Description:TITLE OF THE INVENTION: A FORMULATION FOR GASTROESOPHAGEAL REFLUX DISEASE AND METHOD OF SYNTHESIS THEREOF
FIELD OF THE INVENTION
The present disclosure is generally related to gastroesophageal reflux disease. Particularly, the present disclosure is related to treatment of gastroesophageal reflux disease. More particularly, the present disclosure is related to: a formulation for gastroesophageal reflux disease; and method of synthesis thereof.
BACKGROUND OF THE INVENTION
Existing techniques and/or medications for managing gastroesophageal reflux disease suffer from at least the following drawbacks: are dependent on lifestyle changes; and/or high risks of complications, allergies, and/or side effects, including, but not limited to: Barrett's esophagus, headaches, flatulence, abdominal pain, joint pain, rashes, and/or diarrhoea.
There is, therefore, a need in the art, for: a formulation for gastroesophageal reflux disease; and method of synthesis thereof, which overcome the aforementioned drawbacks and shortcomings.
SUMMARY OF THE INVENTION
A synergistic formulation, for gastroesophageal reflux disease, and method of synthesis thereof, are disclosed. Said synergistic formulation broadly comprises: powdered fruits of Emblica officinalis; powdered roots of Glycyrrhiza glabra; powdered stems of Tinospora cordifolia; powdered rhizomes of Zingiber officinale; a dry powder fruit extract of Aegle marmelos; a soft liquid fruit extract of Aegle marmelos; a powder of shankha bhasma; a powder of kapardik bhasma; a powder of shuddha suvarnagirik; methylparaben; propylparaben, starch; talc; and magnesium stearate.
Said powdered fruits of Emblica officinalis are in a ratio of: about 20.7:1 with said powdered roots of Glycyrrhiza glabra; about 3.2:1 with said powdered stems of Tinospora cordifolia and powdered rhizomes of Zingiber officinale; about 4.4:1 with said dry powder fruit extract of Aegle marmelos; about 13.2:1 with said soft liquid fruit extract of Aegle marmelos; about 12.2:1 with said powder of shankha bhasma and said powder of kapardik bhasma; about 1.6:1 with said powder of shuddha suvarnagirik; about 270:1 with said methylparaben and said propylparaben; about 27:1 with said starch; and about 38.6:1 with said talc and said magnesium stearate.
The disclosed formulation offers at least the following synergistic advantages and effects: improved efficacy; a higher percentage of reduction in symptoms like heartburn, acidic taste, and pain in the stomach; reduced risk of complications; and/or lower incidence of side effects or allergies.
DETAILED DESCRIPTION OF THE INVENTION
Throughout this specification, the use of the words “comprise” and “include”, and variations, such as “comprises”, “comprising”, “includes”, and “including”, may imply the inclusion of an element (or elements) not specifically recited. Further, the disclosed embodiments may be embodied, in various other forms, as well.
Throughout this specification, the use of the word “synthesis”, and its variations, is to be construed as: “produce; manufacture; and/or the like”.
Throughout this specification, the use of the phrase “synthesised formulation” is to be construed as: “synthesised formulation for treating GERD/gastrointestinal diseases”.
Throughout this specification, the use of the acronym “GERD” is to be construed as: “gastroesophageal reflux disease”.
Throughout this specification, the use of the acronym “GSRS” is to be construed as: “Gastrointestinal Symptom Rating Scale”.
Throughout this specification, the use of the acronym “NLT” is to be construed as: “not less than”.
Throughout this specification, the use of the acronym “NMT” is to be construed as: “not more than”.
Throughout this specification, the use of the acronym “RDQ” is to be construed as: “Reflux Disease Questionnaire”.
Throughout this specification, the use of the acronym “OTE” is to be construed as: “Overall Treatment Evaluation”.
Throughout this specification, the disclosure of a range is to be construed as being inclusive of: the lower limit of the range; and the upper limit of the range.
Throughout this specification, the words “the” and “said” are used interchangeably.
Also, it is to be noted that embodiments may be described as a method. Although the operations, in a method, are described as a sequential process, many of the operations may be performed in parallel, concurrently, or simultaneously. In addition, the order of the operations may be re-arranged. A method may be terminated, when its operations are completed, but may also have additional steps.
A synergistic formulation for treating gastroesophageal reflux disease (also referred to as “synthesised formulation” and/or “formulation”) is disclosed. The disclosed formulation was synthesised and tested as follows:
Said formulation comprises: powdered fruits of Emblica officinalis (about 250 mg to about 350 mg); powdered roots of Glycyrrhiza glabra (about 10 mg to about 20 mg); powdered stems of Tinospora cordifolia (about 50 mg to about 100 mg); powdered rhizomes of Zingiber officinale (about 50 mg to about 100 mg); a dry powder fruit extract of Aegle marmelos (about 50 mg to about 100 mg); a soft liquid fruit extract of Aegle marmelos (about 10 mg to about 30 mg); a powder of shankha bhasma (or shankh bhasm; a composition of calcium carbonate; about 10 mg to about 30 mg); a powder of kapardik bhasma (or kapardika bhasma; composed of mainly calcium carbonate; about 10 mg to about 30 mg); a powder of shuddha suvarnagirik (a composition of purified red ochre, about 150 mg to about 200 mg); methylparaben (about 0.5 mg to about 1 mg); propylparaben (about 0.5 mg to about 1 mg); starch (about 5 mg to about 10 mg); talc (about 5 mg to about 10 mg); and magnesium stearate (about 5 mg to about 10 mg). Further, a person skilled in the art will appreciate the fact that the formulation may comprise distilled water as per requirements.
Said powdered fruits of Emblica officinalis are in a ratio of: about 20.7:1 with said powdered roots of Glycyrrhiza glabra; about 3.2:1 with said powdered stems of Tinospora cordifolia and powdered rhizomes of Zingiber officinale; about 4.4:1 with said dry powder fruit extract of Aegle marmelos; about 13.2:1 with said soft liquid fruit extract of Aegle marmelos; about 12.2:1 with said powder of shankha bhasma and said powder of kapardik bhasma; about 1.6:1 with said powder of shuddha suvarnagirik; about 270:1 with said methylparaben and said propylparaben; about 27:1 with said starch; and about 38.6:1 with said talc and said magnesium stearate.
Said fruits of Emblica officinalis; said roots of Glycyrrhiza glabra; said stems of Tinospora cordifolia; and said rhizomes of Zingiber officinale were procured from Aditya Ayurvedic Supply Company, Maharashtra, India.
Said fruits of Aegle marmelos were procured from Aryaansh Bionaturals Private Limited, Maharashtra, India. Said powder of shankha bhasma and said powder of kapardik bhasma were procured from Raj Ayurvedic Pharmacy, Uttar Pradesh, India. Said powder of shuddha suvarnagirik was procured from Manakarnika Aushadhalaya, Maharashtra, India.
Preparation of Dry Powder and Soft Liquid Fruit Extracts of Aegle marmelos
Said fruits of Aegle marmelos were sun dried, pulp were removed, and ground finely to obtain coarse powders. To the obtained coarse powders, a polar solvent (for example, water) was added to obtain two portions of water soluble extracts.
One portion of obtained water soluble extract was fully evaporated to remove the water to obtain a solid mass. The obtained solid mass was then spray dried and milled to obtain a milled powder extract. The obtained milled powder extract was further milled and ground to obtain said dry powder fruit extract.

Another portion of the obtained water soluble extract was partially evaporated to remove the water to obtain a soft extract. To the obtained soft extract, water was added to obtain the soft liquid fruit extract.
Synthesis of the Formulation
About 270 mg of said powdered fruits of Emblica officinalis, about 13 mg of said powdered roots of Glycyrrhiza glabra, about 85 mg of said powdered stems of Tinospora cordifolia, about 85 mg of said powdered rhizomes of Zingiber officinale, about 61.5 mg of the dry powder fruit extract of Aegle marmelos, about 22 mg of said powder of shankha bhasma, about 22 mg of said powder of kapardik bhasma, and about 171 mg of said powder of shuddha suvarnagirik were weighed, sieved with (or through) a mesh (size of about 300 µm), and mixed in a mixer for about 30 minutes to obtain a dry mixture.
About 20.5 mg of the prepared soft liquid fruit extract, about 1 mg of methylparaben, and about 1 mg of propylparaben were added with water to obtain a mixture. The obtained mixture was then mixed with the obtained dry mixture for granulation to obtain a wet mixture.
The obtained wet mixture was then passed through a multi-mill (a screen of about 6 mm) to obtain wet granules. The wet granules were then dried in a fluidized bed dryer at about 70 0C to obtain dried granules. The obtained dried granules were then sieved with (or through) sieve no. 16 (about 1.18 mm) to obtain a coarse material.
The obtained coarse material was then passed through a multi-mill (a mesh size of about 4 mm) and re-sifted through sifters of sieve no. 12 (about 1.7 mm), sieve no. 16 (about 1.18 mm), sieve size of about 3 mm, sieve size of about 1.5 mm, and sieve size of about 0.5 mm, to obtain fine powdered granules.
Said starch (about 10 mg), said talc (about 7 mg), and said magnesium stearate (about 7 mg) (collectively referred to as “lubricants”) were weighed and sifted through the sifter using sieve no. 50 (about 300 µm). The obtained fine powdered granules were then mixed with the lubricants using a mass mixer for about 15 minutes, collected in a drum, and fed into a tablet punching machine to obtain tablets comprising the formulation.
Material Characterisations
Hardness, friability, uniformity of weight, and disintegration tests were performed. Results of said tests were as follows:
S. No. Test Parameter Specification Prior Art Results Present Formulation Results
1. Hardness NLT 4.0 kg/cm2 5.4 kg/cm2 6.2 kg/cm2
2. Friability NMT 1.0 % 0.68 % 0.28 %
3. Uniformity of Weight ± 5.0 % 5.0 % 4.0 %
4. Disintegration Test NMT 60 min. 27 min. 45 Sec. 18 min. 30 Sec.

Efficacy Analyses
Gastrointestinal Symptom Rating Scale (GSRS)Analyses
A total of about 30 patients aged more than or equal to about 18 years (diagnosed with acid peptic disease) were enrolled and symptoms were assessed by a GSRS. A person skilled in the art will appreciate that the GSRS is a globally accepted technique to evaluate gastrointestinal conditions.
The enrolled participants were instructed to take two tablets a day and were called for follow-ups on week 1, week 2, week 3, and week 4 after a baseline visit.
Results
A significant difference was observed between the mean scores before treatment and after 4 weeks of treatment in the GSRS subscales for abdominal pain, reflux, indigestion, and constipation, except for diarrhoea, with a p-value of <0.001.
Reflux Disease Questionnaire (RDQ) and Overall Treatment Evaluation (OTE) Scale Analyses
A person skilled in the art will appreciate that the Reflux Disease Questionnaire and Overall Treatment Evaluation analyses are globally accepted techniques to evaluate gastrointestinal conditions.
Example 1
A total of about 100 patients with a mean age of about 46.9 years (diagnosed with uncomplicated symptomatic GERD) were randomised into two groups.
Group 1 was advised to consume one tablet twice a day for about 15 days, and
Group 2 was advised to consume one tablet of pantaprazole (of about 40 mg) twice a day for about 15 days.
The symptoms were assessed by the RDQ scale and overall symptoms were evaluated by the OTE scale on week 1, week 2, week 3, and week 4 after a baseline visit.
Results
It was observed that the group 1 had a significantly lower average rank (about 35.5204 and about 38.7143) compared to the pantoprazole group (about 63.4796 and about 60.2857), post-treatment. The group 1 showed significant improvements in various GERD symptoms, with greater percentage reductions in symptoms like heartburn, acidic taste, and pain in the centre of the stomach compared to the pantoprazole group.
About 97.96% of patients in the group 1 experienced total relief compared to about 85.71% in the pantoprazole group. No adverse events were observed in either treatment group.
Example 2
A total of about 60 patients with a mean age of about 48.48 (diagnosed with uncomplicated symptomatic GERD) were randomised into three groups.
Group 1 was advised to consume one tablet twice a day for about 14 days,
Group 2 was advised to consume one Emblica officinalis tablet (of about 270 mg) twice a day for about 14 days, and
Group 3 was advised to consume one Zingiber officinale tablet (of about 85 mg) twice a day for about 14 days.
The symptoms were assessed by the RDQ scale and overall symptoms were evaluated by the OTE scale on week 1, week 2, week 3, and week 4 after a baseline visit.
Results
It was observed that about 84.2% of patients in the group 1 had their symptoms resolved. No patients reported adverse outcomes.
Only about 55.6% felt a little better, while 44.4% reported no change in the group 2.
In the group 3, about 5.6% reported worsening symptoms. Most patients (about 66.7%) experienced no change, while about 27.8% felt a little better.
From the above, it was determined that the synthesised formulation (group 1) demonstrated greater efficacy when compared to the Emblica officinalis tablet (group 2) and the Zingiber officinale tablet (group 3), thus demonstrating synergism.
In vivo Efficacy Assessment Using Rat Model
Acute oral toxicity was assessed. About 12 female wistar rats aged between about 8 to about 9 weeks, weighing between about 180 g to about 189 g, were randomly assigned into four subgroups: G1, G2, G3, and G4, with each group containing about 3 rats.
All rats were fasted overnight (before administering a dose) and food was provided after dosing (about 3 to about 4 hours). G1 served as the control group. About one tablet was diluted in about 2,000 mg and about 5,000 mg in distilled water to obtain about 200 mg/mL and about 500 mg/mL solutions, respectively.
All rats were then dosed orally at a volume of about 10 mL/kg body weight. Body weight measurements were taken on the day before the dose was given (day 0), the day of the dose (fasting body weight), then every week after that until the day of death. All the surviving animals were humanely killed (sacrificed) by carbon dioxide asphyxiation.
Results
It was observed that all animals remained healthy throughout about 14-day observation period. Body weight measurements showed normal growth, with no significant differences between control (G1) and treated groups (G2, G3 and G4); necropsy results revealed no organ abnormalities.
As per Globally Harmonized System (GHS) for chemical substances, the synthesised formulation was classified under category 5, with an LD50 of more than 5,000 mg/kg.
The disclosed formulation offers at least the following synergistic advantages and effects: improved efficacy; a higher percentage of reduction in symptoms like heartburn, acidic taste, and pain in the stomach; reduced risk of complications; and/or lower incidence of side effects or allergies.
It will be apparent to a person skilled in the art that the above description is for illustrative purposes only and should not be considered as limiting. Various modifications, additions, alterations, and improvements, without deviating from the spirit and the scope of the disclosure, may be made, by a person skilled in the art. Such modifications, additions, alterations, and improvements, should be construed as being within the scope of this disclosure. , Claims:1. A synergistic formulation, for gastroesophageal reflux disease, comprising:
powdered fruits of Emblica officinalis; powdered roots of Glycyrrhiza glabra; powdered stems of Tinospora cordifolia; powdered rhizomes of Zingiber officinale; a dry powder fruit extract of Aegle marmelos; a soft liquid fruit extract of Aegle marmelos; a powder of shankha bhasma; a powder of kapardik bhasma; a powder of shuddha suvarnagirik; methylparaben; propylparaben, starch; talc; and magnesium stearate, with:
said powdered fruits of Emblica officinalis being in a ratio of 20.7:1 with said powdered roots of Glycyrrhiza glabra;
said powdered fruits of Emblica officinalis being in a ratio of 3.2:1 with said powdered stems of Tinospora cordifolia and said powdered rhizomes of Zingiber officinale;
said powdered fruits of Emblica officinalis being in a ratio of 4:4:1 with said dry powder fruit extract of Aegle marmelos;
said powdered fruits of Emblica officinalis being in a ratio of 13.2:1 with said soft liquid fruit extract of Aegle marmelos;
said powdered fruits of Emblica officinalis being in a ratio of 12.2:1 with said powder of shankha bhasma and said powder of kapardik bhasma;
said powdered fruits of Emblica officinalis being in a ratio of 1.6:1 with said powder of shuddha suvarnagirik;
said powdered fruits of Emblica officinalis being in a ratio of 270:1 with said methylparaben and said propylparaben;
said powdered fruits of Emblica officinalis being in a ratio of 27:1 with said starch; and
said powdered fruits of Emblica officinalis being in a ratio of 38.6:1 with said talc and said magnesium stearate.
2. The synergistic formulation, for gastroesophageal reflux disease, as claimed in claim 1, wherein:
weight of said powdered fruits of Emblica officinalis is 270 mg;
weight of said powdered roots of Glycyrrhiza glabra is 13 mg;
weight of said powdered stems of Tinospora cordifolia and said powdered rhizomes of Zingiber officinale is 85 mg;
weight of said dry powder fruit extract of Aegle marmelos is 61.5 mg;
weight of said soft liquid fruit extract of Aegle marmelos is 20.5 mg;
weight of said powder of shankha bhasma and weight of said powder of kapardik bhasma is 22 mg;
weight of said powder of shuddha suvarnagirik is 171 mg;
weight of said methylparaben and said propylparaben is 1 mg;
weight of said starch is 10 mg; and
weight of said talc and said magnesium stearate is 7 mg.