FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
&
The Patents Rules, 2003 COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention - NOVEL PHARMACEUTICAL COMPOSITION
COMPRISING DPP-4 INHIBITOR, ALPHA-LIPOIC ACID AND VITAMIN B12
2. Applicant(s)
(a) NAME : ZENVISION PHARMA LLP
(b) NATIONALITY : An Indian Company
(c) ADDRESS : First Floor, K.K. Chambers, SIR P.T. Road
Fort, Mumbai, Maharashtra, India 400001

"NOVEL PHARMACEUTICAL COMPOSITION COMPRISING DPP-4 INHIBITOR, ALPHA-LIPOIC ACID AND VITAMIN B12"
FIELD OF THE INVENTION
The present invention relates to novel pharmaceutical composition comprising DPP-4 inhibitor, Alpha-lipoic acid and Vitamin B12 for the treatment of diabetes and associated complications.
BACKGROUND OF THE INVENTION
DPP-4 inhibitors or gliptins are a class of oral hypoglycemics that block DPP-4 (DPP-IV) and they are used in the treatment of type 2 diabetes.
Sitagliptin is anti-diabetic drug of dipeptidyl peptidase-4 inhibitor class. Chemically Sitagliptin phosphate monohydrate is 7-[(3R)-3-amino-1-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l, 2, 4 triazolo [4,3-a] pyrazine phosphate (1:1) monohydrate and its molecular weight is of 523.32. Its empirical formula is C16H15F6N5OH3PO.H2O. Sitagliptin phosphate monohydrate is represented by compound of structural formula I

Sitagliptin phosphate monohydrate is a white to off-white, crystalline, non-hygroscopic powder. It is soluble in water and N, N-dimethyl formamide; slightly soluble in methanol; very slightly soluble in ethanol, acetone, and acetonitrile; and insoluble in isopropanol and isopropyl acetate.

Sitagliptin Phosphate tablet is available in the strength of 25mg, 50mg and 100mg. The product is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Diabetes is a group of metabolic disorders in which there are high blood sugar levels over a prolonged period. Symptoms of high blood sugar include frequent urination, increased thirst, and increased hunger. If left untreated, diabetes can cause many complications.
Long-term complications of diabetes develop gradually. The longer you have diabetes and the less controlled your blood sugar-the higher the risk of complications. Eventually, diabetes complications may be disabling or even life-threatening. Possible complications include Nerve damage (neuropathy), Cardiovascular disease, Kidney damage (nephropathy), Eye damage (retinopathy), Foot damage, skin problems, including bacterial and fungal infections, Hearing impairment, Alzheimer's disease.
Diabetic neuropathies are nerve damaging disorders associated with diabetes mellitus. People with diabetes can, over time, develop nerve damage throughout the body. The symptoms appear such as pain, tingling, or numbness-loss of feeling-in the hands, arms, feet, and legs. Nerve problems can occur in every organ system, including the digestive tract, heart, and sex organs.
About 60 to 70 percent of people with diabetes have some form of neuropathy. People with diabetes can develop nerve problems at any time, but risk rises with age and longer duration of diabetes.
The highest rates of neuropathy are among people who have had diabetes for at least 25 years. Diabetic neuropathies also appear to be more common in people who have problems controlling their blood glucose, also called blood sugar, as

well as those with high levels of blood fat and blood pressure and those who are overweight.
The commercially available product and product known in the prior art for diabetes lowers blood glucose level only; however it does not prevent or resolve the long-term complications of diabetes which develop gradually.
Thus, there is an unmet need in the art to provide a novel pharmaceutical composition for diabetes which will lower blood glucose as well as prevent or reduce the risks of developing long-term complications of diabetes like Nerve damage (neuropathy), Cardiovascular disease, Kidney damage (nephropathy), Eye damage (retinopathy), Foot damage, skin problems, including bacterial and fungal infections, Hearing impairment, Alzheimer's disease.
OBJECTS OF THE INVENTION
Accordingly, it is an object of the present invention to provide novel pharmaceutical composition comprising a DPP-4 inhibitor, alpha-lipoic acid and vitamin B12.
It is another object of the present invention to provide novel pharmaceutical composition comprising DPP-4 inhibitor, Alpha-lipoic acid and Vitamin B12 which controls the high glucose levels in the blood of diabetic patient.
It is another object of the present invention to provide novel pharmaceutical composition comprising DPP-4 inhibitor, Alpha-lipoic acid and Vitamin B12 which prevents or reduces the risks of developing diabetic neuropathy.
It is another object of the present invention to provide novel pharmaceutical composition comprising DPP-4 inhibitor, alpha-lipoic acid and vitamin B12 which prevents or reduces the risks of developing other complications associated with diabetes like cardiovascular disease, kidney damage (nephropathy), eye

damage (retinopathy), foot damage, skin problems, including bacterial and fungal infections, hearing impairment, Alzheimer's disease.
It is an another object of the present invention to provide a synergistic composition comprising DPP-4 inhibitor, Alpha-lipoic acid and Vitamin B12; wherein in DPP-4 inhibitor reduces blood glucose level, alpha-lipoic acid and vitamin B12 helps in preventing or reducing complications associated with diabetes.
SUMMARY OF THE INVENTION
A first aspect of the present invention is to provide novel pharmaceutical composition comprising DPP-4 inhibitor, alpha-lipoic acid and vitamin B12.
In another aspect of the present invention provides novel pharmaceutical composition comprising DPP-4 inhibitor, alpha-lipoic acid and Vitamin B12 along with one or more pharmaceutically acceptable excipient.
In a further aspect of the present invention provides novel pharmaceutical composition comprising a DPP-4 inhibitor preferably Sitagliptin or salt thereof, alpha-lipoic acid and vitamin B12 along with one or more pharmaceutically acceptable excipient.
In yet another aspect of the present invention is to provide a process for manufacturing the novel pharmaceutical composition comprising DPP-4 inhibitor, Alpha-lipoic acid and Vitamin B12 along with one or more pharmaceutically acceptable excipient.
In another aspect of the present invention is to provide novel pharmaceutical composition comprising DPP-4 inhibitor, Alpha-lipoic acid and Vitamin B12 for the treatment of diabetes and associated complications.

In another aspect of the present invention is to provide novel pharmaceutical composition comprising DPP-4 inhibitor, Alpha-lipoic acid and Vitamin B12 for the treatment of diabetes and associated complications preferably diabetic neuropathy.
DETAIL DESCRIPTION OF THE INVENTION
The present invention relates to novel pharmaceutical composition comprising a DPP-4 inhibitor, alpha-lipoic acid and vitamin B12, which is useful in the treatment of diabetes and associated complications.
The novel pharmaceutical composition comprising the DPP-4 inhibitor, alpha-lipoic acid and vitamin B12 is useful in the treatment of diabetes and associated complications preferably diabetic neuropathy.
Diabetes is a metabolic disorder which affects the body's ability to metabolize carbohydrates resulting in high blood sugar levels over a prolonged period. Symptoms of high blood sugar include frequent urination, increased thirst, and increased hunger. If left untreated, diabetes can cause many complications. Possible complications include nerve damage (neuropathy), cardiovascular disease, kidney damage (nephropathy), eye damage (retinopathy), foot damage, skin problems, including bacterial and fungal infections, hearing impairment, Alzheimer's disease.
Diabetic neuropathy affects all peripheral nerves like pain fibers, motor neurons and autonomic nerves. It therefore necessarily affects all organs and systems since they are innervated. Symptoms vary depending on the nerve affected and may include symptoms other than those listed and develop gradually over years. Symptoms may include numbness and tingling of extremities, dysesthesia (decreased or loss of sensation to a body part), diarrhea, erectile dysfunction, urinary incontinence (loss of bladder control), impotence, facial, mouth and eyelid drooping, vision changes, dizziness, muscle weakness, difficulty in swallowing,

speech impairment, fasciculation (muscle contractions), anorgasmia, burning or electric pain.
DPP-4 inhibitors or gliptins are a class of oral hypoglycemics that block DPP-4 and they are used to treat diabetes. Glucagon increases blood glucose levels and DPP-4 inhibitors reduce glucagon and blood glucose levels. The mechanism of DPP-4 inhibitors is to increase incretin levels [glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)] which inhibit glucagon release, which in turn increases insulin secretion, decreases gastric emptying, and decreases blood glucose levels.
DPP-4 inhibitors or gliptins according to present invention may be selected from Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin, Gemigliptin, Anagliptin, Teneligliptin, Alogliptin, Trelagliptin, Omarigliptin, Evogliptin, Dutogliptin or salt thereof and like. DPP-4 inhibitors or gliptins according to present invention may be preferably Sitagliptin or salt thereof.
Alpha-lipoic acid is a vitamin-like chemical called an antioxidant. It helps to prevent cell damage in the body and restores vitamin levels such as vitamin E and vitamin C. Alpha-lipoic acid is used in the body to break down carbohydrates and to make energy for the other organs in the body.
Vitamin B12 or cobalamin is a water-soluble vitamin that plays a very fundamental role in neurological function. Vitamin B12 exerts its physiological effects through mediating two principal enzymatic pathways i.e. the methylation process of homocysteine to methionine and the conversion of methylmalonyl coenzyme A (CoA) to succinyl-CoA. Vitamin B12 as a co-factor facilitates the methylation of homocysteine to methionine which is later activated into S-adenosyl-methionine that donates its methyl group to methyl acceptors such as myelin, neurotransmitters and membrane phospholipids. Metabolically significant vitamin B12 deficiency hence will result in disruption of the methylation process

and accumulation of intracellular and serum homocysteine. Hyperhomocysteinemia has been shown to have potentially toxic effects on neurones and the vascular endothelium.
The synergism of DPP-4 inhibitor, alpha-lipoic acid and vitamin B12 according to present invention play vital role in the treatment of diabetes and associated complications; wherein DPP-4 inhibitor reduces blood glucose level, alpha-lipoic acid and vitamin B12 helps in preventing or reduces the risks of complications associated with diabetes; preferably diabetic neuropathy.
The novel pharmaceutical composition according to present invention comprising DPP-4 inhibitor, Alpha-lipoic acid and Vitamin B12 is effective in the treatment of diabetes which keeps blood sugar level in controlled manner.
Also the novel pharmaceutical composition according to present invention prevent or reduces the risks of diabetic complications like nerve damage (neuropathy), cardiovascular disease, kidney damage (nephropathy), eye damage (retinopathy), foot damage, skin problems, including bacterial and fungal infections, hearing impairment, Alzheimer's disease. It was found that the present composition was particularly useful in preventing or reducing the risks of chances of developing diabetic neuropathy.
The present inventors have formulated the present composition comprising DPP-4 inhibitor, alpha-lipoic acid and vitamin B12 at concentrations such that it provides maximum therapeutic effect., better patient compliance and less adverse effect in the treatment of diabetes and associated complications.
The novel pharmaceutical composition according to present invention can comprise any suitable amount of the DPP-4 inhibitor i.e. Sitagliptin or salt thereof, alpha-lipoic acid and vitamin B12. The weight percentage of Sitagliptin or salt thereof can be 0.1 to 40%; preferably 0.5 to 35%. The amount of Sitagliptin

or salt thereof ranges from 5mg to 400mg; preferably 10mg to 200mg; more preferably 25mg, 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, 200mg. The weight percentage of Alpha-lipoic acid can be 2% to 80%; preferably 5% to 70%. The amount of Alpha-lipoic acid ranges from 50mg to 1000mg, preferably 100mg to 800mg. The weight percentage of Vitamin B12 can be 0.0001% to 5%. The amount of Vitamin B12 ranges from 0.001lmg to 10mg, preferably 0.01mg to 5rng.
The novel pharmaceutical composition according to present invention comprising DPP-4 inhibitor, Alpha-lipoic acid and Vitamin B12 may be in the form of tablet, capsule, granule, pellet, bead, sachet or powder.
The novel pharmaceutical composition according to present invention comprising DPP-4 inhibitor. Alpha-lipoic acid and Vitamin B12 along with one or more pharmaceutically acceptable excipient. The one or more pharmaceutically acceptable excipient according to present invention may be selected from the group consisting of diluents, disintegrants, binders, lubricant, glidant, acidic agent, basic agent, sweeteners, flavor, solubilizing agent, surfactant, stabilizing agent, release modifier and pH regulating agent.
The examples of diluents include but not limited to mannitol, sorbitol, xylitol, cellulose derivatives, starch, maltodextrin, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide or mixture thereof. The diluent is present in the composition in an amount of about 0.5% to 60% based on the total weight of the composition; preferably in an amount of about 5% to 50 % based on the total weight of the composition.
The examples of disintegrants include but not limited to croscarmellose sodium, carboxymethyl, cellulose, chitosan, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium. crospovidone, hydroxypropyl cellulose,

microcrystalline cellulose, methyl cellulose, starch, sodium starch glycolate or mixture thereof. The disintegrant is present in the composition in an amount of about 0.5% to 30% based on the total weight of the composition; preferably in an amount of about 1% to 10 % based on the total weight of the composition.
The examples of binders include but not limited to ethyl cellulose, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose sodium, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose., magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone, starch or mixture thereof. The binder may be present in the composition in an amount of about 0.005% to 10% based on the total weight of the composition.
The examples of lubricant include but not limited to calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate or mixture thereof. The lubricant is present in the composition in an amount of about 0.05% to 5% based on the total weight of the composition.
The examples of glidant include but not limited to talc, colloidal silicon dioxide, starch, magnesium stearate or mixture thereof. The glidant is present in the composition in an amount of about 0.05% to 5% based on the total weight of the composition.
The examples of acidic agent include but not limited to citric acid, malic acid, tartaric acid, fumaric acid, adipic acid, or mixture thereof. The acidic agent may be present in the composition in an amount of about 10% to 40% based on the total weight of the composition.
The examples of basic agent include but not limited to potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate or

mixture thereof. The basic agent may be present in the composition in an amount of about 20% to 80% based on the total weight of the composition.
The examples of sweeteners include but not limited to saccharose, glucose, maltose, galactose, and artificial sweeteners, such as acesulfame potassium, sodium saccharin, cyclamates, sucralose or mixture thereof. The sweetener is present in the composition in an amount of about 0.1% to about 6% based on the total weight of the composition.
The examples of flavor include but not limited to fruit flavor, peppermint flavor or mixture thereof The flavor is present in the effervescent composition in an amount of about 0% to about 5% based on the total weight of the composition.
The examples of solubilizing agent include but not limited to polyethylene glycol, polyvinylpyrrolidone, dextran, or mixture thereof.
The examples of surfactant include but not limited to polysorbate, sodium lauryl sulphate, polyoxyethylene, polyoxypropylene glycol or mixture thereof.
The examples of stabilizing agent include but not limited to tocopherol, cyclodextrin, tetrasodium edetate, nicotinamide or mixture thereof.
The examples of release modifier include but not limited to cellulosic polymers, such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), methylcellulose (MC), powdered cellulose such as microcrystalline cellulose, cellulose acetate, sodium carboxymethylcellulose, calcium salt of carboxymethylcellulose, ethylcellulose; alginates, gums such as guar and xanthan gums; cross-linked polyacrylic acid derivatives such as Carbomers available in various molecular weight grades; carageenan; polyvinyl pyrrolidone and its derivatives such as crospovidone; polyethylene oxides; and polyvinyl alcohol, glyceryl monostearate, mixtures of glyceryl monostearate and

glyceryl monopalmitate, glycerylmonooleate, a mixture of mono, di and tri-glycerides, glycerylmonolaurate, glyceryl behenate, paraffin, white wax, long chain carboxylic acids, long chain carboxylic acid esters and long chain carboxylic acid alcohols. Suitable pH-sensitive enteric polymers include cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinylacetate phthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic monoester copolymer, methyl acrylate-methacrylic acid copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer or mixture thereof
The examples of pH regulating agent include but not limited to fumarate, citrate, phosphate, carbonate, tartrate, acetate, amino acid salts or mixture thereof.
The present invention also provides a process of manufacturing novel pharmaceutical composition comprising DPP-4 inhibitor, alpha-lipoic acid and Vitamin B12 along with one or more pharmaceutically acceptable excipient.
The novel pharmaceutical composition of the present invention can be manufactured by process such as direct compression, dry granulation, wet granulation, roller compaction and hot melt extrusion.
The process of manufacturing novel pharmaceutical composition according to present invention involves admixing DPP-4 inhibitor, alpha-lipoic acid and Vitamin B12 along with one or more one or more pharmaceutically acceptable excipient selected from the group consisting of diluents, disintegrants, binders, lubricant, glidant, acidic agent, basic agent, sweeteners, flavor, solubilizing agent, surfactant, stabilizing agent, release modifier and pH regulating agent.
The novel pharmaceutical composition according to present invention comprising DPP-4 inhibitor- Alpha-lipoic acid and Vitamin B12 were evaluated for

appearance, average weight, thickness, hardness, disintegration time, assay and were found to be within the specifications.
The novel pharmaceutical composition of the present invention packaged in suitable airtight containers and moisture proof packs. The novel pharmaceutical composition of the present invention preferably packaged in to the strip, blister, bottle or sachet.
The present invention also encompasses the use of the novel pharmaceutical composition in the treatment of diabetes and associated complications, in particular diabetic neuropathy.
EXAMPLES:
In. the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not. intended to limit the scope of the present invention in any way.
Example 1:

Sr. No. Ingredients Weight
(mg/tablet) % w/w
1. Sitagliptin 25.0 10
Alpha lipoic acid 150.0 60
Vitamin B12 0.025 0.01
4. Polyvinyl Pyrrolidone 15.0 6.00
5. Microcrystalline cellulose 54.98 21.99
6. Magnesium stearate 2.5 1.00
7. Colloidal silicon dioxide 2.5 1.00
Tablet weight 250 100.00

Manufacturing Process:
1. Vitamin B12, colloidal silicon dioxide, microcrystalline cellulose,
Sitagliptin and alpha lipoic acid were co-sifted through ASTM #30; and
mixed.
2. Polyvinyl Pyrrolidone was sifted through ASTM #30, and mixed.
3. The blend of step 1 was mixed with blend of step 2.
4. The blend of step 3 was lubricated with magnesium stearate previously sifted through ASTM #30 and compressed using suitable tooling fitted to compression machine.
Example 2:

Sr. No. Ingredients Weight (mg/tablet) % w/w
1. Sitagliptin 100.0 9.71
2. Alpha lipoic acid 600.0 58.25
3. Vitamin B12 0.1 0.01
4. Polyvinyl pyrrolidone 15.0 1.46
5. Microcrystalline cellulose
* 264.9 25.72
6. Magnesium stearate 10.0 0.97
7. Colloidal silicon dioxide 10.0 0.97
8. Brown coating Premix 30.0 2.91
Tablet weight 1030 100.00
Manufacturing Process:
1. Vitamin B12, colloidal silicon dioxide, microcrystalline cellulose, Sitagliptin and alpha lipoic acid were co-sifted through ASTM #30; and mixed.
2. Polyvinyl Pyrrolidone was sifted through ASTM #30, and mixed.
3. The blend of step 1 was mixed with blend of step 2.

4. The blend of step 3 was lubricated with magnesium stearate previously sifted through ASTM #30 and compressed using suitable tooling fitted to compression machine.
5. Core tablets were coated using Brown coating premix in a suitable coating machine.
Example 3:

Sr. No. Ingredients Weight (mg/sachet) % w/w
1. Sitagliptin 25.0 1.016
2. Alpha lipoic acid 150.0 6.098
Vitamin B12 0.025 0.001
4. Citric acid 750.0 30.488
5. Sodium bicarbonate 1499.975 60.975
6. Vanilla flavor 20.0 0.813
7 Sucralose 15.0 0.61
Sachet weight 2460 100.00
Manufacturing Process:
1. Sodium bicarbonate sifted through ASTM #40; citric acid was sifted through ASTM#20 and mixed.
2. Vitamin B12, sucralose, vanilla flavor, Sitagliptin and alpha lipoic acid were sifted through ASTM #30, mixed.
?.. The blend of step 1 was mixed with blend of step 2.
4. The powder blend equivalent to one dose was packed in sachet.
Example 4:

Sr. No. Ingredients Weight (mg/tablet) % w/w
1. Sitagliptin 25.0 1.016
2. Alpha lipoic acid 150.0 6.098

3.
Vitamin B12 0.025 0.001
4. Citric acid 750.0 30.488
5. Sodium bicarbonate 1499.975 60.975
6. Vanilla flavor 20.0 0.813
7. Sucralose 15.0 0.61
Tablet weight 2460 100.00
Manufacturing Process:
1. Sodium bicarbonate sifted through ASTM #40; citric acid was sifted through ASTM #20 and mixed.
2. Vitamin 312, sucralose, vanilla flavor, Sitagliptin and alpha lipoic acid were sifted through ASTM #30, mixed.
.?. The blend of step 1 was mixed with blend of step 2.
4. The blend of step 3 was. compressed using suitable tooling fitted to compression machine.

WE CLAIM
1. A pharmaceutical composition comprising a DPP-4 inhibitor, alpha-lipoic acid and vitamin B12.
2. The pharmaceutical composition according to claim 1, wherein the DPP-4 inhibitor is selected from Sitagliptin, Saxagliptin, Vildagliptin, Linagliptin, Gemigliptin, Anagliptin, Teneligliptin, Alogliptin, Trelagliptin, Omarigliptin, Evogliptin, Dutogliptin or salt thereof.
3. A pharmaceutical composition according to claim 1 and 2, wherein the DPP-4 inhibitor is preferably Sitagliptin or salt thereof.
4. A pharmaceutical composition according to claim 1, wherein composition Is in the form of tablet capsule, granule, pellet, bead, sachet or powder.
5. A pharmaceutical composition according to claim 1, 2 and 3, wherein the amount of Sitagliptin or salt thereof ranges from 5mg to 400mg.
6. A pharmaceutical composition according to claim 1, wherein the amount of alpha-lipoic acid ranges from 50mg to 1000mg.
7. A pharmaceutical composition according to claim 1, wherein the amount of Vitamin B12 ranges from 0.001lmg to 10mg.
8. A pharmaceutical composition according to claim 1 further comprises one or more excipient selected from the group consisting of diluents, disintegrants, binders, lubricant, glidant, acidic agent, basic agent, sweeteners, flavor, solubilizing agent, surfactant, stabilizing agent, release modifier and pH regulating agent.
9. A process of preparing pharmaceutical composition according to claim 1 comprising the step of admixing the DPP-4 inhibitor, alpha-lipoic acid and vitamin B12 along with one or more excipient selected from a group consisting of diluents, disintegrants, binders, lubricant, glidant, acidic agent, basic agent, sweeteners, flavor, solubilizing agent, surfactant, stabilizing agent, release modifier and pH regulating agent.