocular hemorrhage and macular degeneration is disclosed.

Description

ORAL DOSAGE FORMULATIONS AND PROCESS OF PREPARATION THEREOF

FIELD OF THE INVENTION

The present invention relates to an oral pharmaceutical composition.

Particularly, the present invention relates to an oral pharmaceutical composition used in the treatment of ischemia and aging.

BACKGROUND OF THE INVENTION

Ischemia is restriction in blood supply due to factors in the blood vessels, with resultant damage or dysfunction of tissue. Ischemia is absolute or relative shortage of the blood supply to an organ. Relative shortage means mismatch between blood supply (oxygen delivery) and blood requirement for adequate oxygenation of tissue. Ischemia results in tissue damage because of lack of oxygen and nutrients.

Ultimately, this causes great damage because of a buildup of metabolic wastes.

Ischemia can also be described as an inadequate flow of blood to a part of the body, caused by constriction or blockage of the blood vessels supplying it.

Depending on the type of organ that is affected, ischemia can be broadly classified in to the following categories:

1. Cardiac ischemia: Ischemia of heart muscle produces angina pectoris.

2. Bowel ischemia: An ischemia in the large bowel caused by an inflammation results in ischemic colitis and ischemia in the small bowel, caused by an inflammation results in mesenteric ischemia.

3. Cutaneous ischemia: Reduced blood flow to the skin layers may result in mottling or uneven, patchy discoloration of the skin.

4. Cerebral ischemia: is the localized reduction of blood flow to the brain or parts of the brain due to arterial obstruction or systematic hyperfusion.

Aging is a universal and inevitable phenomenon that affects all human beings. It can be considered as a product of an interaction between genetic, environmental and lifestyle factors, which in turn influence longevity. Sometimes result of the failure of homeostasis due to the accumulation of damage may lead to aging process.

Very few geroprotective compounds for slowing aging, prolonging lifespan of an individual or cells in an individual, and/or improving quality of life of an individual are known such as melatonin , N-acetylserotonin (NAS), pineal gland peptides [epithalamin and epitalon] and L-Ala-L-Glu-L-Asp-Gly (SEQ ID NO: 1) tetrapeptide.

3-Hydroxy-2,4,6-trimethylpyridine

Structure:

3-Hydroxy-2,4,6-trimethylpyridine succinate salt and other such salts belong to new biologically active compounds which exhibit important pharmacological activities such as antioxidant, geroprotective and ant-ischemic action. 3-Hydroxy- 2,4,6-trimethylpyridine succinate salt produces geroprotective activity by inhibiting lipid peroxide products.

EXISTING KNOWLEDGE

PCT/IB2005/003636 discloses a method of preparing 2,4,6-trimethyl-3- hydroxypyridine derivatives and salts thereof having antioxidant, geroprotective and anti-ischemic activity.

This patent application suggest the use of 2,4,6-trimethyl-3-hydroxypyridine derivatives as a geroprotective and anti ischemic. Disclosure of the said Pet application is limited to a method of synthesis of 2,4,6-trimethyl-3-hydroxypyridine derivative and salts. However, details of the formulations comprising said 2,4,6- trimethyl-3-hydroxypyridine derivative or salts have not been disclosed. Accordingly, it is desirable to prepare a pharmaceutically acceptable dosage form containing 3-hydroxy-2,4,6-trimethylpyridine which will produce rapid onset of action .

OBJECTS OF THE INVENTION

It is an object of the present invention to provide a geroprotective, anti ischemic and antioxidant composition.

It is another objective of the present invention to provide stable, pharmaceutically acceptable oral composition in the form of solid and or liquid formulation.

It is a further object of this invention to provide an oral pharmaceutical composition that provides patient compliance.

It is another object of the present invention to provide an oral pharmaceutical composition which is easy to prepare and is cost effective.

SUMMARY OF THE INVENTION

In accordance with the present invention, there is provided an oral pharmaceutical composition comprising 3-hydroxy-2,4,6-trimethylpyridine, pharmaceutically acceptable salts, esters, derivatives and polymorphs in an amount of about 15 % to about 50 % of the mass of the formulation and pharmaceutically acceptable carrier.

Typically, the pharmaceutically acceptable salt of 3-hydroxy-2,4,6- trimethylpyridine is selected from a group of salts consisting of succinate, maleate, tartrate, oxalate, fumarate, citrate, hydrochloride, salicylate, pamoate, hydrogen sulfate, sulfate methanesulphonate and benzenesulfonate.

Typically, the concentration of 3-hydroxy-2,4,6-trimethylpyridine is in the range of about 20 % to about 40 % of the total mass of the composition.

Typically, the oral pharmaceutical composition in accordance with the present invention is in a tablet form and the pharmaceutically acceptable carrier therein comprises diluents, disintegrants, lubricants, glidents, binders, surfactants, solvents, matrix forming agents, coating polymers, effervescent agents, sweeteners, flavoring agents, colorants and preservatives.

Typically, the oral pharmaceutical composition in accordance with the present invention is in the form of a liquid oral formulation and the pharmaceutically acceptable carrier therein comprises sucrose, sorbitol, glycerol, mannitol, propylene glycol, polyethylene glycol, saccharin, aspartame, methyl Paraben, propyl Paraben, sodium benzoate, sorbic acid, potassium sorbate, benzoic acid, carboxymethylcellulose sodium, hydroxypropylmethylcellulose, colloidal silica, methyl cellulose, gum tragacanth, gum acacia, sodium alginate, povidone, xanthan gum, guar gum, tween 80, simethicon, disodium edentate, citric acid, sodium citrate, sodium acetate, sodium phosphate, sodium hydroxide, hydrochloric acid , colorants and flavoring agents.

Typically, the oral pharmaceutical composition in accordance with the present invention is in the form of a capsule and the pharmaceutically acceptable carrier therein comprises microcrystalline cellulose, lactose, starch , dicalcium phosphate, colloidal silica, magnesium stearate, talc, sodium startch Glycollate, Crospovidone, croscarmellose sodium, methyl paraben, propyl paraben, povidone and pregelatinised starch.

Typically, the oral pharmaceutical composition in accordance with the present invention is in the form of a dry syrup and the pharmaceutically acceptable carrier therein comprises sucrose, mannitol, sorbitol solid, saccharin, aspartame, sodium benzoate, sorbic acid, potassium sorbate, carboxymethylcellulose sodium, hydroxypropylmethylcellulose, colloidal silica, methyl cellulose, gum tragacanth, gum acacia, sodium alginate, Povidone, xanthan gum, guar gum, disodium edentate, sodium lauryl sulphate, citric acid, sodium citrate, sodium acetate, colorants and flavoring agents. Typically, the oral pharmaceutical composition in accordance with the present is in the form of a powder and the pharmaceutically acceptable carrier therein comprises lactose, microcrystalline cellulose, sucrose, mannitol, sorbitol solid, saccharin, aspartame, sodium benzoate, sorbic acid, potassium sorbate, citric acid, sodium citrate, sodium acetate, sodium bicarbonate, povidone, starch, colorants and flavoring agents.

Typically, the diluent is at least one selected from a group consisting of microcrystalline cellulose, starches, lactose, mannitol, calcium phosphate, dibasic calcium phosphate and mixture thereof.

Typically, the disintegrant is at least one selected from a group consisting of starches, clays, cellulose derivatives, gums, aligns including alginic acid, combinations of hydrocarbonates with weak acids, crospovidone, sodium starch glycolate, agar, cation exchange resins, citrus pulp, veegum HV, natural sponge, and bentonite cross-linked polyvinylpyrrolidone, carboxymethyl starch, natural starch, microcrystalline cellulose, cellulose gum, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, guar gum, polacrilin potassium, pregelatinized starch, sodium alginate and sodium starch glycolate.

Typically, the lubricant is at least one selected from a group consisting of magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, stearic acid, talc, and zinc stearate, stearic acid, magnesium lauryl sulfate, and colloidal silicon dioxide.

Typically, the binder is at least selected from a group consisting of acacia, sodium alginate, starch, gelatin, pregelatinized starch, partly pregelatinized starch, saccharides, glucose, sucrose, dextrose, lactose, molasses, panwar gum, guar gum, ghatti gum, carboxy methylcellulose, methylcellulose, veegur, polyethylene glycols, ethylcellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, gum arabic and dextrin. Typically, the surfactant is at least one selected from a group consisting of alkyl polyethylene oxide, alkylphenol polyethylene oxide, sodium laureth sulphate, sodium dodecyl sulphate, alkyl alcohol, sodium lauryl sulfate, polyoxyethylene/polyoxypropylene block polymers (poloxamers), glycerols, polyglycerols, fatty acids, polyethylene glycol hydroxystearate, polyalkyl glucosides, ceramides, polyethylene glycol/alkyl glycol copolymers, and polyethylene glycol/polyalkylene glycol ether di-block or tri-block copolymers, diacetylated monoglycerides, diethylene glycol monostearate, ethylene glycol monostearate, glyceryl monooleate, propylene glycol monostearate, macrogol esters, macrogol stearate, polyoxyethylene 50 stearate, macrogol ethers, cetomacrogol 1000, lauromacrogols, nonoxinols, octoxinols, tyloxapol, polyvinyl alcohols, polysorbate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan sesquioleate, sorbitan trioleate, sorbitan tristearate , sucrose esters, cetyl alcohol, oleyl alcohol, cetylpyridinium chloride, cetyl trimethylammonium bromide, tween 20 and tween 80.

Typically, the glidant is at least one selected from a group consisting of colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, lactose, stearates, dibasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate and silicon dioxide aerogels.

Typically, the matrix forming agent is selected from a group consisting of cellulose derivatives, acrylates, methacrylic acid derivatives, proteins, alginates, chitosan, eudrajit and xanthan gum.

Typically, the coating polymer is at least one selected from a group consisting of polymethacrylate, polymethamethacrylate, ethyl cellulose, hydroxymethyl cellulose, hydroxymethylpropylcellulose, cellulose acetate phthalate, arabinogalactan, carboxymethylcellulose, gelatin, gum arabic, methylcellulose; polyvinyl alcohol, polyamide, silicones, polyvinyl acetate, hydroxypropyl methylcellulose acetate, rosin, partially hydrogenated rosin and glycerol esters of rosin. Typically, the plasticizer is at least one selected from a group consisting of glycerol, polyethylene glycol, propylene glycol, sugar solution, alcohol, sorbitol, diethyl butyl pthalate, silicone, hexanol, pentanol, dimethylsulfoxide, hexane, oil and mixtures thereof.

Typically, the effervescent agent is at least one selected from a group consisting of citric acid, tartaric acid, sodium bicarbonate, potassium bicarbonate and calcium carbonate.

Typically, the sweetener is selected from the group consisting of sodium saccharin, calcium saccharin, cyclamic acid, cyclamate salts, dihydrochalcones, L-aspartyl-L- phenylalanine methyl ester, glycyrrhizin, glycyrrhizic acid, ammonium salt, sorbitol, mannitol, xylitol, aspartame, potassium acesulfame, sodium saccharinate, neohesperidin dihydrochalcone and mixtures thereof.

Typically, the flavoring agent is selected from a group consisting of anise oil, peppermint, lemon, mint, strawberry, banana, pineapple, orange, raspberry and vanilla.

DETAIL DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided an oral pharmaceutical composition comprising 3-hydroxy-2,4,6-trimethylpyridine, pharmaceutically acceptable salts, esters, derivatives and polymorphs thereof in an amount of about 15 to about 50 % and pharmaceutically acceptable carrier.

In accordance with the present invention, the pharmaceutically acceptable salt of 3- hydroxy-2,4,6-trimethylpyridine is selected from a group of salts consisting of succinate, maleate, tartrate, oxalate, fumarate, citrate, hydrochloride, salicylate, pamoate, hydrogen sulfate, sulfate methanesulphonate and benzenesulfonate.

The concentration of 3-hydroxy-2,4,6-trimethylpyridine used in the composition prepared in accordance with the present invention is in the range of about 20 to about 40 % of the total mass of the composition. The oral pharmaceutical composition in accordance with the present invention is in a tablet form and the pharmaceutically acceptable carrier therein comprises diluents, disintegrants, lubricants, glidents, binders, surfactants, solvents, matrix forming agents, coating polymers, effervescent agents, sweeteners, flavoring agents, colorantsand preservatives.

The diluent is at least one selected from a group consisting of microcrystalline cellulose, starches, lactose, mannitol, calcium phosphate, dibasic calcium phosphate and mixture thereof.

The oral pharmaceutical composition prepared in accordance with the present invention includes disintegrant which is at least one selected from a group consisting of starches, clays, cellulose derivatives, gums, aligns including alginic acid, combinations of hydrocarbonates with weak acids, crospovidone, sodium starch glycolate, agar, cation exchange resins, citrus pulp, veegum HV, natural sponge, and bentonite cross-linked polyvinylpyrrolidone, carboxymethyl starch, natural starch, microcrystalline cellulose, cellulose gum, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, guar gum, polacrilin potassium, pregelatinized starch, sodium alginate and sodium starch glycolate.

The lubricant is at least one selected from a group consisting of magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, stearic acid, talc, and zinc stearate, stearic acid, magnesium lauryl sulfate, and colloidal silicon dioxide.

The oral pharmaceutical composition prepared in accordance with the present invention includes at least one binder which is selected from a group consisting of acacia, sodium alginate, starch, gelatin, pregelatinized starch, partly pregelatinized starch, saccharides, glucose, sucrose, dextrose, lactose, molasses, panwar gum, guar gum, ghatti gum, carboxy methylcellulose, methylcellulose, veegur, polyethylene glycols, ethylcellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, starch, gum arabic and dextrin. The oral pharmaceutical composition prepared in accordance with the present invention further includes at least one surfactant which is selected from a group consisting of alkyl polyethylene oxide, alkylphenol polyethylene oxide, sodium laureth sulphate, sodium dodecyl sulphate, alkyl alcohol, sodium lauryl sulfate, polyoxyethylene/polyoxypropylene block polymers (poloxamers), glycerols, polyglycerols, fatty acids, polyethylene glycol hydroxystearate, polyalkyl glucosides, ceramides, polyethylene glycol/alkyl glycol copolymers, and polyethylene glycol/polyalkylene glycol ether di-block or tri-block copolymers, diacetylated monoglycerides, diethylene glycol monostearate, ethylene glycol monostearate, glyceryl monooleate, propylene glycol monostearate, macrogol esters, macrogol stearate, polyoxyethylene 50 stearate, macrogol ethers, cetomacrogol 1000, lauromacrogols, nonoxinols, octoxinols, tyloxapol, polyvinyl alcohols, polysorbate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan sesquioleate, sorbitan trioleate, sorbitan tristearate , sucrose esters, cetyl alcohol, oleyl alcohol, cetylpyridinium chloride, cetyl trimethylammonium bromide, tween 20 and tween 80.

The glidant used in the oral composition prepared in accordance with the present invention is at least one selected from a group consisting of colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, lactose, stearates, dibasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate and silicon dioxide aerogels.

The oral pharmaceutical composition prepared in accordance with the present invention further includes matrix forming agent which is selected from a group consisting of cellulose derivatives, acrylates, methacrylic acid derivatives, proteins, alginates, chitosan, eudrajit and xanthan gum.

The coating polymer is used to prepare film coated tablets which is at least one selected from a group consisting of polymethacrylate, polymethamethacrylate, ethyl cellulose, hydroxymethyl cellulose, hydroxymethylpropylcellulose, cellulose acetate phthalate, arabinogalactan, carboxymethylcellulose, gelatin, gum arabic, methylcellulose; polyvinyl alcohol, polyamide, silicones, polyvinyl acetate, hydroxypropyl methylcellulose acetate, rosin, partially hydrogenated rosin and glycerol esters of rosin.

The plasticizer used in the film coating is at least one selected from a group consisting of glycerol, polyethylene glycol, propylene glycol, sugar solution, alcohol, sorbitol, diethyl butyl pthalate, silicone, hexanol, pentanol, dimethylsulfoxide, hexane, oil and mixtures thereof.

The effervescent agent used to prepare effervescent tablet is at least one selected from a group consisting of citric acid, tartaric acid, sodium bicarbonate, potassium bicarbonate and calcium carbonate.

The sweetener is selected from the group consisting of sodium saccharin, calcium saccharin, cyclamic acid, cyclamate salts, dihydrochalcones, L-aspartyl-L- phenylalanine methyl ester, glycyrrhizin, glycyrrhizic acid, ammonium salt, sorbitol, mannitol, xylitol, aspartame, potassium acesulfame, sodium saccharinate, neohesperidin dihydrochalcone and mixtures thereof.

The flavoring agent is selected from the group consisting of anise oil, peppermint, lemon, mint, strawberry, banana, pineapple, orange, raspberry and vanilla.

In accordance with one of the embodiment of the present invention, the oral pharmaceutical composition is in the form of a liquid oral formulation and the pharmaceutically acceptable carrier therein comprises sucrose, sorbitol, glycerol, mannitol, propylene glycol, polyethylene glycol, saccharin, aspartame, methyl Paraben, propyl Paraben, sodium benzoate, sorbic acid, potassium sorbate, benzoic acid, carboxymethylcellulose sodium, hydroxypropylmethylcellulose, colloidal silica, methyl cellulose, gum tragacanth, gum acacia, sodium alginate, povidone, xanthan gum, guar gum, tween 80, simethicon, disodium edentate, citric acid, sodium citrate, sodium acetate, sodium phosphate, sodium hydroxide, hydrochloric acid , colorants and flavoring agents. In accordance with another embodiment of the present invention, the oral pharmaceutical composition is in the form of a capsule and the pharmaceutically acceptable carrier therein comprises microcrystalline cellulose, lactose, starch , dicalcium phosphate, colloidal silica, magnesium stearate, talc, sodium startch Glycollate, Crospovidone, croscarmellose sodium, methyl paraben, propyl paraben, povidone and pregelatinised starch.

In accordance with still another embodiment of the present invention, the oral pharmaceutical composition is in the form of dry syrup and the pharmaceutically acceptable carrier therein comprises sucrose, mannitol, sorbitol solid, saccharin, aspartame, sodium benzoate, sorbic acid, potassium sorbate, carboxymethylcellulose sodium, hydroxypropylmethylcellulose, colloidal silica, methyl cellulose, gum tragacanth, gum acacia, sodium alginate, Povidone, xanthan gum, guar gum, disodium edentate, sodium lauryl sulphate, citric acid, sodium citrate, sodium acetate, colorants and flavoring agents.

In accordance with yet another embodiment of the present invention, the oral pharmaceutical composition is in the form of a powder and the pharmaceutically acceptable carrier therein comprises lactose, microcrystalline cellulose, sucrose, mannitol, sorbitol solid, saccharin, aspartame, sodium benzoate, sorbic acid, potassium sorbate, citric acid, sodium citrate, sodium acetate, sodium bicarbonate, povidone, starch, colorants and flavoring agents.

Following examples illustrate the invention, but are not intended to limit the scope of the present invention.

Oral formulations, in accordance with the present invention employing different salts of 3-hydroxy-2,4,6-trimethylpyridine were prepared in the form of capsule, tablet, powder, dry syrup, powder and liquid.

Example 1

3-hydroxy-2,4,6-trimethylpyridine succinate capsule A capsule of 3-hydroxy-2,4,6-trimethylpyridine succinate was formulated as follows:

3-hydroxy-2, 4, 6-trimethylpyridine succinate 100.0 mg

Microcrystalline cellulose 95.0 mg

Lactose 30.0 mg

Maize starch 89.7 mg

Maize starch (for paste) 20.0 mg

Methyl paraben 0.2 mg

Propyl paraben 0.1 mg

Sodium starch glycollate 8.0 mg

Purified talc 2.0 mg

Magnesium stearate 2.0 mg

Colloidal anhydrous silica 3.0 mg

Purified water Q.S.

Microcrystalline cellulose, lactose and maize starch were mixed together in a blender and then granulated using starch paste containing methyl paraben and propyl paraben. The granules were dried, passed through No. 30 stainless steel screen to obtain suitable particle size distribution. The granules were blended with 3-hydroxy-2, 4, 6-trimethylpyridine succinate, sodium starch glycollate talc, colloidal anhydrous silica and magnesium stearate. The prepared blended mass was filled in size '0' opaque capsules.

Example 2

3-hydroxy-2,4,6-trimethylpyridine succinate capsule

A capsule of 3-hydroxy-2,4,6-trimethylpyridine succinate was formulated as follows:

3-hydroxy-2,4,6-trimethylpyridine succinate 100.0 mg

Microcrystalline cellulose direct compression grade 90.0 mg

Lactose direct compression grade 90.0 mg

Sodium starch glycollate 13.0 mg

Purified talc 2.0 mg Magnesium stearate 2.0 mg

Colloidal anhydrous silica 3.0 mg

Lubricated blend of 3-hydroxy-2,4,6-trimethylpyridine succinate was prepared with microcrystalline cellulose, lactose, sodium starch glycollate, talc, colloidal anhydrous silica and magnesium stearate. The prepared blended mass was then filled in size '0' opaque capsules.

Example 3

3-hydroxy-2,4,6-trimethylpyridine succinate tablet

A tablet of 3-hydroxy-2,4,6-trimethylpyridine succinate was formulated as follows:

3-hydroxy-2,4,6-trimethylpyridine succinate 100.0 mg

Microcrystalline cellulose 95.0 mg

Lactose 30.0 mg

Maize starch 90.0 mg

Maize starch (For Paste) 20.0 mg

Crospovidone 7.0 mg

Purified talc 2.0 mg

Magnesium stearate 3.0 mg

Colloidal anhydrous silica 3.0 mg

Purified water Q. S.

3-hydroxy-2,4,6-trimethylpyridine succinate, microcrystalline cellulose, lactose and maize starch were granulated using starch paste. The granules were dried, screened through stainless steel screen No. 30 and mixed with a blend of crospovidone, talc, colloidal anhydrous silica and magnesium stearate. The blended mass was then compressed.

Example 4

3-hydroxy-2,4,6-trimethylpyridine succinate tablet

A film coated tablet of 3-hydroxy-2,4,6-trimethylpyridine succinate was formulated as follows: 3-hydroxy-2,4,6-trimethylpyridine succinate 100.0 mg Microcrystalline cellulose direct compression grade 95.0 mg

Dicalcium phosphate compression grade 90.0 mg

Croscarmellose sodium 7.0 mg

Purified Talc 2.0 mg

Magnesium stearate 3.0 mg

Colloidal anhydrous silica 3.0 mg

Lubricated blend of 3-hydroxy-2,4,6-trimethylpyridine succinate was prepared with microcrystalline cellulose, diclacium phosphate, crosscarmellose sodium talc, colloidal anhydrous silica and magnesium stearate. The blended mass was then compressed to form the tablet. Further, the tablet was coated with coating solution containing hydroxypropylmethylcellulose, titanium dioxide, propylene glycol and iron oxide yellow in purified water.

Example 5

3-hydroxy-2,4,6-trimethylpyridine succinate tablet

3-hydroxy-2,4,6-trimethylpyridine succinate 100.0 mg

Microcrystalline cellulose 95.0 mg

Lactose 30.0 mg

Maize starch 90.0 mg

Maize starch (for paste) 20.0 mg

Crospovidone 8.0 mg

Sodium saccharin 3.5 mg

Orange flavor 1.5 mg

Purified talc 2.0 mg

Magnesium stearate 2.0 mg

Colloidal anhydrous silica 3.0 mg

Purified Water Qs Microcrystalline cellulose, lactose, maize starch and 3-hydroxy-2, 4, 6- trimethylpyridine succinate were granulated using starch paste. The granules were dried, screened through stainless steel screen No. 30 and then blended the dried granules with crosspovidone, sodium saccharin, orange flavor, talc, colloidal anhydrous silica and magnesium stearate. Finally the blended mass was compressed.

Example 6

3-hydroxy-2,4,6-trimethylpyridine succinate tablet

3-hydroxy-2,4,6-trimethylpyridine succinate 100.0 mg

Microcrystalline cellulose direct compression grade 95.0 mg

Mannitol direct compression grade 30.0 mg

Pregelatinsed maize starch 50.0 mg

Croscarmellose sodium 8.0 mg

Sodium saccharin 3.5 mg

Sorbitol 2.0 mg

Orange flavor 3.5 mg

Purified talc 2.0 mg

Magnesium stearate 2.0 mg

Colloidal anhydrous silica 3.0 mg

All the ingredients were sifted through stainless steel screen No. 30 and mixed in a blender. The blended mass was then compressed.

Example 7

3-hydroxy-2,4,6-trimethylpyridine succinate powder

A powder of 3-hydroxy-2,4,6-trimethylpyridine succinate was formulated as follows:

3-hydroxy-2,4,6-trimethylpyridine succinate 100 mg

Sucrose 95.0 mg

Maize starch 50 mg Povidone 10 mg

Citric acid 3.0 mg

Sodium citrate 2.0 mg

Sodium saccharin 3.5 mg

Sorbitol 2.0 mg

Orange flavor 3.5 mg

Colloidal anhydrous silica 3.0 mg

Water QS

The granules of sucrose, maize starch and 3-hydroxy-2,4,6-trimethylpyridine succinate were prepared using aqueous povidone solution. The prepared granules were dried and screened through stainless steel screen No. 20. The granules were further blended with sodium saccharin, orange flavor, sorbitol, sodium citrate, citric acid and colloidal anhydrous silica.

Example 8

3-hydroxy-2,4,6-trimethylpyridine succinate effervescent tablet

An effervescent tablet of 3-hydroxy-2,4,6-trimethylpyridine succinate was formulated as follows:

3-hydroxy-2, 4, 6-trimethylpyridine succinate 100.0 mg

Sorbitol instant 43.5 mg

Xylitol 43.5 mg

Citric acid anhydrous 140.0 mg

Sodium bicarbonate 155.0 mg

Sodium saccharin 5.0 mg

Flavor Qs

Color Qs

Magnesium Stearate Qs

3-Hydroxy-2,4,6-trimethylpyridine succinate, sorbitol, xylitol, citric acid, sodium bicarbonate, sodium saccharin, flavor, color and lubricant were blended in a blender. The blended mass was compressed. Example 9

3-hydroxy-2,4,6-trimethylpyridine succinate powder (dry syrup)

Powder of 3-hydroxy-2,4,6-trimethylpyridine succinate was formulated as follows:

3-hydroxy-2,4,6-trimethylpyridine succinate 2.0 % w/v

Sucrose 65.0 %w/v

Mannitol 20.0 %w/v

Sodium benzoate 0.2 %w/v

Citric acid 0.3 %w/v

Sodium citrate 0.3 %w/v

Sodium saccharin 0.5 %w/v

Orange flavor 0.5 %w/v

Xanthan gum 0.2 %w/v

All the ingredients were passed through S. S. sieve No.30 and blended together in a blender. The resultant dry syrup was filled in a bottle.

Example 10

3-hydroxy-2,4,6-trimethylpyridine succinate liquid

A liquid of 3-hydroxy-2,4,6-trimethylpyridine succinate was formulated as follows:

3-hydroxy-2,4,6-trimethylpyridine succinate 2.0%w/v

Sucrose 75.0%w/v

Non crystallizing sorbitol 10.0 %w/v

Methyl paraben 0.2% w/v

Propyl paraben 0.02%w/v

Citric acid 0.3%w/v

Sodium citrate 0.3%w/v

Sodium saccharin 0.5%w/v

Orange flavor Qs

Color Qs

Water Qs Methyl paraben and propyl paraben were dissolved in hot water. To this sucrose was added to obtain syrup. 3-hydroxy-2,4,6-trimethylpyridine succinate, citric acid, sodium citrate and color were added to the syrup with continuous stirring. Flavor was added in the final step. The pH of the syrup in was maintained in between 3 to 6.

Preclinical Trials:

Anti -ischemic activity:

The efficiency of formulation comprising 3-hydroxy-2,4,6-trimethylpyridine succinate prepared in accordance with the present invention, in acute myocardial ischemia was studied by evaluating effect of the formulation on the sizes of necrosis ischemia zones.

The experiment was done on non- linear male rats weighing about 250-300 g. The animals were anesthetized with sodium ethaminale (40 mg/kg intraperitoneally). A myocardial infarction was modeled for the animals. The animals were then transferred to controlled breathing by ligation of a descending branch of the left- hand coronary artery at a level of the lower edge of an auricula atrii.

The sizes of a necrosis zone and ischemia zones were detected in 4 hours after occlusion of a coronary artery by a differential indicator method, which is founded on separate quantitative determination of Evans' blue (indicator of a ischemia zone) and red phormazane (indicator of a necrosis zone).

The results of anti-ischemic activity of 3-hydroxy-2, 4, 6-trimethylpyridine succinate and other 3-oxypyridine derivatives (in 4 hours after occlusion of a coronary artery of rats) are shown in table No. 3. Table 3: Anti-ischemic activity

The results as shown in table No. 3 clearly indicate that the formulation comprising 3-hydroxy-2, 4, 6-trimethylpyridine succinate prepared in accordance with the present invention displays considerably higher anti-ischemic activity than other 3- oxypyridines.

ANECDOTAL TRIALS;

Dramatic and significant results have been obtained in individual anecdotal cases of patients presenting with ischemia, intraocular hemorrhage and macular degeneration in which the condition is either reversed or ameliorated.

The applicant craves leave to submit formal data to establish significant enhancement of efficacy by way of explanation to support these preliminary findings.

While considerable emphasis has been placed herein on the specific ingredients of the preferred formulation, it will be appreciated that many additional ingredients can be added and that many changes can be made in the preferred formulation without departing from the principles of the invention. These and other changes in the preferred formulation of the invention will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not as a limitation.

Claims

Claims:

1. An oral pharmaceutical composition comprising 3-hydroxy-2,4,6- trimethylpyridine, pharmaceutically acceptable salts, esters, derivatives and polymorphs thereof in an amount of about 15 to about 50 % of the mass of the formulation and pharmaceutically acceptable carrier.

2. The oral pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable salt of 3-hydroxy-2,4,6-trimethylpyridine is selected from a group of salts consisting of succinate, maleate, tartrate, oxalate, fumarate, citrate, hydrochloride, salicylate, pamoate, hydrogen sulfate, sulfate methanesulphonate and benzenesulfonate.

3. The oral pharmaceutical composition as claimed in claim 1 which is in a tablet form and the pharmaceutically acceptable carrier therein comprises diluents, disintegrants, lubricants, glidents, binders , surfactants , solvents, matrix forming agents, coating polymers , effervescent agents, sweeteners, flavoring agents , colorants and preservatives.

4. The oral pharmaceutical composition as claimed in claim 1 which is in the form of a liquid oral formulation form and the pharmaceutically acceptable carrier therein comprises sucrose, sorbitol, glycerol, mannitol, propylene glycol, polyethylene glycol, saccharin, aspartame, methyl Paraben, propyl Paraben, sodium benzoate, sorbic acid, potassium sorbate, benzoic acid, carboxymethylcellulose sodium, hydroxypropylmethyl cellulose, colloidal silica, methyl cellulose, gum tragacanth, gum acacia, sodium alginate, Povidone, xanthan gum, guar gum, tween 80, simethicon, Disodium edentate, citric acid, sodium citrate, sodium acetate, Sodium phosphate, sodium hydroxide, hydrochloric acid, colorants and flavoring agents.

5. The oral pharmaceutical composition as claimed in claim 1 which is in the form of a capsule and the pharmaceutically acceptable carrier therein comprises microcrystalline cellulose, lactose, starch , dicalcium phosphate, colloidal silica, magnesium stearate, talc, sodium startch glycollate, crospovidone, croscarmellose sodium, methyl paraben, propyl paraben, povidone and pregelatinised starch.

6. The oral pharmaceutical composition as claimed in claim 1 which is in the form of a dry syrup and the pharmaceutically acceptable carrier therein comprises sucrose, mannitol, sorbitol solid, saccharin, aspartame, sodium benzoate, sorbic acid, potassium sorbate, carboxymethylcellulose sodium, hydroxypropylmethylcellulose, colloidal silica, methyl cellulose, gum tragacanth, gum acacia, sodium alginate, povidone, xanthan gum, guar gum, disodium edentate, sodium lauryl sulphate, citric acid, sodium citrate, sodium acetate, colorants and flavoring agents.

7. The oral pharmaceutical composition as claimed in claim 1 which is in the form of a powder and the pharmaceutically acceptable carrier therein comprises lactose, microcrystalline cellulose, sucrose, mannitol, sorbitol solid, saccharin, aspartame, sodium benzoate, sorbic acid, potassium sorbate, citric acid, sodium citrate, sodium acetate, sodiumbicarbonate, povidone, starch, colorants and flavoring agents.

8. The oral pharmaceutical compositionas claimed in claim 1, wherein the concentration of 3-hydroxy 2, 4, 6 trimethylpyridine is in the range of about 20 to about 40 % of the total mass of the composition.

9. The oral pharmaceutical composition as claimed in claim 3, wherein the diluent is at least one selected from a group consisting of microcrystalline cellulose, starches, lactose, mannitol, calcium phosphate, dibasic calcium phosphate and mixture thereof.

10. The oral pharmaceutical composition as claimed in claim 3, wherein the disintegrant is at least one selected from a group consisting of starches, clays, cellulose derivatives, gums, aligns including alginic acid, combinations of hydrocarbonates with weak acids, crospovidone, sodium starch glycolate, agar, cation exchange resins, citrus pulp, veegum HV, bentonite, cross-linked polyvinylpyrrolidone, carboxymethyl starch, natural starch, microcrystalline cellulose, cellulose gum, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, guar gum, polacrilin potassium, pregelatinized starch, sodium alginate and sodium starch glycolate.

11. The "oral pharmaceutical composition as claimed in claim 3, wherein the lubricant is at least one selected from a group consisting of magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, stearic acid, talc, zinc stearate, stearic acid, magnesium lauryl sulfate, and colloidal silicon dioxide.

12. The oral pharmaceutical composition as claimed in claim 3, wherein the binder is at least selected from a group consisting of acacia, sodium alginate, starch, gelatin, pregelatinized starch, partly pregelatinized starch, saccharides, glucose, sucrose, dextrose, lactose, molasses, panwar gum, guar gum, ghatti gum, carboxy methylcellulose, methylcellulose, veegur, polyethylene glycols, ethylcellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, gum arabic and dextrin.

13. The oral pharmaceutical composition as claimed in claim 3, wherein the surfactant is at least one selected from a group consisting of alkyl polyethylene oxide, alkylphenol polyethylene oxide, sodium laureth sulphate, sodium dodecyl sulphate, alkyl alcohol, sodium lauryl sulfate, polyoxyethylene block polymers, polyoxypropylene block polymers (poloxamers), glycerols, polyglycerols, fatty acids, polyethylene glycol hydroxystearate, polyalkyl glucosides, ceramides, polyethylene glycol/alkyl glycol copolymers, and polyethylene glycol/polyalkylene glycol ether di-block or tri-block copolymers, diacetylated monoglycerides, diethylene glycol monostearate, ethylene glycol monostearate, glyceryl monooleate, propylene glycol monostearate, macrogol esters, macrogol stearate, polyoxyethylene 50 stearate, macrogol ethers, cetomacrogol 1000, lauromacrogols, nonoxinols, octoxinols, tyloxapol, polyvinyl alcohols, polysorbate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan sesquioleate, sorbitan trioleate, sorbitan tristearate , sucrose esters, cetyl alcohol, oleyl alcohol, cetylpyridinium chloride, cetyl trimethylammonium bromide, tweeπ 20 and tween 80.

14. The oral pharmaceutical composition as claimed in claim 3, wherein the glidant is at least one selected from a group consisting of colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, lactose, stearates, dibasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate and silicon dioxide aerogels.

15. The oral pharmaceutical composition as claimed in claim 1, wherein the matrix forming agent is selected from a group consisting of cellulose derivatives, acrylates, methacrylic acid derivatives, proteins, alginates, chitosan, eudrajit and xanthan gum.

16. The oral pharmaceutical composition as claimed in claim 3, wherein the coating polymer is at least one selected from a group consisting of polymethacrylate, polymethamethacrylate, methylcellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxymethylpropylcellulose, cellulose acetate phthalate, arabinogalactan, carboxymethylcellulose, gelatin, gum arabic, polyvinyl alcohol, polyamide, silicones, polyvinyl acetate, hydroxypropyl methylcellulose acetate, rosin, partially hydrogenated rosin and glycerol esters of rosin.

17. The pharmaceutical composition as claimed in claim 3, wherein the plasticizer is at least one selected from a group consisting of glycerol, polyethylene glycol, propylene glycol, sugar solution, alcohol, sorbitol, diethyl butyl pthalate, silicone, hexanol, pentanol, dimethylsulfoxide, hexane, oil and mixtures thereof.

18. The pharmaceutical composition as claimed in claim 3, wherein the effervescent agent is at least one selected from a group consisting of citric acid, tartaric acid, sodium bicarbonate, potassium bicarbonate and calcium carbonate.

19. The pharmaceutical composition as claimed in claim 3, wherein the sweetener is selected from the group consisting of sodium saccharin, calcium saccharin, cyclamic acid, cyclamate salts, dihydrochalcones, L-aspartyl-L-phenylalanine methyl ester, glycyrrhizin, glycyrrhizic acid, ammonium salt, sorbitol, mannitol, xylitol, aspartame, potassium acesulfame, sodium saccharinate, neohesperidin dihydrochalcone and mixtures thereof.

20. The pharmaceutical composition as claimed in claim 3, wherein the flavoring agent is selected from the group consisting of anise oil, peppermint oil, lemon oil, mint, strawberry, banana, pineapple, orange, raspberry and vanilla.