TECHNICAL FIELD OF THE INVENTION;

The present invention relates to a novel liquid pharmaceutical composition comprising a combination of Sucralfate, a gastrointestinal medication and Domperidone a peripheral dopamine receptor antagonist; along with pharmaceutically acceptable exicipients useful for the treatment of gastroesophageal reflux disease (GERD) and other gastrointestinal disorders. The invention further relates to a process for preparation thereof

BACKGROUND OF THE INVENTION:

Gastroesophageal reflux disease (GERD) is defined as chronic symptoms or mucosal damage produced by the abnormal reflux of stomach acid to the esophagus. This is commonly due to transient or permanent changes in the barrier between the esophagus and the stomach. This can be due to incompetence of the lower esophageal sphincter, transient lower esophageal sphincter relaxation, impaired expulsion of gastric reflux from the esophagus.

Sucralfate is an oral gastrointestinal medication primarily indicated for the treatment of active duodenal ulcers and stress ulcers. Sucralfate is an a-D-glucopyranoside, P-D- fructofuranosyl-, octakis-(hydrogen sulfate), aluminum complex that binds to the hydrochloric acid in the stomach and acts like an acid buffer with cytoprotective properties. It is useful as an adjunct in helping to heal and prevent esophageal damage caused by GERD.

Chemically, Sucralfate is Hexadeca-(A-hydroxytetracosahydroxy[8-[l,3,4,6-tetra-o- sulfo-p-Dfructofuranosyl-a-D-glucopyranoside tetrakis (hydrogen sulfate) 8-)]] hexadecaaluminum having structural formula as follows:

Sucralfate is a locally acting substance which in an acidic environment (pH < 4), reacts with hydrochloric acid in the stomach to form a cross-linking, viscous, paste-like material capable of acting as an acid buffer for as long as 6 to 8 hours after a single dose. It also attaches to proteins on the surface of ulcers, such as albumin and fibrinogen, to form stable insoluble complexes. These complexes serve as protective barriers at the ulcer surface, preventing further damage from acid, pepsin, and bile. In addition, it prevents back diffusion of hydrogen ions, and adsorbs both pepsin and bile acids. Recently, it has been indicated that Sucralfate also stimulates the increase of prostaglandin E2, epidermal growth factors (EGF), (bFGF), and gastric mucus.

Sucralfate was approved by the United States Food and Drug Administration (USFDA) in 1981 and is available in many countries in different dosage forms such as solid oral, liquid oral and topical dosage forms. The recommended adult oral dosage of Sucralfate for duodenal ulcer is Ig four times per day on an empty stomach initially for 4-8 weeks followed by Ig two times per day as maintenance dose.

Domperidone is a peripheral dopamine receptor antagonist used to relieve uncomfortable symptoms of stomach bloating, fullness and reflux in adults. Domperidone works primarily by blocking dopamine receptors found in the upper end of the digestive system. This causes tightening of the muscles at the entry to the stomach, relaxation of the muscles at the exit of the stomach and increased contraction of the muscles in the stomach. It also prevents regurgitation of the stomach contents back into the esophagus and mouth.

Chemically, Domperidone is 5-chloro-l-(l-[3-(2-oxo-2,3-dihydro-1H-benzo[D]imidazol- l-yl)propyl]piperidin-4-yl)-1H-benzo[t/limidazol-2(3H)-one having structural formula as follows:

Domperidone is available as its free base and maleate salt. The maximum dosage lies between 10-20 mg, three to four times a day for the treatment of gastrointestinal motility disorders, nausea and vomiting. Domperidone has been marketed outside the USA since 1978 in solid oral, liquid and rectal dosage forms.

WO2009047826 discloses a pharmaceutical composition comprising Sucralfate and mesalazine, and formulated as a gel, cream, enema, or rectal suppository. The use of this formulation is for the treatment of diseases such as actinic proctitis, diversion proctitis, aphthoid lesions of the rectum caused by avitaminosis or viruses, rhagades, fistulizing lesions, solitary ulcer of the rectum, haemorrhoids, anal itching.

EP0437406 discloses a pharmaceutical preparation intended for the administration with oral way, presented in the form of stable suspension, in the absence of viscosant agent associating the Sucralfate substances antiacid, able to neutralize the gastric acidity, like their method of preparation.

US6991806 discloses a stable pharmaceutical composition comprising a mixture of (i) an ibuprofen medicament; (ii) a domperidone medicament and (iii) a carrier material characterized in that the carrier material is substantially free of povidone and comprises at least one diluent combined with at least one release modifying agent.

Gastric ulcers sometimes cause swelling of the tissues (edema) that lead into the small intestine, which may prevent food from easily passing out of the stomach. This blockage may cause bloating, nausea, or vomiting after eating. Sucralfate works by forming a protective coating in the base of an ulcer to promote healing. It works well on peptic ulcers and is a reasonable alternative to antacids. It may, however, cause constipation, and in some cases it reduces the effectiveness of other drugs. Moreover, the side effects of Sucralfate include fatigue, dry mouth, nausea, liver damage, stroke, heart failure etc. In order to reduce the side effects and provide better bioavailability of the Sucralfate, the present invention provides a combination of sucralfate with Domperidone, a peripheral dopamine receptor antagonist which will relieve uncomfortable symptoms of stomach, bloating, fullness and reflux in adults. In addition the combination is useful for treating gastrointestinal motility disorders.

OBJECT OF THE INVENTION;

Thus, the main object of the present invention is to develop novel liquid dosage form of Sucralfate and Domperidone useful for the treatment of gastroesophageal reflux disease (GERD) and other gastrointestinal disorders that can be administered through either oral or nasogastric route.

Another object of the present invention is to provide a process for preparation of the said composition.

SUMMARY OF THE INVENTION;

In accordance with the above objective, the present invention discloses a novel liquid pharmaceutical composition comprising a combination of Sucralfate and Domperidone along with pharmaceutically acceptable exicipients; which is administered through either oral or nasogastric route, for the treatment of gastroesophageal reflux disease (GERD) and other gastrointestinal disorders.

In another aspect, the invention also discloses a process for preparation of said liquid pharmaceutical composition.

DETAILED DESCRIPTION OF THE INVENTION;

In accordance with the above aspects, the invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

The present invention describes a novel liquid pharmaceutical composition comprising a combination of Sucralfate and Domperidone along with pharmaceutical exicipients, suitable for either oral or nasogastric route, useful for the treatment of gastroesophageal reflux disease (GERD) and other gastrointestinal disorders and furthers the process for preparation thereof.

According to a preferred embodiment, a pharmaceutical composition comprising Sucralfate and Domperidone in a liquid dosage form along with the pharmaceutically acceptable excipients selected from the group comprising surfactants, suspending agents. solvents, humectants, preservatives, stabilizers, sweetener, pH adjuster, anticaking agent, colourants, antifoaming agent and flavours.

According to the present invention, the usually recommended dose for oral and nasogastric route is Sucralfate 50-200 mg with Domperidone 0.5-2.0 mg/ml respectively.

Suitable surfactants of the present invention are selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85 or combinations thereof; preferably polysorbate 80 and polysorbate 20 in an amount of 2g/lit.

Suitable suspending agents of the present invention are selected from the group consisting of xanthan gum, hydroxypropylmethylcellulose, methyl cellulose, carrageenan, sodium carboxymethyl cellulose, colloidal silicon dioxide, guar galactomannan or combinations thereof; preferably xanthan gum, methyl cellulose and guar galactomannan in an amount of 1.5 to 3.5 g/lit.

Suitable solvents/humectants of the present invention are selected from the group consisting of sorbitol solution, xylitol, maltitol, glycerin, propylene glycol and glyceryl triacetate or combinations thereof; preferably sorbitol solution and glycerin in an amount of 50-400 g/lit.

Suitable preservative of the present invention are selected from the group consisting of benzyl alcohol, propylparaben, methylparaben, sorbic acid, sodium benzoate and sodium bisulphate or combinations thereof; preferably propylparaben and methylparaben in an amount of 0.5 to 1.0 g/lit.

Suitable stabilizers of the present invention are selected from the group consisting of sodium hydrogen phosphate, sodium chloride, magnesium hydroxide, aluminum hydroxide, calcium acetate, malic acid, citric acid and tartaric acid or combinations thereof; preferably sodium hydrogen phosphate and sodium chloride in an amount of 0.3 to 2.0 g/lit.

Suitable sweeteners of the present invention are selected from the group consisting of sucrose, lactose, glucose, aspartame, saccharine sodium and sorbitol solution or combinations thereof; preferably saccharine sodium in an amount of 0.2 to 0.6 g/lit.
Suitable pH adjusters of the present invention are selected from the group consisting of sodium hydroxide, phosphoric acid, citric acid, sodium citrate; preferably sodium hydroxide and citric acid, where the pH is adjusted between 3.0 to 7.0.

Suitable anti-caking agents of the present invention are selected from the group consisting of talc, microcrystalline cellulose, stearic acid, magnesium stearate, colloidal silicon dioxide and the like; preferably microcrystalline cellulose and colloidal silicon dioxide in an amount of 1.5 to 6.5 g/lit.

Suitable colourants of the present invention are selected from the group consisting of iron oxide, tartrazine, quinoline yellow, sunset yellow, erythrosine, carmoisine, ponceau 4R and allura red and the like; preferably carmoisine and ponceau 4R in an amount of 0.040 g/lit.

Suitable antifoaming agents of the present invention are selected from the group consisting of simethicone emulsion, mineral oils, fats and oils, fatty acids, fatty acid esters, alcohols, silicones, poly(alkylene glycol)s, and mixtures thereof; preferably simethicone emulsion in an amount of 0.5 g/lit.

Suitable flavours of the present invention are selected from the group consisting of yellow plum lemon, aroma, mixed fruit, peppermint, cherry, orange and raspberry; preferably mixed fruit and peppermint flavour in an adequate amount.

In another embodiment, the process for manufacturing the liquid pharmaceutical composition comprising Sucralfate and Domperidone is as follows:-

1) Dissolving preservatives, in sufficient quantity of purified water;

2) mixing and suspending Sucralfate, colloidal silicon dioxide and microcrystalline cellulose with sufficient quantity of purified water was added to the step 1;

3) adding sorbitol to step 2 and mixed continuously;

4) dispersing suspending agents in glycerin and adding it to the step 3, mixing for at least 2 hours to ensure complete swelling of suspending agent;

5) dissolving polysorbate in water and dispersing Domperidone in the said solution and mixing it to the Step 4;

6) dissolving stabilizers, sweetener and colorant separately in purified water and adding to the above step 5 under mixing. Adjusting the pH with pH adjuster; and

7) adding antifoaming agents and flavours to make up the volume with purified water and passing the final preparation through colloid mill.

Some typical examples illustrating the embodiments of the present invention are provided; however, these are exemplary only and should not be regarded as limitations of the present invention.

EXAMPLES:

Example 1:

Example 2:

Example 3:

Example 4:

Example 5:

Example 6:

Example 7:

Example 8:

Example 9:

The said liquid pharmaceutical composition is stable and easily dispersible with homogeneity in drug distribution especially Domperidone, making it suitable for oral and effective nasogastric application. The said liquid pharmaceutical composition does not gel or form hard cake to ensure uniform distribution of drugs suitable for oral and effective nasogastric application.

STABILITY DATA:

Product Name: Sucralfate and Domperidone Susprnsion

Packaging: Amber coloured bottle

Remarks: No significant changes observed after 6 months at 40°C

We Claim,

1. A novel liquid pharaiaceutical composition comprises therapeutically effective amount of Sucralfate and Domperidone along with pharmaceutically acceptable excipients; useful for the treatment of gastroesophageal reflux disease (GERD) and other gastrointestinal disorders.

2. A liquid pharmaceutical composition as claimed in claim 1, wherein the said Sucralfate is present in the amount of 50-200 mg/ml.

3. A liquid pharmaceutical composition as claimed in claim 1, wherein the said Domperidone is present in the amount of 0.5-2.0 mg/ml.

4. A liquid pharmaceutical composition as claimed in claim 1, wherein said pharmaceutical excipients are selected from the group consisting of surfactants, suspending agents, solvents, humectants, preservatives, stabilizers, sweetener, pH adjuster, anti-caking agent, colourants, antifoaming agent and flavours.

5. A liquid pharmaceutical composition as claimed in claim 4, wherein the said surfactants are selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85 or combinations thereof; preferably polysorbate 80 and polysorbate 20 in an amount of2g/lit.

6. A liquid pharmaceutical composition as claimed in claim 4, wherein the said suspending agents are selected from the group consisting of xanthan gum, hydroxypropylmethylcellulose, methyl cellulose, carrageenan, sodium carboxymethyl cellulose, colloidal silicon dioxide, guar galactomannan or combinations thereof; preferably xanthan gum, methyl cellulose and guar galactomannan in an amount of 1.5 to 3.5 g/lit.

7. A liquid pharmaceutical composition as claimed in claim 4, wherein the said solvents/humectants are selected from the group consisting of sorbitol solution, xylitol, maltitol, glycerin, propylene glycol and glyceryl triacetate or combinations thereof; preferably sorbitol solution and glycerin in an amount of 50-400 g/lit.

8. A liquid pharmaceutical composition as claimed in claim 4, wherein the said preservatives are selected from the group consisting of benzyl alcohol, propylparaben, methylparaben, sorbic acid, sodium benzoate and sodium bisulphate or combinations thereof; preferably propylparaben and methylparaben in an amount of 0.5 to 1.0 g/lit.

9. A liquid pharmaceutical composition as claimed in claim 4, wherein the said stabilizers are selected from the group consisting of sodium hydrogen phosphate, sodium chloride, magnesium hydroxide, aluminum hydroxide, calcium acetate, malic acid, citric acid and tartaric acid or combinations thereof; preferably sodium hydrogen phosphate and sodium chloride in an amount of 0.3 to 2.0 g/lit.

10. A liquid pharmaceutical composition as claimed in claim 4, wherein the said sweetener are selected from the group consisting of sucrose, lactose, glucose, aspartame, saccharine sodium and sorbitol solution or combinations thereof; preferably saccharine sodium in an amount of 0.2 to 0.6 g/lit.

11. A liquid pharmaceutical composition as claimed in claim 4, wherein the said pH adjuster are selected from the group consisting of sodium hydroxide, phosphoric acid, citric acid, sodium citrate; preferably sodium hydroxide and citric acid, where the pH is adjusted between 3.0 to 7.0.

12. A liquid pharmaceutical composition as claimed in claim 4, wherein the said anti-caking agent are selected from the group consisting of talc, microcrystalline cellulose, stearic acid, magnesium stearate, colloidal silicon dioxide and the like; preferably microcrystalline cellulose and colloidal silicon dioxide in an amount of 1.5 to 6.5 g/lit.

13. A liquid pharmaceutical composition as claimed in claim 4, wherein the said colourants are selected from the group consisting of iron oxide, tartrazine, quinoline yellow, sunset yellow, erythrosine, carmoisine, ponceau 4R and allura red and the like; preferably carmoisine and ponceau 4R in an amount of 0.040 g/lit.

14. A liquid pharmaceutical composition as claimed in claim 4, wherein the said antifoaming agent are selected from the group consisting of simethicone emulsion, mineral oils, fats and oils, fatty acids, fatty acid esters, alcohols, silicones, poly(alkylene glycol)s, and mixtures thereof; preferably simethicone emulsion in an amount of 0.5 g/lit.

15. A liquid pharmaceutical composition as claimed in claim 4, wherein the said flavours are selected from the group consisting of yellow plum lemon, aroma.
mixed fruit, peppermint, cherry, orange and raspberry; preferably mixed fruit and peppermint flavour in an adequate amount.

16. A liquid pharmaceutical composition as claimed in claim 1, wherein the said composition is administered through either oral or nasogastric route.

17. A liquid pharmaceutical composition as claimed in claim 1, wherein the process for manufacturing of said composition comprises:-

1) Dissolving preservatives, in sufficient quantity of purified water;

2) mixing and suspending Sucralfate with anti-caking agent in sufficient quantity of purified water and adding it to the step 1;

3) adding sorbitol to step 2 and mixed continuously;

4) dispersing suspending agents in solvent (glycerin) and adding it to the step 3, mixing for at least 2 hours to ensure complete swelling of suspending agent;

5) dissolving surfactant (polysorbate) in water and dispersing Domperidone in the said solution and mixing it to the Step 4;

6) dissolving stabilizers, sweetener and colorant separately in purified water and adding to the above step 5 under mixing. Adjusting the pH with pH adjuster; and

7) adding antifoaming agents and flavours to make up the volume with purified water and passing the final preparation through colloid mill.