DESC:TECHNICAL FIELD:
The present invention relates to compositions, e.g., formulations or preparations for treating, ameliorating or preventing chronic idiopathic constipation. Specifically, the present invention relates to compositions comprising a combination of sugar alcohols, preferably Lactitol, and Flaxseed, for treating, ameliorating or preventing chronic idiopathic constipation.

BACKGROUND ART:
The human intestinal microbiota or the gastrointestinal (GI) microbiota is a collection of around 3.3 million microorganisms that live within the gastrointestinal tract. Majority of the GI microbiota is obligate bacteria (e.g. Lactobacillus, Bifidobacterium, and Bacteroides spp.), performs many important health-promoting functions, for example, aiding digestion of important nutrients. Minority of GI microbiota is potentially pathogenic (e.g. Pseudomonas aeruginosa and Campylobacter jejuni) and plays a vital role in the pathogenesis of various diseases.

The alterations in intestinal microbiota i.e., increase in obligate bacteria and parallel increase in pathogenic bacteria leads to various GI disorders such as IBS, Constipation. Constipation is a common gastrointestinal disorder which affects about 28% of the population. This problem is mainly encountered in adults and paediatric patients and can generate considerable suffering for patients due to both the unpleasant physical symptoms and psychological preoccupations that can arise. Constipation occurs when bowel movements become less frequent and stools become difficult to pass. It happens most often due to changes in diet or routine, or due to inadequate intake of fiber.

Constipation may be acute or chronic with the latter usually being defined as a duration of greater than three months. Acute constipation begins suddenly and noticeably. Chronic Idiopathic Constipation (CIC) and Irritable Bowel Syndrome both present as chronic constipation and are distinct from acute constipation. Chronic Idiopathic Constipation (CIC) is a bowel disorder, defined as a state of unsatisfactory defecation characterized by infrequent stools and difficulty in passing stools, or both. Chronic Idiopathic Constipation is without any known cause or identified underlying illness.

Diagnosing of constipation includes Physical examination, Abdominal X-ray, Lower GI (gastrointestinal) series (also called barium enema), Colonoscopy, Sigmoidoscopy, Colorectal transit study, Anorectal function tests, anorectal manometry, defecography, balloon explusion test, MRI defecography.

Treatment for Constipation usually begins with diet and lifestyle changes like physical activity, a high-fiber diet, adequate intake of fluids followed by medications like laxatives. There are several types of Laxatives available as over-the-counter:
• Fiber supplements: Fiber supplements adds bulk to the stool thereby making them softer and easier to pass.
Examples: Psyllium, Calcium Polycarbophil and Methylcellulose
• Stimulants: Stimulants causes contractions in intestine.
Examples: Bisacodyl, Sennosides
• Osmotics: Osmotic laxatives increases secretion of fluid from the intestines and helps to stimulate bowel movements, thereby helps stool move through the colon.
Examples: Lactitol, Oral magnesium hydroxide, Magnesium citrate, Lactulose
• Lubricants: Lubricants such as mineral oil enable stool to move through your colon more easily.
• Stool softeners: Stool softeners moisten the stool by drawing water from the intestines
Examples: Docusate Sodium, Docusate Calcium
• Enemas and suppositories: Enemas soften stools and produce bowel movement. Suppositories aid in moving stool out of the body by providing lubrication and stimulation.
Examples: Tap water enemas with or without soapsuds. Glycerin or Bisacodyl suppositories.

Osmotic Laxatives are widely used in the treatment of Chronic Idiopathic constipation (CIC). Osmotic laxatives alter the balance of fluid with substances such as salts, sugars, and other organic compounds that encourage the movement of water into the lumen. There are several osmotic laxatives used for the treatment of constipation.

Disaccharide sugar is widely prescribed osmotic laxative in India. Lactulose is a disaccharide sugar with osmotic effect and Lactitol is its analog. Lactulose is a nonabsorbable synthetic disaccharide that consists of galactose and fructose linked by a bond resistant to lactase. Both Lactulose and its analog Lactitol are widely used and well tolerated Laxatives.

Lactitol is a sugar alcohol, an analog of Lactulose. Chemically, Lactitol is 4-O-a-D-Galactopyranosyl-D-glucitol with the following structure.

Formula I

Lactitol is available as oral solution and marketed as Pizensy® since 2020 in the United States for the treatment of chronic idiopathic constipation (CIC) in adults.

Lactitol is an osmotic laxative that exerts its pharmacologic effect by creating a hyperosmotic environment within the small intestine. The osmotic effect generated by Lactitol draws water into the small intestine, which loosens stools and ultimately facilitates bowel movements. It is a non-digestible sugar and reaches the intestine in unchanged manner and recalls the water in an osmotic matter and by fermentation it increases the faeces volume and reduce the permanence time in colon. These conditions are related to each other and facilitates the defecation. Therefore, Lactitol is well tolerated by patients and is able to increase the evacuation frequency and faeces consistency and useful in treating chronic constipation.

Patients prefer Lactitol over lactulose due to comparable efficacy and tolerability, better palatability and taste when compared with lactulose which increases patient compliance. Lactitol could be used in diabetic patients as well due to its low glycemic index and hence no effect on glucose and insulin levels. Lactitol is proven to be safe and effective to use at a dosage of 10g per day.

However, the monotherapy of Lactitol have common side effects such as upper respiratory tract infections, flatulence, diarrhea, abdominal distension, dyspepsia, cramps and increased blood creatinine phosphokinase. Among these, most common side effect is flatulence.

Thus there is an unmet need to develop a novel formulation with less side effects and more consistency. The inventors of the present invention surprisingly found that Lactitol when combined with flaxseed has synergistically effective action. Also, this combination has very fewer side effects, improved stool frequency and better consistency when compared with Lactitol compositions.

Flaxseed is a seed from the flax plant, one of several species of the plant genus Linum, containing omega-3 fatty acids and alphalinolenic acid. Flaxseeds are packed with nutrients like protein, potassium, magnesium, protein, and fiber. Flaxseed-derived foods, lignans, and essential fatty acids possess anti-inflammatory, antioxidant, lipid-lowering, and antineoplastic properties.

Flaxseeds contain a good mix of both soluble and insoluble fiber, which helps reduce intestinal transit time and adds bulk to stools. They have natural laxative properties and are used to treat constipation by increasing bowel frequency. 1 to 4 tablespoons of flaxseed as a whole or taken as oil or in a glass of water taken regularly to relieve constipation. Flaxseed is proven to be safe to use in the treatment of constipation.

As a result of intensive studies, the present inventors have found that the combination of Lactitol and Flaxseed showed a synergistic effect in treating chronic constipation and also showed a significant decrease in side effects, especially flatulence, when compared to formulations containing only Lactitol. Lactitol and Flaxseed combination also showed improvement in stool frequency and consistency in the treatment of chronic idiopathic constipation.

Currently there is no approved/marketed composition comprising a combination of Lactitol and Flaxseed.

SUMMARY OF THE INVENTION:

An object of the present invention is to provide a composition containing combination of Lactitol and Flaxseed, useful for the treatment of chronic idiopathic constipation.

In one embodiment, the present specification relates to a pharmaceutical composition comprising combination of
a) an osmotic laxative, and
b) a natural laxative
wherein the pharmaceutical composition is selected from oral solution, powder and granules.

In another embodiment, the present specification relates to a pharmaceutical composition comprising combination of
a) an osmotic laxative selected from sugar alcohol and
b) a natural laxative
In another embodiment, the present specification relates to a pharmaceutical composition comprising combination of
a) sugar alcohol selected from Lactitol, Mannitol, Erythritol, Sorbitol, Xylitol or combinations thereof and
b) a natural laxative selected from flaxseed, chia seed, prune, castor oil

In another embodiment, the present specification relates to a pharmaceutical composition comprising combination of
a) Lactitol, and
b) Flaxseed.

In yet another embodiment, the present specification relates to a pharmaceutical composition comprising combination of
a) Lactitol, and
b) Flaxseed
and further comprising a pharmaceutically acceptable carrier which is selected from diluent, humectant, lubricant, viscosifier, acidifying agent, alkalinizing agent, preservative, flavoring agent and sweetening agent.

In yet another embodiment, the present specification relates to a pharmaceutical composition comprising combination of
a) Lactitol,
b) Flaxseed, and
c) a pharmaceutically acceptable carrier
wherein the pharmaceutical composition is preferably oral solution.

In yet another embodiment, the present specification relates to a pharmaceutical composition comprising combination of
a) 5g of Lactitol,
b) 5g of Flaxseed extract, and
c) a pharmaceutically acceptable carrier,
wherein the pharmaceutical composition is preferably oral solution.

In yet another embodiment, the present specification relates to a pharmaceutical composition comprising combination of
a) 5g of Lactitol,
b) 2.5g of Flaxseed extract, and
c) a pharmaceutically acceptable carrier,
wherein the pharmaceutical composition is preferably oral solution.

In yet another embodiment, the present specification relates to a pharmaceutical composition, wherein a combination of Lactitol and Flaxseed are provided in synergistically effective amounts for use in the treatment of constipation, wherein the constipation is chronic idiopathic constipation.

In yet another embodiment, the present specification relates to a pharmaceutical composition, wherein a combination of Lactitol and Flaxseed are provided in synergistically effective amounts for use in the treatment of chronic idiopathic constipation in patients who experiences an average of fewer than 3 bowel movements per week for more than 3 months.

The composition of Lactitol and Flaxseed of the present specification can be used for the treatment of chronic idiopathic constipation in subjects with less adverse effects compared to formulations comprising only Lactitol.

BRIEF DESCRIPTION OF DRAWINGS:
Figure 1: Effect on Fecal count evaluation parameter for Example 2 and 3
Figure 2: Effect on Fecal weight evaluation parameter for Example 2 and 3
Figure 3: Effect on Fecal scores for Example 2 and 3
Figure 4: Effect on Intestinal transit for Example 2 and 3

DESCRIPTION OF INVENTION:

This invention relates to a formulation comprising combination of Lactitol and Flaxseed, for the treatment of chronic idiopathic constipation, and to improve stool frequency and consistency, with lesser side-effects when compared with compositions comprising only Lactitol.

In one embodiment, the present specification relates to a pharmaceutical composition comprising combination of
a) an osmotic laxative, and
b) a natural laxative
wherein the pharmaceutical composition is selected from oral solution, powder and granules.

In another embodiment, the present specification relates to a pharmaceutical composition comprising combination of
a) an osmotic laxative selected from sugar alcohol and
b) a natural laxative
In another embodiment, the present specification relates to a pharmaceutical composition comprising combination of
a) sugar alcohol selected from Lactitol, Mannitol, Erythritol, Sorbitol, Xylitol or combinations thereof and
b) a natural laxative selected from flaxseed, chia seed, prune, castor oil

In another embodiment, the present specification relates to a pharmaceutical composition comprising combination of
a) Lactitol and
b) Flaxseed.

In yet another embodiment, the present specification relates to a pharmaceutical composition comprising combination of
a) Lactitol, and
b) Flaxseed
and further comprising a pharmaceutically acceptable carrier which is selected from diluent, humectant, lubricant, viscosifier, acidifying agent, alkalinizing agent, preservative, flavoring agent and sweetening agent.

In yet another embodiment, the present specification relates to a pharmaceutical composition comprising combination of
a) Lactitol,
b) Flaxseed, and
c) a pharmaceutically acceptable carrier,
wherein the pharmaceutical composition is preferably oral solution.

In yet another embodiment, the present specification relates to a pharmaceutical composition comprising combination of
a) 5g of Lactitol,
b) 5g of Flaxseed extract, and
c) a pharmaceutically acceptable carrier,
wherein the pharmaceutical composition is preferably oral solution.

In yet another embodiment, the present specification relates to a pharmaceutical composition comprising combination of
a) 5g of Lactitol,
b) 2.5g of Flaxseed extract, and
c) a pharmaceutically acceptable carrier,
wherein the pharmaceutical composition is preferably oral solution.

In yet another embodiment, the present specification relates to a pharmaceutical composition, wherein a combination of Lactitol and Flaxseed are provided in synergistically effective amounts for use in the treatment of constipation, wherein the constipation is chronic idiopathic constipation.

In yet another embodiment, the present specification relates to a pharmaceutical composition, wherein a combination of Lactitol and Flaxseed are provided in synergistically effective amounts for use in the treatment of chronic idiopathic constipation in patients who experiences an average of fewer than three bowel movements per week for more than 3 months.

In yet another embodiment, the present specification relates to a pharmaceutical composition comprising combination of Lactitol and Flaxseed, wherein Lactitol and Flaxseed independently present in an amount between 5 to 80% with respect to total weight of composition.

In yet another embodiment, the present specification relates to a pharmaceutical composition comprising combination of Lactitol and Flaxseed, wherein Lactitol and Flaxseed independently present in an amount between 15 to 60 % with respect to total weight of composition.

In yet another embodiment, the present specification relates to a pharmaceutical composition comprising combination of Lactitol and Flaxseed, wherein Lactitol and Flaxseed independently present in an amount between 25 to 50% with respect to total weight of composition.

In yet another embodiment, the present specification relates to a pharmaceutical composition comprising combination of Flaxseed and Lactitol in a ratio from 1:0.1 to 0.1:10 respectively.

In yet another embodiment, the dose of flaxseed or flaxseed mucilage is in an amount of 0.04 g to 20g/ day. In another preferred embodiment the dose of flaxseed extract is 0.04 g/day, 0.5 g/day, 1 g/day, 2 g/ day, 2.5 g/day, 3 g/day. 3.5 g/day, 4 g/day, 4.5 g/day, 5 g/day, 6 g/day, 7 g/day, 8 g/day, 9 g/day, 10 g/day, 11 g/day, 12 g/day, 13 g/day, 14 g/day, 15 g/day, 16 g/day, 17 g/day, 18 g/day, 19 g/day, 20 g/day.

In yet another embodiment, the dose of lactitol is in an amount of 0.2 g to 20g/ day. In another preferred embodiment the dose of flaxseed extract is 2 g/ day, 2.5 g/day, 3 g/day. 3.5 g/day, 4 g/day, 4.5 g/day, 5 g/day, 6 g/day, 7 g/day, 8 g/day, 9 g/day, 10 g/day, 11 g/day, 12 g/day, 13 g/day, 14 g/day, 15 g/day, 16 g/day, 17 g/day, 18 g/day, 19 g/day, 20 g/day.

In another embodiment of the present invention is provided method of using such composition which comprises administering to a subject in need thereof an effective amount of the composition. In an embodiment when the compositions of the present invention was evaluated in loperadimde induced constipation rat model, the combination showed syngerstic activity. In a further embodiment is provided a method, wherein the composition of the present invention is useful for prophylaxis and/or amelioration and/or treatment of constipation and associated disorders such as gas, bloating, cramps, acidity, irritation, abdominal pain and discomfort. In a still further embodiment is provided a method, wherein the composition of the present invention is useful as a dietary supplement to normalize bowel functions and provide relief from particularly constipation and other associated disorders. In yet another embodiment is provided melhod of using such composition as a dietary supplement to normalize bowel functions and provide relief from particularly constipation or other associated disorders. The compositions of the present invention are also useful in the treatment and/or management of diseases or disorders of the bowel primarily associated with constipation, diarrhea or indigestion.

The term “pharmaceutical formulations” as used herein refers to oral dosage forms preferably in the form of Oral solution, Granules, Syrup, Powder, Sachet and the like. These dosage forms are generally prepared by using one or more suitable pharmaceutically acceptable excipients. The term composition or formulation are used herein interchangeably.

The term “sugar alcohol” as used herein refers to a long chain alcohol having a hydroxyl group (-OH) reduced by a carbonyl group (C=O) of sugar.

The term “laxative” as used herein refers to an active agent which is having a tendency to loosen or relax, specifically producing bowel movements and relieving constipation. Any substance that stimulates evacuation of faeces.

The term “Flaxseed” or “Flaxseed Extract” or “Flaxseed Mucilage” can be used interchangeably.

The term “osmotic” as used herein refers to the concentration of a solute when two solutions are separated by a membrane (which is permeable to solvents) that selectively blocks the passage of solute molecules. Any substance that facilitates the passage of solvent from a low solution to a high solute concentration solution.

The term “constipation” as used herein refers to a condition in which a subject suffers from infrequent bowel movements or painful and / or difficult to pass bowel movements. Subjects who experience constipation often suffer from a feeling of strain during defecation and / or incomplete defecation following defecation. In some embodiments, constipation refers to a subject who experiences an average of fewer than 3 bowel movements per week, where " bowel movement" is the passage and elimination of feces.

The term "chronic," as used herein refers to a long-lasting condition. In various embodiments, chronic can refer to a condition that lasts at least 1, 2, 3, or 4 weeks. Alternatively, chronic can also refer to a condition lasting at least 1, 2, 3, 4, 5 or 6 months. In certain embodiments, the subject is receiving laxative to reduce chronic idiopathic constipation that persisted for atleast 3 months.

The term "subject" as used herein refers to mammals, humans as well as domesticated animals (e.g. horses, dogs, cats, etc.) and laboratory animals (e.g. mice, rats, dogs, chimpanzees, monkeys) Etc.) and other animal subjects. In a particular embodiment, the subject is a human.

The term “combination” is intended to refer to therapy by any route of administration in which two or more active agents are administered together to a subject. The active substances can be in the same dosage formulation or in different formulations. In a particular embodiment, the combination therapy is administering two active agents in a single dosage form.

Flaxseed may be in the form of milled or unmilled seeds or fractions thereof and can be used as starting material. The outer part of flaxseed consists of a water-soluble mucilage i.e., the epidermic layer. Under the mucilage, there is the actual husk substance consisting of three layers, i.e., spermoderm, endosperm, and cotyledon from outermost to innermost. The outer husk surface is spermoderm layer which contains mucilage and lignans. The inner husk surface is the endosperm, and the seed core consists of the cotyledon, which accounts for about half of the weight of the seed. The flaxseed of the present invention is in the form of husk or mucilage, preferably mucilage.

The formulation according to the invention are thus prepared by the skilled man using permitted formulation excipients as described in the prior art for the preparation of compositions for oral administration such as solutions, powders or granules. Examples of such excipients include, but not limited to, diluents, humectants, lubricants, viscosifiers or thickening agents, preservatives, flavoring agents, sweeteners, acidifying and alkalinizing agents and the like.

Examples of suitable diluents include, but not limited to the group consisting of different grades of starches, such as maize starch, potato starch, rice starch, wheat starch, pregelatinised starch, fully pregelatinised starch; cellulose derivatives, such as microcrystalline cellulose or silicified microcrystalline cellulose; sugar alcohols such as mannitol, erythritol, sorbitol, xylitol; monosaccharides like glucose; oligosaccharides like sucrose and lactose such as lactose monohydrate, lactose anhydrous, spray dried lactose or anhydrous lactose; calcium salts, such as calcium hydrogen phosphate; particularly preferably the fillers are selected from the group consisting of, mannitol, sorbitol, xylitol and the like. More preferably the diluent is Mannitol.

Examples of suitable humectants include, but not limited to the group consisting of sorbitol, mannitol, glycerol, propylene glycol, glycerin agar, calcium carbonate, potato starch, tapioca starch, alginic acid, certain silicates, colloidal silicon dioxide, sodium starch glycolate; particularly preferably the humectant is glycerin and the like. In a preferred embodiment, glycerin is present in an amount of from 5 to 15%. In a preferred embodiment, glycerin is present in an amount of from 8 to 12% by weight of formulation.

Examples of suitable lubricants include, but not limited to the group consisting of sodium chloride, stearic acid, talc, glyceryl behenate, sodium stearyl fumarate and magnesium stearate; particularly preferably the lubricant is sodium chloride and the like. In a preferred embodiment, sodium chloride is present in an amount of from 0.1 to 3%. In a preferred embodiment, sodium chloride is present in an amount of from 0.5 to 1.5% by weight of formulation.

Examples of suitable viscosifiers or thickeners include, but not limited to the group consisting of starch, guar gum, Gellan gum, xanthan gum, sodium carboxymethyl cellulose, HPMC, HPC, Sodium CMC. In a preferred embodiment, sodium carboxymethyl cellulose is present in an amount of from 0.1 to 1.5%. In a preferred embodiment, sodium carboxymethyl cellulose is present in an amount of from 0.3 to 1% by weight of formulation.

Examples of suitable anti-oxidants include, but not limited to BHT, Tocopherol acetate, Sodium metabisulfite, BHA.

Examples of suitable Preservatives include, but not limited to the group consisting of sorbic acid and derivatives, sodium benzoate, sodium metabisulphate, Sodium salts of methyl paraben and propyl paraben, benzoic acid, methyl paraben, propyl paraben, sodium benzoate, potassium sorbate, sorbic acid, particularly preferably the preservatives are selected from the group consisting of sodium benzoate, methyl paraben, propyl paraben, sodium methyl paraben, sodium propyl paraben and the like.

Examples of suitable flavors include, but not limited to the group consisting of Jeera flavor, Strawberry flavor, orange flavor, apple flavor, grape flavor, lemon flavor, banana flavor, cherry flavor, etc.

Suitable sweeteners may be selected from, but not limited to the group consisting of sorbitol, sucrose, aspartame, sucralose, saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, thaumatin; particularly preferably the sweeteners are selected from the group consisting of sorbitol, sucrose, sucralose, saccharin sodium and the like. In a preferred embodiment, sweetener is present in an amount of from 0.005 to 0.5%. In a preferred embodiment, sweetener is present in an amount of from 0.01 to 0.1% by weight of formulation.

Composition may contain acidifying and alkalinizing agent. Acidifying agents can be selected from, but not limited to citric acid, succinic acid, fumaric acid, malic acid, maleic acid, glutaric acid, lactic acid and mixtures thereof and the like. Alkalizing agent can be selected from, but not limited to magnesium oxide, aluminium oxide, ammonium hydroxide, magaldrate, an alkali metal salt or alkaline earth metal salt, such as sodium bicarbonate, calcium carbonate or sodium citrate, sodium dihydrogen phosphate, Disodium hydrogen phosphate, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide, or an alkaline earth metal hydroxide such as calcium hydroxide or magnesium hydroxide, with magnesium oxide or calcium carbonate and meglumine and the like.

The preferred composition of the present invention is liquid or solid composition for oral use, even more preferably an aqueous oral solution, powder sachet, granules.

The composition of the present invention contains Lactitol and Flaxseed. The composition according to the present invention can be a medicament, a medicated food, a pharmaceutical composition or a food supplement.

The compositions of the present invention containing combination of Lactitol and Flaxseed are particularly effective in the treatment of constipation allowing increase in the weight of faeces and consistency and overall reduction in adverse effects when compared with Lactitol compositions.

EXAMPLES:
The following examples will further describe certain specific aspects and embodiments of the invention in greater details and are not intended to limit the scope of invention.

Example 1: Oral solution
INGREDIENTS 1a
(w/w%) 1b
(w/w%)
Lactitol 33.0 33.33
Flaxseed mucilage 33.0 16.67
Glycerine 10.0 10
Sorbitol solution 5.0 -
Potassium sorbate - 0.15
Sucralose 0.05 0.01
Methyl paraben 0.2 0.2
Propyl paraben 0.02 0.02
Sodium benzoate 0.2 0.2
Sodium CMC 0.5 0.4
Jeera flavor 0.2 1
Purified water QS to 100 QS to 100

Manufacturing process:
1. To required quantity of water, glycerin was added and heated upto 60oC. Preservatives were added
2. To step 1, Lactitol was added and stirred well until clear solution was formed.
3. Sweetener was added to above step and stirred well.
4. In separate container part quantity of glycerin was taken and sodium CMC was added to form slurry. This was added to step 1 and stirred to form clear solution.
5. Flaxseed mucilage was added to above step and homogenised to form clear solution.
6. Finally, flavour was added followed by weight make up and stirring to form clear solution.

Example 2: Oral solution
INGREDIENTS %w/w
Ex 2a Ex 2b Ex 2c Ex 2d Ex 2e Ex 2f Ex 2g
Lactitol 3.33 13.33 33.33 - - - -
Flaxseed extract - - - 0.27 1.33 6.67 33.33
Glycerine 10 10 10 5 5 5 5
Methyl paraben 0.2 0.2 0.2 0.2 0.2 0.2 0.2
Propyl paraben 0.02 0.02 0.02 0.02 0.02 0.02 0.02
Sodium benzoate 0.2 0.2 0.2 0.2 0.2 0.2 0.2
Xanthan gum 0.2 0.2 0.2 0.2 0.2 0.2 0.2
Sucralose 0.2 0.2 0.2 0.2 0.2 0.2 0.2
Sodium Saccharin - - - - - - 0.1
Cremophor RH40 1 1 1 1 1 1 1
Citric acid - - - - - - 0.1
Sodium citrate - - - - - - 0.2
Flavor 0.1 0.1 0.1 0.5 0.5 0.5 0.5
Purified water Qs Qs qs Qs qs qs Qs

Manufacturing process:
1. To required quantity of water, glycerin was added and heated upto 60oC. Preservatives were added
2. To step 1, Lactitol was added and stirred well until clear solution was formed.
3. Sweetener was added to above step and stirred well.
4. In separate container part quantity of glycerin was taken and sodium CMC was added to form slurry. This was added to step 1 and stirred to form clear solution.
5. Flaxseed extract was added to above step and homogenised to form clear solution. (for examples 2d- 2g)
6. Finally, flavour was added followed by weight make up and stirring to form clear solution.

Example 3: Oral solution
INGREDIENTS %w/w
Ex 3a Ex 3b Ex 3c Ex 3d Ex 3e Ex 3f Ex 3g Ex 3h
Lactitol 3.33 13.33 33.33 33.33 33.33 33.33 33.33 33.33
Flaxseed extract 33.33 6.67 1.33 33.33 33.33 16.67 33.33 16.67
Glycerine 5 5 5 10 10 10 10 10
Methyl paraben - - - - 0.2 0.2 0.2 0.2
Propyl paraben - - - - 0.02 0.02 0.02 0.02
Sodium Benzoate - - - - 0.2 0.2 0.2 0.2
Benzoic acid 0.2 0.2 0.2 0.2 - - - -
Potassium sorbate 0.15 0.15 0.15 0.15 - - - -
Xanthan gum 0.2 0.2 0.2 - - - 0.2 0.2
Sucralose 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2
Flavor 0.5 0.5 0.5 1 1 1 1 1
Purified water Qs Qs Qs Qs Qs Qs Qs Qs

Manufacturing process:
1. To required quantity of water, glycerin was added and heated upto 60oC. Preservatives were added
2. To step 1, Lactitol was added and stirred well until clear solution was formed.
3. Sweetener was added to above step and stirred well.
4. In separate container part quantity of glycerin was taken and sodium CMC was added to form slurry. This was added to step 1 and stirred to form clear solution.
5. Flaxseed extract was added to above step and homogenised to form clear solution.
6. Finally, flavour was added followed by weight make up and stirring to form clear solution.

Example 4: Powder Sachet
INGREDIENTS w/w%
Lactitol monohydrate 20.0
Flaxseed powder 20.0
Sucrose 20.0
Citric acid 5.6
Sodium Chloride 1.0
Sodium methyl paraben 0.2
Sodium Propyl paraben 0.02
Sucralose 0.05
Mannitol Qs to 100

Manufacturing process:
1. Mannitol, Lactitol monohydrate, citric acid and sweeteners were mixed well in blender for appropriate time.
2. Finally, flaxseed and preservatives were added followed by lubrication to form free flowing powder.
3. Bulk is filled in sachets using suitable sachet filling machine.

Example 5: Oral solution
INGREDIENTS w/w%
Ex 5a Ex 5b Ex 5c Ex 5d
Lactitol 33.33 36 30 38
Flaxseed mucilage (2%) 33.33 19 37 29
Glycerine IP 10 15 - 10
Methyl paraben IP 0.2 - - -
Propyl paraben IP 0.02 - - -
sodium benzoate 0.2 0.2 0.2 0.2
Sorbitol solution IP 5 10 5 5
Hydroxyethyl cellulose 0.2 - - -
Gellan gum - 2 - -
Maltitol - - 10 -
Flavor modulator 0.2 - 0.2 -
Sucralose - 0.2 0.2 -
Sodium Saccharin - - - 0.1
Sodium metabisulfite - - - 0.02
Jeera/citrus Flavor 0.1 0.1 0.1 0.1
Citric acid - - - 0.1
Sodium citrate - - - 0.2
Purified water qs qs qs qs

Manufacturing process:
1. To required quantity of water, glycerin/sorbitol solution was added and heated upto 60°C. Preservatives are added
2. To step 1, Lactitol was added and stirred well until clear solution was formed.
3. Sweetener was added to above step and stirred well.
4. In separate container part quantity of glycerin was taken and viscosifier was added to form slurry. This was added to step 1 and stirred to form clear solution.
5. Flaxseed mucilage was added to above step and homogenized to form clear solution. Finally, flavor/flavor modulator was added followed by weight make up and stirring to form clear solution.

Example 6: Oral solution
S No Name of the ingredient Qty (%)
1. Lactitol Monohydrate 16.67 – 66.67
2. Flaxseed extract powder/mucilage 16.67 – 66.67
3. Glycerine 2-15
4. Potassium sorbate 0.01 – 0.2
5. Benzoic acid 0.01 – 0.2
6. Sucralose 0.001 – 0.5
7. Lactic Acid Qs (3.2-3.5 pH)
8. Flavour 0.01 - 3
9. Xanthan Gum 0.01 - 2
10. Purified Water Qs to 100mL

Manufacturing process:
1. To required quantity of water, glycerin/sorbitol solution was added and heated upto 60°C. Preservatives are added
2. To step 1, Lactitol was added and stirred well until clear solution was formed.
3. Sweetener was added to above step and stirred well.
4. In separate container part quantity of glycerin was taken and viscosifier was added to form slurry. This was added to step 1 and stirred to form clear solution.
5. Flaxseed mucilage was added to above step and homogenized to form clear solution. Finally, flavor/flavor modulator was added followed by weight make up and stirring to form clear solution.
Example 7: Animal study
The objective of the study was to evaluate the laxative effects (along with reduction in flatulence/ bloating) of standalone Lactitol and combination of flaxseed mucilage with Lactitol at different concentrations, on rats with loperamide induced constipation. The evaluation parameters were i) faecal score (visual appearance), ii) faecal count iii) faecal weight and iv) % moisture content. Table-1 below represents the study result data.

Study Design
Animals: Sprague–Dawley (SD) rats
Loperamide Dose: 5mg/kg/day
Loperamide Administration Route: Oral
Constipation Induction Period: 5 days before starting the treatment and during treatment
Number of animals per group: 8

Table 1: Results of Animal Study.
Groups Faecal count Day 2 Faecal count Day 8 Faecal count AUEC Faecal % Moisture Faecal Visual Score
Group -I
(LT 5mg) * * Loose stool
Group -II
(LT 10 mg) * ** Extremely loose stool
Group –III
(SM 5 mg + LT 5 mg) * *** ** Normal stool
LT: Lactitol, SM: Flaxseed Mucilage
* Indicates statistical significance vs disease control

Conclusion:
• The combination group (Group-III) showed higher faecal count compared to the standalone Lactitol groups (Group-I and Group- II), indicating the early laxative effect of the combination dose.

• Considering the known bloating effect due to Lactitol alone, on visual evaluation the combination group (Group-III) showed significantly less bloating with normal stool consistency.

• Cumulative consideration for critical parameters (faecal count, AUEC, Moisture and Faecal appearance score) supports the synergistic effect of the combination group (Group-III) over other treatment groups.

Example 8: Animal study
The objective of the study was to evaluate the laxative effects of various Combinations of Flax Seed Mucilage and Lactitol in different concentrations, on rats with loperamide induced constipation. The evaluation parameters were i) faecal score (visual appearance), ii) faecal count iii) faecal weight and iv) Intestinal Transit Ratio. Table-2 below represents the study result data. Results are depicted in figures 1 to 4 for the evaluation parameters

Animals: Sprague–Dawley (SD) rats
Loperamide Dose: 5mg/kg/day
Loperamide Administration Route: Oral
Constipation Induction Period: 5 days before starting the treatment and during treatment
Number of animals per group: 78 rats were randomized into 13 groups

Table 2: Laxative effect of various combinations of flaxseed mucilage and Lactitol in different concentrations
Dose Inference on Evalaution Parameters
Lactitol 2g & Flaxseed Mucilage 0.2g & 1g *
Lactitol 0.5g & Flaxseed Mucilage 5g **
Lactitol 2g + Flaxseed Mucilage 1g ****
Lactitol 5g + Flaxseed Mucilage 0.2g ***
Lactitol 5g + Flaxseed Mucilage 5g ****
* Indicates statistical significance vs disease control

Conclusion:
From the results shown in table 1, the combination of Lactitol and flax seed mucilage were superior and have synergistic therapeutic effect.

While the present disclosure has been illustrated and described with respect to a particular embodiment thereof, it should be appreciated by those of ordinary skill in the art that various modifications to this disclosure may be made without departing from the spirit and scope of the present disclosure.

,CLAIMS:We Claim:
1. A pharmaceutical composition comprising combination of
a) an osmotic laxative, and
b) a natural laxative
2. The pharmaceutical composition as claimed in claim 1, wherein the composition comprises combination of
a) an osmotic laxative selected from sugar alcohol and
b) a natural laxative
3. The pharmaceutical composition as claimed in claim 2, where in sugar alcohol is selected from Lactitol, Mannitol, Erythritol, Sorbitol, Xylitol or combinations thereof
4. The pharmaceutical composition as claimed in claim 3, wherein the sugar alcohol is lactitol
5. The pharmaceutical composition as claimed in claim 2, where in the natural laxative comprises flaxseed
6. The pharmaceutical composition as claimed in claim 2, wherein the sugar alcohol is lactitol and a natural laxative is flaxseed
7. The pharmaceutical composition as claimed in Claim 6, wherein the flaxseed and lactitol are in a ratio from 1:0.1 to 0.1:10 respectively
8. The pharmaceutical composition as claimed in claim 1, further comprises a pharmaceutically acceptable carrier which is selected from diluent, humectant, lubricant, viscosifier, acidifying agent, alkalinizing agent, preservative, flavoring agent and sweetening agent.
9. The pharmaceutical composition as claimed in claim 1, wherein pharmaceutical composition is selected from Oral solution, Granules, Syrup, Powder, Sachet.
10. The pharmaceutical composition as claimed in claim 1 is an oral solution