Technical Field:
The present invention relates to a stable pharmaceutical composition comprising Leucine, Pyridoxine (Vitamin B6) or Pyridoxal 5 phosphate and pharmaceutical^ acceptable excipients. Particularly, the present invention relates to a weight loss composition comprising Leucine, Pyridoxine or Pyridoxal 5 phosphate and pharmaceutical^ acceptable excipients and method of preparing the same. The present invention also relates to a method of administering such composition to enhance weight loss in individuals using them.
Background & Prior Art:
Obesity is a major contributor to the global burden of chronic diseases and disability. While the causes of obesity are complex, major contributors include the increased consumption of high-calorie, nutrient poor foods and the lack of physical activity. When food energy intake exceeds energy expenditure, the excess energy is stored as fat. Measures to prevent obesity generally include promoting the eating of healthy food and increasing physical activity. However, such measures have limited compliance owing to the changes in lifestyle.
A number of compositions have been proposed to address the obesity, for example US20020010192 describes composition comprising combination of nicotine receptor partial agonist and an anti-obesity agent like orlistat and sibutramine. US20120052137 discloses a weight loss formulation comprising a combination of herbal extracts to which further ingredients are added.
US 20150045381 discloses a composition for losing weight and sustaining energy by administering a composition comprising Vitamin B and at least one Lysine, Leucine and Methionine.
US20130237605 discloses compositions, methods, and kits for regulating energy metabolism using branched amino acids and vitamin B6.

The dose requirement for weight management as an adjuvant to exercise is about 2 to 3 gm of Leucine per day which amounts to about 2 tablets twice daily i.e. 4 tablets per day having label claim as: L Leucine 550 mg and Pyridoxine HC1 7.5 mg or Pyridoxal 5 phosphate 7.5 mg.
However due to following physical properties of Leucine there is a challenge in formulating the tablet containing Leucine:
1. Leucine is a crystalline material.
2. It has very low bulk density (about 0.3 gm /ml).
3. It has poor compressibility.
4. The material has typical amino acid odour which becomes intense on storage.
In view of properties above, it makes L Leucine practically difficult to formulate. Hence it is a challenging task to formulate a tablet containing L Leucine.
Thus the tablets manufactured using known process and technique normally results in:
1. Brittle texture
2. Typical amino acid odour
3. Tablets exhibit capping tendency making it difficult to formulate.
Hence there is a need to develop a robust formulation that would overcome the limitations of L Leucine.
In view of above situation a stable composition has been arrived at which has the following attributes:
1. The tablets have adequate strength to withstand the handling during manufacturing and shipment
2. The tablets were coated using flavoured coating system in order to mask typical amino acid odour of L Leucine that develops during storage.

3. A capsule shaped tablet containing 550 mg of Leucine and 7.5 mg of either Pyridoxine or Pyridoxal 5 phosphate in combination, which is easy for oral administration, is developed. An option of administering higher dose of Leucine upto 1100 mg was also evaluated in order to offer flexibility in dose titration. This contained 15 mg of either Pyridoxine or Pyridoxal 5 phosphate in combination.
4. The formulation is stable at accelerated as well as long term storage conditions in the desired packing that will be convenient for patients use.
Object of the Invention:
The object of the present invention is to provide a stable pharmaceutical composition comprising Leucine, Pyridoxine (Vitamin B6) or Pyridoxal 5 Phosphate and pharmaceutically acceptable excipients.
Another object of the present invention is to provide a process for preparing a stable pharmaceutical composition comprising Leucine, Pyridoxine (Vitamin B6) or Pyridoxal 5 Phosphate and pharmaceutically acceptable excipients.
Yet another object of the present invention is to provide a stable pharmaceutical composition comprising Leucine, Pyridoxine (Vitamin B6) or Pyridoxal 5 Phosphate and pharmaceutically acceptable excipients for weight management.
Further object of the present invention is to provide a stable solid dosage form comprising Leucine, Pyridoxine (Vitamin B6) or Pyridoxal 5 Phosphate and pharmaceutically acceptable excipients.
Still further object of the present invention is to provide a stable pharmaceutical composition for oral administration for weight management.

Summary of the Invention:
The present invention relates to a stable pharmaceutical composition comprising Leucine, Pyridoxine or Pyridoxal 5 phosphate, Macrocrystalline Cellulose, Polyethylene glycol, Hypromellose, croscarmellose sodium and pharmaceutically acceptable excipients.
The present invention relates to a process of manufacturing the stable pharmaceutical composition comprising Leucine, Pyridoxine, or Pyridoxal 5 Phosphate, Macrocrystalline Cellulose, Polyethylene glycol, Hypromellose and pharmaceutically acceptable excipients.
The active ingredients viz.L Leucine, Pyridoxine HC1 or Pyridoxal 5 Phosphate are dry mixed in a suitable high shear granulator and wet granulated with binders like Hypromellose or Hydroxy propyl cellulose combined with Polyethylene glycol. Such a granulated mass is then dried and lubricated with a co processed blend of Microcrystalline cellulose, Croscarmellose sodium and Hypromellose alongwith magnesium stearate. This blend is then compressed using suitable tooling and coated thereafter with a flavoured coating system.
Detailed Description:
The present invention relates to a stable pharmaceutical composition comprising of Leucine, Pyridoxine or Pyridoxal 5 Phosphate and pharmaceutically acceptable excipients and method of preparing the same.
In one embodiment, the present invention provides the stable pharmaceutical composition comprising Leucine, Pyridoxine or Pyridoxal 5 Phosphate, Microcrystalline cellulose, Polyethylene glycol, Hydroxy propyl methyl cellulose, Hydroxy propyl cellulose Croscarrmellose sodium and pharmaceutically acceptable excipients.

In one embodiment, the present invention provides the stable pharmaceutical composition comprising Leucine, Pyridoxine, Macrocrystalline Cellulose, Polyethylene glycol, Hydroxy propyl methyl cellulose, Croscarmellose sodium and pharmaceutically acceptable excipients.
In one embodiment, the present invention provides the stable pharmaceutical composition comprising Leucine, Pyridoxal 5 Phosphate, Microcrystalline Cellulose, Polyethylene glycol, Hydroxy propyl cellulose, Croscarmellose sodium and pharmaceutically acceptable excipients.
In one embodiment, the present invention provides the stable pharmaceutical composition comprising Leucine, Pyridoxine or Pyridoxal 5 Phosphate, Microcrystalline Cellulose, Hydroxy propyl methyl cellulose, Croscarmellose sodium and pharmaceutically acceptable excipients.
In one embodiment, the present invention provides the stable pharmaceutical composition comprising Leucine, Pyridoxine or Pyridoxal 5 Phosphate, Microcrystalline Cellulose, and pharmaceutically acceptable excipients.
In one embodiment, the present invention provides the stable pharmaceutical composition comprising Leucine, Pyridoxine, 9% Microcrystalline Cellulose, and pharmaceutically acceptable excipients.
In one embodiment, the present invention provides the stable pharmaceutical composition comprising Leucine, Pyridoxal 5 Phosphate, 9% Microcrystalline Cellulose, and pharmaceutically acceptable excipients.
In accordance with the present invention, methods of preparing pharmaceutical compositions employed are wet granulation, dry granulation and direct compression.

In one embodiment, method of preparing pharmaceutical composition is by dry granulation. Method of manufacturing by dry granulation includes mixing of Leucine, Pyridoxine HC1 or Pyridoxal 5 Phosphate with one or more pharmaceutically acceptable excipients, further compaction followed by milling, sieving and addition of pharmaceutically acceptable excipients, lubrication, compression and coating.
In one embodiment, method of preparing pharmaceutical composition is by direct compression. Method of manufacturing by direct compression includes mixing of Leucine, Pyridoxine HC1 or Pyridoxal 5 Phosphate with pharmaceutically acceptable excipients and then lubricants followed by compression and then coating.
In one embodiment, method of preparing pharmaceutical composition is by wet granulation. Method of manufacturing by wet granulation includes dry mixing of Leucine, Pyridoxine HC1 or Pyridoxal 5 Phosphate in a therapeutically effective amount with other pharmaceutically acceptable excipients, then granulation, drying, milling, addition of extra-granular excipients, lubrication, and compression of the lubricated blend into tablets and coating of the compressed tablets.
In one embodiment, the present invention relates to a process of making tablet by wet granulation comprising: providing mixture of Leucine, Pyridoxine HC1 or Pyridoxal 5 Phosphate, atleast one diluent, atleast one binder and water; blending the mixture to obtain wet granulate; drying the wet granulate at a temperature of less than 60 Deg. C to obtain dried granulate; the dried granulate is lubricated with co-processed blend of atleast one diluent, atleast one binder and atleast one disintegrant; this blend is further lubricated with lubricating agents; and compressed into tablets; optionally film coating.

In one embodiment, the present invention involves wet granulating Leucine, Pyridoxine HC1 or Pyridoxal 5 Phosphate using non aqueous solvents, and one or more pharmaceutically acceptable excipients to develop a solid dosage form.
In preferred embodiment the present invention provides the stable pharmaceutical composition comprising Leucine, Pyridoxine HC1 or Pyridoxal 5 Phosphate, Macrocrystalline Cellulose, Polyethylene glycol, Hypromellose, Hydroxy propyl cellulose and pharmaceutically acceptable excipients.
In one embodiment, the pharmaceutical composition is in the form of solid oral dosage form.
In one embodiment, the pharmaceutical composition is in the form of tablet.
In one embodiment, the tablet is coated using a flavoured coating ready mix dispersion of hydro alcoholic system, or aqueous system.
In one embodiment, the pharmaceutical composition is in the form of capsule.
In accordance to the present invention, the pharmaceutical composition contains in parts by weight from about 55% to 65% Leucine, 0.4% to 1.5% Pyridoxine HC1 or Pyridoxal 5 Phosphate , from about 10% to 35% diluent, from about 0.5 % to 3% binder, from about 3% to 10% disintegrant, from about 3% to 7% of lubricants and glidants
Diluents include, but are not limited to Microcrystalline cellulose, Lactose, Pregelatinized starch, Powdered cellulose, Tricalcium Phosphate and Dicalcium phosphate.
Binders include, but are not limited to Hypromellose, Hydroxypropyl cellulose, Hydroxyethyl cellulose, Ethyl cellulose and Polyols.

Glidants include, but are not limited to Talc, Colloidal anhydrous silica and Hydrous Colloidal silica.
Lubricants include, but are not limited to Calcium stearate, Magnesium stearate, Powdered polyethylene glycol, Stearic acid and Siliconised talc.
Disintegrants include, but are not limited to Sodium starch glycolate, Crospovidone, Croscarmellose Sodium, Dried Maize Starch and Pregelatinised Starch.
Coating agents include, but not limited to Hypromellose, Titanium dioxide. Macrogols, Varillin, Talc and Ferric oxide yellow.
Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to person skilled in the art upon reference to the description. It is therefore contemplated that such modifications can be made without departing from spirit or scope of the present invention as defined. The invention is further exemplified with following examples and is not intended to limit the scope of the invention.
Table 1: COMPOSITION FOR Pyridoxine Hydrochloride:
The composition in the table mentioned below is for the dose proportionate option employing Pyridoxine HCL in combination with L Leucine.

Sr.
No Ingredients Quantity
(mg/Tab) Quantity (mg/Tab)
I. CORE TABLET
Dry Mixing & Wet granulation
1. Leucine 1100 550.0
2. Pyridoxine Hydrochloride 15 7.5
Microcrystalline cellulose 200 100
4. Polyethylene glycol -6000 35 17.5
Granulation
6 Hypromellose E 15 (Hydroxy methyl propyl cellulose) 25 12.5
7 Purified water Qs Qs
Lubrication
8 Combination of Microcrystalline
cellulose, Crosscarmellose
sodium and Hydroxy methyl
propyl cellulose 100 50.0
9 Talc 50 25.0
10 Crosscarmellose sodium 80 40.0
11 Aerosil-200 15 7.5
12 Magnesium stearate 30 15.0
Total 1650 825.0

Manufacturing Process:
1. Pyridoxine Hydrochloride was geometrically mixed with Macrocrystalline cellulose.
2. The same was then mixed with Leucine, Polyethylene Glycol mixture in suitable granulator and mixer.
3. Hypromellose was dispersed in water to form a uniform colloidal dispersion
4. Contents of step 2 were granulated in suitable granulator using the suspension of step 3.
5. Resultant granulated mass was dried in suitable fluidised bed drier.
6. The dried granules were sized through 16 mesh SS sieve (less than 1000 microns granules) and milled suitably for ensuring below 16 mesh granules.
7. Moisture contents of the granules was ensured to be below 2.5%
8. Combination of MCC, Croscarmellose and HPMC with talc Croscarmellose sodium and Colloidal Silicon Dioxide were blended in a suitable blender
9. To the blend of step 8, dried granules of step 7 were mixed for a suitable time in a blender of suitable capacity.
10. The same was then compressed using suitable tooling (preferably capsule shaped for proper swallowing)
11. Compressed tablets were coated using a flavoured coating ready mix dispersion of hydro alcoholic system, or aqueous system.
12. Such coated tablets were packed in desired counts in HDPE containers having induction seal and HDPE lid.

Table 2: COMPOSITION FOR Pyridoxal 5 Phosphate:
The composition in the table mentioned below is for the dose proportionate option employing Pyridoxine 5 Phosphate in combination with L Leucine.

Sr.
No Ingredients Quantity
(mg/Tab) Quantity (mg/Tab)
I. CORE TABLET
Dry Mixing & Wet granulation
1. Leucine 1100 550.0
2. Pyridoxal 5 phosphate 15 7.5
3. Macrocrystalline cellulose 200 100
4. Polyethylene glycol -6000 35 17.5
Granulation
6 Hydroxy propyl cellulose 25 12.5
7 Isopropyl alcohol Qs Qs
Lubrication
8 Combination of
Microcrystalline cellulose,
Crosscarmellose sodium and
Hydroxy methyl propyl
cellulose 100 50.0
9 Talc 50 25.0
10 Crosscarmellose sodium 80 40.0
11 Aerosil-200 15 7.5
12 Magnesium stearate 30 15.0
Total 1650 825.0

Manufacturing Process:
1. Pyridoxal 5 phosphate was geometrically mixed with Macrocrystalline cellulose
2. The same was then mixed with Leucine, Polyethylene Glycol mixture in suitable granulator and mixer.
3. Hydroxy propyl cellulose was dispersed in Isopropyl alcohol to form a uniform colloidal dispersion
4. Contents of step 2 were granulated in suitable granulator using the suspension of step 3,
5. Resultant granulated mass was dried in suitable fluidised bed drier.
6. The dried granules were sized through 16 mesh SS sieve (less than 1000 microns granules) and milled suitably for ensuring below 16 mesh granules.
7. Moisture contents of the granules was ensured to be below 2.5%
8. Combination of MCC, Croscarmellose and HPMC with talc Croscarmellose sodium and Colloidal Silicon Dioxide were blended in a suitable blender
9. To the blend of step 8, dried granules of step 7 were mixed for a suitable time in a blender of suitable capacity.
10. The same was then compressed using suitable tooling (preferably capsule shaped for proper swallowing)
11. Compressed tablets were coated using a flavoured coating ready mix dispersion of hydro alcoholic system, or aqeous system.
12. Such coated tablets were packed in desired counts in HDPE containers having induction seal and HDPE lid.

We Claim:
1. A stable pharmaceutical composition comprising of Leucine, Pyridoxine or Pyridoxal 5 phosphate, and pharmaceutically acceptable excipients.
2. The pharmaceutical composition of claiml, wherein the pharmaceutical composition is a solid dosage form.
3. The pharmaceutical composition of claiml, wherein the pharmaceutical composition is a solid dosage form prepared by dry granulation.
4. The pharmaceutical composition of claiml, wherein the pharmaceutical composition is a solid dosage form prepared by wet granulation.
5. The pharmaceutical composition of claiml, wherein the pharmaceutical composition is a solid dosage form prepared by direct compression.

6. The pharmaceutical composition of claim 2, wherein the solid dosage form is tablet or capsule.
7. The pharmaceutical composition of claim 2, wherein the solid dosage form is coated.
8. The pharmaceutical composition of claim 7, wherein the tablet comprises up to 65% by weight of Leucine.
9. The pharmaceutical composition of claim 7, wherein the tablet comprises up to 1.5% by weight of Pyridxine or Pyridoxal 5 phosphate.

10. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable excipients comprises of one or more of diluents, binders, lubricants, glidants, disintegrants, coating agents, or a mixture thereof.