DESC:FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition of docusate or pharmaceutically acceptable salt thereof, preferably sodium salt and process for its preparation. The pharmaceutical composition optionally further comprises sennosides.

BACKGROUND OF THE INVENTION
Bis(2-ethylhexyl) sulfosuccinate anion is commonly known as docusate or dioctyl sulfosuccinate abbreviated as DOSS. Salts of this anion such as sodium, potassium and calcium, particularly sodium, are widely used in medicine as laxatives and as stool softeners. It reduces the surface tension of the stool, allowing more intestinal water and fat to combine with the stool that decreases the strain and discomfort associated with constipation. Docusate salts are also used as food additives, emulsifiers, dispersants, and wetting agents, among other uses.

US 2,028,091 patent discloses various esters of sulphodicarboxylic acids including the dioctyl esters of sulphodicarboxylic acids.

US 2,441,341 patent discloses water-soluble composition comprising a dry mixture of dialkyl sulfosuccinate such as docusate and an alkali metal benzoate.

US 3,035,973 patent discloses compositions comprising dioctyl calcium sulfosuccinate dissolved in oils, such as corn oil, peanut oil, cotton seed oil or non-aqueous solvents such as polyethylene glycols 200-400, containing up to 10% by volume of glyceryl monooleate. The oily mixture is then formulated into soft gelatin capsules that can be used as fecal softeners.

US 4,070,456 patent discloses soft gelatin capsule compositions containing solution of dioctyl calcium sulfosuccinate and non-aqueous solvents like polyol ester of mixed caprylic and capric acids and glyceryl monooleate.

US 5,525,355 patent discloses hard gelatin capsule compositions containing stool softener like poloxamers (polyoxyethylene-polyoxypropylene block copolymers) in combination with stimulant laxative like danthron (1,8-dihydroxyanthraquinone), bisacodyl, casanthranol, cascara, sennosides and sodium picosulphate.

US 8,637,570 patent discloses pharmaceutical composition comprising docusate, an osmotic laxative like sorbitol and a benzoate like sodium benzoate, wherein said pharmaceutical composition is in the form of a solution.

Docusate sodium is a waxy substance and sparingly soluble in water. It is difficult to process into a common preparation like tablets avoiding tablet defect such as lamination during compression and providing tablets having desirable attributes such as adequate hardness, friability, disintegration time, dissolution profile and content uniformity.
IN 4294/CHE/2012 patent application discloses non-aqueous wet granulation process for preparing tablet compositions comprising docusate sodium either alone or in combination with sennosides. This patent states that the non-aqueous solvents employed as wet granulating fluid includes methanol, ethanol, acetone, methylene chloride or combination thereof. This patent further states that the preferred granulation fluid is acetone.

SUMMARY OF THE INVENTION
The present invention relates to a pharmaceutical composition of docusate or pharmaceutically acceptable salt thereof, preferably sodium salt and process for its preparation. The pharmaceutical composition optionally further comprises sennosides.

One embodiment of the present invention relates to a granulating solution comprising docusate or pharmaceutically acceptable salt thereof, Eudragit EPO and isopropanol.

Another embodiment of the present invention relates to a pharmaceutical composition of docusate comprising docusate or pharmaceutically acceptable salt thereof, Eudragit EPO, calcium silicate and one or more pharmaceutically acceptable excipient.

In one embodiment, the present invention relates to a pharmaceutical composition of docusate comprising:
10-50 % w/w docusate or pharmaceutically acceptable salt thereof,
5-25 % w/w Eudragit EPO,
5-25 % w/w calcium silicate,
10-70 % w/w diluent,
2-20 % w/w disintegrant,
0.1-2% w/w glidant and
0.1-2% w/w lubricant.

In another embodiment, the present invention provides a process for the preparation of pharmaceutical composition of docusate comprising steps of
i. preparing a granulating solution comprising docusate or pharmaceutically acceptable salt thereof and Eudragit EPO in isopropanol,
ii. mixing calcium silicate with one or more pharmaceutically acceptable excipient,
iii. granulating the mixture of step ii using granulating solution of step i,
iv. drying the granules and
v. packing the dried granules for bulk supply or
v. mixing the dried granules with one or more pharmaceutically acceptable excipient and compressed into tablet or filled into sachet or capsule.

DETAILED DESCRIPTION OF THE INVENTION
The ‘pharmaceutically acceptable salt’ according to the present invention includes sodium, potassium and calcium salt.

One embodiment of the present invention relates to a granulating solution comprising docusate or pharmaceutically acceptable salt thereof, Eudragit EPO and isopropanol.

Isopropanol used in the granulating solvent may contain upto 10% water.

Another embodiment of the present invention relates to a pharmaceutical composition of docusate comprising docusate or pharmaceutically acceptable salt thereof, Eudragit EPO, calcium silicate and one or more pharmaceutically acceptable excipient.

In one embodiment, the present invention relates to a pharmaceutical composition of docusate comprising:
10-50 % w/w docusate or pharmaceutically acceptable salt thereof,
5-25 % w/w Eudragit EPO,
5-25 % w/w calcium silicate,
10-70 % w/w diluent,
2-20 % w/w disintegrant,
0.1-2% w/w glidant and
0.1-2% w/w lubricant.
The pharmaceutical composition of docusate of the present invention is preferably prepared by wet granulation. In one embodiment, the present invention provides a process for the preparation of pharmaceutical composition of docusate comprising steps of
i. preparing a granulating solution comprising docusate or pharmaceutically acceptable salt thereof and Eudragit EPO in isopropanol,
ii. mixing calcium silicate with one or more pharmaceutically acceptable excipient,
iii. granulating the mixture of step ii using granulating solution of step i,
iv. drying the granules and
v. packing the dried granules for bulk supply or
v. mixing the dried granules with one or more pharmaceutically acceptable excipient and compressed into tablet or filled into sachet or capsule.

The pharmaceutical composition of docusate further comprises one or more pharmaceutically acceptable excipient selected from diluent, binder, disintegrant, glidant, lubricant, colouring agent or coating agent.

Suitable diluent may be selected from microcrystalline cellulose, starch, pregelatinized starch or lactose.
Suitable binder may be selected from copovidone, povidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose or pregelatinized starch.
Suitable disintegrant may be selected from croscarmellose sodium, crospovidone, starch, maize starch, pregelatinized starch, sodium starch glycollate, hydroxypropyl starch or microcrystalline cellulose.

Suitable glidant may be selected from colloidal silicon dioxide, talc or magnesium trisilicate,

Suitable lubricant may be selected from magnesium stearate, stearic acid, talc or sodium stearyl fumarate.

The pharmaceutical composition is solid composition such as granules for bulk supply, granules in a sachet, tablet or capsule. The tablets optionally further coated with coating agent to improve elegance and/or palatability.

The tablet formulations of the present invention comply with USP, BP, EP and/or IP.

In another embodiment, the tablet formulations of the present invention are stable for at least one month, at least two months or at least three months when stored at 40 °C/75% RH.

In yet another embodiment, the tablet formulations of the present invention are stable for at least three months when stored at 30 °C/75% RH.
In further embodiment, the tablet formulations of the present invention are stable for at least three months when stored at 25 °C/60% RH.

The dose of docusate required to act as a stool softener or as emollient laxative is in the range of from about 20 mg to about 200 mg, preferably 30 mg to about 150 mg, more preferably 50 mg or more preferably 120 mg.

The pharmaceutical composition of docusate of the present invention optionally further comprises sennosides. Sennosides includes sennoside A, sennoside B and mixture thereof. The preferred sennoside is sennoside B. The dose of sennoside is in the range of from about 5 mg to about 50 mg, preferably 8 mg.

Examples
The following examples are given for the purpose of illustration rather than limitation of the invention.

Example 1
Tablet compositions of Docusate Sodium
Table 1: Tablet compositions of Docusate Sodium
Ingredients % w/w
Intra-granular part
Calcium silicate 8.0
Microcrystalline cellulose 27
Drug solution
Docusate Sodium 32
Eudragit EPO 10
Isopropanol q.s.
Extra-granular part
Povidone K30 1.3
Calcium silicate 2.6
Microcrystalline cellulose 6.3
Croscarmellose Sodium 10.2
Colloidal silicon dioxide 1.3
Magnesium stearate 1.3
Total 100

Manufacturing Process:
Docusate Sodium and Eudragit EPO were dissolved in isopropanol under continuous stirring to get granulating solution. Microcrystalline cellulose and calcium silicate were mixed in RMG. Granulation was performed using the granulating solution. Wet mass was transferred into fluid bed processor and dry at inlet temperature of 40±10ºC for 10-15 minutes. Semi-dried granules were sifted through ASTM #6 mesh and collect in a polybag. These granules were transferred into fluid bed processor and dry at inlet temperature of 40±10ºC and granules were dried till LOD of NMT 2 % w/w is attained. Granules were sifted through ASTM #16 mesh and collected in a polybag. Granules, povidone K30, calcium silicate, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide were mixed in a blender. The resulting blend was lubricated with magnesium stearate and compressed with suitable punch tooling at target hardness. The final weight of tablet was 350 mg.

Example 2
Tablets of example 1 were coated with film coating agent Opadry® TF till 5% weight gain.
Opadry® TF is commercially available from Colorcon.

Example 3
Stability study
Tablets of example 2 were stored at 40 °C/75% RH, 30 °C/75% RH and 25 °C/60% RH. The results of the stability study are provided in Table 2.
Table 2: Stability data of Tablets of example 2
Strength Storage Condition Dissolution Test
(Stimulated Gastric Fluid) Assay
(% w/w) Water Content By KF
50 mg Initial 26:27 104.20 5.02
1M (40/75) 25:45 102.00 5.84
2M (40/75) 25:33 101.80 5.78
3M (40/75) 27:00 101.10 5.81
3M (30/75) 26:47 101.80 5.38
3M (25/60) 25:43 102.40 5.53
120 mg Initial 18:04 102.50 5.45
1M (40/75) 20:58 101.00 5.93
2M (40/75) 20:45 100.80 5.71
3M (40/75) 21:55 99.30 5.86
3M (30/75) 21:56 100.70 5.69
3M (25/60) 20:08 100.50 5.67

Following are the various aspects of the invention.
Aspect 1. A granulating solution comprising docusate or pharmaceutically acceptable salt thereof, Eudragit EPO and isopropanol.
Aspect 2. A pharmaceutical composition of docusate comprising docusate or pharmaceutically acceptable salt thereof, Eudragit EPO, calcium silicate and one or more pharmaceutically acceptable excipient.
Aspect 3. A pharmaceutical composition of docusate comprising:
10-50 % w/w docusate or pharmaceutically acceptable salt thereof,
5-25 % w/w Eudragit EPO,
5-25 % w/w calcium silicate,
10-70 % w/w diluent,
2-20 % w/w disintegrant,
0.1-2% w/w glidant and
0.1-2% w/w lubricant.
Aspect 4. A process for the preparation of pharmaceutical composition of docusate comprising steps of
i. preparing a granulating solution comprising docusate or pharmaceutically acceptable salt thereof and Eudragit EPO in isopropanol,
ii. mixing calcium silicate with one or more pharmaceutically acceptable excipient,
iii. granulating the mixture of step ii using granulating solution of step i,
iv. drying the granules and
v. packing the dried granules for bulk supply or
v. mixing the dried granules with one or more pharmaceutically acceptable excipient and compressed into tablet or filled into sachet or capsule.
Aspect 5. The granulating solution according to aspect 1 further comprises upto 10% water.
Aspect 6. The process according to aspect 4 further comprises upto 10% water in a granulating solution of step i).
Aspect 7. The pharmaceutical composition according to aspect 3 wherein the composition is granules, tablets or capsules.
Aspect 8. The pharmaceutical composition according to aspect 7 wherein the tablets are further coated with coating agent.
Aspect 9. The pharmaceutical composition according to aspect 3 wherein the composition is stable for at least three months when stored at 40 °C/75% RH.
Aspect 10. The pharmaceutical composition according to aspect 3 wherein the composition is stable for at least three months when stored at 30 °C/75% RH and/or 25 °C/60% RH.
,CLAIMS:1. A granulating solution comprising docusate or pharmaceutically acceptable salt thereof, Eudragit EPO and isopropanol.
2. A pharmaceutical composition of docusate comprising docusate or pharmaceutically acceptable salt thereof, Eudragit EPO, calcium silicate and one or more pharmaceutically acceptable excipient.
3. A pharmaceutical composition of docusate comprising:
10-50 % w/w docusate or pharmaceutically acceptable salt thereof,
5-25 % w/w Eudragit EPO,
5-25 % w/w calcium silicate,
10-70 % w/w diluent,
2-20 % w/w disintegrant,
0.1-2% w/w glidant and
0.1-2% w/w lubricant.
4. A process for the preparation of pharmaceutical composition of docusate comprising steps of
i. preparing a granulating solution comprising docusate or pharmaceutically acceptable salt thereof and Eudragit EPO in isopropanol,
ii. mixing calcium silicate with one or more pharmaceutically acceptable excipient,
iii. granulating the mixture of step ii using granulating solution of step i,
iv. drying the granules and
v. packing the dried granules for bulk supply or
v. mixing the dried granules with one or more pharmaceutically acceptable excipient and compressed into tablet or filled into sachet or capsule.
5. The granulating solution as claimed in claim 1 further comprises upto 10% water.
6. The process as claimed in claim 4 further comprises upto 10% water in a granulating solution of step i).
7. The pharmaceutical composition as claimed in claim 3 wherein the composition is granules, tablets or capsules.
8. The pharmaceutical composition as claimed in claim 7 wherein the tablets are further coated with coating agent.
9. The pharmaceutical composition as claimed in claim 3 wherein the composition is stable for at least three months when stored at 40 °C/75% RH.
10. The pharmaceutical composition as claimed in claim 3 wherein the composition is stable for at least three months when stored at 30 °C/75% RH and/or 25 °C/60% RH.