FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
TITLE OF THE INVENTION:
"NOVEL COMPOSITION OF LIPOIC ACID STABLE COMPRESSED TABLET"
NAME OF APPLICANT: RUPESH DATTATRYA DAMKONDWAR
NATIONALITY: INDIA
ADDRESS: C/O R.V.BANDEWAR,
102-SAMRAT ASHOK, FLAT NO-102, GORAI-II, BORIVALI (W). MUMBAI - 400092
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

NOVEL COMPOSITION OF L1POIC ACID STABLE COMPRESSED
TABLET
TECHNICAL FIELD OF INVENTION:
The present invention relates to lipoic acid stable pharmaceutical composition in the form of compressed tablet and the process for preparing the same.
BACKGROUND:
Lipoic acid is a powerful antioxidant, a critical co-factor in ATP production, regulates lipid and carbohydrate metabolism. Lipoic acid (oxidized form) and DHLA (reduced form) are able to regenerate antioxidants including glutathione, ascorbic acid, and alpha-tocopherol (indirectly). Both lipoic acid and DHLA also protect the integrity of cell membranes by interacting with antioxidants—GSH, and vitamins E and C. Lipoic acid is found useful in the treatment of Diabetes II; it improves glucose transport and metabolism, diabetic neuropathy, cataracts, heavy metal poisoning, burning mouth syndrome, neurodegenerative disorders like Alzheimer and Parkinson's. It also protects body against free radical damage and oxidative stress.
Lipoic acid occurs in different forms: R-Lipoic acid (R (+) enantiomer) is the pure form found in nature from the simplest organisms up to the humans. Life does not exist without it, and it is found in every cell of the body. Alpha-lipoic acid consists of 50/50 racemic mixture of the R and S enantiomers and is the commonly commercially available form of lipoic acid.
Alpha Lipoic Acid has poor solubility and absorption from the GI tract, as only 30% reaches the plasma vs an iv dose and extensively gets metabolized in liver during its absorption through intestine.
The S-S bond on lipoic acid may be homolytically cleavaged by near ultraviolet light or by heating; the formed thiyl radical can react with another lipoic acid molecule, resulting in a linear chain of disulfides. This process is associated with disappearance of the UV

absorption at 333 nm, indicating the destruction of the 1, 2-dithiolane ring. Visually, lipoic acid is transformed from yellow crystals into a colorless glass. The polymers undergo depolymerization in basic solution. It is proposed that this proceeds via reaction of the thiolate anion with the disulfide linkages. Recovery of the monomer by this method is of practical significance, since it is hard to avoid formation polymeric material during the synthesis of lipoic acid.
Lipoic acid (oxidized) is labile to chemical degradation and gets converted into dihydrolipoic acid, which produces characteristics garlic like smell in formulation. Lipoic acid suffers from certain disadvantages, when it comes develop a stable oral dosage form in the form of compressed tablets. In particularly, lipoic acid has a low melting point of 60-61°C; the natural form R-LA is unstable above 40°C. During tablet compression lipoic acid get polymerized due to the heat generated during compression leading to capping problem in tablets, partially polymerized product can cause significant stability problems for the dosage form. The polymerization reduces dissolution, GI absorption and lowers the bioavailability lipoic acid, since it is so poorly absorbed from the GI tract.
It has been scientifically proven that lipoic acid act synergistically against free radicals when combined with other antioxidants like carnitine, CoQ10, ascorbic acid, vitamin E folic acid and glutathione or N-acetyl cystine etc.
Sethumadhavan Savitha, et al., Clinica Chimica Acta.,355(l-2),173-180(2005)have studied the role of Role of dl-a-lipoic acid and 1-carnitinee in mitochondrial oxidative stress. They found that co-supplementation of lipoic acid with carnitinee has a beneficial effect in reversing the age-related abnormalities seen in aging. This effect was associated with the decrease in free radical production and rise in antioxidant levels within mitocondria by carnitinee and lipoic acid, thereby lowering oxidative stress.
Hagen TM, et al., Proc Natl Acad Sci U S A., 99(4), 1870-1875(2002) studied the effect of acetyl-L-carnitinee and lipoic acid on metabolic function and oxidative stress in rats.

They found that Feeding Acetyl-Lcarnitine in combination with Lipoic Acid increased metabolism and lowered oxidative stress more than either compound alone.
Kumaran S, et al., Mech Ageing Dev, 125(7), 507-512(2004) have studied the glutathione redox system as a function of age in rat heart and muscle. A decline in reduced glutathione (GSH) levels is associated with aging and many age-related diseases. The objective of study was to determine whether L-carflitinee and DL-alpha-lipoic acid could compensate for GSH depletion in protection against oxidative insults. In conclusion, our study suggests that supplementation of earnitinee and lipoic acid to aged rats improves the glutathione redox system.
Lee D, et al, Proc Amer Assoc Cancer Res, Volume 45, 2004, abstract - 143 reported the synergistic antioxidant capacity of six antioxidant combinations: ascorbic acid, vitamin E, glutathione, and ubiquinone-coenzyme Q10 (CoQ10), rutin and lipoic acid. They found evidence of synergistic intracellular antioxidant networking. Vitamin E in double combinations with lipoic acid, glutathione, ascorbic acid and COQ10 showed synergism values 5.4, 5.7, 5.1, and 5.4 -fold respectively above expected values.
US Patent 6733793 discloses a composition containing alpha lipoic Acid, chromium, lutein, bioflavonoids(quercetin and rutin), mormordica charantia extract, corosolic acid, and gymnema sylvestre extract, as well to assist in the maintenance of insulin sensitivity and healthy blood sugar levels.
PCT application WO2000072854 discloses a dietary supplementation in animals which includes administering to an animal a composition which includes synergistically effective amounts of vanadvl sulfate, alpha-lipoic acid and taurine and continuing administration of the composition until normalization of serum triglyericeds is achieved.
US patent application 20080268066 discloses a combined formulation for preventing and/or treating diabetes, comprising Vitamin E, chromium, selenium, lutein, folic acid, Vitamin C, alpha lipoic acid, zinc, glutathione, lycopene, nicotinamide, L-arginine,

vanadium and a pharmaceutical acceptable carrier, which further comprising coenzyme Q10 , a vitamin complex and mineral
US patent application 20050037073 discloses alpha-lipoic acid in self-emulsifying controlled release tablet formulation containing oil phase i.e. alpha-tocopherol acetate arid tocopherol acid succinate PEG 1000 ester as a surfactant.
A. Segail., et al., J cosmet Sci., 55, 449-461 (2004) have studied stability of lipoic acid in the presence of vitamin A and vitamin E in o/w emulsion for cosmetic application. They report that vitamin A favors Hpoic acid stability but vitamin E could not prevent lipoic acid degradation.
Anjana Sarkar, et al., radiation chemistry and chemical dynamics division BARC Mumbai have studied free radical reactions between folic acid and a-lipoic acid. They found that folic acid regenerate lipoic acid from the lipoic acid free radical showing potential new synergistic combination.
Most of the marketed compositions containing lipoic acid are in the form of soft gelatin capsules, involving special technology and machine, which increases the overall cost of formulation. Thus there is constant need to formulate a physically and chemically stable oral formulation of lipoic acid in the form of compressed tablet, which will not only stabilize the Hpoic acid but also improve its water solubility, especially at low acidic pH, which can be prepared by economically suitable and simple manufacturing process

OBJECTIVE OF INVENTION:
1. One of the objectives of the invention is to prepare stable compressed tablet of lipoic acid, optionally with one or more pharmaceutically active agents.
2. Another objective of invention is to prevent polymerization of lipoic acid during tablet compression and storage.
3. Another objective of invention is to prevent chemical degradation of lipoic acid in compressed tablets on storage which gives garlic like smell to tablets,
4. Another objective of invention is to improve stability of lipoic acid in compressed tablets.
5. Another objective of invention is to prepare water soluble complex of lipoic acid with surfactant.
6. Yet another objective of invention is to prevent tabletting problems like picking, sticking, lamination, capping and the like.
SUMMARY OF THE INVENTION
The present invention relates to lipoic acid stable pharmaceutical composition in the form of compressed tablet and the process for preparing the same. Lipoic acid (oxidized form) is labile to chemical degradation and gets converted into dihydrolipoic acid, which produces characteristics garlic like smell in the formulation. Lipoic acid get polymerized during tablet compression due to the heat generated during compression leading to capping problem in tablets and partially polymerized product also causes significant stability problems. The polymerization reduces dissolution, GI absorption and lowers the bioavailability of lipoic acid.
According to the present invention it is found that polymerization and degradation of lipoic acid in compressed tablets can be avoided by using stabilizer, which is a combination of combination of surfactant and antioxidant.

DETAILED DESCRIPTION:
* The present invention relates to lipoic acid stable pharmaceutical composition in the form
of compressed tablet and the process for preparing the same.
According to the present invention it is found that polymerization and degradation of lipoic acid in compressed tablets can be prevented by using stabilizer, which is a combination of surfactant and antioxidant.
According to present invention the process of preparing stable lipoic acid pharmaceutical composition in the form of compressed tablet comprising the steps of:
Step (i) dissolve or disperse lipoic acid and surfactant in organic solvent
and/or water to this add whole or part of antioxidant(s), optionally add binder and mix well, Step (ii) to the above step add one or more adsorbent(s) and mix well to get
wet mass. Step (iii) pass the wet mass of step (ii) through suitable mesh to get wet
granules and dry the granules at a temperature not exceeding 100°C, preferably below 60°C. Step (iii) sizing the dried granules of above step to desired size by through
suitable mesh. Step (iv) mix the sized granules of above step with remaining part of
antioxidant in step (i), optionally with one or more pharmaceutically active agents, Step (v) finally mix the one or more pharmaceutically acceptable additives and compress the blend into tablets. Wherein the pharmaceutically active agent in step (iv) may be in the form of granules, comprising pharmaceuticalJy active agent and one or more pharmaceutically acceptable additives prepared by wet granulation or by dry granulation.
According to the above process lipoic acids along with antioxidant and surfactant get adsorbed on to the adsorbent. Thus avoids the liDoic acid narticle interaction and

stabilizes the lipoic acid against polymerization due to heat generated during tablet compression. Surfactant will helps in adsorption of lipophilic lipoic acid molecules on the adsorbent and also helps in improving lipoic acid solubility at low acidic pH. The use of antioxidants along with surfactant will maintain lipoic acid in its oxidized state thus avoids chemical degradation of lipoic acid into reduced form i.e. dihydrolipoic acid which gives garlic like smell to formulation.
According to present invention compressed tablet preferably prepared by wet granulation method, granulating fluid may be organic solvent and / or water, preferably organic solvent like ethanol, isopropyl alcohol. Additionally co-solvents like, propylene glycol, polyethylene glycol may be used along with granulating fluid.
According to present invention compressed tablets may be in the form of film coated or uncoated, preferably film coated with Colorcoat FL80 (Corel Pharma Chem, Ahmedabad, India) which is HPMC based ready to use coating polymer, which is used for flavor coating in solvent and aqueous system of tablet, pills, pellets and granules. It is colored free flowing powder with added flavor and sweetner. The film is sweallable and permeable at any pH. Optionally the tablets may be seal coated before giving film coating. Usually 1-4% (by weight of the tablet) of film coating is applied.
According to the present invention lipoic acid may be selected from alpha lipoic acid (racemic form) or R-lipoic acid. The dosage may be of any desired size in terms of the Alpha lipoic acid as active ingredients. However, sizes in a range of about 1 mg to about 1,000 mg are generally used in case of Alpha lipoic acid, preferably about 100 mg to 600
mg.
According to the present invention one or more pharmaceutically active agents may be selected from the group of Nutraceuticals, Vitamins, Minerals, Amino acids, Extracts of plant origin as follows.
Nutraceuticals like lypocane, curcumin, vinpocetine, soya flavonides, bee pollen, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), S-adenosyl-L-methionine, 5-

hydroxytryptophan, ubiquinone, idebenone. superoxide dismutase, choline alfosderate, pipeline, biotin, niacin, benfotiamine, rutin, a-glucosyl rutin, a-maltosyl rutin, a-maltotriosyl rutin, a-maltotetraosyt rutin, a-maltopentaosyl rutin., L-carnitine, Acetyl-L-carnitine, propionyl L-carnitine, valeryf L-carnitine, isovaleryl L-carnitine and its salts, L-glutathione reduced, L-glutathione oxidized, N-acetyl cystine, omega B fatty acid, luetin ester, beta carotene, inositol, N-alpha acetylcarnosine, carnosine, quercitin, hesperidin, citicoline, DL-methionine , choline (bitartrate),
Vitamins like vitamin A palmitate, vitamin A acetate, ascorbic acid, Ascorbic acid, , ascorbyl laurate, ascorbyl myristate, ascorbyl stearate, a-tocopherol, P-tocopherol, gamma-tocopherol, delta-tocopherol, tocoquinone, tocotrienol, Vitamin E esters which readily undergo hydrolysis to Vitamin E such as Vitamin E acetate, Vitamin E succinate, vitamin D, folic acid, vitamin K, vitamin Bl, vitamin B2, vitamin B12, vitamin B3 jvitamin B6, nicotinamide, pyridoxine HCL, Methylcobalamine.
Minerals like, calcium (elemental), magnesium (elemental), potassium (elemental), chromium (picolinate), iodine (as kelp), boron (as gluconate), vanadyl sulfate, zinc ,molybdenum, copper, selenium, iron (II) sulfate, phosphorous.
Amino acids like L-argenine, L-methionone, L-threonine, L-tryptophan, L-isoleucine, L-leucine, L-phenylalanine, L-histidine, L-lysine, L-taurine, L-glutamine, L-glutathione, L-carnitine, L-tyrosine, L-theanine, L-proline, L-histidine and the like.
Extracts of arjuna bark {Terminalia arjuna), olive leaf {plea europaea), indian snakeroot {Rauwolfia serpentina), black cumin seeds (Nigella sativa), pepper (Piper nigrum), cardemom {Elettaria and Amomum), clove (Syzygium aromaticum, syn. Eugenia aromaticwn or Eugenia caryophyllata), aloe (Aloe vera), turmeric {Curcuma longd), pine tree (Pinus pinea), Grape seed extract {Vitis vinifer), ginseng (Panax ginseng) , soybean (Glycine max), {Camellia sinensis) green tea, {Cassia cinnamon) Cinnamon, Cranberry (Vaccinium microcarpum) Garlic {Allium sativum), ginger {Zinziber officinale), Ginkgo {Ginkgo biloba), Hoodia {Hoodia gordonii), Saw Palmetto {American Dwarf Palm Tree), St. John's Wort {Hypericum perforatum), Valerian {Valeriana officinalis), Licorice Root

(Glycyrrhiza glabra), Wild Golden Root ( Rhodiola rosea L.), Capsicum (C Annuum) ,
« •
Horsetail (Equisetum laevigatum).
Acetyl L-carnitine / L-camitine are a naturally occurring substance required in mammalian energy metabolism. It has been shown to facilitate long-chain fatty acid entry into cellular mitochondria, thereby delivering substrate for oxidation and subsequently boosts the energy production in mitochondria. L-carnitine is highly soluble in water. Adsorption of L-carnitine from the stomach and duodenum is discussed to occur on a passive way by diffusion of non-ionic L-carnitine (pKa 3.8), whereas the intestinal absorption occurs partly via carried-mediated transport and partly via passive diffusion. Oral bioavailability of L-carnitine is 20%.
According to the present invention carnitine may be selected from the group of L-carnitine, Acetyl L-carnitine, propionyl L-carnitine, valeryl L-carnitine, isovaleryl L-carnitine and the like.
Curcumin is the principal curcuminoid of the popular Indian spice turmeric, which is a member of the ginger family (Zingiberaceae). Curcumin has antioxidant, antiinflammatory, antiviral and antifungal actions. Studies have shown that curcumin is not toxic to humans. Curcumin inhibits the growth of Helicobacter pylori, which causes gastric ulcers and has been linked with gastric cancers.Curcumin can bind with heavy metals such as cadmium and lead, thereby reducing the toxicity of these heavy metals. This property of curcumin explains its protective action to the brain.R-PLUS Curcumin vegcaps is a product marketed by GeroNova Research, Inc (US) as dietary supplement contains R-Lipoic acid and curcumin.
Taurine or L-Taurine is an amino acid that is considered to be the second most abundant in the body's muscle after glutamine. However, with new research scientists are beginning to think that taurine is the most abundant in the body's Type II muscle fibers, even more so than glutamine, which has led to much speculation for power athletes (45). Dairy products, meat, poultry, eggs, and fish are excellent natural sources of taurine.

Taurine has been known to increase muscle mass, muscle strength, power, reduces muscle damage caused by exercise, accelerate recovery between workouts, and may also have an insulin-like effect in the body.
N-Acetyl Cysteine is a steady form of the sulfur-containing amino acid L-Cysteine, it is rapidly metabolized to intracellular glutathione.
According to the present invention the stabilizer essentially comprises one or more surfactant and antioxidant, optionally comprise of one or more chelating agent, or mixture thereof.
According to present invention the surfactant and lipoic acid were used in ratio 1:3. According to the present invention nonlimiting examples of surfactants are as follows. Especially preferred family of surfactants are a: b: a triblock co-polymers of ethylene oxide: propylene oxide: ethylene oxide. The"a"and"b" represent the average number of monomer units for each block of the polymer chain. These surfactants are commercially available from BASF Corporation of Mount Olive, New Jersey, in a variety of different molecular weights and with different values of'a" and"b"blocks. For example, Lutrolo F127 has a molecular weight range of 9,840 to 14,600 and where"a"is approximately 101 and"b"is approximately 56, Lutrol F87 represents a molecular weight of 6,840 to 8,830 where"a"is 64 and"b"is 37, Lutrol F108 represents an average molecular weight of 12,700 to 17,400 where"a"is 141 and "b"is 44, and Lutrol F68 represents an average molecular weight of 7,680 to 9, 510 where"a"has a value of about 80 and"b"has a value of about 27. Other sources of information on properties of solid surfactants include BASF Technical Bulletin Pluronic & Tetronic Surfactants 1999 and General Characteristics of Surfactants from ICI Americas Bulletin 0-1 10/80 5M. One of the characteristics of surfactants is the HLB value, or hydrophilic lipophilic balance value. This value represents the relative hydroplicility and relative hydrophobicity of a surfactant molecule. Generally, the higher the HLB value, the greater the hydrophilicity of the surfactant while the lower the HLB value, the greater the hydrophobicity. For the Lutrol'@ molecules, for example, the ethylene oxide fraction represents the hydrophilic moiety and the propylene

oxide fraction represents the hydrophobic fraction. The HLB values of Lutrol F127, F87, Fl 08, and F68 are respectively 22.0, 24.0, 27.0, and 29.0.
Other surfactants include members selected from the group essentially consisting of sorbitan monopalmitate, sorbitan monostearate, glycerol monostearate, polyoxyethlene stearate (self emulsifying), polyoxyethylene 40 sorbitol lanolin derivative, polyoxyethylene 75 sorbitol lanolin derivative, polyoxyethylene 6 sorbitol beeswax derivative, polyoxyethylene 20 sorbitol beeswax derivative, polyoxyethylene 20 sorbitol lanolin derivative, polyoxyethylene 50 sorbitol lanolin derivative, polyoxyethylene 23 lauryl ether, polyoxyethylene 23 lauryl ether with butylated hydroxyanisole and citric acid added as preservatives, polyoxyethylene 2 cetyl ether with butylated hydroxyanisole and citric acid added as preservatives, polyoxyethylene 10 cetyl ether with butylated hydroxyanisole and citric acid added as preservatives, polyoxyethylene 20 cetyl ether with butylated hydroxyanisole and citric acid added as preservatives, polyoxyethylene 2 stearyl ether with butylated hydroxyanisole and citric acid added as preservatives, polyoxyethylene 10 stearyl ether with butylated hydroxyanisole and citric acid added as preservatives, polyoxyethylene 20 stearyl ether with butylated hydroxyanisole and citric acid added as preservatives, polyoxyethylene 21 stearyl ether with butylated hydroxyanisole and citric acid added as preservatives, polyoxyethylene 20 oleyl ether with butylated hydroxyanisole and citric acid added as preservatives, polyoxyethylene 40 stearate, polyoxyethylene 50 stearate, polyoxyethylene 100 stearate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, polyoxyethylene 4 sorbitan monostearate, polyoxyethylene 20 sorbitan tristearate, and the like, glyceryl mnoleate, glyceryl monostearate, glyceryl palmitostearate, medium chain triglycerides, Span, tween, SLS, polyoxyl 40 stearate, polyoxyl 50 stearate, glycerol monostearate (Self emulsifying) and polyoxyethlene stearate, medium chain triglycerides, Sorbitan Esters (Sorbitan Fatty Acid Esters), Phospholipids, Soya lecithin, cholesterol, and mixture thereof.
Antioxidants are added in tablet formulation to protect drug from undergoing oxidation. Antioxidants undergo oxidation in place of drug or they block the oxidation reaction or they act as synergists to other antioxidants. Chelators may also act as antioxidant.

According to present invention combination of antioxidants is used preferably the antioxidants of vitamin origin are used and the amount of antioxidant vitamins used to stabilize lipoic acid is up to their maximum daily intake allowed for human.
According to the present invention nonlimiting examples of antioxidants includes ascorbic acid, folic acid, vitamin A, and their pharmaceutically acceptable salts or esters. Other antioxidants that can be used are sodium sulphite, sodium hydrogen sulphite, sodium metabisulphite, propyl gallate, thioglycerol, selenium, inorganic and organic selenium compounds and salts such as sodium selenite, gallic acid, gallic acid alkyl ester, butylated hydroxyanisole, butylated hydroxytoluene nordihydroguaiacic acid, , Dodecyl gallate; ethyl gallate; octyl gallate , and mixture thereof.
According to the present invention nonlimiting examples of adsorbent includes colloidal silicon dioxide (Aerosil), microcrystalline cellulose (Avicel), crospovidone, croscarmellose sodium, hydroxypropyl cellulose (HPC), carboxymethylcellulose calcium, carboxymethylcellulose sodium, low substituted hydroxypropyl cellulose (L-HPC), starch, inulin, sodium starch glycolate, polyethylene glycol (PEG), pregelatinized starch, lactose, sucrose, kaoline, bentonite, cellulose acetate, hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose (HEC), chitosan, guar gum, methyl cellulose (MC), ethylcellulose (EC), xanthan gum, methacrylic acid copolymer, carbomer, acacia, agar, alginate, sodium alginate, calcium alginate, carrageenan, cellulose acetate phthalate (CAP), cellulose acetate, hypromellose acetate succinate, hypromellose phthalate, cross linked PEG, polymethacrylate, polyvinyl pyrrolidone (PVP), and mixture thereof.
According to the present invention non-limiting examples of chelating agents includes disodium EDTA, edetic acid, disodium edentate, dipotassium edentate, edetate calcium disodium, sodium edentate, phosphoric acid ethylene, diamine tetraacetic acid, citrates,, tartrates, and mixture thereof.
According to the present invention non-limiting examples of adsorbent includes those pharmaceutically acceptable excipients which are covered under diluents, binder, sustained release polymer and disintegrating agent.

According to the present invention one or more pharmaceutically acceptable additives may be selected from the group comprising of diluent or filler, binder, sustained release polymer, disintegrnt, glidant, lubricant and buffering agent.
According to the present invention non-limiting examples of filler includes mannitol, xylitol, sorbitol, lactose, sucrose, cellulose, microcrystalline cellulose (Avicel), carboxymethylcellulose calcium, carboxymethylcellulose sodium, low substituted hydroxypropyl cellulose (L-HPC), calcium phosphate dibasic anhydrous, calcium phosphate dibasic dihydrate, calcium phosphate tribasic, calcium phosphate, , starch, calcium trisilicate, magnesium trisilicate, cellulose acetate, dextrose, sugar compressible, and mixture thereof..
According to the present invention nonlimiting examples of binders includes pregelatinized starch, polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), hydroxypropyl cellulose HPC, hydroxypropylmethyl cellulose (HPMC), starch, hydroxyethyl cellulose (HEC), ethyl cellulose (EC), chitosan, guar gum, methyl cellulose (MC), carbomer, acacia, agar, alginate, sodium alginate, calcium alginate, and mixture thereof..
According to the present invention nonlimiting examples of sustained release polymers includes hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC, hypromellose), hydroxyethyl cellulose (HEC). chitosan, guar gum, methyl cellulose (MC), ethylcellulose (EC), xanthan gum, methacrylic acid copolymer, carbomer,acacia, agar, alginate, sodium alginate, calcium alginate, carrageenan , cellulose acetate phthalate (CAP), cellulose acetate, hypromellose acetate succinate, hypromellose phthalate, cross linked PEG, polyethylene glycol (PEG), polymethacrylate, propylene glycol alginate, chitosan, Polyvinyl alcohol (PVA), and mixture thereof-According to the present invention nonlimiting examples of disintegrant includes microcrystalline cellulose (Avicel), crospovidone, croscarmellose sodium,

carboxymethylcellulose calcium, carboxymethylcellulose sodium, low substituted hydroxypropyl cellulose (L-HPC), starch, sodium starch glycolate and mixture thereof.
According to the present invention nonlimiting examples of lubricant includes sodium stearyl fumarate, stearic acid, magnesium stearate, glyceryl benhenate, polysiloxane like dimethicone, simethicone, calcium stearate, zinc stearate, polyethylene glycol, poloxamer, and mixture thereof.
According to the present invention nonlimiting examples of glidant includes talc, colloidal silicon dioxide (Aerosil), and mixture thereof.
According to the present invention buffering agent is selected from the group comprising of an alkali metal or alkali earth metal carbonate or bicarbonate such as sodium or potassium bicarbonate, sodium bicarbonate, potassium bicarbonate, citric acid, tartaric acid succinic acid, and mixture thereof.
EXAMPLES:
Following examples are illustrative, does not limit the scope of the invention. Example 1,2 and 3


Manufacturing process - Example 1
1. Dissolve lipoic acid in sufficient quantity isopropyl alcohol, add lutrol F127, PVP K 30 mix well.
2. Add avicel pH 102 whole quantity to the above step, add 60% quantity of crospovidone and 40% quantity of aerosil and mix well.
3. Pass the wet mass through 16 mesh and dry the wet granules at temperature below 40°C in FBD.
4. Pass the dried granules through 18 mesh and mix with remaining quantity of crospovidone, aerosil and mix well
5. Finally lubricate the blend with magnesium stearate and compress in to tablets.
6. Film coat the tablets.
Manufacturing process - Example 2
1. Dissolve lipoic acid in sufficient quantity isopropyl alcohol; add PVP K 30 mix well.
2. Then add folic acid, vitamin A acetate, and mix well.
3. Add avicel pH 102 whole quantity to the above step, add 60% quantity of crospovidone and 40% quantity of aerosil and mix well.
4. Pass the wet mass through 16 mesh and dry the wet granules at temperature below 40°C in FBD.
5. Pass the dried granules through 18 mesh and mix with remaining quantity of crospovidone, aerosil and mix well
6. Finally lubricate the blend with magnesium stearate and compress in to tablets.
7. Film coat the tablets.
Manufacturing process - Example 3
1. Dissolve lipoic acid in sufficient quantity isopropyl alcohol, add lutrol F127, PVP K 30 mix well.
2. Then add folic acid, vitamin A acetate, and mix well.
3. Add avicel pH 102 whole quantity to the above step, add 60% quantity of crospovidone and 40% quantity of aerosil and mix well.

4. Pass the wet mass through 16 mesh and dry the wet granules at temperature below 40°C in FBD.
5. Pass the dried granules through 18 mesh and mix with remaining quantity of crospovidone, aerosii and mix well
6. Finally lubricate the blend with magnesium stearate and compress in to tablets.
7. Film coat the tablets.
Example 4 and 5 Floating sustained release tablets
I I I I I
Manufacturing process - Example 4 Floating sustained release tablet of Lipoic acid
1. Dissolve lipoic acid in sufficient quantity isopropyl alcohol, add lutrol F127, PVP K 30 mix well.
2. Then add folic acid, vitamin A acetate, and mix well.
3. Add avicel pH 102, HPMC K15M to above step, and 40% quantity aerosii and mix well.
4. Then add citric acid and sodium carbonate and mix well.

5. Pass the wet mass through 16 mesh and dry the wet granules at temperature below 40°C in FBD.
6. Pass the dried granules through 18 mesh and mix with remaining quantity of aerosil and mix well.
7. Finally lubricate the blend with magnesium stearate and compress in to tablets.
8. Film coat the tablets.
Manufacturing process - Example 5 Floating sustained release bilayered tablet with Lipoic acid in immediate release layer and L-carnitine in sustained release layer.
1. Dissolve lipoic acid in sufficient quantity isopropyl alcohol, add lutrol F127, 35% of PVPK 30 mix well.
2. Then add folic acid, vitamin A acetate, and mix well.
3. Add 40% quantity of avicel pH 102 to the above step add 20% quantity aerosil and mix well.
4. Pass the wet mass through 16 mesh and dry the wet granules at temperature below 40°C in FBD.
5. Pass the dried granules through 18 mesh, add 30% aerosil, 40% of magnesium stearate, mix well and store in air tight container
6. Separately mix l-carnitine, 60% avicel pH 102, HPMC K15M and 20% aerosil then add citric acid and sodium carbonate and mix well.
7. Prepare binder solution by dissolving 65% of PVP in sufficient quantity of alcohol.
8. Granulate the blend of step 6 using step 7 binder solution
9. Pass the wet mass through 16 mesh and dry the wet granules at temperature 60°C in FBD
10. Pass the dried granules through 18 mesh, add 30% aerosil, 40% of magnesium stearate, mix well and store in air tight container
11. Compress blend of step 5 and step 10 in to bilayered tablets.
12. Film coat the tablets.

Manufacturing process - Example 6
1. Dissolve lipoic acid in sufficient quantity isopropyl alcohol, add Lutrol F127, PVP K 30 mix well.
2. Then add vitamin A acetate, folic acid, Ascorbic acid, alpha-tocopherol acetate, ubiquinone and mix well.
3. Add avicel pH 102 whole quantity to the above step, add 60% quantity of crospovidone and 40% quantity of aero si 1 and mix well, then add taurine, rutin, acetyl L-carnitine, N-acetyl cystine mix well.
4. Pass the wet mass through 16 mesh and dry the wet granules at temperature below 40°C in FBD.
5. Pass the dried granules through 18 mesh and mix with remaining quantity of crospovidone, aero si 1, sodium bicarbonate, methylcobalamine, chromium, manganese, selenium, vanadyl and mix well
6. Finally lubricate the blend with magnesium stearate and compress in to tablets.
7. Films coat the tablets.
The tablet prepared according to the example 1 to 6 provided hardness of between 5 kg and 8 kg with a friability of less than 1%. Dissolution tests were carried using USP apparatus type II at 37° C, at 75 rpm, using 900ml of 0.1 N HCL (pH 1.2). Dissolution was carried out for 60 minutes for tablets of example 1, 2, 3, 5 and 6 and for tablets of example 4 which are sustained release floating tablet for 8 hours.
Example 7: Lipoic acid water soluble complex with Lutrol F127
According to the present invention a method for preparing water soluble complex of
lipoic acid with surfactant comprises the steps of:
Step (i) dissolving 3gm lipoic acid and 1 gm Lutrol F127in sufficient quantity of
isopropyl alcohol,
Step (ii) spray drying the solution of step (i) to get dried powder comprising mixture of
lipoic acid and surfactant.
The lipoic acid/Lutrol F127 complex prepared according to the above process showed
very good water solubility. The ratio suitable for preparing water soluble complex
between the lipoic acid and the surfactant is in the range from 0.001:1 to 100:1.

Stability data:
Compressed tablets obtained from examples 1 to 6 were packed in blister packs and subjected to stability test at 40±2°C, 75±5%RH for six months. Chemical degradation of lipoic acid (i.e. presence of garlic like smell) in compressed tablets is checked by removing the tablet film coating and smelling the tablets. Polymerization of lipoic acid in compressed tablet (i.e. presence of lipoic acid particle agglomerates) is checked by physical observation after breaking the tablet.
Stability test data of Examples 1,2 and 3

Above stability data shown that tablets of example 1 (without antioxidant and with surfactant) showed chemical degradation (presence of garlic like smell) and polymerization at 3 months and 6 months respectively, tablets prepared according to

example 2 (without surfactant and with antioxidant vitamins) showed chemical degradation and polymerization at 6 months and 3 months. Assay value and percentage dissolution also decreased considerably for tablets of example 1 and 2 at the end of 6 months. The tablets of example 3 prepared using antioxidant and surfactant lutrol F 127 showed no chemical degradation and polymerization also showed stable assay and dissolution values at the end of 6 months at 40±2°C, 75±5%RH. Tablets of example 4, 5 and 6 also found stable for six months at 40±2°C, 75±5%RH. Thus from the stability data it is clear that use of surfactant and antioxidant combination is necessary to prepare stable compressed tablet of lipoic acid, neither surfactant nor antioxidant alone can stabilize lipoic acid in compressed tablets.

I claim:
1. A stable pharmaceutical composition in the form of compressed tablet comprising of Hpoic acid, stabilizer, one or more pharmaceutically acceptable additives, and optionally comprising of one or more pharmaceutically active agents.
2. A stable pharmaceutical composition in the form of compressed sustained release tablet comprising of lipoic acid, stabilizer, one or more pharmaceutically acceptable additives, and optionally comprising of one or more pharmaceutically active agents.
3. A stable pharmaceutical composition in the form of compressed tablet comprising synergistic combination of lipoic acid with carnitine, stabilizer, one or more pharmaceutically acceptable additives, and optionally comprising of one or more pharmaceutically active agents.
4. A stable pharmaceutical composition in the form of compressed tablet comprising synergistic combination of lipoic acid with carnitine and/or CoQ10 and/or ascorbic acid and/or vitamin E and/or folic acid and/or glutathione and/or N-acetyl cystine, stabilizer, one or more pharmaceutically acceptable additive, and optionally comprising of one or more pharmaceutically active agents.
5. A stable pharmaceutical composition in the form of compressed tablet comprising of lipoic acid, taurine and/or rutin, stabilizer, one or more pharmaceutically acceptable additives, and optionally comprising of one or more pharmaceutically active agents.
6. A stable pharmaceutical composition in the form of compressed tablet comprising of lipoic acid, curcumin, stabilizer, one or more pharmaceutically acceptable additives, optionally comprising of one or more pharmaceutically active agents.

7. A stable pharmaceutical composition in the form of compressed tablet according
to present invention the process of preparing stable lipoic acid pharmaceutical
composition in the form of compressed tablet comprising the steps of:
Step (i) dissolve or disperse lipoic acid and surfactant in organic solvent
and/or water to this add whole or part of antioxidant(s), optionally add binder and mix well, Step (ii) add to the above step one or more adsorbent(s), optionally add one or
more pharmaceutically active agent and mix well to get wet mass Steps (iii) pass the wet mass of step (ii) through suitable mesh to get wet granules and dry the granules using suitable drying method to get dried granules. Step (iv) sizing the dried granules of above step to desired size by through
suitable mesh. Step (v) mix the sized granules of above step with remaining part of
antioxidant in step (i), optionally with one or more pharmaceutically active agents, Step (vi) finally mix the one or more pharmaceutically acceptable additives and compress the blend into tablets.
8. A stable pharmaceutical composition in the form of compressed tablet according
to any of the preceding claim, wherein
(i) one or more pharmaceutically active agents may be selected from the group
comprising of antioxidants, neutraceuticals, dietary supplements, plant extracts,
vitamins, enzymes, amino acids, minerals, or mixture thereof,
(ii) one or more pharmaceutically acceptable additives may be selected from the
group comprising of binder, sustained release polymer, disintegrnt, diluent or
filler, glidant, lubricant, and
(iii) the stabilizer essentially consists of one or more surfactant and antioxidant,
optionally consists of buffering agent.

9. A method for preparing water soluble complex of lipoic acid with surfactant comprising the steps of:
Step (i) dissolving or dispersing lipoic acid and surfactant in organic solvent
and/or water optionally with antioxidant(s), Step (ii) spray drying the solution of step (i) to get dried powder comprising mixture of lipoic acid and surfactant, Wherein the weight ratio between the lipoic acid and the surfactant is in the range from 0.001:1 to 100:1.