FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
[See section 10, Rule 13]

"AN IMPROVED LAXATIVE COMPOSITION"
(a) CIPLA LTD.
(b) 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India
(c) Indian Company incorporated under the Companies Act 1956
The following specification describes the nature of the invention and the manner in which it is to be performed:





Technical Field of Invention
The present invention relates to an improved alcohol free stable laxative preparation comprising novel combination of sennosides and polyols.
Background and Prior Art
Hazardous effects of alcohol can never be underestimated. Even though being the most effective cure for several disorders and a very common solvent for most of the water insoluble substances, often its side effects overweigh the beneficial therapeutic properties resulting in strict regulatory controls being exercised over its use in the pharmaceutical formulations.
The side effects of alcohol include dilation of blood vessels (which causes flushed skin) and increased gastric secretion in the stomach. It also causes blackouts; impaired sleep, drowsiness and sedation and above all, alcohol is habit-forming.
Therefore it becomes imperative to avoid the use of alcohol in the pharmaceutical formulations. This is extremely important when the dosage form is an oral liquid where alcohol is frequently used as a solvent for the active drug substance in the formulation.
One such field of application where alcohol is frequently used is laxatives. Laxatives that are known to be used for treatment of constipation include synthetic chemical compounds such as phenolphalein, bisacodyl (diphenyl methane laxatives), milk of magnesia and the like. These laxatives, although effective, have been found to exhibit undesirable side effects, the commonest of which are abdominal pain, cramps, nausea, skin rash, intestinal and rectal bleeding. Bulk laxatives available in the market, such as Isaphgul husk, Psyllium and Calcium polycarbophil are effective only in respect of mild to moderate constipation, and have to be administered in high doses which is not desirable keeping in view the after effects of such applications.
In recent years, herbal laxatives have grown in importance owing to their attributes of lack of undesirable side effects and thus ensuring safe and yet effective application.


Natural laxatives that are available commercially include NATURE'S REMEDY (Smith Kline Beecham), SENOKOT (Purdue Frederick) and GENTLE NATURE (Novartis). Such known natural laxative formulations usually comprise of Aloe, Senna, Cascara and other such herbal plants or their parts which are of therapeutic importance. The laxative action of the above mentioned herbal laxatives is mainly due to the presence of a class of chemical compounds in such plants viz. anthraquinones and its glycosides.
Senna, known as Cassia angustifolia, family Leguminosae (Fabaceae) contains the anthraquinone glycosides, mainly in its pods and leaves, which are responsible for the laxative activity and in particular, sennosides A and B are the major constituents responsible for laxative activity.
US 2871158 discloses a laxative syrup formulations in concentrations of more than 2 gms per liter whereby solubilization is aided by employing organic solvents, solubilizing agents or by mixtures of 2 or more of these agents.
EP0597414 and US 5389372, disclose a granulate consisting essentially of Senna extract concentrate and, for each part by weight of Senna extract concentrate, 1 to 3 parts of weight of sucrose where ethyl alcohol is used as a vehicle for the syrup.
The present invention avoids the abovementioned side effects of alcohol by substituting alcohol by a suitable non alcoholic vehicle. The solution so formed is further stabilized by employing polyols instead of sucrose. By doing this, another distinct advantage achieved is that polyols cause very little increase in blood plasma glucose levels, making the formulation ideal to be administered to diabetic and such other patients for whom low glucose levels are desired. Polyols have also proved to possess laxative activity.
Prior art US 6251875 discloses an aqueous laxative syrup having a viscosity of about 5 to 70 mPa.s at about 20°C comprising of about 1 part by weight of lactulose and about 0.66 to about 1.5 parts by weight of a polyol selected from the group of lactitol, maltitol wherein the lactulose and the polyol are present in the syrup in an amount effective use as a laxative composition. But since lactulose is a synthetic sugar it is


not suitable for administration to diabetic patients or to patients who require a low calorie diet.
By avoiding the use of lactulose in the present invention, the dosage form achieves better physical and therapeutic properties. It is well known in the art that in the absence of sucrose, molds and bacteria do not grow as well on these sweeteners, as they do on sucrose, and so products last longer. When used in medicines, polyols generally do not react with active ingredients as much as sometimes happens with sugar.
Object
Hence the object of the present invention is to provide a formulation, which is stable and alcohol-free, thereby eliminating all side effects associated with the use of alcohol.
Another object of the present invention is to provide a formulation which being alcohol free is extremely safe to administer to patients of all age groups especially geriatrics and pediatrics patients.
Yet another object of the present invention is to provide a formulation, which is alcohol free and is stabilized by employing polyols in the formulation.
Yet another object of the present invention is to provide a formulation for use in the treatment of intestinal immobility, constipation, pre-operative sterilization of bowels and such other related disorders thereof.
Summary
According to the present invention there is provided an improved, liquid laxative formulation comprising the active ingredient selected from the class of anthraquinone glycosides along with at least one polyol.


In another aspect of the of the present invention there is provided a process for the manufacture of the said formulation comprising dissolving the anthraquinone glycoside with at least one preservative agent, at least one buffering agent, at least one polyol, in an suitable vehicle.
In yet another aspect of the present invention there is provided the said formulation for the use in treatment of intestinal immobility, constipation, pre-operative sterilization of bowels and such other related disorders thereof
A method for the prophylaxis or treatment in a mammal, such as a human, of conditions for which administration of one or more anthraquinone glycoside is required which method comprises administration of a therapeutically effective amount of the said pharmaceutical composition.
Detailed description
Senna, known as Cassia angustifolia, family Leguminosae (Fabaceae) contains the anthraquinone glycosides in its leaves and pods, which are responsible for the laxative activity. Particularly sennosides A and B, which are chemically the anthraquinone glycosides, are the major constituents. Preferably senna is administered as syrup because syrups provide a pleasant means of administering a liquid form of a disagreeable tasting drug. They are particularly useful in administration of drugs to children and geriatric, since their pleasant taste usually dissipates any reluctance on the part of the patient to take the medicine.
The active component, the sennosides are administered as a salt of the group I, II alkali metal, preferably the calcium salts. Sennosides are solubilised in water along with the polyols. Polyols help to stabilize this solution and therefore prevent its degradation. Polyols such as mannitol, lactitol, sorbitol, maltitol, erythritol, isomalt, and xylitol among the others of this class may be used in the formulation.
Polyols also have the distinct advantage of being less sweet than natural sugars therefore being very safe for administration to diabetics and related disorders. This is because polyols are slowly and incompletely absorbed from the small intestine in the


blood and this absorbed portion is metabolized by processes that require little or no insulin. Being less sweet than sucrose they also do not cause tooth decay and are also advisable for conditions where low calorie count is desired.
Polyols also exert a laxative effect of their own. Therefore when used in combination with sennosides, the laxative activity is potentiated. Therefore the formulation shows better therapeutic performance.
The formulation of the present invention provides laxation within 4-6 hours.
Among the various polyols, the preferred ones are mannitol, sorbitol, maltitol, and isomalt. This combination of sennosides and polyols may be used in the ratio of 1:10 to 1:500 respectively with respect to the formulation.
The other components of the syrup are selected from conventional excipients known in the art. The antimicrobial preservative agents may be selected from benzoic acid, sodium benzoate, sodium citrate, various combinations from methyl parabens, ethyl parabens, propyl parabens, and butyl parabens and the like and may be added in the range of 0.001% to 0.1%.
The formulation may also comprise of buffering agents such as phosphates, citrates and their salts and derivatives thereof in order to stabilize the formulation, humectants such as propylene glycol, glycerol, and the like may also be added to the formulation in a range of about 10 to 70%.
The formulation of the present invention has a pH in the range of 4 to 8, more preferably in the range of 5 to 7.
The formulations of the present invention also possess appropriate viscosity. The formulations according to the present invention have a viscosity in a range of 10 cps to 500 cps. More preferably in a range of 20 cps to 200 cps.


The present invention may optionally contain viscosity building agents such as polyvinylpyrrolidone, celluloses-methyl cellulose, carboxymethylcellulose, may be added to increase the viscosity of the formulation.
Coloring agents are added for aesthetic appearance. Flavoring agents are added to mask the bitterness of the formulation and to increase palatability of the formulation. The color and the flavor are added complementary to each other. Any such other suitable ingredients that contribute to make a stable syrup may also be included in the present formulation.
It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be falling within the scope of the invention, which is limited only by the following claims. The present invention is further illustrated but not limited to the following examples: -
EXAMPLES
Example 1:

Sr. No. Ingredients. %w/v
1. Calcium sennosides 0.165
2. Methyl paraben 0.2
3. Propyl paraben 0.02
4. Maltitol 60.00
5. Citric acid monohydrate 0.0019
6. Sodium citrate 0.03
7. Glycerol 10.00
8. Mannitol 3.0
9. Chocolate flavour 0.15


10. Butter scotch flavour 0.06
11. Purified water q.sto 100 ml.
Process: -
1. Methyl paraben and propyl paraben were boiled in purified water.
2. Maltitol was added and dissolved in (1). To this mannitol was added and boiled for 2 minutes.
3. This sugar syrup as prepared in (2), was strained and cooled. Glycerol was added to this solution.
4. Sodium citrate was dissolved in water and was added to (3) and the pH of the solution was checked. [This was called as solution I]
5. Citric acid monohydrate was dissolved in water.
6. Presifted mannitol and pre-sifted calcium sennosides were mixed together. This was called as a premix.
7. This premix was added to the solution containing citric acid monohydrate with stirring. The pH of this solution was checked. [This was called as solution 2].
8. Solution 2 was added with stirring to solution 1 at temperatures below the degradation temperature of the solution. This was called as solution 3. The pH of solution 3 was checked.
9. Chocolate and Butterscotch flavors were added with stirring to solution 3 while maintaining pH.
10. The solution of (9) was strained and the volume made up with purified water.
Example 2:

Sr. No. Ingredients. %w/v
1. Calcium sennosides 0.165
2. Methyl paraben 0.2
3. Propyl paraben 0.02
4. Isomalt 20.00
5. Citric acid monohydrate 0.0019
6. Sodium citrate 0.03
7. Glycerol 10.00


8. Mannitol 3.0
9. Chocolate flavour 0.15
10. Butter scotch flavour 0.06
11. Purified water q.s to 100 ml
Process: -
1. Methyl paraben and propyl paraben were boiled in purified water.
2. Isomalt was added and dissolved in (1). To this mannitol was added and boiled for 2 minutes.
3. This sugar syrup as prepared in (2), was strained and cooled. Glycerol was added to this solution.
4. Sodium citrate was dissolved in water and was added to (3) and the pH of the solution was checked. [This was called as solution 1]
5. Citric acid monohydrate was dissolved in water.
6. Presifted mannitol and pre-sifted calcium sennosides were mixed together. This was called as a premix.
7. This premix was added to the solution containing citric acid monohydrate with stirring. The pH of this solution was checked. [This was called as solution 2].
8. Solution 2 was added with stirring to solution 1 at temperatures below the degradation temperature of the solution. This was called as solution 3. The pH of solution 3 was checked.
9. Chocolate and Butterscotch flavors were added with stirring to solution 3 while maintaining pH.
10. The solution of (9) was strained and the volume made up with purified water.
Example 3:

Sr. No. Ingredients. %w/v
1. Calcium sennosides 0.165
2. Methyl paraben 0.2
3. Propyl paraben 0.02
4. Sorbitol 60.00
5. Citric acid monohydrate 0.0019


6. Sodium citrate 0.03
7. Glycerol 10.00
8. Mannitol 3.0
9. Chocolate flavour 0.15
10. Butter scotch flavour 0.06
11. Purified water q.s to 100 ml.
Process: -
1. Methyl paraben and propyl paraben were boiled in purified water.
2. Sorbitol was added and dissolved in (1). To this mannitol was added and boiled for 2 minutes.
3. This sugar syrup as prepared in (2), was strained and cooled. Glycerol was added to this solution.
4. Sodium citrate was dissolved in water and was added to (3) and the pH of the solution was checked. [This was called as solution 1]
5. Citric acid monohydrate was dissolved in water.
6. Presifted mannitol and pre-sifted calcium sennosides were mixed together. This was called as a premix.
7. This premix was added to the solution containing citric acid monohydrate with stirring. The pH of this solution was checked. [This was called as solution 2].
8. Solution 2 was added with stirring to solution 1 at temperatures below the degradation temperature of the solution. This was called as solution 3. The pH of solution 3 was checked.
9. Chocolate and Butterscotch flavors were adde3d with stirring to solution 3 while maintaining pH.
10. The solution of (9) was strained and the volume made up with purified water.
Example 4

Sr. No. Ingredients. %w/v
1. Calcium sennosides 0.1725
2. Methyl paraben 0.200
3. Propyl paraben 0.020
4. Maltitol 60.00


5. Citric acid monohydrate 0.0019
6. Sodium citrate 0.03
7. Glycerol 10.00
8. Mannitol 3.0
9. Chocolate flavour 0.15
10. Butter scotch flavour 0.06
11. Purified water q.s to 100 ml.
Process: -
1. Methyl paraben and propyl paraben were boiled in purified water.
2. Maltitol was added and dissolved in (1). To this mannitol was added and boiled for 2 minutes.
3. This sugar syrup as prepared in (2), was strained and cooled. Glycerol was added to this solution.
4. Sodium citrate was dissolved in water and was added to (3) and the pH of the solution was checked. [This was called as solution 1]
5. Citric acid monohydrate was dissolved in water.
6. Presifted mannitol and pre-sifted calcium sennosides were mixed together. This was called as a premix.
7. This premix was added to the solution containing citric acid monohydrate with stirring. The pH of this solution was checked. [This was called as solution 2],
8. Solution 2 was added with stirring to solution 1 at temperatures below the degradation temperature of the solution. This was called as solution 3. The pH of solution 3 was checked.
9. Chocolate and Butterscotch flavors were added with stirring to solution 3 while maintaining pH.
10. The solution of (9) was strained and the volume made up with purified water.
Example 5

Sr. No. Ingredients. %w/v
1. Calcium sennosides 0.1725
2. Methyl paraben 0.200


3. Propyl paraben 0.020
4. Sorbitol 60.00
5. Citric acid monohydrate 0.0019
6. Sodium citrate 0.03
7. Glycerol 10.00
8. Mannitol 3.0
9. Chocolate flavour 0.15
10. Butter scotch flavour 0.06
11. Purified water q.s to 100 ml.
Process: -
1. Methyl paraben and propyl paraben were boiled in purified water.
2. Sorbitol was added and dissolved in (1). To this mannitol was added and boiled for 2 minutes.
3. This sugar syrup as prepared in (2), was strained and cooled. Glycerol was added to this solution.
4. Sodium citrate was dissolved in water and was added to (3) and the pH of the solution was checked. [This was called as solution 1]
5. Citric acid monohydrate was dissolved in water.
6. Presifted mannitol and pre-sifted calcium sennosides were mixed together. This was called as a premix.
7. This premix was added to the solution containing citric acid monohydrate with stirring. The pH of this solution was checked. [This was called as solution 2].
8. Solution 2 was added with stirring to solution 1 at temperatures below the degradation temperature of the solution. This was called as solution 3. The pH of solution 3 was checked.
9. Chocolate and Butterscotch flavors were added with stirring to solution 3 while maintaining pH.
10. The solution of (9) was strained and the volume made up with purified water.


Example 6

Sr. No. Ingredients. %w/v
1. Calcium sennosides 0.1725
2. Methyl paraben 0.200
3. Propyl paraben 0.020
5. Citric acid monohydrate 0.0019
6. Sodium citrate 0.03
7. Glycerol 10.00
8. Propylene glycol 2.50
9. Chocolate flavour 0.15
10. Butter scotch flavour 0.06
11. Water 5.00
12. Liquid Maltitol q.s to 100 ml.
1. Methyl paraben and propyl paraben were dissolved in propylene glycol.
2. Glycerol was added to the solution 1
3. Sodium citrate and citric acid are dissolved in 1% water and this solution was added to solution formed in step 2
4. Calcium sennosides is added to 4% water
5. Solutions of step 3 was added Maltitol.
6. Solution of step 4 was added to step 5
7. Chocolate and Butterscotch flavors, glycerol were added to step 6 with stirring and the volume made up with Maltitol.
While the present invention is described above in connection with preferred or illustrative embodiments, these embodiments are not intended to be exhaustive or limiting of the invention. Rather, the invention is intended to cover all alternatives, modifications and equivalents included within its spirit and scope.


Claims:
1. An improved, liquid laxative formulation comprising the active ingredient selected from the class of anthraquinone glycosides along with at least one polyol.
2. The improved, liquid laxative formulation as claimed in claim 1, wherein the said active ingredients are selected from the class of anthraquinone glycosides, is sennosides, or its salts, or derivatives, or enantiomers, or prodrugs or racemic mixtures thereof.
3. The improved, liquid laxative formulation as claimed in claim 2, wherein the said salts of sennosides are metallic salts of sennosides of group I or II metal.
4. The improved, liquid laxative formulation as claimed in claim 3, wherein the said metallic salt of sennosides is preferably Calcium salt of sennosides.
5. The improved, liquid laxative formulation as claimed in claim 1 wherein the said at least one polyol is selected from the group comprising mannitol, erythritol, xylitol, sorbitol, maltitol, lactitol, isomalt, or such other compounds of this class.
6. The improved, liquid laxative formulation as claimed in claims 1 to 5, wherein the said sennosides and the said polyols are present in a ratio of 1:10 to 1:500.
7. The improved, liquid laxative formulation according to any of claims 1 to 6, wherein the said formulation has a pH in the range of 4 to 8
8. The improved, liquid laxative formulation according to any of claims 1 to 7, wherein the said formulation has a pH preferably in the range of 5 to 7
9. The improved, liquid laxative formulation according to any of the claims I to
8, wherein the said formulation has a viscosity of 10cps to 500cps.
10. The improved, liquid laxative formulation according to any of the claims 1 to
9, wherein the said formulation has a preferred viscosity of 20cps to 200cps.
11. A process for preparing an improved, liquid laxative formulation as claimed in claims 1 to 10, which comprises combining the active ingredient selected from the class of anthraquinone glycosides, at least one polyol along with the other excipients.
12. The process as claimed in claim 11, which comprises dissolving at least one preservative agent, at least one buffering agent, at lease one polyol in a suitable vehicle.


13. The process as claimed in claim 11, which further comprises preparation of
the drug solution by dissolving ingredients comprising the active ingredient, at least one polyol, at least one buffering agent in suitable vehicle.
14. The process as claimed in claims 12 and 13, wherein the suitable vehicle is a pharmaceutically acceptable liquid such as water and/or polyol.
15. The process as claimed in claims 12, 13 and 14 which still further comprises mixing of solution prepared in claim 12 to the solution prepared in claim 13 and further adding suitable colouring and flavouring agents to it.
16. The process as claimed in claim 11, comprising dissolving at least one preservative agent, at least one buffering agent, at lease one polyol.
17. The process as claimed in claim 11 which further comprises preparation of the drug solution by dissolving ingredients comprising the active ingredient in the said suitable vehicle.
18. The process as claimed in claims 16 and 17 which still further comprises mixing of solution prepared in claim 17 to the solution prepared in claim 16 and further adding suitable colouring and flavouring agents to it.
19. A method for the prophylaxis or treatment in a mammal, such as a human with conditions for which administration of one or more anthraquinone glycoside is required comprises administration of a therapeutically effective amount of the improved liquid laxative formulation according to any of the claims 1 to 10.
20. The improved, liquid laxative formulation as claimed in any of the preceding claims 1 to 10 wherein the said formulation is used in treatment of intestinal immobility, constipation, pre-operative sterilization of bowels and such other related disorders thereof.