FIELD OF INVENTTON

The present invention relates to a stable pharmaceutical tablet composition, comprising desmopressin or a pharmaceutically acceptable salt thereof (e.g., acetate) as a therapeutically active ingredient, and to a method for manufacturing thereof.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ART

Desmopressin (also known as l-desamino-8-D-arginine vasopressin, DDAVP) is a modified form of the normal human hormone arginine vasopressin, containing nine amino acids and the therapeutically active ingredient in the marketed pharmaceutical product is its acetate salt form. Desmopressin is primarily used in the treatment of primary nocturnal enuresis, i.e. bedwetting, in children by decreasing nocturnal urine production, but it is approved also for the treatment of nocturia and diabetes insipidus.

Desmopressin is currently marketed under the trade name DDAVP® tablets for treating enuresis and blood disorders, DDAVP® tablets of 0.1 mg and 0.2 mg strengths are available in the market and consists of desmopressin acetate together with lactose, potato starch, magnesium stearate and povidone as excipients.

U.S. Patent No. 5,047,398 ("the '398 patent") discloses an anti-diuretic composition of desmopressin with acceptable carrier in solid dosage form for absorption in the gastrointestinal tract of humans.

U.S. Patent No. 7,018,653 ("the '653 patent") discloses a method for the preparation of a solid dosage form of desmopressin or a pharmaceutically acceptable salt thereof, e.g., acetate, using a fluid bed granulation technique.

U.S. Patent No. 7,022,340 ("the '340 patent") discloses pharmaceutical composition in a solid dosage form containing desmopressin or a pharmaceutically acceptable salt thereof and a lubricant in an amount of from 0.05 to less than 0.5 percent by weight of the pharmaceutical composition.

U.S. Patent No. 7,094,545 ("the '545 patent") discloses a method for manufacturing a pharmaceutical composition in a solid dosage form comprising desmopressin acetate, and a disaccharide diluent having an average particle size in the range of 70 to 500 microns. The '545 patent further discloses that the use of such disaccharides allows for a compressing speed of up to about 250,000 tablets/hour with the desired tablet quality and retained low level of wear on the tableting machinery.

U.S. Patent application Nos: 2008/014265 and 2006/0252696 disclose pharmaceutical tablet comprising desmopressin together with a pharmaceutically acceptable excipient, diluent or carrier, or mixture thereof, wherein at least one of the excipient, diluent or carrier is a disaccharide, wherein the disaccharide has an average particle size in the range of from 70 to 500 m.

WO 2007/098945 discloses solid pharmaceutical composition comprising desmopressin, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient, diluent or carrier, or mixture thereof, silica and an oxidizing agent.

WO 2008/035172 discloses a pharmaceutical composition in solid dosage form comprising desmopressin acetate, lubricants and one or more disaccharides, wherein disaccharides have average particle size of less than about 60 microns.

These afore-mentioned prior art disclose compositions of desmopressin wherein disaccharides in one or the other way form an integral part of the composition, imparting stability to the composition.

We have surprisingly found that stable pharmaceutical tablet composition comprising desmopressin acetate together with pharmaceutically acceptable excipients can be prepared, by incorporating a sugar alcohol, optionally together with one or more saccharides and by avoiding use of disaccharide and still resulting in tablets of desired quality and stability.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide a stable pharmaceutical tablet composition comprising desmopressin acetate and atleast one sugar alcohol, together with pharmaceutically acceptable excipients, wherein the composition is devoid of disaccharides.

According to one aspect of the invention there is also provided a process to make the above stable desmopressin composition.

Another object of the present invention is to provide a method of achieving in-vitro dissolution between the tablets of the present invention and the commercially available tablets marketed under the brand name of DDAVP®.

Another object of the invention is to provide stable desmopressin acetate tablet composition packaged in an Alu-Alu blisters, wherein the blisters are layered with silica gel.

SUMMARY OF THE INVENTION

In accordance with one embodiment the present invention provides stable pharmaceutical tablet composition, comprising desmopressin acetate as a therapeutically active ingredient together with atleast one sugar alcohol, wherein the composition is devoid of disaccharides.

In accordance with a second embodiment the present invention provides, a stable pharmaceutical tablet composition comprising desmopressin acetate together with mannitol, and one or more lubricants, wherein the lubricant concentration is between about 0.5% and 2% w/w.

In accordance with a third embodiment the present invention provides, stable pharmaceutical tablet composition comprising desmopressin acetate together with mannitol, atleast one saccharide, and one or more lubricants, wherein the lubricant concentration is between about 0.75% w/w.

In accordance with a fourth embodiment the present invention provides, stable pharmaceutical tablet composition comprising about 0.1% w/w of desmopressin acetate together with 40 to 60% w/w of mannitol, 25 to 35% w/w of atleast one starch, and one or more lubricants, wherein the lubricant concentration is between about 0.75% w/w.

In a preferred embodiment, the composition prepared in accordance to the second, third and fourth embodiment is further devoid of disaccharides.

In accordance with a sixth embodiment the present invention provides, a wet granulation process for preparing a stable pharmaceutical tablet composition comprising

a) dissolving atleast one binder and desmopressin in ethanol/ water solution,

b) blending atleast one starch and atleast one sugar alcohol,

c) granulating the blend of step [b] with dispersion of step [a],

d) dry the granules and mill through suitable screen,

e) blending atleast one lubricant together with pharmaceutically acceptable excipient and granules of step[d], in a blender for appropriate time,

f) compressing the blend of step [e] to form tablets.

In accordance with a seventh embodiment the present invention provides a dry granulation process for preparing a stable pharmaceutical tablet composition comprising blending desmopressin acetate together with atleast one starch and atleast one sugar alcohol and other pharmaceutically acceptable excipient, subjecting the blend to compression to form a coprimate, converting the coprimate to form a granulate and compressing the granulate to form the tablet composition.

In accordance with an eighth embodiment the present invention provides stable desmopressin acetate tablet composition packaged in an Alu-Alu blisters, wherein the blisters are further layered with silica gel.

In accordance with a ninth embodiment the present invention provides stable desmopressin acetate tablet composition, wherein the composition exhibits friability which is less than 1% w/w.

DETAILED DESCRIPTION

The present invention relates to a pharmaceutical composition in a solid dosage form such as tablets containing therapeutically effective amount of desmopressin or a pharmaceutically acceptable salt thereof, e.g., desmopressin acetate, atleast one sugar alcohol, together with a pharmaceutically acceptable excipient, carrier, or mixture thereof, wherein the composition is devoid of disaccharide and the lubricant concentration is above 0.5% w/w and below 2% w/w. Suitable pharmaceutically acceptable excipients or additive and carriers include, but are not limited to, diluents or fillers, binders, lubricants, glidants, disintegrants, and the like and mixtures there of.

In a stable pharmaceutical tablet composition according to the invention the active agent desmopressin acetate is present in the amount of from O.I to about 1.0% w/w.

The marketed formulation [commercially available today] contains desmopressin, pharmaceutically acceptable excipients and a lubricant, wherein the lubricant concentration is below 0.5%. On further reading of the prior arts it was revealed that this teaching is consistent and use of lubricant below 0.5% is recommended. Lubricant in the instant concentration has shown problem of sticking and capping, not attaining desired hardness and friction on machine while tableting.

The formulation prepared in accordance with the present invention, is robust and provides advantage over the marketed formulation, and is free from problems like capping, hardness and friability. The present invention also allows a high compressing speed for manufacturing tablets with the desired quality and retains low level of wear on the tableting machinery.

The present invention provides stable pharmaceutical tablet composition comprising desmopressin acetate, and to a method for manufacturing thereof together with a pharmaceutically acceptable excipient, diluents, carrier, or mixture thereof; wherein the pharmaceutical composition is composed of a compressed granulate containing atleast one sugar alcohol and lubricant in an amount of from 0.51 to less than 2.00 percent by weight of said pharmaceutical composition and is devoid of disaccharide.

By the term "sugar alcohol" is meant a polyol, polyhydric alcohol, or polyalcohol. A sugar alcohol is a hydrogenated form of carbohydrate, wherein the carbonyl group (aldehyde or ketone, reducing sugar) has been reduced to a primaiy or secondary hydroxy 1 group. The general formula of a sugar alcohol is H(HCHO)n+1H, whereas the general formula of sugar is H(HCHO)„HCO. Suitable sugar alcohol according to the present invention can be selected from sorbitol, erythritol, xylitol, mannitol, lactitol and maltitol. The amount of sugar alcohol may vary within a range of 30 to 75% w/w, preferably 40 to 60% w/w.

In one embodiment, the pharmaceutical compositions of the present invention may further include one or more saccharides, but excluding disaccharides. Representative examples of saccharides used herein include starch such as potato starch, wheat starch, com starch, pregelatinised maize starch and combinations thereof The amount of saccharide may vary within a range of about 20 to 45% w/w, preferably 30 to 40% w/w. The saccharides for use herein have an average particle size of less than about 200 microns, e.g., from 60 micron to less than 160 microns. Representative examples of disaccharides, to be excluded from the present invention, are lactose, sucrose and maltose.

The term "diluent" or " filler" as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of tablets and capsules. Such compounds include dibasic calcium phosphate, kaolin, sucrose, galactose, mannitol, microcrystalline cellulose, com starch, pregelatinized starch, powdered cellulose, precipitated calcium carbonate, sorbitol, potato starch and polysaccharide (except disaccharide) or combinations thereof and other such materials known to those of ordinary skill in the art.

The term "binders" is intended to mean substances used to cause adhesion of powder particles in tablet granulations. Suitable binders according to the present invention can be selected from hydroxypropyl cellulose, pregelatinized starch, polyvinyl pyrrolidone, acacia alginic acid, tragacanth, carboxymethylcellulose sodium, poly (vinylpyrrolidone), compressible sugar (e.g., NuTab), hydroxypropyl methyl cellulose, ethyl cellulose, gelatm, liquid glucose, methylcellulose, povidone and starch, poly (ethylene glycol), guar gum, polysaccharide, bentonites, sugars, invert sugars, collagen, albumin, celluloses in non-aqueous solvents.

combinations thereof and the like. Other binders include, for example, poly (propylene glycol), polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, poly (ethylene oxide), microcrystalline cellulose, dibasic calcium phosphate, or combinations thereof and other such materials known to those of ordinary skill in the art.

The term "lubricant" as used herein is intended to mean substances used in tablet formulations to reduce friction during tablet compression. Suitable lubricants according to the present invention can be selected from calcium stearate, magnesium stearate, talc, mineral oil, stearic acid, zinc stearate, colloidal silicon dioxide, glyceryl behenate, sodium stearyl fumarate, leucine or combinations thereof and other such materials known to those of ordinary person skilled in the art. The pharmaceutical compositions of the present invention contain the lubricants in a concentration of more than abut 0.5% w/w but below 2% w/w.

The term "glidant" as used herein is intended to mean agents used in tablet and capsule formulations to improve flow-properties and to produce an anti-caking effect. Such compounds include colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc and combinations thereof and other such materials known to those of ordinary skill in the art.

The term "disintegrant" is intended to mean a compound used in solid dosage form to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Suitable disintegrants according to the present invention can be selected from starches such as com starch, potato starch, crospovidone, croscarmellose sodium, pre-gelatinized and modified starch, sweeteners, clays such as bentonite, microcrystalline cellulose (e.g., Avicel(TM)), carsium (e.g., Amberlite(TM)), alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth or combinations thereof and other such materials known to those of ordinary skill in the art.

The pharmaceutical composition of the present invention is preferably in solid unit dosage form, more preferably in tablet or capsule form. The tablets or capsule can be made by using wet granulation as well as slugging/ dry granulation methods. In general, slugging/ dry granulation will involve a) blending all the ingredients and preparing slugs with, for example a slugging machine; b) sizing and lubricating the slugs; and c) compressing the lubricated slugs into tablets using suitable compression machine or filling the lubricated slugs into capsules of suitable size.

When using wet granulation in forming the pharmaceutical composition of the present invention, a solvent such as isopropyl alcohol, ethanol, water and mixtures thereof are advantageously employed. Wet granulation typically involves mixing of the ingredients, granulating the ingredients using binder solution, screening the damp, drying, lubricating, and compressing the resultant admixture into tablets or filling the admixture into capsules of suitable size.

In a preferred embodiment, there is provided a process for preparing a stable pharmaceutical composition in a solid dosage form is provided comprising a) dissolving copovidone and desmopressin acetate in dehydrated alcohol/ water solution to form dispersion, b) blending starch and mannitol, c) granulating the blend of step [b] with dispersion of step [a], d) dry the granules and mill through suitable screen, e) blending talc, colloidal silicon dioxide, sodium stearyl flimarate and granules of step[d], in a blender for appropriate time, f) compressing the blend of step [e] to form tablets.

In another embodiment, the pharmaceutical composition of desmopressin is prepared by dry granulation/ roller compaction process that includes the steps of: a) blending desmopressin acetate together with mannitol, starch and optionally other excipients; b) dry granulating the blend by roller compactor or slugging to form granules; c) sizing the granules; d) optionally blending the sized granules with one or more pharmaceutically inert excipients to form a blend; and e) compressing that blend into tablets.

The compression of granulate to tablet can be carried out in a conventional tableting machine, eccentric tableting machine or a rotary compression machine.

The tablets can further be coated by using any of the conventional coating techniques, such as pan or perforated pan, well known to the persons skilled in the art. These coating layers comprise of one or more excipients selected from the group comprising coating agents, opacifiers, taste-masking agents, colouring agents, antitacking agents and the like.

Coating agents which are useful in the coating process, include, but are not limited to, polysaccharides such as maltodextrin, alkyl celluloses such as methyl or ethyl cellulose, hydroxyalkylcelluloses (e.g. hydroxypropylcellulose or hydroxypropyl methyl cellulose); polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinylpyrrolidone and vinyl acetate (e.g. marketed under the brand name of Plasdone) and polymers based on methacrylic acid such as those marketed under the brand name of Eudragit.

These may be applied from aqueous or non-aqueous systems or combinations of aqueous and non aqueous systems as appropriate. Additives can be included along with the film formers to obtain satisfactory films. These additives can include plasticizers such as dibutyl phthalate, triethyi citrate, polyethylene glycol and the like, antitacking agents such as talc, stearic acid, magnesium stearate and colloidal silicon dioxide and the like, surfactants such as polysorbates and sodium lauryl sulphate and opacifying agents such as titanium dioxide and the like. All these excipients can be used at levels well known to the persons skilled in the art.

The following examples serve to illustrate the invention.

Example 1:

Sr. No. Ingredient Quantity (mg)

1 Desmopressin Acetate 0.20
2 Mannitol 123.10
3 Starch 73.40
4 Povidone 1.90
5 Colloidal silicon dioxide 0.40
6 Magnesium Stearate 1.00

Brief Manufacturing Process:

1. Sift starch and Manniol through mesh #30.

2. Dissolve Povidone and Desmopressin in ethanol and purified water.

3. Granulate the contents of step 1 with step 2 binder solution in fluid bed granulator.

4. Dry the granules and mill through 1.0 mm screen.

5. Sift magnesium stearate through mesh #40 and to blend of step no. 4 and blend for 20 minutes.

Example 2:

Sr. No. Ingredient Quantity (mg)

1 Desmopressin Acetate 0.20

2 Mannitol 122.50

3 Starch 73.40

4 Povidone 1.90

5 Sodium Stearyl fumarate 2.00

Brief Manufacturing Process:

1. Sift Desmopressin acetate, starch and mannitol through mesh #30.

2. Dissolve Povidone in purified water.

3. Granulate the contents of step 1 with step 2 binder solution.

4. Dry the granules at room temperature and mill through 1.0 mm screen.

5. Sift magnesium stearate through mesh #40 and to blend of step no. 4 and blend for 20 minutes.

Example 3:

Sr. No. Ingredient Quantity (mg)

1 Desmopressin Acetate 0.20

2 Mannitol 122.50

3 Starch 73.40

4 Povidone 1.90

5 Glyceryl behenate 2.00

Brief Manufacturing Process:

1. Sift Desmopressin acetate, starch and mannitol through mesh #30.

2. Dissolve Povidone in purified water.

3. Granulate the contents of step 1 with step 2 binder solution.

4. Dry the granules at room temperature and mill through 1.0 mm screen.

5. Sift Glyceryl behenate through mesh #40 and to blend of step no. 4 and blend for 20 minutes.

EXAMPLE 4:

Sr. No. Ingredient Quantity (mg)

1 Desmopressin Acetate 0.20

2 Mannitol 122.10

3 Starch 73.40

4 Povidone 1.90

5 Colloidal silicon dioxide 0.40

6 Leucine 2.00

Brief Manufacturing Process:

1. Sift Desmopressin acetate, starch and mannitol through mesh #30.

2. Dissolve Povidone in purified water.

3. Granulate the contents of step 1 with step 2 binder solution.

4. Dry the granules at room temperature and mill through 1.0 mm screen.

5. Sift Leucine and colloidal silicon dioxide through mesh #40 and to blend of step no. 4 and blend for 20 minutes.

Example 5:

Sr. No. Ingredient Quantity (mg)

1 Desmopressin Acetate 0.20

2 Mannitol 113.50

3 Potato Starch 76.40

4 Povidone (Plasdone S-630) 6.00

5 Colloidal silicon dioxide 0.40

6 Talc 2.00

7 Sodium Stearyl fumarate 1.50

Brief Manufacturing Process:

Sift Desmopressin acetate, potato starch, colloidal silicon dioxide, talc and Mannitol
through mesh #30.

Mix the step 1 ingredients geometrically and blend for 10 min in blender.

Sift sodium stearyl fiimarate through mesh #40 and to blend of step no. 2 and blend for 5 minutes.

Example 6:

Sr. No. Ingredient Quantity (mg)

1 Desmopressin Acetate 0.20

2 Povidone (Plasdone S-630) 6.00

3 Absoulte Ethanol/purified water Q.S

4 Mannitol 113.50

5 Potato Starch 76.40

6 Talc 2.00

7 Colloidal silicon dioxide 0.40

8 Sodium stearyl fumarate 1.50

Brief Manufacturing Process:

1. Sift potato starch and mannitol through mesh #30.

2. Dissolve Povidone and Desmopressin in ethanol and purified water.

3. Granulate the contents of step 1 with step 2 binder solution in granulator.

4. Dry the granules and mill through 1.0 mm screen.

5. Sift talc, colloidal silicon dioxide and sodium stearyl fiimarate through mesh #40 and to blend of step no. 4 and blend for 20 minutes.

Example 7:

Sr. No. Ingredient Quantity (mg)

1 Desmopressin Acetate 0.20

2 Povidone (Plasdone S-630) 6.00

3 Mannitol 85.00

4 Potato Starch 80.00

5 Talc 2.00

6 Colloidal silicon dioxide 0.50

7 Sodium stearyl fumarate 1.50

Brief Manufacturing Process:

1. Sift potato starch, mannitol. Povidone, Desmopressin through mesh #30.

2. Compact the contents of step 1 in roll compactor.

3. Pass the granules and mill through 1.0 mm screen.

4. Sift talc, colloidal silicon dioxide and sodium stearyl fumarate through mesh #40 and to blend of step no. 4 and blend for 20 minutes.

Example 8:

Sr. No. Ingredient Quantity (mg)

1 Desmopressin Acetate 0.20

2 Mannitol 110.00

3 Starch 76.40

4 Copovidone 6.00

5 Dehydrated Alcohol q.s.

6 Purified water q.s

7 Colloidal Silicon Dioxide 0.40

8 Talc 2.00

9 Sodium Stearyl fumarate 2.00

Brief Manufacturing Process:

1. Desmopressin acetate and copovidone were dissolved in dehydrated alcohol and
purified water mixture.

2. Starch and mannitol were passed through #40 ASTM and mixed for 5 min.

3. Granulate the dry mix of step no.2 with binder solution of step no. 1.

4. Wet mass was dried in rapid dryer at 40°C till LOD(at 60°C) reaches bellow 2.0%w/w

5. Dried granules were passed through suitable mesh.

6. Talc and colloidal silicon dioxide together passed through suitable mesh.

7. Step no.5 granules were mixed with step no 6 for suitable period of time.

8. Sodium Stearyl fumarate passed through #60 ASTM

9. Step no.7 blend were mixed with step no 8 for suitable period of time.

10. Compress the blend of step no. 8 using rotary compression machine.

Example 9:

Sr. No. Ingredient Quantity (mg)

1. Desmopressin Acetate 0.20

2. Povidone (Plasdone S-630) 6.00

3. Mannitol 76.50

4. Potato Starch 76.0

5. Talc 2.00

6. Colloidal silicon dioxide 0.40

7. Sodium stearyl fumarate 1.50

Brief Manufacturing Process:

1. Sift potato starch, mannitol. Povidone, Desmopressin through mesh #30.

2. Sift talc, colloidal silicon dioxide and sodium stearyl fumarate through mesh #40 and to blend of step no. 1 and blend for 20 minutes.

3. Compress the lubricated blend in to tablets. Example 10:

Example 10:

Sr. No. Ingredient Quantity (mg)

1. Desmopressin Acetate 0.200

2. Mannitol 79.900

3. Starch 110.000

4. Copovidone 6.000

5. Dehydrated Alcohol q.s

6. Purified water q.s

7. Colloidal Silicon Dioxide 0.400

8. Talc 2.000

9. Sodium Stearyl fumarate 1.500

Brief Manufacturing Process:

1. Desmopressin Acetate and Copovidone were dissolved in Dehydrated Alcohol and
Purified water mixture.

2. Starch and mannitol were passed through #40 ASTM and mixed for 5 min.

3. Granulate the dry mix of step no.2 with binder solution of step no. 1.

4. Wet mass was dried in rapid dryer at 40°C till LOD(at 60°C) reaches bellow 2.0%w/w

5. Dried granules were passed through suitable mesh.

6. Talc and colloidal silicon dioxide together passed through suitable mesh.

7. Step no.5 granules were mixed with step no 6 for suitable period of time.

8. Sodium Stearyl fumarate passed through #60 ASTM

9. Step no.7 blend were mixed with step no 8 for suitable period of time.

10. Compress the blend of step no. 8 using rotary compression machine.

Example 11:

S.No. Ingredients Qty/tablet (mg)

1 Desmopressin Acetate 0.200

2 Mannitol 59.900

3 Starch 130.000

4 Copovidone 6.000

5 Dehydrated Alcohol q.s

6 Purified water q.s

7 Colloidal Silicon Dioxide 0.400

8 Talc 2.000

9 Sodium Stearyl fumarate 1.500

Tablet weight 200.000

Brief Manufacturing Process:

1. Desmopressin Acetate and Copovidone were dissolved in Dehydrated Alcohol and
Purified water mixture.

2. Starch and mannitol were passed through #40 ASTM and mixed for 5 min.

3. Granulate the dry mix of step no.2 with binder solution of step no. 1.

4. Wet mass was dried in rapid dryer at 40°C till LOD(at 60°C) reaches bellow 2.0%w/w

5. Dried granules were passed through suitable mesh.

6. Talc and colloidal silicon dioxide together passed through suitable mesh.

7. Step no.5 granules were mixed with step no 6 for suitable period of time.

8. Sodium Stearyl fumarate passed through #60 ASTM

9. Step no.7 blend were mixed with step no 8 for suitable period of time.

10. Compress the blend of step no. 8 using rotary compression machine.

Dissolution Study: The dissolution test is done using USP II apparatus (Paddle) at 75 RPM, 500ml of deaerated water at 37 ± 0.5 °C.

Table 1: Results of the comparative dissolution study of Example 6 and DDAVP®

Effect of lubricant concentration on Tablet Parameters: Different lubricant concentration trials were designed with different concentrations of Sodium Stearyl Fumarate i.e. 0.25%, 0.50%, 0.60%, 0.75% and 1.00% w/w. Tablet were evaluated against various physical parameters like thickness, hardness, friability and disintegration time The compositions of the trial batches is given in the below table 2 and the results are given in table 3.

Table 2: Comparative trial batches composition.

Brief Manufacturing Process:

1. Desmopressin Acetate and Copovidone were dissolved in Dehydrated Alcohol and Purified water mixture.

2. Starch and mannitol were passed through #40 ASTM and mixed for 5 min.

3. Granulate the dry mix of step no.2 with binder solution of step no. 1.

4. Wet mass was dried in rapid dryer at 40°C till LOD(at 60°C) reaches bellow 2.0%w/w

5. Dried granules were passed through suitable mesh.

6. Talc and colloidal silicon dioxide together passed through suitable mesh.

7. Step no.5 granules were mixed with step no 6 for suitable period of time.

8. Sodium Stearyl fumarate passed through #60 ASTM

9. Step no.7 blend were mixed with step no 8 for suitable period of time.

10. Compress the blend of step no. 8 using rotary compression machine.

Table 3: Physical parameter data of comparative trial batches composition.

Conclusion: During compression with 0.25% and 0.50% w/w concentration of Sodium Stearyl Fumarate, striations were observed on tablet edges, the tablets were showing low hardness in comparison to the marketed DDAVP® tablets and tablets of the instant invention, the tablets were failing in friability test and were associated with ejection problem. While tablets with 0.60% w/w, 0.75% w/w and 1.00 % w/w of Sodium Stearyl Fumarate, the disintegration time was similar to that of marketed product and no process related problems were observed.

Stability Study: The composition of the instant invention were subjected to stability studies at 40°C± 2°C & 75± 5 % relative humidity and tested for related substances by storing in HOPE containers, Alu-Alu blisters and desiccant layered Alu-Alu blisters, the results are enumerated in Table 4.

Table 4: Stability study of Example 6 by storing in HDPE containers, Alu-Alu blisters and desiccant layered Alu-Alu blisters

Conclusion: As per British Pharmacopoeia monograph for Desmopressin acetate tablets the maximum unknown impurity should be not more than 2.0 % and total impurities should not be more than 4.0%. From the assay, related substances and dissolution data it appears that the formulation was more stable in HDPE and desiccant Alu-Alu blister than Alu-Alu blister. The total impurities were high when the tablets were packed in Alu-Alu blister without desiccant layer. The pack laminate of Alu-Alu blisters with desiccant layer should preferably have 152 mm thickness.

The stability study indicate that the finalized composition was stable with respect to assay, related substances, dissolution profile and water content, when stored at 40°C± 2°C & 75± 5 % relative humidity in HDPE container fitted with child resistant closure and sealed with aluminum liner and Alu-Alu Desiccant layered blisters.

WE CLAIM

1. A pharmaceutical tablet composition comprising: 0.1 to 1.0% w/w of desmopressin acetate, 35 to 70% w/w of atleast one sugar alcohol, 25 to 45% w/w of at least one saccharide, at least one lubricant in an amount greater than 0.5% w/w and one or more other pharmaceutically acceptable excipients, wherein said composition is devoid of disaccharide.

2. The pharmaceutical tablet composition according to claim 1, comprising about 0.2 % w/w of desmopressin acetate.

3. The pharmaceutical tablet composition according to claim 1, wherein sugar alcohol is selected from sorbitol, erythritol, xylitol, mannitol, lactitol and maltitol.

4. The pharmaceutical tablet composition according to claim 1, wherein saccharide(s) are selected from potato starch, wheat starch, com starch, pregelatinised maize starch and combinations thereof, having average particle size of less than about 200 microns.

5. The pharmaceutical tablet composition according to claim 1, wherein said composition has friability not greater than about 1% by weight as per the United States Pharmacopoeia (USP) friability test.

6. A pharmaceutical composition according to claim 1, wherein the percentage of desmopressin acetate released from said composition during in-vitro dissolution is comparable to that of desmopressin acetate marketed under the trade name of DDAVP and wherein said composition releases more than 80% of desmopressin acetate in 10 min, when tested in a USP II apparatus (Paddle) at 75 RPM, 500 ml of deaerated water at 37 ± 0.5 °C.

7. A pharmaceutical tablet composition prepared by wet granulation technique comprising effective amount of desmopressin acetate, copovidone, mannitol, starch, sodium stearyl fumarate and pharmaceutically acceptable additives, such that the amount of sodium stearyl fumarate concentration is greater than 0.5% w/w, wherein said composition is devoid of disaccharide.

8. A pharmaceutical composition according to claim 7, wherein said composition is prepared by granulating desmopressin and mannitol and starch using hydro-alcoholic copovidone solution, to obtain an intra-granular portion of a granulate, and converting said granulate into a pharmaceutical tablet composition.

9. A pharmaceutical tablet composition according to claim 7, packaged in Alu-Alu blisters layered with silica gel, wherein the said composition shows enhanced stability as compared to Alu-Alu blisters devoid of silica gel.

10. A method for the manufacturing of a pharmaceutical tablet composition comprising desmopressin acetate, as a therapeutically active ingredient, wherein said method comprises the steps of:

i) blending atleast one sugar alcohol with atleast one saccharide;

ii) preparing binder solution by dissolving desmopressin acetate and atleast one binder in water/ alcohol mixture;

iii) granulating blend of step i) using said binder solution to form granulate;

iv) blending atleast one lubricant with granulate of step iii), wherein the lubricant concentration is greater than about 0.5% w/w of tablet;

v) compressing blend of step iv) to form tablets.