CLIAMS:We claim:

1. A process for preparation of oral suspension having Mebeverine pamoate, the process comprising the steps of:
(a) preparing a solution of disodium pamoate and citric acid monohydrate in water;
(b) preparing a solution of Mebeverine hydrochloride in water;
(c) mixing the solution of step (b) into solution of step (a) to obtain a suspension having mebeverine pamoate; and
(d) optionally adding one or more pharmaceutically acceptable excipients.

2. A process for preparation of physicochemically stable oral suspension comprising Mebeverine or pharmaceutically acceptable salts thereof, optionally with one or more pharmaceutically acceptable excipient(s), the process comprising the steps of:
(a) preparing a dispersion of a thickening agent in water,
(b) mixing the dispersion with a solution of disodium pamoate and citric acid monohydrate in water;
(c) preparing Mebeverine hydrochloride solution in water;
(d) heating surfactant and solubilizer in a vessel to obtain a molten liquid and adding water to form an aqueous solution;
(e) adding the solution of step (d) to the solution of step (c);
(f) adding a neutralizer to the solution of step (e) to form a resultant solution; and
(g) transferring the solution of step (f) to dispersion solution of step (b) followed by addition of buffer solution to prepare the final suspension.

3. The process as claimed in any of the preceding claims, wherein the formulation comprises disodium pamoate as reactant in the range of 25 mg to 75 mg per 5ml of suspension.

4. The process as claimed in any of the preceding claims, wherein the process comprises in situ conversion of mebeverine hydrochloride into mebeverine pamoate.

5. The process as claimed in claim 2, optionally comprising;
adding disodium pamoate solution in water and citric acid monohydrate solution in water to a first portion (75-90%) of the dispersion obtained in step (a); and
adding sweetener solution to the remaining second portion (10-25%) of the dispersion and adding to step (g).

6. The process as claimed in any of the preceding claims, wherein the pharmaceutically acceptable excipients comprises reactant, suspending agent, buffering agents, surfactant, complexing agents, preservative, solubilizer, sweetener, anti-foaming agent, flavoring agent, solvents or a combination thereof.

7. The process as claimed in any of the preceding claims, wherein the thickening agents comprises xanthan gum, guar gum, locust bean gum, gum tragacanth, dispersible cellulose, polyvinylpyrrolidone, hydroxypropylcellulose or mixtures thereof.

8. The process as claimed in any of the preceding claims, wherein the surfactant and solubilizer comprises polysorbates, sodium lauryl sulphate, poloxamers, hydrogenated vegetable oil or a combination thereof.

9. The process as claimed in any of the preceding claims, wherein the neutralizer comprises weak acids, carboxylic acid, and weak acids strong base.

10. The process as claimed in any of the preceding claims, wherein the sweetener is selected from fructose, glucose, sucrose, sugar alcohol, artificial sweeteners or a combination thereof.

11. The process as claimed in any of the preceding claims, optionally comprising adding anti foaming emulsion in water to step (b), wherein the anti foaming emulsion comprises insoluble oils dimethyl polysiloxanes and silicones, alcohols, stearates and glycols, simethicone emulsion or a combination thereof.

12. The process as claimed in any of the preceding claims, optionally comprising dissolving preservative in water and adding to step (g), wherein the preservative comprises benzoic acid and sorbic acid and their salts, methyl paraben, butylparaben, propylparaben or a combination thereof;

13. The process as claimed in any of the preceding claims, optionally comprising adding flavor to step (g), wherein the flavor comprises fruity flavours, frescofort flavour permaseal, grenadine flavour permaseal and tutti frutti flavour or combinations thereof.

14. The process as claimed in any of the preceding claims, where in the suspension containing mebeverine or pharmaceutically acceptable salts thereof is used for the treatment of irritable bowel syndrome.
,TagSPECI:FIELD OF INVENTION
The present invention in general relates to a process for preparation of a physicochemically stable oral suspension formulation comprising Mebeverine or a pharmaceutically acceptable salt thereof, optionally with one or more pharmaceutically acceptable excipient(s), wherein the process of preparation specifically involves an in situ conversion of the Mebeverine hydrochloride salt to Mebeverine pamoate, which in turn increases its palatability and patient compliance. The present invention is used for the treatment of irritable bowl syndrome and /or a disease or condition associated with these.

BACKGROUND OF THE INVENTION
Mebeverine is a musculotropic antispasmodic drug, which relieves painful muscle spasms of the gut, without affecting it's normal motility. It is specifically used to relieve symptoms associated with irritable bowel syndrome and related intestinal disorders that are the result of spasms in the intestinal muscles. Mebeverine is currently administered orally in the form of conventional tablet and liquid dosage forms globally by various companies. The drug compound having the adopted name "Mebeverine hydrochloride" has chemical names 3,4-dimethoxybenzoic acid 4-(ethyl(2-(4-methoxyphenyl)-1-methylethyl)- amino)butyl ester, is disclosed in the Merck Index, Tenth Edition (1983), M. Windholz, ed., No. 5590, page 821. It has a structural formula as below:

European patent number EP 0 393 747 A2 discloses a novel dosage form and method of administering mebeverine in order to achieve superior antispasmodic activity of the drug in the lower GIT.

Moreover, a review of the above prior art reveals that there still exists an unmet medical need for development of a physicochemically stable pharmaceutical suspension composition and its process for preparation thereof, which is simple, reproducible.

Further, being immensely bitter the syrup product of Mebeverine hydrochloride is difficult to develop and would pose problem w.r.t. patient acceptability for such a highly soluble and highly bitter drug substance unless higher concentrations of sweetener or sugars is added, which further may lead to problem associated with permissible limits of these sweeteners & patient compliance suffering with diabetic issues. Due to such issues, use of sweetener approach was not successful in general as well.

The inventors of the present invention with considerable expense of intellectual effort have done extensive research and conducted several experiments to develop a physicochemically stable pharmaceutical composition and process for preparation thereof, wherein the process specifically involves an in-situ conversion of the Mebeverine hydrochloride salt to Mebeverine pamoate and to provide a therapy for the treatment of symptomatic relief of irritable bowl syndrome and /or a disease or condition associated with these. The present invention also provides safe and effective compositions and process for preparation for the management of irritable bowl syndrome and /or associated disease or condition, which are particularly devoid of the side effects and therefore provides a significant advancement in the said field.

OBJECTS AND SUMMARY OF THE INVENTION
It is an object of present invention to provide a process for preparation of a physicochemically stable oral suspension formulation comprising Mebeverine or a pharmaceutically acceptable salt thereof, optionally with one or more pharmaceutically acceptable excipient(s).

It is an objective of the present invention to provide a process for preparation of a physicochemically stable oral suspension formulation comprising Mebeverine or a pharmaceutically acceptable salt thereof, wherein the process of preparation specifically involves an in-situ conversion of the Mebeverine hydrochloride salt to Mebeverine pamoate.

According to the present invention there is provided a process for preparation of oral suspension having Mebeverine pamoate, the process comprises the steps of:
(a) preparing a solution of disodium pamoate and citric acid monohydrate in water;
(b) preparing a solution of Mebeverine hydrochloride in water;
(c) mixing the solution of step (b) into solution of step (a) to obtain a suspension having mebeverine pamoate; and
(d) optionally adding one or more pharmaceutically acceptable excipients.

In accordance to one embodiment, the present invention provides a process for preparation of physicochemically stable oral suspension comprising Mebeverine or pharmaceutically acceptable salts thereof, optionally with one or more pharmaceutically acceptable excipient(s), the process comprises the steps of:
(a) preparing a dispersion of a thickening agent in water,
(b) mixing the dispersion with a solution of disodium pamoate and citric acid monohydrate in water in 0.5 % to 1.5% weight/volume;
(c) preparing Mebeverine hydrochloride solution in water;
(d) heating surfactant and solubilizer at 40-50 °C in a vessel to obtain a molten liquid and adding water to form an aqueous solution;
(e) adding the solution of step (d) to the solution of step (c);
(f) adding a neutralizer to the solution of step (e) to form a resultant solution; and
(g) transferring the solution of step (f) to dispersion solution of step (b) followed by addition of buffer solution to prepare the final suspension.

In other embodiment of the present invention, the formulation used in the process comprises disodium pamoate as reactant in the range of 25 mg to 75 mg per 5ml of suspension.

In yet another embodiment of the present invention, the process comprises in situ conversion of mebeverine hydrochloride into mebeverine pamoate.

In accordance with the second embodiment, the process optionally comprises;
adding disodium pamoate solution in water and citric acid monohydrate solution in water to a first portion (75-90%) of the dispersion obtained in the step (a); and
adding sweetener solution to the remaining second portion (10-25%) of the dispersion and adding to the step (g).

In furthermore embodiment of the present invention, the pharmaceutically acceptable excipients used in the process comprises reactant, suspending agent, buffering agents, surfactant, complexing agents, preservative, solubilizer, sweetener, anti-foaming agent, flavoring agent, solvents or a combination thereof.

In further embodiment of the present invention, the thickening agents used in the process comprises xanthan gum, guar gum, locust bean gum, gum tragacanth, dispersible cellulose, polyvinylpyrrolidone, hydroxypropylcellulose or mixtures thereof.

In still another embodiment of the present invention, the surfactant and solubilizer used in the process is selected from polysorbates, sodium lauryl sulphate, poloxamers, hydrogenated vegetable oil or a combination thereof. The vegetable oil is selected from derivatives of polyoxyethylene alkyl ethers and polyoxyethylene stearates.

In other embodiment of the present invention, the neutralizer used in the process comprises weak acids, carboxylic acid, and weak acids strong base.

In furthermore embodiment of the present invention, the sweetener is selected from fructose, glucose, sucrose, sugar alcohol, artificial sweeteners or a combination thereof.

In other embodiment of the present invention, the process optionally comprises adding anti foaming emulsion in water to the step (b). The anti foaming emulsion used in the process comprises insoluble oils dimethyl polysiloxanes and silicones, alcohols, stearates and glycols, simethicone emulsion or a combination thereof.

In furthermore embodiment of the present invention, the process optionally comprises dissolving preservative in water and adding to the step (g). The preservative used in the process comprises benzoic acid and sorbic acid and their salts, methyl paraben, butylparaben, propylparaben or a combination thereof;

In other embodiment of the present invention, the process optionally comprises adding flavor to the step (g). The flavor used in the process comprises fruity flavours, frescofort flavour permaseal, grenadine flavour permaseal and tutti frutti flavour or combinations thereof.

In other embodiment of the present invention, the suspension containing mebeverine or pharmaceutically acceptable salts thereof as obtained from the process is used for the treatment of irritable bowel syndrome.

In furthermore embodiment of the present invention, the mebeverine or its pharmaceutically acceptable salts thereof as obtained from the process is simple and reproducible.

It is an objective of the present invention to provide a process for preparation of Mebeverine oral suspension formulation, wherein the process comprising the steps of;
(a) Preparing a dispersion of dispersible cellulose and mixing with a solution of disodium pamoate and citric acid monohydrate in water.
(b) Preparing Mebeverine hydrochloride solution in water.
(c) Heating surfactant and solubilizer in a vessel to obtain a molten liquid and add water to form an aqueous solution followed by addition of this solution to step 2.
(d) Neutralizer was added to step 3 solution.
(e) Optionally prepared sweetener solution was added to previously prepared dispersible cellulose
(f) Optionally preparing anti foaming emulsion in water and adding to step 1.
(g) Transferring solution of step 4 to dispersion of step 6.
(h) Preparing buffer solution using sodium salt and acid reagent and adding in dispersion of step 7.
(i) Optionally dissolving preservative in water and adding to step 8.
(j) Optionally adding flavor to step 9.
(k) Optionally prepare sweetener solution and add this to the remaining portion (around 20 %) of dispersible cellulose dispersion from step 1 and add to step 10.
(l) Make up the volume and fill the final suspension in suitable containers.
The suspension containing mebeverine or pharmaceutically acceptable salts thereof is used for the treatment of irritable bowel syndrome and /or a disease or condition associated with these.

It is yet an objective of the present invention to provide a process for preparation of Mebeverine oral suspension formulation, wherein the process specifically involves an in-situ conversion of the Mebeverine hydrochloride salt to Mebeverine pamoate.

It is another objective of the present invention to provide a process for preparation of Mebeverine oral suspension formulation, wherein the composition releases the active in an immediate release manner.

DETAILED DESCRIPTION OF THE INVENTION

It is believed that one skilled in the art can based upon the description herein; utilize the present invention to its fullest extent. The following specific embodiments are in accordance with the best mode of practice, and scope of the invention is not restricted to the described embodiments herein after.

The present invention provides a process for preparation of a physicochemically stable oral suspension formulation comprising Mebeverine or pharmaceutically acceptable salts thereof, optionally with one or more pharmaceutically acceptable excipient(s). The process of preparation in the meaning of the invention specifically involves an in-situ conversion of the Mebeverine hydrochloride salt to Mebeverine pamoate.

The suspension formulations containing mebeverine or pharmaceutically acceptable salts thereof are prepared by using various simple and reproducible processes to obtain a stable suspension formulation. While preparing suspensions the approaches normally used includes adsorbing or adding or suspending active Mebeverine using suitable carrier vehicle and /or after appropriate coating/complexation in a suitable vehicle the active Mebeverine can be adsorbed into the suspending medium.

Further, the suspending medium used here is usually prepared by dispersing it in suitable concentration in water or suitable vehicle and allow it to swell to get transformed into homogeneous viscous liquid dispersion having suitable viscosity, which was achieved here by normal mechanical stirring or homogenization under high speed depending upon the type of material and desired viscosity.

Furthermore, instant suspension formulation involves a widely used and easily available ingredients that are commonly used for a suspension preparation. However, instant invention uses the active ingredient Mebeverine pamoate in equivalent concentration of Mebeverine hydrochloride which is an in situ by product of two active precursor Mebeverine hydrochloride and disodium pamoate.

Currently there are different dosage forms available in the market for the treatment of irritable bowl syndrome which uses only Mebeverine hydrochloride as an active pharmaceutical ingredient. These include both immediate release & modified release tablets and capsules.

Mebeverine was reported to undergo rapid and extensive first pass metabolism following oral administration. It has a rapid absorption reaching tmax in 1 hr & rapid onset of action which is essential for the indication for which it is recommended i.e. symptomatic relief of irritable bowl syndrome.

An alternative dosage form of Mebeverine or Mebeverine hydrochloride or any other salt thereof to deliver phamcokinetically similar active moiety is in need. The alternate dosage could be either syrup or suspension which can easily fulfill the requirement. However, being immensely bitter the syrup product of Mebeverine hydrochloride is difficult to develop and would pose problem w.r.t. patient acceptability for such a highly soluble and highly bitter drug substance unless higher concentrations of sweetener or sugars is added, which further may lead to problem associated with permissible limits of these sweeteners & patient compliance suffering with diabetic issues. Due to such issues use sweetener approach was not successful in general as well.

Inventor of the instant invention by expense of intellectual efforts have done extensive research and conducted several experiments, develop an liquid suspension dosage form using simple reproducible manufacturing process which has overcome the existing problem of bitterness by reacting two active precursor viz. Mebeverine hydrochloride and disodium pamoate to form Mebeverine pamoate in situ.

The pharmaceutical compositions according to present invention will, in general comprise of one or more excipients. Examples of pharmaceutical excipients include, but are not limited to reactant, suspending agent, buffering agents, surfactant, complexing agents, preservative, solubilizer, sweetener, anti-foaming agent, flavoring agent and solvents. A combination of excipients may also be used. The amount of excipient(s) employed will depend upon the quantity of active agent used. One excipient can perform more than one function.

Suitable thickening agents function as suspending agents and include, but are not limited to, hydrocolloid gums known for such purpose, examples of which include xanthan gum, guar gum, locust bean gum, gum tragacanth, dispersible cellulose (microcrystalline cellulose and carboxymethylcellulose sodium), polyvinylpyrrolidone, hydroxypropylcellulose and the like or mixtures thereof.

Buffers, which include, but are not limited to sodium citrate, citric acid, potassium citrate, sodium bicarbonate, potassium bicarbonate, sodium dihydrogen phosphate and potassium dihydrogen phosphate. The buffer should have sufficient capacity to maintain the desired pH range throughout the product shelf life.

The oral suspension according to the present invention will preferably also include a preservative to prevent the growth of micro-organisms such as bacteria, yeasts and fungi.
Suitable preservatives include, but are not limited to, benzoic acid and sorbic acid and their salts, methyl paraben, butylparaben, propylparaben and the like.

Surfactants and solubilizer include, but are not limited to, the polysorbates, sodium lauryl sulphate, poloxamers, hydrogenated vegetable oil and the like.

Complexing agents include, but are not limited to various cyclodextrin compounds, ion exchange resins and like.

Suitable sweeteners include, but are not limited to, natural sweeteners such as sugars e.g. fructose, glucose, sucrose, sugar alcohols such as mannitol, sorbitol or mixtures thereof and artificial sweeteners such as sucralose, sodium saccharine, sodium cyclamate and aspartame.

Antifoaming agents include, but are not limited to insoluble oils, dimethyl polysiloxanes and other silicones, certain alcohols, stearates and glycols, simethicone emulsion and the like.

Flavouring agents are well known to persons skilled in the art and include, but are not limited to fruity flavours, Frescofort Flavour Permaseal, Grenadine Flavour Permaseal and Tutti Frutti Flavour or combinations thereof are preferred.

The formulation according to present invention also comprises a reactant and includes, but not limited to disodium pamoate and the like.

In a further embodiment the present invention provides a process of preparation of physicochemically stable oral suspension formulation containing mebeverine or pharmaceutically acceptable salts thereof, which is simple and reproducible, for the treatment of irritable bowel syndrome.

In yet another embodiment the present invention provides a process of preparation of physicochemically stable oral suspension containing mebeverine or pharmaceutically acceptable salts thereof, which is simple and reproducible, for the treatment of irritable bowel syndrome, which comprises:
a) Preparing a dispersion of dispersible cellulose and mixing with a solution of disodium pamoate and citric acid monohydrate in water.
b) Preparing Mebeverine hydrochloride solution in water.
c) Heating surfactant and solubilizer in a vessel to obtain a molten liquid and add water to form an aqueous solution followed by addition of this solution to step 2.
d) Neutralizer was added to step 3 solution.
e) Optionally prepared sweetener solution was added to previously prepared dispersible cellulose.
f) Optionally preparing anti foaming emulsion in water and adding to step 1.
g) Transferring solution of step 4 to dispersion of step 6.
h) Preparing buffer solution using sodium salt and acid reagent and adding in dispersion of step 7.
i) Optionally dissolving preservative in water and adding to step 8.
j) Optionally adding flavor to step 9.
k) Optionally prepare sweetener solution and add this to the remaining portion (around 20 %) of dispersible cellulose dispersion from step 1 and add to step 10.
l) Make up the volume and fill the final suspension in suitable containers.

In yet another embodiment the present invention provides a process of preparation of physicochemically stable oral suspension containing mebeverine or pharmaceutically acceptable salts thereof, which is simple and reproducible, for the treatment of irritable bowel syndrome, wherein the formulation comprises disodium pamoate as reactant in the range of 25 mg to 75 mg per 5ml of suspension.

In yet another embodiment the present invention provides a process of preparation of physicochemically stable oral suspension containing mebeverine or pharmaceutically acceptable salts thereof, which is simple and reproducible, for the treatment of irritable bowel syndrome, wherein the formulation comprises disodium pamoate as reactant in the range of 0.9 moles to 2.5 moles with respect to mebeverine.

Table 1

TESTS SPECIFICATION INITIAL
1 Months 2 Months 3 Months 6Months
Dissolution (By HPLC) Not less than 75% (Q) of label amount in 30 minutes. 98.9% (94.9-101.5%) 97.2%(95.4%-99.1%) 97.6%(97.2%-99.1%) 91.5% (86.9%-96.05) 93.55(88.9%-96.3%)
Preservative content (By HPLC) Sodium Benzoate Between 8.0mg to 12.0 mg per 5ml Between 80% to 120.0% per 5 ml 9.78mg97.8% 10.17 mg101.7% 10.47 mg104.7% 10.20mg102.0% 9.84mg98.4%
Related Substances(By HPLC)a) Veratric acidb) Any other impurityc) Total Impurities Not more than 0.5%Not more than 0.2%Not more than 2.0% Not detected0.05 %0.13 % Not detected0.06 %0.27 % Not detected0.06 %0.22 % Not detected0.13 %0.28 % Not detected0.20 %0.35 %
Assay (By HPLC)Each 5 ml contains Mebeverine pamoate equivalent to Mebeverine HCl50mg Between 47.5 mg and 52.5 mgBetween 95.0 % and 105.0 % of label claim. 49.5mg99.0% 50.2mg100.45% 51.4mg102.8% 50.6mg101.2% 50.25mg100.5 %

Above table 1 represents stability data of the composition as exemplified in example 3, when subjected to specific condition of temperature and humidity (40°C±2°C/75%±5%RH) for 6 months. It would be note worthy that no significant change has been observed in the pysico chemical property of the drug during this period. All the parameters like dissolution, Assay, impurity are coming within the specified limit.

It will be evident to one skilled in the art that the present invention is not limited to the above description or illustrative examples provided below, and that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the description and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Example: 1
Manufacturing formula:
Sr. No. Name of the Ingredient mg/5 ml
1 Mebeverine Hydrochloride 50.00
2 Disodium Pamoate monohydrate 30.00
3 Dispersible cellulose 200.00
4 Citric Acid Monohydrate 8.00
5 Polysorbate 20 2.50
6 Sodium Benzoate 5.00
7 Sodium Citrate 5.00
8 Polyoxyl hydrogenated Castor oil 2.50
9 Simethicone Emulsion 2.50
10 Saccharin Sodium 10.00
11 Banana Flavour 20.00
12 Purified Water q.s.

Process:
Part A
1. Dissolve Mebeverine hydrochloride in purified water.
Part B
2. Dissolve disodium pamoate in purified water.
Part C
3. Mix simultaneously part A and part B in purified water.
4. Disperse dispersible cellulose in purified water.
5. Add dispersion of step 3 to the dispersion of step 4.
6. Dissolve sodium saccharine in purified water and add in to step 3.
7. Dissolve sodium benzoate in purified water and add in to step 3.
8. Disperse Polyoxyl hydrogenated castor oil and Polysorbate 20 in purified water and add this to step 3.
9. Add Simethicone emulsion in purified water and add this to step 3.
10. Dissolve sodium citrate in purified water and add this to step 3.
11. Dissolve citric acid in purified water and add this to step 3.
12. Add flavour.
13. Add purified water and make up the volume.

Example: 2
Manufacturing formula:
Sr. No. Name of the Ingredient mg/5 ml
1 Mebeverine Hydrochloride 50.00
2 Disodium Pamoate 50.00
3 Dispersible cellulose 75.00
4 Citric Acid Monohydrate 33.544
5 Polysorbate 20 25.00
6 Sodium Benzoate 10.0
7 Sodium Citrate 44.055
8 Polyoxyl hydrogenated Castor oil 60.00
9 Saccharin Sodium 30.00
10 Simethicone Emulsion 2.50
11 Banana Flavour 20.00
13 Purified Water q.s.

Process:
1. Dissolve sodium benzoate in water.
2. Add dispersible cellulose into the above solution from step (1) to prepare a dispersion in water.
3. Divide the dispersion in portions (which can range in various ratios like 75:25, 80:20, 90:10).
4. Add Disodium pamoate solution made in water and Citric acid monohydrate solution made in water to one of the portions (around75 - 90%) of dispersion dispersible cellulose from step 3.
5. Prepare Mebeverine hydrochloride solution in water.
6. Heat Polyoxyl hydrogenated Castor oil and Polysorbate 20 in a jacketed vessel to get a molten liquid, Add this liquid to step 5.
7. Prepare sodium citrate solution and add to step 6.
8. Add the resultant solution of step 7 to one of the remaining portions of dispersible cellulose dispersion (10 – 25%) from step 3 under stirring.
9. Add the dispersion of step 8 to the resultant dispersion of step 4.
10. Prepare Simethicone emulsion in water and add to step 9.
11. Prepare buffer solution of sodium citrate and citric acid and add in dispersion of step 10.
12. Prepare sodium saccharine solution and add to dispersion of step 11.
13. Add banana flavour to step 12.
14. Make up the volume and fill the final suspension in suitable containers.

Note : The quantity of citric acid and sodium citrate to be used in divided portions. The part quantities of citric acid and sodium citrate each to be reserved for making buffer.

Example: 3
Manufacturing formula:

Sr. No. Name of the Ingredient mg/5 ml
1 Mebeverine Hydrochloride 50.00
2 Disodium Pamoate 50.00
3 Dispersible cellulose 40.00
4 Citric Acid Monohydrate 33.544
5 Polysorbate 20 25.00
6 Sodium Benzoate 10.0
7 Sodium Citrate 53.378
8 Polyoxyl hydrogenated Castor oil 60.00
9 Saccharin Sodium 10.00
10 Simethicone Emulsion 2.50
11 Banana Flavour 20.00
12 Purified Water q.s.

Process:
1. Prepare a dispersion of Dispersible cellulose in water. Divide the dispersion in portions (which can range in various ratios like 80:20).
2. Add Disodium pamoate solution made in water and Citric acid monohydrate solution made in water to one of the portions (around 80%) of Dispersible cellulose dispersion from step 1.
3. Prepare Simethicone emulsion in water and add to step 2.
4. Prepare Mebeverine hydrochloride solution in water.
5. Heat Polyoxyl hydrogenated Castor oil and Polysorbate 20 in a jacketed vessel to get a molten liquid. Add this liquid to step 4.
6. Prepare sodium citrate solution and add to step 5.
7. Transfer solution of step 6 to dispersion of step 3.
8. Prepare buffer solution of sodium citrate and citric acid and add in dispersion of step 7.
9. Dissolve sodium benzoate in water and add to step 8.
10. Add flavour to step 9.
11. Prepare sodium saccharine solution and add this to the remaining portion (around 20 %) of Dispersible cellulose dispersion from step 1 and add to step 10.
12. Make up the volume and fill the final suspension in suitable containers.

Note : The quantity of citric acid and sodium citrate to be used in divided portions. The part quantities of citric acid and sodium citrate each to be reserved for making buffer.

Example: 4
Manufacturing formula:
Sr. No. Name of the Ingredient mg/5 ml
1 Mebeverine Hydrochloride 50.00
2 Disodium Pamoate 50.00
3 Dispersible cellulose 45.00
4 Citric Acid Monohydrate 33.544
5 Polysorbate 20 25.00
6 Sodium Benzoate 10.0
7 Sodium Citrate 52.87
8 Polyoxyl hydrogenated Castor oil 60.00
9 Saccharin Sodium 10.00
10 Simethicone Emulsion 2.50
11 Banana Flavour 20.00
12 Sodium CMC 1.00
13 Purified Water q.s.

Process:
1. Prepare a dispersion of Dispersible cellulose in water. Divide the dispersion in portions (which can range in various ratios like 80:20).
2. Add Disodium pamoate solution made in water and Citric acid monohydrate solution made in water to one of the portions (around 80%) of Dispersible cellulose dispersion from step 1.
3. Prepare Simethicone emulsion in water and add to step 2.
4. Prepare Mebeverine hydrochloride solution in water.
5. Heat Polyoxyl hydrogenated Castor oil and Polysorbate 20 in a jacketed vessel to get a molten liquid. Add this liquid to step 4.
6. Prepare sodium citrate solution and add to step 5.
7. Transfer solution of step 6 to dispersion of step 3.
8. Prepare buffer solution of sodium citrate and citric acid and adding in dispersion of step 7.
9. Dissolving sodium benzoate in water and add to step 8.
10. Add flavour to step 9.
11. Add sodium carboxymethylcellulose in water to form dispersion free of lumps.
12. Prepare sodium saccharine solution and add to dispersion of step 11.
13. Add the above mixture of sodium Carboxymethylcellulose & sodium saccharine solution (step 12) to the remaining portion (around 20 %) of Dispersible cellulose dispersion from step 1.
14. Add the suspension from step 13 to the suspension of step 10 under stirring.
15. Make up the volume and fill the final suspension in suitable containers.

Note: The quantity of citric acid and sodium citrate to be used in divided portions. The part quantities of citric acid and sodium citrate each to be reserved for making buffer.

Example: 5
Manufacturing formula:
Sr. No. Name of the Ingredient mg/5 ml
1 Mebeverine Hydrochloride 50.00
2 Disodium Pamoate 50.00
3 Dispersible cellulose 30.00
4 Citric Acid Monohydrate 33.544
5 Polysorbate 20 25.00
6 Sodium Benzoate 10.0
7 Sodium Citrate 46.142
8 Polyoxyl hydrogenated Castor oil 60.00
9 Saccharin Sodium 10.00
10 Simethicone Emulsion 1.00
11 Banana Flavour 20.00
12 Sodium CMC 22.50
13 Purified Water q.s.

Process:
1. Preparing a dispersion of Dispersible cellulose water.
2. Add Disodium pamoate solution made in water and Citric acid monohydrate solution made in water to Dispersible cellulose dispersion from step 1.
3. Preparing Simethicone emulsion in water and adding to step 1.
4. Preparing Mebeverine hydrochloride solution in water.
5. Heat Polyoxyl hydrogenated Castor oil and Polysorbate 20 in a jacketed vessel to get a molten liquid. Add this liquid to step 4.
6. Preparing sodium citrate solution and add to step 5.
7. Transfer solution of step 6 to dispersion of step 3.
8. Preparing buffer solution of sodium citrate and citric acid and add in dispersion of step 8.
9. Dissolving sodium benzoate in water and add to step 9.
10. Adding banana flavour to step 10.
11. Add sodium Carboxymethylcellulose in water to form dispersion free of lumps.
12. Prepare sodium saccharine solution and add to dispersion of step 11.
13. Finally adding sodium Carboxymethylcellulose and sodium saccharine dispersion prepared in step 12 to step 10.
14. Making up the volume and fill the final suspension in suitable containers.

Note : The quantity of citric acid and sodium citrate to be used in divided portions. The part quantities of citric acid and sodium citrate each to be reserved for making buffer.

We claim:

1. A process for preparation of oral suspension having Mebeverine pamoate, the process comprising the steps of:
(a) preparing a solution of disodium pamoate and citric acid monohydrate in water;
(b) preparing a solution of Mebeverine hydrochloride in water;
(c) mixing the solution of step (b) into solution of step (a) to obtain a suspension having mebeverine pamoate; and
(d) optionally adding one or more pharmaceutically acceptable excipients.

2. A process for preparation of physicochemically stable oral suspension comprising Mebeverine or pharmaceutically acceptable salts thereof, optionally with one or more pharmaceutically acceptable excipient(s), the process comprising the steps of:
(a) preparing a dispersion of a thickening agent in water,
(b) mixing the dispersion with a solution of disodium pamoate and citric acid monohydrate in water;
(c) preparing Mebeverine hydrochloride solution in water;
(d) heating surfactant and solubilizer in a vessel to obtain a molten liquid and adding water to form an aqueous solution;
(e) adding the solution of step (d) to the solution of step (c);
(f) adding a neutralizer to the solution of step (e) to form a resultant solution; and
(g) transferring the solution of step (f) to dispersion solution of step (b) followed by addition of buffer solution to prepare the final suspension.

3. The process as claimed in any of the preceding claims, wherein the formulation comprises disodium pamoate as reactant in the range of 25 mg to 75 mg per 5ml of suspension.

4. The process as claimed in any of the preceding claims, wherein the process comprises in situ conversion of mebeverine hydrochloride into mebeverine pamoate.

5. The process as claimed in claim 2, optionally comprising;
adding disodium pamoate solution in water and citric acid monohydrate solution in water to a first portion (75-90%) of the dispersion obtained in step (a); and
adding sweetener solution to the remaining second portion (10-25%) of the dispersion and adding to step (g).

6. The process as claimed in any of the preceding claims, wherein the pharmaceutically acceptable excipients comprises reactant, suspending agent, buffering agents, surfactant, complexing agents, preservative, solubilizer, sweetener, anti-foaming agent, flavoring agent, solvents or a combination thereof.

7. The process as claimed in any of the preceding claims, wherein the thickening agents comprises xanthan gum, guar gum, locust bean gum, gum tragacanth, dispersible cellulose, polyvinylpyrrolidone, hydroxypropylcellulose or mixtures thereof.

8. The process as claimed in any of the preceding claims, wherein the surfactant and solubilizer comprises polysorbates, sodium lauryl sulphate, poloxamers, hydrogenated vegetable oil or a combination thereof.

9. The process as claimed in any of the preceding claims, wherein the neutralizer comprises weak acids, carboxylic acid, and weak acids strong base.

10. The process as claimed in any of the preceding claims, wherein the sweetener is selected from fructose, glucose, sucrose, sugar alcohol, artificial sweeteners or a combination thereof.

11. The process as claimed in any of the preceding claims, optionally comprising adding anti foaming emulsion in water to step (b), wherein the anti foaming emulsion comprises insoluble oils dimethyl polysiloxanes and silicones, alcohols, stearates and glycols, simethicone emulsion or a combination thereof.

12. The process as claimed in any of the preceding claims, optionally comprising dissolving preservative in water and adding to step (g), wherein the preservative comprises benzoic acid and sorbic acid and their salts, methyl paraben, butylparaben, propylparaben or a combination thereof;

13. The process as claimed in any of the preceding claims, optionally comprising adding flavor to step (g), wherein the flavor comprises fruity flavours, frescofort flavour permaseal, grenadine flavour permaseal and tutti frutti flavour or combinations thereof.

14. The process as claimed in any of the preceding claims, where in the suspension containing mebeverine or pharmaceutically acceptable salts thereof is used for the treatment of irritable bowel syndrome.

Novel Process for Preparation of Physicochemically Stable Oral Suspension

Abstract of the Invention

The present invention describes process of preparation of physicochemically stable oral suspension formulation containing mebeverine or pharmaceutically acceptable salts thereof, optionally with one or more pharmaceutically acceptable excipient(s), wherein the process of preparation specifically involves an in-situ conversion of the Mebeverine hydrochloride salt to Mebeverine pamoate. The present invention used for the treatment of irritable bowl syndrome and /or a disease or condition associated with these.