DESC:FIELD OF THE INVENTION:
The present invention relates to a synergistic composition for treating chronic inflammatory diseases in the gastrointestinal tract. Particularly, the invention relates to effective polysaccharide ester mediated glucocorticosteroid therapy for treating gastrointestinal inflammation. More particularly, the invention provides synergistic combination of propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl](n-1)-D-fructofuranosides and (11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione present in specific weight ratio along with pharmaceutically acceptable excipients. Further, the synergistic composition is useful in the treatment of gastrointestinal diseases.

BACKGROUND OF THE INVENTION:
Gastrointestinal inflammation is one of the most common types of inflammatory process which affects humans. Gastrointestinal inflammation is a complex biological response to injury as a result of different stimuli such as pathogens, damaged cells, toxins, or irritants. Symbiotic microbiome in digestive tract is considered to protect gut by removing harmful stimuli and to enhance healing process.
The gastrointestinal tract is essential for digestion, nutrient absorption, and waste elimination. It also plays a critical role in maintaining overall health through interactions with the immune system and the gut microbiota. Disorders of the GI tract, such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and gastrointestinal infections, can lead to significant morbidity and a decrease in the quality of life. Patients with IgA nephropathy have an increased risk of inflammatory bowel disease both before and after their nephropathy diagnosis.

It is observed that, nutritional elements, such as n-3 polyunsaturated fatty acids, antioxidants, probiotics, and prebiotics directly or indirectly modulate GI immunity. Diets high in fat change the populations of innate microbiome in digestive tract and alter signaling to the brain and satiety, leading to obesity and inflammation.
US7638507B2 discloses a pharmaceutical composition comprising: 5-aminosalicylic acid and N-acetylcysteine together disposed in a pharmaceutically- acceptable carrier suitable for rectal delivery to a colon of a subject.
US5863910A discloses an oral formulation for treating gastrointestinal inflammation comprising a suspension of an effective amount of corticosteroid.
US20200179485A1 discloses a method of preventing or reducing the risk of inflammation of the bowel by administering a composition containing beta-casein.
US8263582B2 discloses a method of treating an inflammatory bowel disease selected from the group consisting of ulcerative colitis, proctitis, sigmoiditis, pan-colitis and Crohn's disease, comprising administering to a patient at least two separate oral dosage forms of beclomethasone dipropionate or a pharmaceutically active salt thereof.
Commonly used glucocorticosteroids (GCs) are prednisone, methylprednisolone, and hydrocortisone. They can be used alone or in combination with mesalamine for the induction and maintenance of clinical remission in patients suffering from chronic IBD. Glucocorticosteroids are powerful medicines that fight inflammation and work with the immune system to treat wide range of health problems. Despite the efficacy of first-generation GCs, several serious side effects can be associated with their use, including osteoporosis, hyperglycemia, hypertension, mood disorders, gastric ulcer, and increased susceptibility to infections. This characteristic limit the long-term use of GCs.
Steroids like prednisone and prednisolone, aminosalicylates, hydrocortisone are commonly used for managing inflammation in conditions like IBD. These treatments aim to reduce inflammation and control symptoms but often come with significant side effects.
Steroids remain a critical tool in the management of inflammatory GI disorders, particularly for their rapid and potent anti-inflammatory effects. However, due to the potential for significant side effects, their use is typically limited to short-term management of flare-ups, with other treatments preferred for long-term maintenance.
Moreover, the corticosteroid effectiveness diminishes with prolonged use, and patients often require additional treatments to maintain remission and prevent relapses. Further after stopping corticosteroids, patients may experience a return of symptoms, as the underlying inflammatory process is not fully controlled.
In view of above the potential side effects associated with long-term steroid use, there is a strong emphasis on using steroid-sparing agents to reduce the reliance on corticosteroids. Combination therapy with other medications is often necessary to achieve and maintain full control of the disease, prevent relapses, and minimize side effects associated with long-term steroid use.
Functional oligosaccharides are carbohydrates with a low degree of polymerization and exhibit beneficial effects on human intestinal health [Molecules. 2022 Nov; 27(21): 7622]. The experiments and clinical studies indicate that functional oligosaccharides repair the damaged intestinal tract and maintain intestinal homeostasis by regulating intestinal barrier function, immune response, and intestinal microbial composition. Functional oligosaccharides treat intestinal diseases such as inflammatory bowel disease (IBD) and colorectal cancer (CRC) and have excellent prospects for therapeutic application. Hence there is a need to do research into the effects of functional oligosaccharides on intestinal health.

The use of probiotics (live beneficial bacteria) and prebiotics (non-digestible fibers that stimulate the growth of beneficial bacteria) has been explored to improve gut health and manage conditions like IBS and colitis. However, variability in efficacy and patient response has limited widespread adoption. Further the effectiveness of probiotics is often strain-specific and may not be consistent across different patient populations.
Various dietary strategies, including the low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet, short-chain carbohydrates (sugars), and fiber supplementation, are used to manage GI disorders [Compr Rev Food Sci Food Saf. 2022;21:1491–1516]. These approaches focus on modulating gut microbiota and reducing inflammation but require strict adherence and may not be effective for all patients. The strict diets can be difficult for patients to adhere to, and the benefits may be limited to specific subgroups of patients.

The gastrointestinal (GI) tract is colonized by a dense community of commensal microorganisms referred to as the gut microbiota. The gut microbiota contributes to the maintenance of host health. However, when healthy microbial structure is disturbed, it leads to a condition termed dysbiosis, Gut dysbiosis is a broad term that can be defined as the imbalance of gut microbiota associated with an unhealthy outcome. Particularly, dysbiosis is a state in which there is an imbalance of microorganisms on or within human bodies. The altered gut microbiota can trigger the development of various GI diseases including inflammatory bowel disease, colon cancer, celiac disease, and irritable bowel syndrome (IBS). Dysbiosis is characterized by a decrease in microbial diversity and increase in proinflammatory species. Dysbiosis is thought to trigger pro-inflammatory effects and immune dysregulation associated with various disease states, including non-alcoholic steatohepatitis (NASH). Communication between the gut microbiota and the brain is an important field of research. A vital bidirectional signaling system between the gastrointestinal tract and the brain helps maintain metabolic homeostasis and is regulated via neural (central and enteric nervous systems, CNS and ENS, respectively), immunological, and hormonal systems. Further it is observed that reduced gut level of SCFA and SCFA producing bacteria are linked to gastrointestinal inflammation development.
Therefore, it is needed to treat gut infections resulting from dysbiosis by reducing depleted diversity, inflammation, enhancing abundance of short chain fatty acids (SCFAs) producers. SCFAs, such as acetate, propionate, and butyrate are important metabolites in maintaining intestinal homeostasis. They have many effects on host physiology including acting as an energy source for colonocytes, regulating the gut barrier, and influencing inflammatory responses. SCFAs have been suggested as key mediators in microbiota-gut-brain interactions.
It is observed that emerging approaches are focused on combining traditional treatments with novel agents (e.g., prebiotics or short-chain fatty acids like propionate) to enhance efficacy and reduce side effects. Advances in targeted drug delivery systems aim to release medications directly at the site of inflammation within the GI tract, potentially reducing systemic exposure and side effects.
Understanding the role of gut microbiota in health and disease has led to the development of therapies aimed at modulating the microbiome to restore balance and promote gut health.
Therefore, there is need of a novel drug delivery system, or a unique dietary supplement that improves GI health more effectively or with fewer side effects. Moreover, there is required significant advancement in the field of gastrointestinal health for managing GI disorders.
In view of current unmet need for treatment of gut inflammation, the present invention provides an effective pharmaceutical composition for treatment of gastrointestinal inflammation, that improving gut bacterial diversity, reducing the intestinal inflammation and increasing the levels of small chain fatty acid in the gut thus maintaining intestinal homeostasis.

OBJECTIVE OF THE INVENTION:
The primary objective of the present invention is to provide an effective combination of corticosteroids and prebiotic fiber to address unmet needs in the treatment of gastrointestinal disorders.
One more objective of the present invention is to develop a novel pharmaceutical composition that combines a corticosteroid with potent anti-inflammatory properties, and a prebiotic fiber that promotes gut health and modulates the gut microbiota.
Another objective of the present invention is to enhance the therapeutic efficacy in gastrointestinal disorders by improving gut barrier function and reducing the risk of relapse.
Yet another objective of the present invention is to support long-term gut health, potentially reducing the frequency and severity of disease flares.
Another object of the present invention is to provide therapeutically effective synergistic composition for the treatment of gastrointestinal diseases and inflammation such as inflammatory bowel disease, ulcerative colitis, mild-to-moderate Crohn's disease, rheumatoid arthritis, inflammatory arthritis, psoriatic arthritis, liver cirrhosis and idiopathic urticaria.
SUMMARY OF THE INVENTION:
To meet the above objects, the inventors of the present invention carried out thorough experiments to establish significant effects of the active ingredients or saccharide or fatty acids or nutrients or glucocorticosteroid that ameliorate therapeutic efficacy in the treatment of gastrointestinal disorders.
In a particular aspect, the present invention relates to novel therapeutically active composition comprising polysaccharide ester mediated glucocorticosteroid therapy for treating gastrointestinal disorders.
In another aspect, the present invention provides a synergistic combination of propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl](n-1)-D-fructofuranosides and (11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione present in specific weight ratio along with pharmaceutically acceptable excipients.
In a further aspect, the present invention provides a synergistic pharmaceutical composition comprising combination of propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl](n-1)-D-fructofuranosides which is present in the range of 0.1-1000 mg, particularly 1- 800 mg and (11ß,16a)-16,17-[butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione which is present in the range of 0.1-1000 mg, particularly 1- 100 mg along with pharmaceutically acceptable excipients/carriers.
In another aspect, the present invention provides a synergistic composition which is useful in the treatment of gastrointestinal diseases such as Crohn's disease, ulcerative colitis, microscopic colitis, eosinophilic oesophagitis, IBD and IBS and IgA nephropathy (Berger's disease).

BRIEF DESCRIPTION OF THE FIGURES:
Figure 1 illustrates the effect of test substances on serum IL-6 levels in rats.
Figure 2 illustrates the effect of test substances on serum TNF-alpha levels in rats.

DETAILED DESCRIPTION OF THE INVENTION:
It is to be understood that all terminology used herein is for the purpose of describing particular embodiment only and is not intended to be limiting in any manner or scope. Unless defined otherwise, all technical and scientific expressions used herein have the same meaning as commonly understood by one of ordinary skill in the art to which embodiments of the invention pertains.
The salient features including embodiments and examples of the present invention are not to limit the scope of the subject matter.
In describing and claiming the embodiments of the present invention, the following terminology will be used in accordance with the definitions set out below which are known in the state of art.
The singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. Also, the term ‘composition’ does not limit the scope of the invention for multiple compositions that can be illustrated for best mode of the invention.
The term “pharmaceutically/nutraceutically acceptable salt,” as used herein, represents those salts which are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
Particularly the term “pharmaceutically acceptable salts” refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds, amino acid salt, sugar based salt, alkali or alkaline earth metal salts, as well as solvates, co-crystals, polymorphs and the like of the salts.
All modifications and substitutions that come within the meaning of the description and the range of their legal equivalents are to be embraced within their scope. A description using the transition “comprising” allows the inclusion of other elements to be within the scope of the invention.
The term "therapeutically effective amount " denotes an amount that reduces the risk, potential, possibility or occurrence of a disease or disorder, or provides advanced alleviation, mitigation, and/or reduction or restoration or modulation, regulation of at least one indicator/biomarker (e.g., blood or serum CRP level), and/or minimize at least one clinical symptom related to gastrointestinal disorder.
The term ‘subject in need thereof’ pertains to a subject preferably mammal, more preferably a human suffering or suspected with gastrointestinal diseases.
Gastrointestinal (GI) diseases primarily affect the digestive system, which includes organs like the stomach, intestines, liver, pancreas, and gallbladder.
In the context of the present invention, the term “treatment” refers to alleviate, mitigate, prophylaxis, attenuate, manage, regulate, modulate, control, minimize, lessen, decrease, downregulate, up regulate, moderate, inhibit, restore, suppress, limit, block, decrease, prevent, inhibit, stabilize, ameliorate, cure, heal gastrointestinal disorders observed in the patients.
Notably, the present composition is non-hazardous, non-toxic, and safe for human consumption without any severe adverse effects, therefore the present medicinal composition can also be used as preventive therapy/ adjuvant therapy/ add-on therapy/ combination/ adjunctive therapy in a subject in need thereof.
Certain compounds of the present invention exist in unsolvated forms as well as solvated forms, including hydrated forms. Further, some compounds of the present invention exist in multiple crystalline or amorphous forms (“polymorphs”). Compounds of the invention are formulated in geometric or, enantiomeric or stereoisomeric forms.
In general, all physical forms are of use in the methods contemplated by the present invention and are intended to be within the scope of the invention.
Compound or pharmaceutically acceptable salts includes, hydrates, polymorphs, solvates, enantiomers or racemates. Some of the crystalline forms of the compound exist as polymorphs and as such are intended to be included in the present disclosure. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are intended to be encompassed by some embodiments.
In one embodiment, the invention provides medicinal compositions present in effective amount along with pharmaceutically acceptable excipients.
As used herein, the term “pharmaceutically acceptable carriers, diluents or excipients” is purported to mean, without limitation, any adjuvant, carrier, excipient, sweetening agent, diluents, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, or encapsulating agent, encapsulating polymeric delivery systems or polyethyleneglycol matrix, which is acceptable for use in the subject, preferably humans. Excipients also include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, fragrances, glidants (flow enhancers), lubricants, preservatives, sorbents, suspending or dispersing agents, sweeteners, surfactant, anticaking agent, food additives, or waters of hydration, salts.
In a preferred embodiment, the present invention provides a synergistic medicinal composition for treating chronic inflammatory diseases in the gastrointestinal tract.
Particularly, the present invention relates to effective polysaccharide ester mediated glucocorticosteroid therapy for treating gastrointestinal disorders.
In another preferred embodiment, the present invention provides synergistic compositions comprising specific combination of propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl] (n-1)-D-fructofuranosides and (11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione present in specific weight ratio along with pharmaceutically acceptable excipients.
In another embodiment, the present invention provides a synergistic composition that prevents the onset of gut microbiota dysbiosis wherein polysaccharide ester moiety regulates gut bacterial populations and enhances propionate carrier to increase the levels of small chain fatty acid (SCFA) in intestine thus, maintaining intestinal homeostasis; concurrently glucocorticosteroid moiety works inside the intestines (bowels) to reduce inflammation.
In some embodiment the propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl](n-1)-D-fructofuranosides has ability to stimulate the growth of beneficial gut bacteria, such as Bifidobacteria and Lactobacilli. This can improve digestion, enhance immune function, and support overall gut health. It further increases fiber intake, which can help regulate bowel movements, lower cholesterol levels, and control blood sugar.
Further, the present synergistic composition is useful in the treatment of gastrointestinal diseases such as Crohn's disease, irritable bowel syndrome (IBS) ulcerative colitis, microscopic colitis, eosinophilic oesophagitis, gastroesophageal reflux disease (GERD), peptic ulcer disease, celiac disease, gallbladder disease, pancreatitis, hepatitis, diverticular disease, gastrointestinal Infections. Additionally, it is useful to control IgA nephropathy (Berger's disease), diabetic nephropathy and chronic kidney disease (CKD).
In yet another embodiment, the present invention provides an oral supplementation with SCFA propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl] (n-1)-D-fructofuranosides reduces intra-abdominal fat and prevents weight gain and that oral propionate intake enhances resting fat oxidation. SCFA fight inflammation by activating G-protein coupled receptor protein and inhibition of histone deacetylase enzyme, suppressing innate immune responses. It also promotes intestinal barrier integrity by regulating networks of cytokines.
Moreover, the propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl] (n-1)-D-fructofuranosides enhances the growth of indigenous lactobacilli and/or bifidobacteria by inducing colonic production of short chain fatty acids (SCFA's) and thus decreases mucosal lesion scores and diminished mucosal inflammation.
In some embodiment, the present composition shows complimentary therapeutic effect while (11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione is primarily used for its anti-inflammatory effects in treating active GI diseases, and propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl] (n-1)-D-fructo(11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione furanosides is used to support overall gut health, particularly in maintaining remission, improving gut microbiota composition, and preventing relapses.
Further, this moiety retains microbial populations and to support epithelial barrier function by their prebiotic effect which helps in the host defense against invasion and pathogens translocation (endogenous and/or exogenous) and in the inhibition of gastrointestinal diseases.
Additionally, the propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl](n-1)-D-fructofuranosides are mainly comprised of fructose units, typically with a terminal glucose. In the molecules D-fructofuranosyl ß-(1?2) linkages are the main glycosidic bonds (Lower case n refers to the number of fructose residues in the fructofuranosides chain). The chain length of fructofuranosides in plant could range from 2 to 170 fructose units.
In another embodiment, the present invention provides a synergistic medicinal composition wherein (11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione works inside the intestines (bowels) to reduce inflammation and symptoms of the disease. It further reduces levels of protein in the urine (proteinuria) in subjects who have a kidney disease called primary immunoglobulin A nephropathy (IgAN).
In another embodiment the invention provides a synergistic medicinal composition wherein (11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione directly reduces inflammation, while propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl] (n-1)-D-fructofuranosides indirectly supports anti-inflammatory effects by modulating gut microbiota and increasing the production of propionate. The combined effect may lead to a more significant reduction in inflammation than either agent alone.
In yet another embodiment, the propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl] (n-1)-D-fructofuranosides potentially help to mitigate some of the side effects associated with long-term corticosteroid use, such as dysbiosis (imbalance of gut microbiota). This combination may support overall gut health while effectively managing inflammation. Further the combination might allow for lower doses of (11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione, potentially reducing the risk of corticosteroid-related side effects.
In some embodiment, the present invention provides a synergistic medicinal composition that can significantly reduce proteinuria and stabilize renal function in IgAN patients. When paired with propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl] (n-1)-D-fructofuranosides, the overall reduction in systemic inflammation and improved gut health and enhances renal protective effects, potentially leading to better clinical outcomes.
The gut-kidney axis is an important concept in nephrology, where gut health influences kidney function. The present invention provides a synergistic combination of propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl] (n-1)-D-fructofuranosides and (11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione that helps to restore gut-kidney axis, providing a dual approach to managing IgAN by addressing both the immune dysregulation and the gut microbiome.
Moreover, the synergistic effect of propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl] (n-1)-D-fructofuranosides and (11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione in IgA nephropathy involves a multifaceted approach targeting inflammation, immune regulation, and gut health, which may collectively enhance renal function and mitigate disease progression.
In some embodiment, the present invention provides synergistic combination that provides targeted and controlled release of active pharmaceutical ingredients within the GI tract.
The present composition further supports and enhances the growth of beneficial gut microbiota through the prebiotic effects of polysaccharide ester. Also, it offers a biodegradable and biocompatible solution for therapeutic and nutritional applications.
In another embodiment, the present invention relates to a synergistic medicinal composition prepared in a manner well known in the pharmaceutical art and administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. The preferable route of administration includes but is not limited to sublingual, rectal, topical, parenteral, nasal, or oral.
In one of the embodiment, the present synergistic medicinal composition are administered to a subject in need thereof, in the form which is suitable for oral use, such as a tablet, capsule (in the form of delayed release, extended release, sustained release, enteric coated release); hard gelatin capsules, soft gelatin capsules in an oily vehicle, veg capsule, hard or soft cellulose capsule, granulate for sublingual use, effervescent or carbon tablets, aqueous or oily solution, suspension or emulsion, encapsulate, matrix, coat, beadlets, nanoparticles, caplet, granule, particulate, agglomerate, spansule, chewable tablet, lozenge, troche, solution, suspension, rapidly dissolving film, elixir, gel, tablets, pellets, granules, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, sprays or reconstituted dry powdered form with a liquid medium or syrup; for topical use including transmucosal and transdermal use, such as a cream, ointment, gel, aqueous or oil solution or suspension, salve, parch or plaster; for nasal use, such as a snuff nasal spray or nasal drops; for vaginal or rectal use, such as a suppository; for administration by inhalation, such as a finely divided powder or a liquid aerosol; for sub-lingual or buccal use, such as a tablet, capsule, film, spray.
In a further embodiment, the present composition is formulated in the form of age-appropriate pediatric oral dosage forms such as syrup, inhalation, spray minitablets, chewable formulations, orodispersible films and orodispersible tablets.
The magnitude of a prophylactic or therapeutic dose typically varies with the nature and severity of the condition to be treated and the route of administration. The dose, and perhaps the dose frequency, will also vary according to the age, body weight and response of the individual patient.
In some embodiments, the synergistic medicinal composition is formulated with an effective oral unit dose ranging from 1-800 mg.
In general, the total daily dose (in single or divided doses) ranges from about 1 mg per day to about 5000 mg per day, preferably about 1mg per day to about 1000 mg per day.
In some embodiments, the total daily dose can be administered in the range of about 1 mg to about 3000 mg per day and preferably about 1 mg to about 1000 mg per day.
In yet another embodiment the invention provides a synergistic combination of propionate ester of alpha-d-glucopyranosyl-[ß-d-fructofuranosyl] (n-1)-d-fructofuranosides and (11ß,16a)-16,17-[butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione present in specific ratio, wherein this combination is primarily explored for its potential in treating inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis.
The rationale is that (11ß,16a)-16,17-[butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione provides direct anti-inflammatory effects, while propionate ester of alpha-d-glucopyranosyl-[ß-d-fructofuranosyl] (n-1)-d-fructofuranosides supports gut health by modulating the microbiome and enhancing anti-inflammatory effects through short-chain fatty acid production.
An “effective amount of bioactive agent” is an amount sufficient to prevent, treat, reduce, and/or ameliorate the symptoms and/or underlying causes of gastrointestinal disorders.
In the context of the present invention, the terms “treatment” and the like refer to alleviate, slow the progression, prophylaxis, attenuation, or cure of existing renal diseases. The present synergistic composition is used for treating gastrointestinal diseases in a subject in need thereof, means either the administration of the remedy to prevent the onset or occurrence of gastrointestinal, renal, disorders.
In another preferred embodiment, the composition comprises synergistic combination of propionate ester of alpha-d-glucopyranosyl-[ß-d-fructofuranosyl] (n-1)-d-fructofuranosides and (11ß,16a)-16,17-[butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione or salts thereof, which are present in the weight ratio of 1: 0.001 to 1:0.1.
In yet another embodiment the present invention provides synergistic medicinal composition that downregulates the gastrointestinal inflammation by 3 to 4 folds over its individual constituents.
In yet another preferred embodiment, the present invention relates to synergistic medicinal composition comprising a combination of propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl] (n-1)-D-fructofuranosides which is present in the range of 1 to 800 mg and (11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione present in the range of 1 mg to 500 mg, particularly 1 mg to 100 mg along with pharmaceutically acceptable excipients / carriers.
As used herein, the term “therapeutically effective amount” is intended to mean the therapeutically effective dose of present bioactive compounds namely propionate ester of alpha-d-glucopyranosyl-[ß-d-fructofuranosyl](n-1)-d-fructofuranosides and (11ß,16a)-16,17-[butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione or salts thereof in combination to give significant therapeutic efficacy, which is otherwise not obtained by use of single ingredient of the composition.
The term “pharmaceutically acceptable salt” refers to a salt prepared from pharmaceutically acceptable non-toxic acids or bases, metal ions, minerals, chelates, complex, esters, oxide, amines which are well known in the art.
As used herein, the term “pharmaceutically acceptable carriers/vehicles / diluents or excipients” is intended to mean, without limitation, any adjuvants, carriers, excipients, sweetening agents, diluents, preservative, dye/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, suspending agents, complexing agents, stabilizers, isotonic agent, solvent, emulsifier, solubilizer, encapsulating agent, polymers, coating agent, wax, encapsulating polymeric delivery systems. Excipients may also include, antiadherents, antioxidants, binders, pH-modifier, solvents, coatings, compression aids, disintegrants, emollients, , fillers (diluents), film formers, fragrances, glidants (flow enhancers), lubricants, preservatives, sorbents, anticaking agent, food additives, or waters of hydration.
In some embodiment of the present invention, the diluents are selected from starches, hydrolyzed starches, and partially pregelatinized starches, anhydrous lactose, lactose monohydrate, and sugar alcohols such as sorbitol, xylitol and mannitol, cellulose powder, silicified microcrystalline cellulose, ammonium alginate, calcium carbonate, calcium lactate, dibasic calcium phosphate (anhydrous/ dibasic dehydrate/ tribasic), calcium silicate, calcium sulfate, cellulose acetate, corn starch, pregelatinized starch, dextrin, ß-cyclodextrin, dextrates, dextrose, erythritol, ethylcellulose, fructose, fumaric acid, glyceryl palmitostearate, magnesium carbonate, magnesium oxide, magnesium sulphate ,maltodextrin, maltose, medium-chain triglycerides, polydextrose, polymethacrylates, sodium alginate, sodium chloride, potassium, sterilizable maize, sucrose, sugar spheres, talc, trehalose, xylitol, vehicles like petrolatum, dimethyl sulfoxide and mineral oil or the like. The amount of diluent in the pharmaceutical composition/formulation of the present invention ranges from 0.1% to 35% by wt. of the composition/formulation.
In further embodiment, the binder is selected from disaccharides such as sucrose, lactose, polysaccharides and their derivatives like starches, cellulose or modified cellulose such as microcrystalline cellulose and cellulose ethers such as hydroxypropyl cellulose (HPC); hydroxypropyl methyl cellulose (HPMC); sugar alcohols such as xylitol, sorbitol or mannitol; protein like gelatin; synthetic polymers such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), starch, acacia, agar, alginic acid, calcium carbonate, calcium lactate, carbomers, carboxymethylcellulose sodium, carrageenan, cellulose acetate phthalate, chitosan, copovidone, corn starch, pregelatinized starch, cottonseed oil, dextrates, dextrin, dextrose, ethylcellulose, guar gum, hydrogenated vegetable oil type I, hydroxyethyl cellulose, hydroxymethyl cellulose hydroxy-ethylmethyl cellulose, hydroxypropyl cellulose, inulin, cellulose, methyl cellulose, polyvinylpyrrolidone and polyethylene glycol, lactose, liquid glucose, hypromellose, magnesium aluminum silicate, maltodextrin, maltose, methyl-cellulose, microcrystalline cellulose, pectin, poloxamer, polydextrose, polymethacrylates, povidone, sodium alginate, stearic acid, sucrose, sunflower oil, various animal vegetable oils, and white soft paraffin, paraffin, flavorants, colourants and wax.
The amount of binder in the pharmaceutical composition/formulation of the present invention ranges from 0.1 % by wt. to 25 % by wt. of the composition/formulation.
Further, according to the present invention, the lubricant is selected from magnesium stearate, zinc stearate, calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil type, light mineral oil, magnesium lauryl sulfate, medium-chain triglycerides, mineral oil, myristic acid, palmitic acid, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, potassium benzoate or the like. The amount of Lubricant in the pharmaceutical composition/formulation of the present invention ranges from 0.1 % by wt. to 10 % by wt. of the composition/formulation.
In some embodiment, the glidant is selected from colloidal silicon dioxide, magnesium stearate, fumed silica (colloidal silicon dioxide), starch, talc, calcium phosphate tribasic, cellulose powdered, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate, silicon dioxide or the like.
The amount of glidant in the pharmaceutical composition/formulation of the present invention ranges from 0.1% by wt. to 10 % by wt. of the composition/formulation.
In another embodiment of the present invention, the amount of solubilizing agent or surfactant in the composition/formulation ranges from 0.1% to 10% by weight of the composition/formulation.
In some embodiment, the solvent is selected from water, alcohol, isopropyl alcohol, propylene glycol, mineral oil, benzyl alcohol, benzyl benzoate, butylene glycol, carbon dioxide, castor oil, corn oil (maize), cottonseed oil, dimethyl ether, albumin, dimethylacetamide, ethyl acetate, ethyl lactate, medium-chain triglycerides, methyl lactate, olive oil, peanut oil, polyethylene glycol, polyoxyl, castor oil, propylene carbonate, pyrrolidone, safflower oil, sesame oil, soybean oil, sunflower oil, water-miscible solvents, organic polar or non-polar solvents or mixtures thereof.
The amount of solvent in the pharmaceutical composition/formulation of the present invention is used in a quantity sufficient to 100% by wt. of the composition/formulation.
The additional additives include polymer, a plasticizer, a sweetener, and a powdered flavour, preservative, colorant, surfactant, and other excipients. The powdered flavour composition includes a flavourant associated with a solid carrier. coating materials are used, for example synthetic polymers, shellac, corn protein zein or other polysaccharides, gelatin, fatty acids, waxes, shellac, plastics, and plant fibers and like thereof. The additives are used in the range of 1 to 25% w/w of unit dose.
Taste-masking agents are selected from Fructose/starch, sucrose, maltodextrin, saccharine, sorbitol, magnesium citrate, sodium citrate, trehalose, maltose, isomalt, xylitol and beta-cyclodextrin.
Coating materials are selected from synthetic polymers, shellac, corn protein (zein) or other polysaccharides, gelatin, fatty acids, waxes, shellac, plastics, and plant fibers and like thereof are used.
Further optionally the antioxidant is selected from vitamins such as vit E, vit C, amino acid or its derivatives such as lipoid acid, uric acid, caffeic acid, acetyl-L-carnitine, caffeic acid, sodium ascorbate and like thereof and which are present in the range of 0.1 to 10% w/w of total composition.
In the context of the present invention, the terms “treatment” and the like refer to alleviate, mitigate, prophylaxis, attenuate, manage, regulate, modulate, improve, control, minimize, lessen, decrease, down regulate, up regulate, moderate, prevent, inhibit, stabilize, ameliorate or cure, heal the indications of gastrointestinal disorders.
The treatment further includes delaying or reversing or preventing or reducing the development or progression or formation or occurrence of conditions or indications related to gastrointestinal disorders and /or gastrointestinal diseases and /or gastrointestinal disruption or gastrointestinal dysfunction.
In a preferred embodiment, the present invention provides the novel and stable composition wherein the pharmaceutically acceptable excipients are selected from a group consisting of the diluent is present in a range of 1 to 30%; the binder is present in a range of 0.1 to 25%; the lubricant is present in a range of 0.1 to 10.0%; the glidant is present in a range of 0.1 to 5.0%; the additive is present in a range of 0.1 to 10%; the surfactant is present in a range of 0.1 to 5.0%; the stabilizer is present in a range of 0.1 to 5.0%; %; the antioxidant is present in a range of 0.1 to 5.0%; and the plasticizer is present in a range of 0.1 to 5.0%; by weight of total composition.
Notably, the present synergistic composition is non-hazardous, non-toxic, and safe for human consumption without any side effects, therefore the present composition can also be used under preventive therapy in healthy subjects.
The present efficient pharmaceutical composition is used to maintain proper gastrointestinal function in the subject in need thereof, means the administration of the remedy either to prevent occurrence or pre-existing cause of gastrointestinal disorders.
In yet another embodiment, the present invention provides a method of treating a subject suffering from gastrointestinal dysfunction or diseases related to gastrointestinal dysfunction, the method comprising administering to the subject an efficient amount of the present synergistic medicinal composition to enhance the gastrointestinal function.
The ‘subject in need thereof’ pertains to subject preferably mammal, more preferably human having pre-existing or onset symptoms of gastrointestinal disorders. The subject can be healthy person and use the present composition under preventive therapy.
The therapeutically effective amount of the active ingredients may be varied depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
The method of treating gastrointestinal disorders, wherein the present composition is administered parenterally, orally, topically, buccally, sublingually, transdermally, subcutaneously, intramuscularly, via a medical device, via a stent, by inhalation or via injection. Therapeutic (prescription) supplements are generally administered by the oral or parenteral or nasal routes for treating gastrointestinal disorders. The therapeutic administration of materials of the present invention may be in conjunction with other therapies.
Further, the present synergistic medicinal composition can be administered to subject in need thereof, in a form suitable for oral use, such as a tablet, capsule (in the form of delayed release, extended release, sustained release, enteric coated release); hard gelatin capsules, soft gelatin capsules in an oily vehicle, granulate for sublingual use, effervescent tablets, aqueous or oily solution, suspension or emulsion, encapsulate, matrix, coat, beadlets, nanoparticles, caplet, granule, particulate, agglomerate, spansule, chewable tablet, lozenge, troche, solution, suspension, rapidly dissolving film, elixir, gel, as tablets, pellets, granules, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, sprays or reconstituted dry powdered form with a liquid medium or syrup; for topical use including transmucosal and transdermal use, such as a cream, ointment, gel, aqueous or oil solution or suspension, salve, parch or plaster; for nasal use, such as a snuff nasal spray or nasal drops; for vaginal or rectal use, such as a suppository; for administration by inhalation, such as a finely divided powder or a liquid aerosol; for sub-lingual or buccal use, such as a tablet or capsule, film. Further the composition can be formulated for parenteral use including intravenous, subcutaneous, intramuscular, intravascular, infusion, intraperitoneal, intracerebral, intracerebroventricular, or intradermal.
In some embodiment, the present invention provides a synergistic medicinal composition(s) for improving gut health influences kidney function. Particularly, the composition encompasses synergistic blend of propionate ester of alpha-d-glucopyranosyl-[ß-d-fructofuranosyl](n-1)-d-fructofuranosides and (11ß,16a)-16,17-[butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione in the ratio of 1:0.001 to 1:0.1.
In yet another embodiment, the present composition is useful for treating irritable bowel syndrome characterized by symptoms such as abdominal pain, bloating, and changes in bowel habits (diarrhea and constipation), dyspepsia, inflammation of the gastrointestinal tract, inflammatory bowel disease, crohn's disease, ulcerative colitis, gastritis, inflammation of the stomach lining, achalasia, gastroesophageal reflux disease, diverticulitis, eosinophilic esophagitis, gallstones, glomerular diseases, polycystic kidney disease, renal vascular disorders and end-stage renal disease.
In further embodiment, the present invention relates to method for treating cellular dysfunction in a subject in need thereof by administering the present synergistic composition in effective oral dosage form wherein the unit dose is formulated in the range of 5-1000 mg, which can be administered once or twice or thrice a day based on the indications.
The invention may be further illustrated by the following examples, which are for illustrative purposes only and should not be construed as limiting the scope of the invention in anyway.
This invention may be embodied in other forms or carried out in other ways without departing from the spirit or essential characteristics thereof. The present disclosure is therefore to be considered as in all respects illustrative and not restrictive, the scope of the invention being indicated by the appended claims, and all changes or alterations which come within the ambit of equivalency are intended to be embraced therein.

EXAMPLES:
Having described the basic aspects of the present invention, the following non-limiting examples illustrate specific embodiments thereof. Those skilled in the art will appreciate that many modifications may be made in the invention without changing the essence of invention.
Example: 1
i. Composition 1: Tablet / Capsule
Ingredient mg per unit dose
Propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl] (n-1)-D-fructofuranosides 100 mg
(11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione 4 mg
Magnesium Stearate 1-10
Hydroxypropyl Methylcellulose 1-10
Microcrystalline Cellulose 1-20
Dibasic calcium phosphate dehydrate 1-10
PVP 1-10
Silicon dioxide 1-10
Starch 1-10
Talc 1-10
Propylene Glycol QS
Water QS
Average weight 105-125 mg

ii. Composition 2: Tablet / Capsule
Ingredient mg per unit dose
Propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl] (n-1)-D-fructofuranosides 500 mg
(11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione 9 mg
Magnesium Stearate 1-20
Ascorbic acid 1-10
Microcrystalline Cellulose 1-20
Colloidal Silicon dioxide 1-15
Hydroxypropyl Methylcellulose 1-10
polyethylene glycol 1-10
PVP 1-10
Talc 1-10
Tween 80 1-10
Mannitol 5-20
Alcohol QS
Water QS
Average weight 510-550mg

iii. Composition 3: Tablet / Capsule
Ingredient mg per unit dose
Propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl] (n-1)-D-fructofuranosides 250 mg
(11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione 6 mg
Microcrystalline Cellulose 1-20
Silicon dioxide 1-10
Hydroxypropyl Methylcellulose 1-10
Stearic acid 1-10
Dibasic calcium phosphate 1-20
Pregelatinized starch 1-10
Talc 1-10
Tween 80 1-10
Polydextrose 1-10
PEG QS
Water QS
Average weight 260-300 mg

iv. Composition 4: Tablet / Capsule
Ingredient mg per unit dose
Propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl] (n-1)-D-fructofuranosides 500 mg
(11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione 3 mg
Crosslinked carboxymethyl cellulose sodium 1-10
Silicon dioxide 1-10
Butylated hydroxytoluene 1-5
Glycerin 1-10
Ethyl Cellulose 1-10
Hydroxypropyl Methylcellulose 1-10
Magnesium Stearate 1-10
Polyvinylpolypyrrolidone 1-10
Talc 1-10
Polysorbate 20 1-10
Mannitol 1-10
IPA QS
Water QS
Average weight 510-550 mg

v. Composition 5: Tablet / Capsule
Ingredient mg per unit dose
Propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl] (n-1)-D-fructofuranosides 250
(11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione 3
Zinc ascorbate 1-5
Sodium alginate 1-10
Silicon Dioxide 1-10
Triglycerides 1-5
Microcrystalline Cellulose 1-20
Dibasic Calcium Phosphate 1-10
Magnesium Stearate 1-10
Croscarmellose sodium 1-10
Polyvinylpyrrolidone 1-20
Talc 1-10
Corn Starch 1-10
Sodium ascorbate 1-10
Propylene glycol 1-10
Sucrose 1-5
Water QS
Average weight 255-300 mg

vi. Composition 6: Tablet / Capsule
Ingredient mg per unit dose
Propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl] (n-1)-D-fructofuranosides 600 mg
(11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione 1 mg
Microcrystalline Cellulose 1-10
Colloidal silicon dioxide 1-10
Hydroxypropyl Methylcellulose 1-10
Magnesium Stearate 1-10
Polyvinylpyrrolidone 1-10
Calcium Phosphate 1-10
Ascorbic Acid 1-10
Polysorbate 20 1-10
Talc 1-5
Sucrose 1-10
Mannitol 1-10
Glycerol 1-10
Average weight 610-650 mg

vii. Composition 7: Tablet / Capsule
Ingredient mg per unit dose
Propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl] (n-1)-D-fructofuranosides 60 mg
(11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione 6 mg
Microcrystalline Cellulose 1-10
Colloidal silicon dioxide 1-10
Hydroxypropyl Methylcellulose 1-10
Magnesium Stearate 1-10
Polyvinylpyrrolidone 1-10
Sodium alginate 1-10
Polysorbate 20 1-10
Talc 1-5
Sucrose 1-10
Sorbitol 1-10
Glycerol 1-10
Average weight 70-75 mg

viii. Composition 8: Tablet / Capsule
Ingredient mg per unit dose
Propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl] (n-1)-D-fructofuranosides 500
(11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione 3
Microcrystalline Cellulose 1-10
Silicon dioxide 1-10
Hydroxypropyl Methylcellulose 1-10
Magnesium Stearate 1-10
Zinc Stearate 1-5
Polyvinylpyrrolidone 1-10
Mineral Oil 1-10
Sodium benzoate 1-10
Citric Acid 1-10
Polysorbate 80 1-10
Talc 1-5
Sucrose 1-10
Mannitol 1-10
Water QS
Average weight 510-600mg

Example 2: Animal Study (Anti-inflammatory study)
Test System and Animal Husbandry
Species: Rat
Strain: Wistar; Sex: Male / Female
No. of animals: 42 Animals (n=6 per group)
Body weight: 180-200gm
Animal House conditions:
Lighting: 12 / 12 hour light-dark cycle
Temperature: 22 ± 3 °C
Relative Humidity: 30 to 70%
Temperature and relative humidity were recorded thrice daily.
Group, Designation and Dose Levels:
Table 1: Animal grouping and treatment details
Groups Group Description Human Dose No. of animals
Group 1 Normal control Vehicle 6
Group 2 Positive Control Carrageenan
(0.9% NaCl solution) 6
Group 3 Propionate ester of propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl](n-1)-D-fructofuranosides 500 mg 6
Group 4 (11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione 3 mg 6
Group 5 Propionate ester of propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl](n-1)-D-fructofuranosides + (11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione [Low dose 1:0.001] 6
Group 6 Propionate ester of propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl](n-1)-D-fructofuranosides + (11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione [High dose 1:0.1] 6
Group 7 Propionate ester of propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl](n-1)-D-fructofuranosides + (11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione [Optimum dose 1:0.01] 6

Experimental procedure:
In the study forty two (42) rats, were divided into total nine (07) groups.
Group 1 (G1) served as the normal control, Group 2 (G2) served as the positive control, Group 3 (G3), Group 4 (G4) and served as active ingredient Propionate ester of propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl](n-1)-D-fructofuranosides and (11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione respectively, Group 5 (G5) served as composition with low ratio, Group 6 (G6) served as composition with high ratio and Group 7 (G7) served as composition with optimum ratio. Acute anti-inflammatory activity was measured using carrageenan induced rat paw edema model. Acute inflammation was induced by the sub planter administration of 0.1 ml of 1% carrageenan (0.9% NaCl solution) in the right hind paw of the rats. Group 1 was treated with normal saline. Group 2 positive control was treated with normal saline (with paw edema induction). Group 3, Group 4, Group 5, Group 6 and Group 7 were treated with test substance respectively. Excluding control group, all groups were pretreated 1 hour before eliciting paw edema. After the completion of 240 minutes animals were anesthetized and blood was collected for biochemical parameter analysis. The values were expressed in Mean±SEM. The significance of in vivo data was analyzed by One-way anova followed by Dunnet test. P < 0.05 was considered as statistically significant.
Results:
Table 1: Effect of test substances on serum IL-6 levels
Group Treatment IL-6(pg/ml) % Reduction in IL-6 alpha over Disease Control
G1 Normal control 62.6±0.2 --
G2 Disease control 124.9±0.1 --
G3 Propionate ester of propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl](n-1)-D-fructofuranosides 115.5±0.7*** 7.52%
G4 (11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione 108.7±0.5*** 12.97%
G5 Propionate ester of propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl] (n-1)-D-fructofuranosides + (11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione [Low dose] 71.8±0.2***

42.51%
G6 Propionate ester of propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl](n-1)-D-fructofuranosides + (11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione [High dose] 65.1±0.5***

47.87%
G7 Propionate ester of propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl] (n-1)-D-fructofuranosides + (11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione [Optimum dose] 68.8±0.5***

44.91%

Table 2: Effect of test substances on serum TNF-Alpha levels
Group Treatment TNF-Alpha (pg/ml) % Reduction in TNF alpha over Disease Control
G1 Normal control 138.2±3.2 --
G2 Disease control 254.7±5.3 --
G3 Propionate ester of propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl](n-1)-D-fructofuranosides 230.5±5.4*** 9.50%

G4 (11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione 221.1±4.6*** 13.19%

G5 Propionate ester of propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl](n-1)-D-fructofuranosides + (11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione [Low dose] 160.1±3.6*** 37.14%

G6 Propionate ester of propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl](n-1)-D-fructofuranosides + (11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione [High dose] 144.5±4.1*** 43.26%

G7 Propionate ester of propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl](n-1)-D-fructofuranosides + (11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione [Optimum dose] 153.9±5.4*** 39.57%

Discussion:
In this study, Carrageenan induced acute inflammation test was used to screen the anti-inflammatory effect. The biochemical parameters such as Serum interleukin-6 and TNF-Alpha decreased in (G3) and (G4) and significantly decreased in the combination of (G5), (G6) and (G7) treated groups when compared with positive control (G2) (Table 2 and 3).
Conclusion: Based on the above trials, it is concluded that the combination of propionate ester of alpha-d-glucopyranosyl-[ß-d-fructofuranosyl](n-1)-d-fructofuranosides and (11ß,16a)-16,17-[butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione (G5), (G6) and (G7) showed better anti-inflammatory activity than individual test substances (G3) and (G4).
,CLAIMS:1. A synergistic medicinal composition for treating gastrointestinal disorders comprising a combination of propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl] (n-1)-D-fructofuranosides and (11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna -1,4-diene-3,20-dione along with pharmaceutically acceptable excipients.
2. The synergistic medicinal composition as claimed in claim 1, wherein the composition comprises therapeutic blend of propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl] (n-1)-D-fructofuranosides and (11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione or salts thereof present in the weight ratio of 1:0.001 to 1:0.1 along with pharmaceutically acceptable excipients.
3. The synergistic medicinal composition as claimed in claim 1, wherein the propionate ester of alpha-D-glucopyranosyl-[ß-D-fructofuranosyl] (n-1)-D-fructofuranosides is present in the range of 10-800 mg by weight of the total composition.
4. The synergistic medicinal composition as claimed in claim 1, wherein the (11ß,16a)-16,17-[Butylidenebis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione is present in the range of 1 to 100 mg by weight of the total composition.
5. The synergistic medicinal composition as claimed in claim 1, wherein the pharmaceutically acceptable excipient is selected from a group consisting of: diluent in a range of 1 to 30%; binder in a range of 0.1 to 25%; lubricant in a range of 0.1 to 10.0 %; glidant in a range of 0.1 to 5.0%; additive in a range of 0.1 to 10%; surfactant in a range of 0.1 to 5.0%; stabilizer in a range of 0.1 to 5.0%; %; antioxidant in a range of 0.1 to 5.0%; and plasticizer in a range of 0.1 to 5.0% and solvent; by weight of the total composition.
6. The synergistic medicinal composition as claimed in claim 1, wherein the effective oral unit dose ranges from 1-800 mg.
7. The synergistic medicinal composition as claimed in claim 1, wherein the composition is useful in the treatment of inflammatory bowel disease, Crohn’s disease, ulcerative colitis, inflammatory Bowel Disease (IBD), irritable bowel syndrome (IBS) , gastritis, achalasia, gastroesophageal reflux disease, diverticulitis, eosinophilic esophagitis, gallstones, glomerular diseases, polycystic kidney disease, renal vascular disorders, end-stage renal disease, diabetic nephropathy, chronic kidney disease, achalasia, IgA nephropathy (Berger's disease).
8. The synergistic medicinal composition as claimed in claim 1, wherein the composition synergistically downregulates the gastrointestinal inflammation by 3 to 4 folds over its individual constituents.