WO2007057924A1

WO2007057924A1 - Laxative composition on the basis of triphala

Info

Publication number: WO2007057924A1
Application number: PCT/IN2006/000462
Authority: WO
Inventors: Rajesh Jain; Kour Chand Jindal
Original assignee: Panacea Biotec Ltd
Current assignee: Panacea Biotec Ltd
Priority date: 2005-11-21
Filing date: 2006-11-20
Publication date: 2007-05-24
Anticipated expiration: 2008-05-21

Abstract

Laxative composition comprising ispaghula, a saccharide component and optionally triphala mixed with optionally one or more excipient(s). Also provided are a process and a method of using such compositions. The compositions of the present invention are useful as pharmaceuticals or dietary supplements and are highly effective in the overall management of constipation and associated disorders thus providing a better relief to the user.

Description

NOVEL COMPOSITIONS FOR MANAGEMENT OF CONSTIPATION

FIELD OF THE INVENTION

The present invention relates Io novel compositions comprising at least one bowel evacuant and a saccharide component optionally with at least one component selected from a group comprising antacid, antiflatυlant, prokinetic, antispasmodic, anticholinergic, stool softener, anti-nauseating/anti-emetic agent, ton i Tier and the like or their mixtures, and optionally with one or more excipient(s); the process of preparation and method of using such compositions. The compositions of the present invention are useful as a pharmaceutical or a dietary supplement. The compositions of the present invention are highly effective in the overall management of constipation including the prophylaxis and/or amelioration and/or treatment of not only the constipation but also associated disorders thus providing a better relief to the user.

BACKGROUND OF THE INVENTION

Constipation is a condition in which a person has uncomfortable or infrequent bowel movements. Generally, a person is considered to be constipated when bowel movements result in passage of smal l amounts of hard, dry stool, usually fewer than three times a week. People who are constipated may find it difficult and painful to have a bowel movement. Other symptoms of constipation include feeling bloated, uncomfortable, and sluggish. The hard and dry stools of constipation occur when the colon absorbs too much water or if the colon's muscle contractions arc slow or sluggish, causing the stool to move through the colon too slowly. Common causes of constipation are not enough fiber in the diet, not enough liquids, lack of exercise, medications, irritable bowel syndrome, changes in life or routine such as pregnancy or older age or travel, abuse of laxatives, ignoring the urge to have a bowel movement, specific diseases such as stroke, problems with the colon and rectum and problems with intestinal function such as chronic idiopathic constipation. Sometimes constipation can lead to complications such as hemorrhoids caused by straining to have a bowel movement or anal fissures caused when hard stool stretches the sphincter muscle or rectal prolapse caused by straining which leads to a small amount of intestinal lining to push out from the anal opening. Constipation may also cause hard stool to pack the intestine and rectum so tightly that normal pushing action of colon is not enough to expel stool. This condition, called fecal impaction, occurs mostly in children and older adults.

5 US patent no. 5,320,847 relates to a method of agglomerating, and thereby increasing the dispensability and mixability of, a powdered psyllium hydrop)τilic miicilloid combinate utilizing acacia dissolved in water as the agglomerating agent. US patent no. 5,651 ,988 claims a combination osmotic and bulk-forming laxative comprising lactitol and psyllium hydrophilic miicilloid powder. US patent no. 4,32 1 ,263 describes a

I O method of increasing the water dispensability of psyllium hydrophilic miicilloid by granulating or agglomerating the psyllium with an alcoholic solution of polyethylene glycol and/or polyvinylpyrrolidone. Yet another method is disclosed in US patent no. 4,548,806 which describes a method for coating psyllium hydrophilic miicilloid with from about 3-1 1 percent by weight of a water soluble maltodextrin.

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US publication no. 200501529S9 claims a method for treating irritable bowel syndrome (IBS), using an osmotic laxative and a fiber which specifically provides relief from I BS by simultaneously ameliorating both constipation and diarrhea. Particularly described fibers are psyllium, partial ly-hydnolyzed guar gum and cellulose. PCT publication no. 0 WO2005051361 relates to solid dosage form colonic purgative formulations particularly comprising at least one soluble binder and at least one purgative and methods of their use.

PCT publication bearing no. WO20040781 82 relates to a novel composition which 5 combines defined proportions of a soluble saccharide which is poorly absorbed by the organism (the most widely known being disaccharides such as lactulose, lactitol, trehalose) and an antiflatulent from the siloxane group (the most widely known being polydimethylsiloxanes such as simethicone, dimethicone). German patent publication bearing no. 10262005 claims compositions containing hydrogenated condensed 0 palatinose together with bifidobacteria cultures or with at least one other dietary fiber component selected from long- or short-chain fructo-oligosaccharides, galacto-, xylo-, malto-, isomalto-, gentio-, soybean-, chito- or chitosan-oligosaccharides, hydrolyzed guar gum, lactulose, Iacto-sucrose, pectic materials, hydrolases, sugar condensation products, glυcosyl-sυciOse, resistant starch, cellulose or oat-, wheat-, vegetable-, fruii- or sugar beet fiber. European patent no. 0334407 relates to a method of preparing a solid composition of lactulose in a simple way. According to the European patent no. 0334407, the lactulose syrup is mixed with Fiberforni ^{f M} i.e. a fiber product based on 5 the husks of corn grains having a fiber content of more than 80%. The mixture is spread, dried, crushed and optionally sieved. US patent no. 5,81 7,330 describes jellied and translucent emulsion, characterized in that it consists essentially of about 75 (o 85 parts by weight of liquid paraffin oil and 25 to 15 parts by weight of a sweetened aqueous solution of lactulose containing a total of 54 to 66% by weight dry matter.

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Laxatives are among the most commonly used drugs or additives for treatment of constipation. Most are quite safe when used judiciously, intermittently when possible, and in the absence of contraindications. Bulking agents and nonabsorbable compounds such as lactulose can cause bloating. Osmotic laxatives containing poorly absorbable

15 ions such as magnesium or phosphate can cause metabolic disturbances, particularly in the presence of renal impairment. Polyethylene glycol solutions are emerging as an effective and safe mode of treatment for chronic constipation. Purgatives are drastic laxatives causing a cleansing or watery evacuation of the bowels, usually with a griping pain. 0

Triphala is an ayurvedic herbal formula composed of three fruits namely Harada (Hantaki), AmIa (Ainalaki) and Behada {Bibhitaki), and is an effective laxative which also supports the body's strength. The major components of Triphala are condensed tannins, catechins, along with gallic and ellagic acid which are the building blocks of 5 the tannins. Because of its high nutritional value, Triphala uniquely cleanses and detoxifies at the deepest organic levels without depleting the body's reserves. Triphala corrects constipation, cleanses and tonify the gastrointestinal tract; detoxifies the whole body and improves digestion and assimilation; reduces high blood pressure and hypertension and improves blood circulation; acts as anti-viral, anti-bacterial, powerful 0 anti-oxidant; and has anticancer and anti-allergy properties. Triphala is also helpful in liver disorders, acts as an expectorant and corrects diverticulitis. It is very effective in Irritable Bowel Syndrome (IBS) and Ulcerative Colitis. Triphala is a powerful eye rejuveπator for treatment of conjunctivitis, progressive myopia, the early stages of glaucoma and cataracts. H is highly anti-inflammatory, anti-viral and also stimulates bile-flow and peristalsis. Triphala is mild, non-habit forming, and a rejuvenative. Triphala (trifala) is so effective because its three herbs are potent healers. The herb Amalalci (Emblica officinalis or PhyUanthυs emblica) is one of ayurveda's 5 greatest rejuvenators and a strong natural anti-oxidant, which also helps to boost the immune system and balances 'PiUa '. The herb Haritaki (Terminal ia chebitla) the Tibetan "king of medicine" is a classic heart-brain-longevity tonic and balances " VcUo '. The herb Bibhitaki (Terminalia be/erica) is a powerful rejuvenative that reduces liver and heart disease; improves the voice, vision and promotes the growth of hair and

I O balances 'Kapha^". Triphala helps to feel pure, light and revitalized; removes toxins, accumulations, gas and distention; nourishes the nervous system, blood and muscle; increases digestion, assimilation and reduces fat; detoxifies almost every system in the body and regulates the metabolism. Recent studies have shown that triphala extract possess the ability to scavenge free radicals such as DPPH and superoxide primarily

15 due to the presence of phenolic compounds. Studies have also shown the strong inhibitory activity of triphala on PϊvTN-type MMPs involved in the extracellular matrix (ECM) degradation during periodontitis. The in vitro cytotoxic and apoptotic activity of Triphala had also been demonstrated, which may be due to the gallic acid - a major polyphenol observed in Triphala. However, no medicinal compositions had been 0 described in prior art comprising Triphala and an osmotic laxative for treatment of constipation and associated disorders.

Ajwain oil is an essential oil obtained from the dried fruits of Trachysperimmi amwi. The essential oil (2.5 to 5% in the dried fruits) is dominated by thymol (35 to 60%); 5 furthermore, α-pinene, p-cymene, limonene and γ-terpinene have been found. The oil of ajwain is an almost colorless to brownish liquid with characteristic odour and a sharp hot taste. Ajwain oil is highly effective as a remedy for gastrointestinal disorders such as for relieving flatulence, dyspepsia, colic, diarrhea, spasmodic disorders and indigestion. 0

Fibers are often used for the treatment of constipation. A fiber is the non-digested part of plant food and adds bulk to the stools by absorbing water. There are two types of Fiber namely soluble and insoluble. Soluble fiber dissolves in water and is found in oat bran, barley, peas, beans, and citrus fruits. Insoluble fibers arc found in wheat bran and some vegetables. Fiber increases the transit time of the colon and decrease the pressures within the colon. Fibers such as Psyllium have been reported to inhibit lactulose- induced colonic mass movements and to benefit patients with irritable bowel syndrome, 5 improving both constipation and diarrhea (Washinton N et al. The American journal of clinical nutrition, 1998, 67(2), 3 1 7-321 ). Psyllium is the common name used for several members of the plant genus Plantago whose seeds are used commercially for the production of mucilage. The genus Plantago contains over 200 species. P ovula and P psyllium are produced commercially in several European countries, the former Soviet

I O Union, Pakistan, and India. Plantugo seed known commercially as black, French or Spanish psyllium is obtained from P psyllium and P arenaria. Seed produced from P ovala is known in trading circles as white or blonde psyllium, Indian Plantago or lspaghula or Isabgol. Senna is the common name for many species in the genus Cassia, both in the subfamily Caesalpinioideae. The term '"Senna'^" is often used specifically for

1 5 the medicinal herb Cas sia anguslijoha. Senna contains hydro\yanthracene glycosides known as sennosides. These glycosides stimulate colon activity and thus have a laxative effect. Also, these glycosides increase fluid secretion from the colon, with the effect of softening the stool and increasing its bulk (Leng-Peschlow E. Dual; effect of orally administered sennosides on large intestinal transit and fluid absorption in the rat. 0 J P harm Pharmacol 1986; 38:606-10). Double-blind trials have confirmed the benefit of senna in treating constipation (Passmore AP, Davies KW, Flanagan PG, ct al; A comparison of Agiolax and Lactulose in elderly patients with chronic constipation. Pharmacol I 993;47(suppl l ):249-52 & Kinnunen O, Winblad 1, Koistincn P, Salokannel J; Safety and efficacy of a bulk laxative containing senna versus lactulose in 5 the treatment of chronic constipation in geriatric patients. Pharmacol 1993; 47(suppl l ):253-5). Constipation induced by drugs such as the anti-diarrheal medicine loperamide (Imodium®) has also been shown to be improved by senna in a clinical trial (Ewe K, Ueberschaer B, Press AG; Influence of senna, fibre, and fibre & senna on colonic transit in loperamide-induced constipation. Pharmacol 1993; 47(stιppl 1 ):242- 0 8).

Constipation is often associated with several disorders such as gas, bloating, cramps, acidity, nausea, irritation, abdominal discomfort and pain. Although several prior art literature is available for the treatment of constipation but still there exists an unmet need for compositions which would be effective in the overall management of constipation including the prophylaxis or amelioration or treatment of not only the constipation but also associated disorders thus providing a better relief to the user. The novel compositions of the present invention overcomes such limitations of prior art.

SUMMARY OF THE INVENTION

It is an objective of the present invention to provide novel compositions comprising at least one bowel evacuant as the active agent and a saccharide component, optionally with at least one component selected from a group comprising antacid, stool softener, antiflatulant, prokinetic, anti-emetic and tonifier, and optionally one or more excipient(s).

It is an objective of the present invention to provide novel compositions comprising at least one laxative and/or a purgative as the bowel evacuant and a saccharide component, optionally with at least one component selected from a group comprising antacid, stool softener, antiflatulant, prokinetic, anti-emetic and tonifier, and optionally one or more excipient(s).

It is an objective of the present invention to provide novel compositions comprising at least one laxative and/or a purgative as the bowel evacuant, a saccharide component and at least one tonifier, optionally with at least one component selected from a group comprising antacid, stool softener, antiflatulant, prokinetic and anti-emetic, and optionally one or more excipient(s).

It is an objective of the present invention to provide novel compositions comprising ispaghula as the bowel evacuant and lactulose as the saccharide component, triphala as the tonifier, optionally with at least one component selected from a group comprising docusate sodium as the stool softener, simethicone as the antiflatulant, antacid and prokinetic, and one or more excipients.

It is an objective of the present invention to provide novel compositions comprising ispaghula and triphala as bowel evaαiants and lactulose as the saccharide component, optionally with at least one component selected from a group comprising docusate sodium as the stool softener, simethicone as the antiflatulant, antacid and prokinetic, and one or more excipients.

It is an objective of the present invention to provide novel compositions comprising tπ^'phala as the as the bowel evacuant and lactulose as the saccharide component, optionally with at least one component selected from a group comprising peppermint, fennel, ajwain, mentlia extract and lactobacillus optionally with at least one antacid and/or an antiflatulant and/or a prokinetic, and one or more excipients,

It is another objective of the present invention to provide process for preparation of such compositions.

It is yet another objective of the present invention to provide method of using such compositions which comprises administering to a subject in need thereof an effective amount of the composition.

The novel compositions of the present invention can be manufactured for pharmaceutical use or can be used as a dietary supplement and are useful in the overall management of constipation including the prophylaxis and/or amelioration and/or treatment particularly of constipation and associated disorders.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel composition comprising at least one bowel evacuant as the active agent and a saccharide component, optionally with at least one component selected from a group comprising antacid, stool softener, antiflatulant, prokinetic, anti-emetic and tonifier, and optionally one or more excipient(s).

In an embodiment of the present invention is provided novel compositions comprising at least one laxative and/or a purgative as the bowel evacuant and a saccharide component, optionally with at least one component selected from a group comprising antacid, stool softener, antiflatulant and prokinetic agent, and one or more excipients. In an embodiment of the present invention is provided novel compositions comprising at least one laxative and/or a purgative as the bowel evacuant, a saccharide component and at least one tonifier, optionally with at least one component selected from a group comprising antacid, stool softener, antiflatulant and prokinetic, and one or more excipients.

Preferably the bowel evacuant is a laxative such as triphala or ispaghula or a purgative such as senna; the saccharide component is lactulose, the stool softener is docusate sodium, the antiflatulant is simethicone; the prokinetic/anti-nauseating/anti-emetic agent is domperidone or tegaserod.

In an embodiment of the present invention is provided a novel composition comprising ispaghula as the bowel evacuant, lactulose as the saccharide component, triphala as the tonifier and optionally with at least one component selected from a group comprising docusate sodium as the stool softener and/or simethicone as the anliflatulant optionally with at least one antacid and/or a prokinetic, and one or more excipients.

In an embodiment of the present invention is provided a novel composition comprising ispaghula and triphala as bowel evacuants and lactulose as the saccharide component. optionally docusate sodium as the stool softener and/or simethicone as the antiflatulant optional ly with at least one antacid and/or a prokinetic, and one or more excipients. In a preferred embodiment, the composition of the present invention comprises ispaghula as the bowel evacuant, lactulose as the saccharide component, and triphala as the tonifier, optionally with one or more excipients.

In another embodiment, the composition of the present invention comprises triphala as the as the bowel evacuant and lactulose as the saccharide component, optional ly with at least one component selected from a group comprising peppermint, fennel, ajwain, inentha extract and lactobacillus optionally with at least one antacid and/or an antiflatulant and/or a prokinetic, and one or more excipients.

In an embodiment of the present invention, the bowel evacuant is selected from but not limited to a group comprising triphala; bulk laxatives such as ispaghula powder, methylcellulose (Citrucel), polycarbophil, malt soup extract, ethulose, sterculia, linseed, triticum or mixtures thereof; osmotic laxatives such as magnesium carbonate, magnesium oxide, magnesium peroxide, magnesium sulfate, mineral salts in combination, sodium sulfate, pentaerithrityl, macrogol, glycerol, sodium phosphate, magnesium citrate, sodium tartrate, or mixtures thereof; stool softeners such as docusate, poloxamer 188, dioctyl sodium sulfosuccinate, or mixtures thereof; lubricant/emollient such as mineral oil; hydrating agents such as dibasic sodium phosphate, magnesium citrate, magnesium hydroxide (Milk of Magnesia), magnesium sulphate, monobasic sodium phosphate, sodium biphosphate, or mixtures thereof; carbon dioxide releasing laxatives such as potassium bitartrate, sodium bicarbonate, or mixtures thereof; and the like used either alone or in combination thereof.

In a prefered embodiment, the bowel evacuant of the present invention is lspaghula or Triphala either used as an extract or in the powder form. The extract can be aqueous or non-aqueous. The solvents used in the non-aqueous extraction process is selected from but not limited to a group comprising alcohols such as methanol, ethanol, butanoL isopropyl alcohol or the like; acetone; glycerol; ethylacetate and alkylene glycols such as methylene glycol, ethylene glycol, propylene glycol or the like used either alone or in combination thereof. A hydro-alcoholic extract is prefered. The general procedure for the preparation of the Triphala extract is as follows: Equal parts of dried Amalaki (Emblica officinalis or Phy/lanlhiis embhea), Haritaki ( Terminalia chebula) and Bibhitaki {Terminalia be/erica) arc taken and mixed together followed by pulverization. The powder thus obtained (hereinafter referred to as 'Triphala powder^") is then extracted with a suitable solvent (aqueous, non-aqueous or hydro-alcoholic) preferably by applying heat. The extraction is preferably done 3-5 times under heat and reflux conditions to ensure proper extraction. Then the solvent is removed from the liquid extract to obtain the dry extract. The dry extract (referred to hereinafter as 'Triphala extract') thus obtained is preferably sifted through a suitable sieve to break any lumps or agglomerates. The general procedure for the preparation of the psyllium seed husks extract is as follows: Milled psyllium seed husks were stirred with potassium hydroxide containing sodium borohydride in a nitrogen atmosphere. The mixture was centπ^'fuged. The supernatant was decanted from an insoluble fraction that had settled out in the centrifuge bottle. The insoluble fraction was stirred with fresh potassium hydroxide-sodium borohydride solution and re-centrifuged. The supernatants from both centrifugations were combined. The pH of the combined supernatants was adjusted to 4.5 with glacial acetic acid, with stirring, at ambient temperature, then again centrifuged. The supernatant was decanted from a gel mass that had settled out in the 5 centrifuge bottle. The gel was washed gently with water to remove adhering supernatant solution and this wash water was added to the supernatant. The gel fraction was desiccated by treatment with 95% ethanol and finally washed with diethyl ether and dried. Prior to desiccating, in some instances the fraction was further purified by repeating the alkaline solubilization and acidification steps described above. The gel I O was re-suspended in potassium hydroxide, acidified to pH 4.5 and centrifuged to recover the gel.

In another embodiment of the present invention, the tonifier used in the composition is triphala. In further embodiment of the present invention, the bowel evacuant comprises 5 a mixture of Triphala and lspaghula. In the present invention, the Triphala particularly acts as a tonifier and deloxifier especially for the gastro-intestinal tract (GIT). Such compositions are employed for prophylaxis, amelioration or therapeutic treatment of constipation and other associated disorders and also serve as an effective remedy particularly for extended periods of time thus leading to considerable patient 0 compliance.

In another embodiment, the saccharide component is selected from but not limited to a group comprising lactulose, lactitol, sorbitol, mannitol, maltodextrin, dextran. sucrose, maltitol, dextrose and the like or mixtures thereof. 5

The purgatives useful in the present invention include but not limited to a group comprising casanthranol, cascara, aloe, castor oil, dehydrocholate, phenolphthalein, senna, sennosides, sodium picosulfate, dantron, bisoxatin or the like used either alone or in combination thereof. The dried ripe fruits, pods or leaves of Senna (preferably 0 Cassia angustifolia) as powder, concentrated infusion or liquid extract can be used in the present invention.

Particularly preferred bulk laxatives for use in the present invention are fibers. Two types of fibers namely soluble and insoluble can be used in the composition of the present invention. Soluble fibers are viscous, gel-forming fibers which absorb water and makes stools softer and easier to pass. Further, soluble fibers are the edible parts of plants or similar carbohydrates resistant to digestion and absorption in the human small intestine with complete or partial fermentation in the large intestine. Fermentation of the undigested soluble fibers occurs by the action of colonic bacteria, producing gases and short-chain fatty acids such as butyric, acetic, propionic, and valeric acids. Soluble fibers found in psyllium seed husk (about 66% soluble fibers); vegetable gums from legumes (guar gum, locust bean gum) and gummy exudates (gum acacia and tragacanth); seed mucilages from oats, rye and barley; mucilages from certain vegetables and roots such as broccoli, carrots, lady fingers, yam; pectin from fruits and vegetables are particularly used. Insoluble fibers are indigestible cellulosed and ligπified vegetable fibers found in cereal brans and fruit skins, which absorb water but do not dissolve in it. The insoluble fibers are also not fermented in the intestine. Insoluble fibers useful in the present invention are found in fruits, vegetables, whole grain breads, and cereals. Wheat bran contains mostly insoluble fiber, while oat bran contains about 7% soluble fiber. Synthetic fibers may also be useful in the present invention. Several synthetic water soluble or water absorbing fibers have been prepared by modification of cellulose and other natural fibers such as methyl cellulose, carboλymelhyl cellulose, polycarbophil and the like.

The novel composition of the present invention can be manufactured for pharmaceutical use or can be used as a dietary supplement. The composition of the present invention particularly upon daily use help in restoring normal bowel functions, and also tonifies and detoxifies the GlT.

In a further embodiment of the present invention, a blend of Lactobacillus cultures and/or other useful microorganisms with or without an amino acid such as L-lysine which colonize the intestine can also be used as an additional component. These cultures continually produce enzymes which support the digestive system and normalize the intestine, which aids normal digestion. It also provides relief for cramps, bloating, diarrhea, constipation and urgency. Such probiotics are preferably selected from but not limited to different Lactobacillus species used either alone or in combination such as Lactobacillus reiiieri and Lactobacillus paracasei.

Antacids useful in the present invention are selected from but not limited to a group comprising alkaline earth metal oxides, peroxides, hydroxides, and the like or mixtures 5 thereof. Aπti-gas/antiflatulant agents useful in the present invention is selected from but not limited to a group comprising simethicone, dimethicone, bisacodyl, alpha- galactosidase enzyme, activated charcoal and the like or mixtures thereof. These agents particularly aid in the reduction of acid and gas/ flatulence and the accompanying lower abdominal pain.

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Prokinetic agents useful in the compositions of the present invention primarily to improve the motility of the gastrointestinal tract are selected from but not limited to a group comprising 5HT4 agonist and 5HT3 antagonist such as cisapride, itopride, mosapride, domperidone. metoclopramide, tegaserod and the like or mixtures thereof.

15 Natural prokinetics such as Dai-kenchii-to can also be used. Smooth muscle relaxants such as mebeverine, peppermint oil and ajwain oil that have direct relaxant properties on gut smooth muscle are also useful. Antispasmodic agents such as dicyclomine and hyoscyamine are also useful. Anticholinergic agents that can be used in the present compositions as additional components act by decreasing the abnormal sensitivity of 0 cholinergic (muscarinic M 2) receptors in gut smooth muscle leading to significant improvement in abdominal pain and rectal urgency. Other categories of active agents suitable for the treatment of disorders associated with constipation can also be used in the composition of the present invention. The stool softener useful in the compositions of the present invention is selected from but not limited to a group comprising docusate 5 sodium, soluble fibers and the like or mixtures thereof. Such agents are employed to keep stool soft for easy natural passage and avoid painful anorectal conditions.

Additionally other ingredients such as carminatives, ginger, turmeric, chamomile, caraway, fennel, mentha extract, or any other natural or semi-synthetic or synthetic 0 ingredient useful for the management of constipation or associated disorders can be used in the present invention to relax and calm the stomach and promote healthy digestion, preferably incorporated into the composition as oils. The novel compositions of the present invention also assist in relief and discomfort of gas, acid indigestion, sour stomach, upset stomach or cramps associated with constipation. Various enzymes either

- 1 7 - alone or in combination that can be used in the present invention include but not limited to lactase that helps in digesting the lactose, or milk sugar, found in dairy products; alpha-galactosidase that helps in digesting the complex sugars found in beans and other legumes and in cruciferous vegetables; protease that helps to break down the peptide bonds in protein foods; amylase that helps to digest the starchy carbohydrates in foods and lipase which helps to digest the fats in food. Sweeteners such as aspartame, acesulfame, saccharine, cyclamate, glycyrrhizin, steviosides, talin, dihydrochalcone compounds and mixtures thereof can also be used in the present invention, preferably in a quantity from about 0.001 % to about 3% by weight of the composition.

The one or more excipient(s) that can be used for preparation of such compositions are selected from but not limited to diluents, disintegrants, binders, fillers, bulking agents, anti-adherants, anti-oxidants, buffering agents, colorants, flavoring agents, coating agents, plasticizers, organic solvents, stabilizers, preservatives, lubricants, glidaπts, chelating agents, release modifiers and the like known to the art used either alone or in combination thereof. In an embodiment, the fillers used in the present invention is selected from but not limited to a group comprising lactose, mannitol, sorbitol, starch, microcrystalline cellulose, xylitol, fructose, sucrose, dextrose, dicalcium phosphate, calcium sulphate, maltodextrin; polyethylene glycol such as PEG 100, PEG 2000, and PEG 6000; polyvinylpyrrolidone; sodium chloride; sodium citrate; citric acid; water soluble celluloses such as low viscosity hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose and the like or mixtures thereof. The disintegranls used in the present invention include but not limited to starch or its derivatives, prege latinized starch, croscarmellose sodium, sodium starch glycollatc, and the like used either alone or in combination thereof. The lubricants used in the present invention include but not limited to talc, magnesium stearate, calcium slearate, stearic acid, hydrogenated vegetable oil and the like used either alone or in combination thereof. The release modifiers used in the present invention is selected from but not limited to a group comprising methacrylic acid copolymers such as Eudragit®, cellulosic polymer such as alkyl celluloses or hydroxyalkyl celluloses, gums, hydrophilic polysaccharides such as alginates, chitosan, scleroglucan or semi-synthetic polysaccharides; lipid components such as hydrogenated vegetable oi ls, waxes, glyceryl behenate and the like, or mixtures thereof. In an embodiment, the compositions of the present invention arc in the form of immediate release or controlled release or a combination of immediate release and controlled release particularly intended for delivery of the active agent(s) for an extended time period. The dosage form may be in the form of tablets, minitablets, 5 capsules, pellets, granules, patches, powders, sachets or liquids or other dosage forms suitable for preferably oral administration, or enemas or suppositories. In a preferred embodiment, the composition of the present invention is in the form of granules ,or powder filled into sachets or capsules, or granules or powder compressed into tablets that may be optionally filled into capsules.

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In another embodiment, the composition of the present invention is highly effective in the management of constipation including prophylaxis and/or amelioration and/or treatment of constipation and associated disorders such as gas, bloating, cramps, acidity, irritation, abdominal pain and discomfort thus providing a better relief to the

15 user. In a still further embodiment, the composition of the present invention is useful in the treatment and/or management of diseases or disorders of the bowel primarily associated with constipation, diarrhea or indigestion.

The present invention also provides process for preparation of such compositions. In an 0 embodiment, the process for preparation comprises mixing the active agent(s) and saccharide component optionally with at least one component selected from a group comprising antacid, stool softener, antiflatulant, prokinetic, anti-emetic and tonifier, and one or more excipient(s) and formulating into a suitable dosage form.

5 In yet 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 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, 0 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 compositions of the present invention are also useful for the treatment/management of Irritable Bowel Syndrome (IBS) predominantly associated with constipation.

The examples given below serve to illustrate embodiments of the present invention. However they do not intend to limit the scope of the present invention in any manner whatsoever.

EXAMPLES Example-1 S. No. Ingredient Quantity (per serving)

1 . lspaghula husk powder 3.5O g

2. Lactulose powder 1 0.00 g

3. Tiϊphala powder 1 .00 g

4. Methyl paraben sodium 30, .00 mg 5. Propyl paraben sodium 3. .00 mg

6. Sodium saccharin 20, .00 mg

7. Purified water q.s. (lost in processing) Procedure: i) lspaghula husk powder, Lactulose powder and Triphala powder were sifted through # 40 mesh sieve and mixed well. ii) Methyl paraben sodium, Propyl paraben sodium and Sodium saccharin were dissolved in Purified water. iii) The material of step (i) was granulated with the solution of step (ii). iv) Granules of step (iii) were dried and sifted through # 30 mesh sieve and delivered in the form of sachets.

ExamρIe-2

5. No. Ingredient Quantity (mg/tablet)

I . Triphala extract 325.0 2. Lactulose 1 000.0

3. Polyvinylpyrrol idone 50.0

4. Dried Starch powder 50.0

5. Magnesium stearate 10.0 Procedure: i) Triphala extract and Lactulose were sifted through # 30 mesh sieve and mixed, ii) Polyvinylpyrrol idone and Dried Starch powder were sifted through //40 mesh sieve. iii) The material of step (i) was mixed the material of step (i i). iv) Magnesium stearate was sifted through #60 mesh sieve and added to the material of step (i i i) fol lowed by m ixing, v) The material of step (iv) was compressed into tablets.

Example-3 S. No. Ingredient Quantity (per serving)

1 . Triphala extract 325.0 mg

2. Lactitol 1 0.O g

3. Aj wain oil 50.0 mg

4. Purified water q.s. (lost in processing) 5. Sodium saccharin 0.0 1 g

Procedure: i) Triphala extract and Lactitol were sifted through # 30 mesh sieve and mixed, ii) Aj wain oi l was added to the material of step (i) and m ixed, iii) Sodium saccharin was d issolved in Puri fied water. iv) The material of step (i i) was granulated using the material of step (ii i) to obtain the granules which were then dried, v) The material of step (iv) was passed through #30 mesh sieve to yield the product.

Example-4

5. No. Ingredient Quantity (per serving)

1 . Triphala extract 0.65 g

2. Maltitol 10.00 g 3. Alpha-galactosidase enzyme 380 GaIU

4. Purified water q.s. (lost in processing)

5. Sodium saccharin 0.0 1 g Procedure:

5 i) Triphala extract, Alpha-galactosidase enzyme and a part of Maltitol were m ixed, ii) Remaining part of Maltitoi and Sodium saccharin were dissolved in Purified water. iii) The material of step (i) was granulated using the material of step (ii) to obtain I O the granules which were then dried. iv) The material of step (iii) was passed through #30 mesh sieve to yield the product.

Example-5 1 5 S. No. Ingredient Quantity (per serving)

1 . Ispaghiila powder 1 .5O g

2. Triphala powder 1 .20 g

3. Dextrose 8.00 g

4. Purified water q.s. (lost in processing) 0 5. Sodium saccharin 0.01 g

Procedure: i) Ispaghiila powder, Triphala powder and a part of Dextrose were mixed, ii) Sodium saccharin was dissolved in Purified water. ii i) The material of step (i) was granulated using the material of step (ii) to obtain 5 the granules which were then dried. iv) The material of step (i i i) was passed through #30 mesh sieve to yield the desired granules which is then provided in a suitable package,

Example-6 0 S. No. Ingredient Quantity (per serving)

1. Triphala extract 0.65 g

2. Lactulose 15.00 g

3. Peppermint oil 0.05 ml 4. Fennel oi l ^' 0.03 m l

5. Purified water q.s. (lost in processing)

6. Glycirrhizin 0.01 g Procedure:

5 i) Triphala extract and a part of Lactulose were m ixed, ii) Peppermint oil and Fennel oil were dissolved in ethanol. iii) Remaining pail of Lactulose and Glycirrhizin were dissolved in Puri fied water, iv) The material of step (ii) was added to material of step (ii i) with continuous stirring. I O v) The material of step (i) was granulated using the material of step (iv) to obtain granules which were then dried. vi) The material of step (iii) was passed through #30 mesh sieve to yield the product.

5 Example-7

S. No. Ingredient Quantity (per serving)

1 . Triphala powder 2.O g

2. Maltitol 12.O g

3. Lactobacillus 1 0⁶ CFU 0 4. Ginger oil 2.0 m l

5. Sodium saccharin 0.008 g

Procedure: i) Triphala powder and a part of Maltitol were m ixed together, ii) Remaining part of Maltitol, Sodium saccharin, Lactobacillus and Ginger oil 5 were mixed together. ii i) The material of step (i) and the material of step (ii) were then m ixed thoroughly, iv) The material of step (i ii) was passed through #30 mesh sieve to yield the powder.

0 Example-8

S. No. Ingredient Quantity (mg/tablet)

1. Triphala extract 325.0

2. Polycarbophil 80.0 3. Sorbitol 400.0

4. Docusate sodium 50.0

5. Citric acid 1 .0

6. Purified water q.s. (lost in processing) 7. Aspartame 1 .0

8. Magnesium stearate 9.0 Procedure: i) Triphala extract, Polycarboph il and Sorbitol were mixed, ii) Docusate sodium and Citric acid were dissolved in Purified water. iii) The material of step (i) was granulated using the material of step (ii ) to obtain the granules which were then dried, iv) The material of step (i i i) was passed through #30 mesh sieve and m ixed with

Magnesium stearate sifted through #40 mesh sieve, v) The materia) of step (iv) were compressed into tablets.

Example-9

S. No. Ingredient Quantity (mg/tablet)

1 . Triphala extract 325.0

2. Mannitol 220.0 3. Simethicone 125.0

4. Calcium phosphate tribasic 40.0

5. Docusate sodium 50.0

6. Citric acid 1 .0

7. Purified water q.s. (lost in processing) 8. Aspartame 1 .0

9. Col loidal si l icon dioxide 7.0 Procedure: i) Triphala extract, Mannitol, Simethicone and Calcium phosphate tribasic were m ixed, ii) Docusate sodium, Citric acid and Aspartame were dissolved in Puri fied water, iii) The material of step (i) was granulated using the material of step (ii) to obtain the granules which were then dried. iv) The material of step (iii) was passed through #30 mesh sieve and mixed with

Colloidal sil icon dioxide sieved through #40 mesh sieve, v) The granules were compressed into tablets.

Example-10

S. No. Ingredient Quantity (g/100 ml)

1. Tπphala extract 13.00

2. Bisacodyl 0.01

3. Magnesium hydroxide 1 .20 4. Mannitol 6.05

5. Sodium carboxymethyl cellulose 1 .20

6. Methyl paraben 0.75

7. Propyl paraben 0.1 5

8. Flavoring agent 0.03 9. Acesiilfame potassium 0.05

10. Ethanol q.s. (lost in processing)

1 1 . Purified water q.s. to 100 ml Procedure: i) Triphala extract, Bisacodyl, Magnesium hydroxide and Mannitol were mixed. ii) Propyl paraben and the Flavoring agent were dispersed in Elhanol with stirring. iii) Sodium carboxymethyl cellulose, Methyl paraben and Acesulfame potassium were dispersed in Purified water. iv) The material of step (ii) was added to the material of step (iii) with stirring. v) The material of step (i) was added to the material of step (iv) with continuous stirring to obtain a homogeneous dispersion.

Eχample-11

S. No. Ingredient Quantity (mg/tablet)

1. Triphala extract 325.0 2. Senna powder 300.0

3. Maltodextrin 340.0

4. Sodium cyclamate 1 1 .5

5. Sodium bicarbonate 68.5 6. Tartaric acid 110.0

7. Flavoring agent 0.025

8. Ethanol q.s. (lost in processing)

9. Demineralized water q.s. (lost in processing) Procedure: i) Triphala extract, Senna powder, Maltodextrin and Sodium cyclamate were mixed together and sieved, ii) The mixture of step (i) was kneaded with a mixture of Ethanol and

Demineralized water, granulated and dried. iii) Sodium bicarbonate, Tartaric acid, and the Flavoring agent were mixed and sieved to give a mixture, iv) The mixture obtained in step (ii) and (iii) are mixed together and compressed into effervescent tablets.

Example-12

S. No. Ingredient Quantity (g/sachet)

1. Triphala powder 2.50

2. Lactulose 11.00

3. Calcium hydroxide 0.10 4. Sodium saccharin . 0.01

5. Peppermint oil 0.06 ml

6. Orange oil 0.04 ml Procedure: i) Triphala powder, Lactulose and Calcium hydroxide were mixed. ii) The powder of step (i) was screened on a #80 mesh sieve, and to it, were added

Sodium saccharin, Peppermint oil and Orange oil, and mixed, iii) The mixture was filled into sachets.

Example-13 S. No. Ingredient Quantity (per serving)

1. Triphala extract 0.65 g

2. Senna 1.0 g

3. Dextran 2.Og

4. Talcum 0.5 g

-2) - 5. Gum acacia 0.1 g

6. Ethanol q.s. (lost in processing)

7. Purified water q.s. (lost in processing)

8. Peppermint oil 0.04 m l

9. Sodium saccharin 0.02 _r

Procedure: i) Triphala extract, Senna and Dextran were sifted through #30 mesh sieve and m ixed together. ii) Gum acacia and Sodium saccharin was dispersed in Puri fied water by stirring. i i i) Pepperm int oil was dissolved in ethanol and mixed with the material of step (ii). iv) The material of step (i) was granulated by using the material of step (iii) to obtain granules. v) The granules were dried using fluidized bed dryer. vi) The dried granules were then mixed with Talcum thus yielding the final product.

Example-14

S. No. Ingredient Quantity

I . Flour (#30 mesh passed) 100.0 g

2. Ispaghula husk (#30 mesh passed) 1 00.0 g

3. Triphala extract 32.5 g

4. Lactulose l iquid 200.0 m l

5. Shortening (fat) 120.O g

6. Cocoa powder 1 0.0 g

7. Baking powder 2.O g

8. Liquid glucose 5.0 g

9. Milk powder 5.0 g

10 Vanilla essence 2.0 m l

] ] Almond essence I drop

Pr ocedure: i) Shortening (fat) and Lactulose were tilled together very lightly until a fluffy consistency was obtained. ϋ) Liquid glucose was added to step (i) and mixed. iii) Flour, lspaghula husk and Triphala extract were sifted through a #30 mesh sieve and the fraction passing through the sieve was collected, iv) Cocoa powder, Baking powder. Milk powder, Vanilla essence and Almond essence were mixed with the material of steps (ii) & (iii). v) The mixture of step (iv) was made into smooth & soft dough, rolled into required thickness and cut into desired size and baked at optimum temperature to obtain biscuits.

Example-15 S. No. Ingredient Quantity (g)

1 . lspaghula powder 0.120

2. Maltodextrin 1 .669

3. Domperidone 0.01

4. Sodium cyclamate 0.1 15 5. Sodium bicarbonate 0.7

6. Tartaric acid 1 .12

7. Flavoring agent 0.025

8. Ethanol q.s. (lost in processing)

9. Demineralized water q.s. (lost in processing) Procedure: i) lspaghula powder, Maltodextrin, Domperidone and Sodium cyclamate were mixed together and sieved, ii) The mixture of step (i) is kneaded with a mixture of Ethanol and Demineralized water, granulated and dried. iii) Sodium bicarbonate, Tartaric acid, and the Flavoring agent are sieved and mixed well, iv) The mixture obtained in step (ii) and (iii) are mixed together and compressed into effervescent tablets.

Example-16

5. No. Ingredient Quantity (g)

1. " lspaghula husk 3.50

2. Lactulose 10.00 3. Purified water q.s. (lost in processing)

4. Sodium saccharin 0.0 1 Total 1 3.5 1

Procedure: i) Ispaghula husk and a part of Lactulose were mixed. ii) Remaining part of Lactulose and Sodium saccharin were dissolved in Puri fied water, iii) The material of step (i) was granulated using the material of step (ii) to obtain the granules which were then dried. iv) The material of step (iii) was passed through #30 mesh sieve to yield granules.

Example-17

5. No. Ingredient Quantity

I . Lactulose powder 21 5.O g 2. Triphala extract 32.5 g

3. Flour 200.0 g

4. Shortening (fat) 1 10.0 g

5. Salt 1 .0 g

6. Milk 60 m l 7. Milk powder ! 0.O g

8. Cocoa powder 10.0 g

9. Chocolate Chips 100.O g

10. Vanilla essence 3 m l

I 1 . Almond essence I drop 12. Baking powder 4.O g

Procedure: i) Shortening (fat) is tilled lightly until a fluffy consistency is obtained, ii) Add M ilk to step (i) & stirred continuously to give a creamy consistency, iii) Add Vanilla & Almond essence to step (i i) and m ix. iv) Mix Triphala extract, Lactu lose powder, Flour, Salt, Milk powder. Cocoa powder, Baking powder & Chocolate Chips uniform ly & add to step (i ii) and make smooth & soft dough. v) Roll the dough to required thickness & cut to desired size and bake at optimum temperature to obtain biscuits.

Exaniple-I8

S. No. Ingredient Quantity

]. Flour 100 g

2. Husk (mesh no.30) lOOg

3. Lactulose liquid 200 ml

4. Shortening (fat) 12Og

5. Cocoa powder 1Og

6. Baking powder 2g

7. Liquid glucose 5g

8. Milk powder 5g

9. Vanilla essence 2 m! 1 100 A Allmmoonndd eesssseennccee 1 drop

Proced luurree:: i) Shortening (fat) and Lactulose are tilled together very lightly until a fluffy consistency is obtained. ii) Add Liquid glucose to step (i) & mix again. iii) Sift Flour and Husk through a sieve of mesh no.30. iv) Mix Cocoa powder, Baking powder, Milk powder. Vanilla essence and Almond essence, and mix with step (ii) & (iii). v) The mixture of step (iv) is made into smooth & soft dough, rolled into required thickness and cut into desired size and baked at optimum temperature.

Claims

We claim:

1 . A novel composition comprising at least one bowel evacuant as the active agent and a saccharide component, optionally with at least one component selected from a group comprising antacid, stool softener, antiflatulant, prokinetic, anti-emetic

5 and toπifier, and optionally one or more excipient(s).

2. A composition according to claim I , wherein the bowel evacuant is a laxative or a purgative or mixtures thereof.

I O 3. A composition according to claim 2, wherein the laxative is selected from a group comprising bulk laxatives such as ispaghula powder, inethylcellulose, polycarbophil, malt soup extract, ethulose, sterculia, linseed, triticum, or mixtures thereof; osmotic laxatives such as magnesium carbonate, magnesium oxide, magnesium peroxide, magnesium sulfate, mineral salts in combination, sodium 5 sulfate, pentaerithrityl, macrogol, glycerol, sodium phosphate, magnesium citrate, sodium tartrate, or mixtures thereof; carbon dioxide releasing laxatives such as potassium bitartrate, sodium bicarbonate, or mixtures thereof.

4. A composition according to claim 2, wherein the purgative is selected from a 0 group comprising casanthranol, cascara, aloe, castor oil, dehydrocholaie. phenolphthalein, senna, sennosides, sodium picosulfate, daπtron, bisoxatin, used either alone or in combination thereof.

5. A composition according to claim 1 , wherein the saccharide component is selected 5 from a group comprising lactulose, lactitol, sorbitol, mannitol, maltodextrin, dextran, sucrose, maltitol, dextrose, or mixtures thereof.

6. A composition according to claim I , wherein the composition comprises ispaghula as the bowel evacuant, lactulose as the saccharide component, lriphala as the 0 tonifier, optionally with one or more excipients.

7. A composition according to claim I , wherein the composition comprises ispaghula and triphala as bowel evacuants and lactulose as the saccharide component. optionally with at least one component selected from a group comprising stool softener, antiflatulant, antacid, anti-emetic and prokinetic, and one or more excipients.

5 8. A composition according to claim I , which comprises triphala as the bowel evaciiant and lactulose as the saccharide component, optionally with at least one component selected from a group comprising peppermint, fennel, ajvvain, mentha extract and lactobacillus optionally with at least one antacid and/or an antiflatulant and/or a prokinetic, and one or more excipients. I O

9. A composition according to claim 1 , wherein the composition is in the form ol^" tablets, minitablets, capsules, pellets, granules, patches, powders, sachets or liquids.

15 10. A composition according to any of the preceding claims which is useful as a pharmaceutical or a dietary supplement.

1 1. A composition according to any of the preceding claims which is highly effective in the management of constipation including prophylaxis and/or amelioration 0 and/or treatment of constipation and associated disorders such as gas, bloating. cramps, acidity, irritation, abdominal pain and discomfort thus providing a better relief to the user.

12. A composition according to any of the preceding claims 1 - 1 0 which is useful as a 5 dietary supplement to normalize bowel functions and provide relief from particularly constipation and other associated disorders.

13. A composition according to any of the preceding claims 1 - 10 which is useful in the treatment and/or management of diseases or disorders of the bowel primarily 0 associated with constipation, diarrhea or indigestion.

14. A process of preparation of the composition according to claim I , which comprises mixing the active agent(s) and saccharide component optionally with at least one component selected from a group comprising antacid, stool softener, antiflatulant, prokinetic, anti-emetic and tonifier, and one or more excipient(s) and formulating into a suitable dosage form.

15, A method of using the composition according to claim I , which comprises administering to a subject in need thereof an effective amount of the composition.

16. A method according to claim 15, wherein the composition according to claim I 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.

1 7. A method according to claim 15, wherein the composition according to claim I is useful as a dietary supplement to normalize bowel functions and provide, relief from particularly constipation and other associated disorders.

18. A method according to claim 15, wherein the composition according to claim I is useful in the treatment and/or management of diseases or disorders of the bowel primarily associated with constipation, diarrhea or indigestion comprising administering to a subject in need thereof a composition according to claim I .

19. Use of a composition according to claim 1 for prophylaxis and/or amelioration and/or treatment of constipation and associated disorders such as gas, bloating, cramps, acidity, irritation, abdominal pain and discomfort.

20. The pharmaceutical compositions substantially as herein described and illustrated by the examples.

2 1 . The processes for the preparation of pharmaceutical compositions substantially as herein described and illustrated by the examples.