FIELD OF INVENTION

The present invention pertains to tablet compositions comprising docusate sodium as well as docusate sodium in combination with sennosides. More particularly, this invention pertains to a tablet compositions comprising docusate sodium in combination with sennosides, wherein said tablet compositions are prepared by wet granulation technique, preferably utilizing non-aqueous solvents.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ART

Docusates are anionic surfactants which are used as stool softener or as emollient laxative. Docusate are used in the form of a pharmaceutically acceptable salt, like docusate sodium (sodium 1, 4-bis(2-ethylhexyl) sulfosuccinate), docusate calcium (calcium l,4-bis(2-ethylhexyl)sulfosuccinate) or docusate potassium (potassium l,4-bis(2-ethylhexyl)sulfosuccinate). Docusate (docusate sodium) inhibits the water uptake from the human gut and reduce surface tension of the fluids permitting them to penetrate into the faeces and thereby softening the stools. Docusate sodium is a waxy substance, sparingly soluble in water and is difficult to process into a common preparation like tablets avoiding tablet defect like lamination during compression and providing tablets having desirable attributes like adequate hardness, friability, disintegration time, dissolution profile and content uniformity. The dose of docusate sodium 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 and more preferably 50 mg to about 100 mg.

Sennosides is a partially purified natural complex of anthraquinone glycosides, isolated from senna leaflets and/or senna pods. Sennosides are insoluble in water, and barely soluble in methanol; sennosides dissolves in a mixture of 30% water and 70% methanol. Sennosides degrades into rhein anthrone molecules during shelf-life if exposed to moisture, and hence it is recommended to avoid moisture and heat during storage of senna plants, extract, or pills/ capsules containing sennosides.

These glycosides are absorbed from the intestinal tract are excreted into the colon, where these anthraquinone glycosides stimulates the colon and increases the peristaltic movements of the colon by local action, resulting in decreased absorption of water and thereby forming bulky and softer fecal mass.
United States Patent No. 2,028,091 discloses various esters of sulphodicarboxylic acids including the dioctyl esters of sulphodicarboxylic acids.

United States Patent No. 2,441,341 discloses water-soluble composition comprising a dry mixture of dialkyl sulfosuccinate such as docusate and an alkali metal benzoate.

United States Patent No. 3,035,973 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.

United States Patent No. 4,070,456 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.

United States Patent No. 5,525,355 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.

United States Patent Application No. 20110015268 discloses stable liquid pharmaceutical composition comprising combination of docusate, an osmotic laxative like sorbitol or lactitol and a benzoate like sodium benzoate.

European Patent No. EP 0 682 946 Bl discloses hard gelatin capsules containing plurality of multiparticulates each comprising a combination of stimulant laxative such as danthron(l,8-dihydroxyanthraquinones), bisacodyl, casanthranol, cascara, sennosides and sodium picosulfate with a stool softener such as Poloxamers (polyoxyethylene-polyoxypropylene block copolymers).
PCT Application No. WO 95/17174 discloses process of preparing ingestible, neutral tasting laxative composition containing dioctyl sulfosuccinate by coating dioctyl sulfosuccinate with a material selected from the group consisting of Q4-18 fats, C16-20 fatty acids, sucrose polyesters, ci4-i8 fats and waxes, pH sensitive polymers, food gums, and combinations thereof.

PCT Application No. WO 20000/67747 discloses composition comprising docusate, glyceride derivatives, polyethylene glycols and mixtures thereof, filed in hard capsules.

Process of preparing compositions comprising docusate sodium disclosed in prior art are cumbersome and are commercially not feasible, these processes either involving use of melt granulation/ melt extrusion technique wherein docusate and a fusible carrier are melted together, optional excipients are added to this molten mass and then processed to form compressed tablets or the wet granulation involving water as a granulating fluid.

However, there is still a need to develop alternate process for preparing tablet composition comprising docusate sodium alone or a combination of docusate sodium and sennosides avoiding the treatment of heat or application of aqueous solvents during granulation process.

There is no disclosure in the prior art that teaches wet granulation process for preparing tablet compositions comprising docusate sodium alone or docusate sodium in combination with sennosides involving use of non-aqueous granulating fluids.

The invention now provides non-aqueous wet granulation process for preparing tablet compositions comprising docusate sodium either alone or in combination with sennosides.

OBJECT OF THE INVENTION

According to the invention, there is provided a tablet composition comprising docusate sodium and optionally sennosides, wherein said compositions are prepared by wet granulation technique.
It is an object of the present invention to provide tablet composition comprising a combination of docusate sodium, sennosides and optional pharmaceutically acceptable excipients, wherein said tablets are prepared by wet granulation technique.

Another object of the present invention to provide tablet composition comprising combination of docusate sodium, sennosides and optional pharmaceutically acceptable excipients, wherein said tablets are prepared by wet granulation technique employing non-aqueous solvent as a granulating fluid.

Another object of the present invention to provide tablet composition comprising combination of docusate sodium, sennosides, atleast one diluent/ filler, atleast one binder, atleast one disintegrant and optional pharmaceutically acceptable excipients, wherein said tablets are prepared by wet granulation technique employing acetone as granulating fluid.

Another object of the present invention to provide a composition comprising docusate sodium and optionally sennosides prepared by a process comprising the steps of:

i. blending atleast one pharmaceutically acceptable excipients and optional sennosides to form a blend;

ii. granulating the blend of step i) with a binder solution comprising docusate sodium and povidone in an non-aqueous solvent;

iii. screening and lubricating the granules of step ii);

iv. processing the granules of step iii) to form compressed tablets or filing the granules in hard gelatin capsules;

v. optionally coating said compressed tablets.

SUMMARY OF THE INVENTION

The present invention relates to compositions comprising docusate sodium and optionally sennosides, wherein said compositions are prepared by wet granulation technique employing non-aqueous solvent(s) as granulating fluid.

In one embodiment the present invention provides tablet composition comprising a combination of docusate sodium, sennosides, atleast one diluent, atleast one binder, atleast one disintegrant and optional other pharmaceutically acceptable excipients, wherein said tablets are prepared by wet granulation technique employing acetone as a granulating fluid.

In another embodiment the present invention to provide tablet compositions comprising docusate sodium optionally in combination with sennosides prepared by a process comprising the steps of:

i. blending atleast one pharmaceutically acceptable excipients and optional sennosides to form a blend;

ii. granulating the blend of step i) with a binder solution comprising docusate sodium and a binder in an non-aqueous solvent;

iii. screening and lubricating the granules of step ii);

iv. processing the granules of step iii) to form compressed tablets or filing the granules in hard gelatin capsules;

v. optionally coating said compressed tablets.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention is directed to compositions comprising docusate sodium and optionally sennosides.

Tablet composition according to the invention is prepared by wet granulation technique, employing non-aqueous solvent(s) as granulating fluid. The preferred non-aqueous solvent is acetone. The tablet compositions prepared according to the invention are free of tablet defects/ problems like lamination and capping, that arises during compression process and provides tablet composition having adequate hardness, friability, content uniformity, desirable hardness, uniform disintegration and dissolution profile.
Docusate sodium is available as a white waxy material, and hence not an ideal candidate for wet granulation. Prior art teachings involve use of melt granulation/ melt extrusion process, wherein the docusate and atleast one fusible carrier are melted together, to this melted mixture optional excipients are added and then processed to form compressed tablets or granules filed in capsules. Prior art also teaches preparing soft gelatin capsule composition by dissolving docusate in a suitable carrier liquid and filed in soft gelatin capsule.

Sennosides are natural product, hence when making composition comprising docusate sodium in combination with sennosides it is not suitable to employ melt granulation/ melt extrusion process as the heat employed during manufacturing process may degrade the sennosides component resulting in loss of potency. The normal storage instruction for products containing sennosides is that such product should be stored away from heat, moisture and direct sun light as heat or moisture may cause the medicine to break down. Use of wet granulation process involving water a granulating fluid has several process related disadvantages.

The present invention now provides tablet composition comprising docusate sodium and optionally sennosides, wherein said tablets are prepared by wet granulation process, preferably employing non-aqueous solvent.

The inventive process provides various advantages over the prior art that are enumerated below:

degradation of sennosides is avoided by not employing heat during manufacturing process;

aqueous solvents are not employed hence avoiding the moisture catalyzed degradation of sennosides;
tablet compositions according to the invention exhibits tablet attributes like uniformity in content, desirable hardness, uniform disintegration and dissolution profile as well as avoids tabletting defects or processing issues like lamination and picking.

The term docusate means docusate in the form of a salt, for example docusate sodium, docusate calcium and docusate potassium. Docusate sodium may be present in an amount from about 20 mg to about 200 mg, e.g. 50 mg, 100 mg or 150 mg. The percentage weight of docusate sodium may vary from about 10% to about 40% by weight of the total weight of the composition.

Sennosides are hydroxyanthracene glycosides derived from Senna leaves. They have been used as natural, safe time-tested laxatives traditional as well as in modern systems of medicine. Sennosides means sennoside A, sennoside B and sennoside A & B or in the form of a salt. The preferred sennoside is sennoside B in an amount from about 5 mg to about 50 mg. The percentage weight of sennosides may vary from about 2% to about 10% by weight of the total weight of the composition.

In a preferred embodiment the tablet compositions according to the invention contains 50 mg of docusate sodium and 8 mg as sennosides or 100 mg docusate sodium and 8 mg as sennosides.

The non-aqueous solvents employed as wet granulating fluid includes methanol, ethanol, acetone, methylene chloride or combination thereof. The preferred granulation fluid is acetone.

Tablet compositions according to the invention may optionally contain pharmaceutically acceptable excipients like diluents, binders, disintegrants, surfactants and lubricants/ glidant.

Fillers/ diluents according to the invention include but not limited to: lactose, kaolin, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powder, starches, calcium phosphate, dibasic calcium phosphate, compressible sugars, sucrose, sorbitol, xylitol, fructose, dextrates, dextrin, dextrose, mannitol, maltodextrin, polymethacrylates and mixtures thereof. Said fillers/ diluents may be present in an amount from about 30% to about 80% by weight, preferably, from about 40% to about 70% by weight of the tablet composition.

Binders according to the invention include but not limited to: acacia, guar gum, alginic acid, sodium alginate, carbomer, dextrin, gelatin, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, polyvinylpyrrolidone, liquid glucose, maltodextrin, polymethacrylates, starch, pregelatinised starch, hydrogenated vegetable oil (type I), zein and mixtures thereof. Said binders may be present in an amount from about 1% to about 10% by weight, preferably, from about 2% to about 7% by weight of the tablet composition. The preferred binder according to the invention is polyvinylpyrrolidone.

Disintegrants according to the invention include but not limited to: alginic acid, powdered cellulose, methylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, L-hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, guar gum, sodium alginate, sodium starch glycolate, microcrystalline cellulose, starches and pre-gelatinized starch, polyvinylpyrrolidone, polacrilin potassium, magnesium aluminum silicate and mixtures thereof. Said disintegrant may be present in an amount from about 1% to about 20% by weight, preferably, from about 2% to about 10% by weight of the tablet.

Surfactants according to the invention include but not limited to anionic and cationic surfactants, such as benzalkonium chloride, cetylpyridinium chloride, cetrimide, docusate sodium, glyceryl monooleate, sodium lauryl sulfate, lauric acid, sorbitan fatty acid esters (sorbitan monolaurate, sorbitan mono- stearate, sorbitan monooleate, sorbitan monopalmitate, sorbitan trioleate), polyoxyethylene sorbitan fatty acid esters, polyoxyethylene cetyl stearyl ether, polyoxyethylene cetyl lauryl ethers, polyhydroxyethylene fatty acid esters and mixtures thereof.

Lubricants/ glidant according to the invention include but not limited to: hydrated silica, colloidal silicon dioxide, stearic acid, aluminum-stearate, calcium stearate, magnesium stearate, magnesium silicate, magnesium trisilicate, sodium stearyl fumarate, zinc stearate, glyceryl behenate, glyceryl dibehenate, glyceryl monostearate, glyceryl palmitostearate, highly disperse silica (aerosil), hydrogenated castor oil, hydrogenated cotton seed oil, hydrogenated vegetable oil, light mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, talc and mixture thereof.

The tablet according to the invention may further be coated with optional film coating layer employing a film forming polymers. Film coating suspensions include combinations of one, two or three of the following components: carboxymethylcellulose sodium, carnauba wax, cellulose acetate phthalate, cetyl alcohol, confectioner's sugar, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, liquid glucose, maltodextrin, methyl cellulose, microcrystalline wax, Opadry and Opadry II, polymethacrylates, polyvinyl alcohol, shellac, sucrose, talc, titanium dioxide, and zein, preferably Opadry. Film coat concentration can be varied up to about 10% to complement the drug amount, and preferably about 5% to about 9%.

In a preferred embodiment the tablet compositions according to the invention contains 50 mg of docusate sodium and 8 mg as sennoside or 100 mg docusate sodium and 8 mg as sennosides and filler/ diluent is selected from lactose, microcrystalline cellulose, di-calcium phosphate or a mixture thereof. When a mixture of lactose, microcrystalline cellulose, di-calcium phosphate is employed as filler/ diluent then the weight ratio of lactose: microcrystalline cellulose: di-calcium phosphate is 1: 1: 0.5 to about 3:2: 1.

In an embodiment the present invention provides tablet compositions comprising docusate sodium and optionally sennosides prepared by a process comprising the steps of:

i. blending atleast one pharmaceutically acceptable excipients and optional sennosides to form a blend;

ii. preparing a binder solution comprising docusate sodium and povidone in an non-aqueous solvent;

iii. granulating the blend i) with a binder solution of step ii);

iv. screening and lubricating the granules of step iii);

v. processing the granules of step iv) to form compressed tablets or filing the granules in hard gelatin capsules;

vi. optionally coating said compressed tablets.

In another embodiment the present invention to provide tablet compositions comprising docusate sodium optionally in combination with sennosides prepared by a process comprising the steps of:

i. blending atleast one pharmaceutically acceptable excipients and optional sennosides to form a blend;

ii. blending one or more diluent/ filler to form a blend;

iii. preparing a binder solution comprising docusate sodium and povidone in an non-aqueous solvent;

iv. granulating the blend ii) with a binder solution of step iii);

v. screening and mixing the granules of step iv) with blend of step i);

vi. processing the granules of step v) to form compressed tablets or filing the granules in hard gelatin capsules;

vii. optionally coating said compressed tablets.

In one specific embodiment the present invention to provides tablet compositions comprising docusate sodium, sennosides prepared by a process comprising the steps of:

i. sifting lactose, maize starch, microcrystalline cellulose, di-calcium phosphate dihydrate, hydrated silica and sennosides to form a blend;

ii. dissolving docusate sodium and povidone in acetone to form binder solution;

iii. granulate the blend i) with binder solution of step ii);

iv. drying and screening the granules of step iii);

v. sift silicified microcrystalline cellulose, colloidal silicon dioxide to form a blend;

vi. blending the granules of step iv) with the blend of step v);

vii. lubricating the blend of step vii) with sodium steryl fumarate;

viii. compressing the blend of step vii) to form compressed tablets;

ix. coating the tablets of step viii) with opadry.

In another specific embodiment the present invention provides tablet composition comprising docusate sodium, sennosides prepared by a process comprising the steps of:

i. sifting lactose, maize starch, microcrystalline cellulose, di-calcium phosphate dihydrate, and hydrated silica to form a blend;

ii. dissolving docusate sodium and povidone in acetone to form binder solution;

iii. granulate the blend i) with binder solution ii);

iv. drying and screening the granules of step iii);

v. sift sennosides, silicified microcrystalline cellulose, colloidal silicon dioxide to form blend;

vi. blending the granules of step iv) with the blend of step v);

vii. lubricating the blend of step vi) with sodium steryl fumarate;

viii. compressing the blend of step vii) to form compressed tablets;

ix. coating the tablets of Step viii) with opadry.

The following examples further exemplify the invention and are not intended to limit the scope of the invention.

Dissolution Study:

The dissolution test was done using USP I apparatus (Basket) at 150 RPM, 900ml of purified water at 37 ± 0.5 °C. The results of the dissolution test performed are given in Table 1.

Table 1: Results of the dissolution study of Example 2, with comparative composition Ex. 5.

Processing problems and tablet defects:

Tablet lamination during processing was observed in Ex. 5 where mixture of water and acetone was employed as a granulating fluid, while tablet lamination was not observed during processing of Ex2, where water was excluded as a granulating fluid and only acetone was employed.

We claim:

1. A wet granulated, tablet composition comprising docusate sodium, optionally in combination with sennosides and atleast one pharmaceuticaHy acceptable excipientCs), wherein said tablet composition is essentially prepared by employing non-aqueous granulating fluids.

2. The composition according to claim 1, wherein said docusate sodium is present in an amount form about 10% to about 40% by weight of the composition.

3. The composition according to claim 1, wherein said sennosides is present in an amount form about 2% to about 10% by weight of the composition.

4. The composition according to claim 1, wherein said sennosides means sennoside A, sennoside B or sennoside A and B or a pharmaceuticaHy acceptable salt thereof.

5. The composition according to claim 1, wherein said pharmaceuticaHy acceptable excipients includes one or more selected from filler/ diluent, binders, disintegrants, surfactants, lubricants and glidant.

6. The composition according to claim 1, wherein said non-aqueous granulating fluid is selected from methanol, efhanol, acetone, methylene chloride or combination thereof.

7. The composition according to claim 6, wherein the preferred non-aqueous granulating fluid is acetone.

8. A process of preparing a wet granulated, tablet composition comprising docusate sodium in combination with sennosides, prepared by a process comprising the steps of:

i. blending sennosides and atleast one pharmaceuticaHy acceptable excipients to form a blend;

ii. preparing a binder solution comprising docusate sodium and polyvinylpyrrolidone in an non-aqueous solvent;

iii. granulating said blend of step i) with said binder solution of step ii);

iv. screening and lubricating the granules of step iii);

v. processing the granules of step iv) to form compressed tablets.

9. A process of preparing a wet granulated, tablet composition comprising docusate sodium in combination with sennosides, prepared by a process comprising the steps of:

i. blending sennosides and atleast one pharmaceutically acceptable excipients to form a blend;

ii. blending one or more diluent(s) to form a blend;

iii. preparing a binder solution comprising docusate sodium and
polyvinylpyrrolidone in an non-aqueous solvent;

iv. granulating said blend ii) with said binder solution of step iii);

v. screening and mixing the granules of step iv) with said blend of step i);

vi. processing the granules of step v) to form compressed tablets.

10. A wet granulated, tablet composition comprising docusate sodium, sennosides, lactose, macrocrystalline cellulose, di-calcium phosphate and optional other pharmaceutically acceptable excipients, wherein said composition is essentially prepared by employing acetone as a granulating fluids.