Title of Invention	ORAL FORMULATIONS FOR ENAHANCING GASTRIC EMPTYING AND SPHINCTER RELAXATION INSTANTLY AND A PROCESS OF PREPARTATION THEREOF
Abstract	The present invention relates to a synergistic pharmaceutical formulation for enhancing gastric emptying and sphincter relaxation comprising of two components wherein the first component is in the form of a floating formulation and second component is in the form of a mucoadhesive formulation. The synergistic effect of these components has shown to enhance the gastric emptying time and this in turn results in instantaneous and fast forward propulsion of gastric contents (also called gastric prokinetic action) thereby helping in digestion.

Title of Invention

ORAL FORMULATIONS FOR ENAHANCING GASTRIC EMPTYING AND SPHINCTER RELAXATION INSTANTLY AND A PROCESS OF PREPARTATION THEREOF

Abstract

The present invention relates to a synergistic pharmaceutical formulation for enhancing gastric emptying and sphincter relaxation comprising of two components wherein the first component is in the form of a floating formulation and second component is in the form of a mucoadhesive formulation. The synergistic effect of these components has shown to enhance the gastric emptying time and this in turn results in instantaneous and fast forward propulsion of gastric contents (also called gastric prokinetic action) thereby helping in digestion.

Full Text	Oral formulations for enhancing gastric emptying and sphincter relaxation instantly and a process of preparation thereof FIELD OF INVENTION The present invention relates to an oral synergistic formulation that acts within minutes of reaching the stomach and acts purely or predominantly by local action, producing a short-lasting potent effect in a low dose. The formulation thus is safe, more cost-effective and more efficacious. BACKGROUND AND PRIOR ART Gastroparesis (slow gastric emptying) is a very frequently occurring condition, associated with various types of acute dyspepsia, nausea, chronic conditions like diabetes mellitus and renal failure. Group of drugs comprising of gastric prokinetic agents like cisapride, domperidone, metochlopramide and erythromycin are often prescribed for gastroparesis. However, in the long run the use of these drugs leads to lack of appetite, weight loss and chronic dyspepsia. The conventional prokinetic agents act systemically (pharmacological action takes place after therapeutic concentration is achieved in the blood), resulting in slow, prolonged and less potent action. As a result, a higher dose is required which is not just expensive but has higher side effects too. It is well known that antacids like Digene, Mucain, Gelucil etc (both as tablets or liquids) acts by neutralizing the gastric acid. However, H-2 blockers like ranitidine and omaprazole group of drugs are also given to reduce the production of gastric acid. Also it is known in the art to correct slow gastric emptying by making dietary adjustments as liquid diet has faster gastric clearance than the solid food. Oral administration of carminatives and effervescent mixtures that act by opening up the gastro-esophageal sphincter (by action of carbon dioxide gas) and release of intragastric pressure. This reduces the feeling of bloating and dyspeptic symptoms. Also oral administration of spices and herbal extracts that have mild carminative and / or purgative action. These are also expected to reduce the gastric emptying time and the feeling of nausea and vomiting. By administering drugs such as phenergan, stemetil provides anticholinergic or antihistaminic action. Administration of prokinetic drugs like cisapride, domperidon, metochlopramide or erythromycin that have gastric prokinetic action. Domperidon and metochlopramide additionally have anti-vomiting action at central level and are a preferred treatment where gastric prokinetic effect is desired for the benefit of the patient for many years. All the above stated forms of medical treatment have one or the other lacuna. All the drugs mentioned so far except the prokinetic group deals with the resultant symptoms only and not the actual cause of the symptoms, namely, the slowdown or reversal of the gastrointestinal peristalsis. For example, antacids, H-2 blockers, carminatives, mild purgatives, digestants and anticholinergics do not address the main problem and therefore provide short-term relief while the problem persists. Hence these agents are of no practical value where gastroparesis is chronic, and may actually reduce the gastric emptying further. Prokinetic agents, therefore, provide the mainstay of medical treatment of diseases and conditions where gastrointestinal motility either slows down or shows dysmotility. However, these are quite slow acting and require prolonged use before any clinical benefit is apparent. The diseases associated with upper GIT motility disorders are very common and recurrent or chronic in nature, the current management is considered inadequate (though beneficial) by the experts in the art. Whereas the morbidity caused by gastric motility disorders is widespread and associated with a number of disease conditions, many of these chronic in nature. Moreover, the drugs in prior art are either slow acting or not potent enough, or mainly address the symptoms rather than the cause, and may not be suitable as a long-term solution, it is preferable that a new line of treatment be introduced. Antacids only provide short-term relief of symptoms pertaining to gastritis and may cause electrolyte imbalance or constipation on prolonged use. Moreover, carminatives, household and herbal concoctions have very mild action for a short interval, their efficacy and is yet to be established in long term or chronic use. The action of anticholinergic and antihistaminic drugs are limited to slowing down peristalsis and relaxation of upper GIT resulting further enhancement in gastric emptying time, this precludes their use as prokinetic agents. A need is felt both by patients and experts of the Art for a new group of drugs that could enhance the gastric emptying significantly and promptly mitigating the symptoms using a single or lesser number of formulations. In contrast, the present day management strategy is dependant upon a number of groups of drugs based on different therapeutic concepts, and sometimes acting at cross-purposes rather then synergistically. Many of these groups of drugs have no gastric prokinetic action what so ever but still are frequently used for. want of better alternative. The inventors have given a great thought in the matter to develop new formulations based on a new concept considering the problems faced by the patients, those conversant with the Art, the lacunae seen and the management of conditions and diseases involving slowing down of gastrointestinal peristalsis (increased gastric emptying time) particularly when occurring frequently or in a recurrent or chronic fashion. The present invention provides an oral formulation that acts instantly or within minutes of reaching the stomach, which is safe, cost-effective and more efficacious than the treatment options known in the art and is based on an entirely new concept and mechanism of action that has not been used therapeutically till now. Active components of the different embodiments of the formulation are well known drugs that are used independently for different purposes (other than what is intended here) but have been combined for the first time to give very clear synergistic action that is not possible without employing the particular combination of active ingredients and excipients characteristics that have been employed in the present invention. In the present invention, oral calcium salts are given in higher doses for their systemic effect namely, bone absorption. No floating formulations of the particular calcium salts contained in the present invention have been made before nor has a therapeutic effect of floating preparation of calcium salts on gastric (fundus) musculature been previously described. Moreover, the carminative action of bicarbonates is well known in the literature (by the action of carbon dioxide on gastro-esophageal sphincter), its action on pyloric sphincter has not been demonstrated before, nor a mucoadhesive preparation for increasing gastric emptying time has been attempted. Still further, we have demonstrated its action on sphincter of Oddi for relieving spasm which has not been demonstrated before. An advantage of the new concept is that it is based on synergistic action of contraction of muscles of upper part of stomach (Fundus region) and relaxation of lower portion of stomach and upper GIT (pyloric sphincter and jejunum) that propels the stomach content forward and increase the gastric emptying significantly. The action mimics the physiological process of peristalsis and is equivalent to accelerated peristalsis. The mechanism of this twin relaxation is different to that of the conventional prokinetic drugs (metrochlopramide, domperidon) which acts on central nervous system and on the upper GIT musculature through systemic route. The advantage of the present invention is that it only has a direct local action on the upper GIT musculature as specified above. OBJECTS OF THE INVENTION The main object of the present invention is to provide a synergistic formulation for enhancing gastric emptying and sphincter relaxation comprising of two components. Another object of the invention is to provide first component in the form of a floating formulation and second component in the form of a mucoadhesive formulation. Yet another object of the invention is to provide both components which can be administered either individually or in combination Another object of the invention is to provide processes for the production of both the components. Another object of the invention is to provide the synergistic formulation in the form of syrup, tablet, capsule, spansule, or a granule. BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS Figure 1 show contraction of fundus wherein (a) is for control study i.e. liquid gastric emptying study and (b) after administering the drug to patient shows dramatic fundus opening. Figure 2 shows graphs generated from the nuclear medicine data; wherein a) Curve of falling radioactivity: normal gastric emptying b) Continuity of the effect for a longer duration. Figure 3 is a different type of nuclear medicine study called Tc-99m pertechnetate scintigraphy showing instant enhancement of gastric juice secretion after administering the synergistic formulation. SUMMARY OF THE PRESENT INVENTION Accordingly, the present invention provides a synergistic pharmaceutical formulation for enhancing gastric emptying and sphincter relaxation comprising of: i. a first component selected from a group consisting of calcium salt, ex-receptor agonists, /3-receptor antagonists, parasympathoniimetics, and a combination thereof in the range of from 0.1 mg to 1000 mg; and ii. a second component selected from a group consisting of bicarbonate, calcium channel blockers, a-receptor antagonists, /3-receptor agonists, anticholinergic drug and a combination thereof in the range of from 0.1 mg to 2000 mg. The formulation consists of one or more preferred ingredients and employs an instant contraction of smooth muscles of the gastric fundus and simultaneous relaxation of pyloric sphincter to increase the gastric emptying many folds (by almost 500 %) by the synergistic action. Another aspect of the present invention is to provide a capsule or tablet containing both the components which can be administered either individually or in combination. DETAILED DESCRIPTION OF THE INVENTION The present invention provides a synergistic formulation containing two types of components: first component and second component, in the form of granules. First component contains a calcium salt, preferably calcium citrate less than 200mg as a floating preparation, while second Component contains preferably 200mg or less of sodium or potassium bicarbonate in a mucoadhesive environment produced by an appropriate combination of excipients. This combination is for mild cases. These two components can also be provided as separate tablets, one to be given before and the other one after the meals. The synergistic formulation consists of two types of active components: First component contracts the musculature of fundus and body of stomach by local action. These include a-agonists, /3-antagonists, parasympathoniimetics, particularly pilocarpine, or direct acting drugs that contracts smooth muscles, or a combination thereof. These include particularly a salt of Calcium, preferably gluconate, citrate or chloride (0.1-500 mg), while rest of the active ingredients are preferable, particularly to increase the strength of the contraction. The present invention discloses that pilocarpine (50-5000 microgram) in addition stimulates gastric acid production by local action. Second component relaxes the musculature of pyloric sphincter and upper jejunum as a result of local action. These include o-antagonists, /3-agonists, anti-cholinergics, or direct acting drugs that relax smooth muscles, or a combination thereof. These particularly include bicarbonates of sodium or potassium (10-2000 mg) and calcium channel blockers, preferably nifedipine (5-3000 microgram). The invariable component of the formulation is bicarbonate, rest being preferable but optional. First component is given as a floating formulation and second component is given as a mucoadhesive formulation. The excipients preferably include HPMC (Hydroxypropyl Methylcellulose) of different grades, other forms and derivatives of cellulose, lactose or glucose, PVP (Polyvinylpyrrolidone) of various molecular weights, carbopole of various grades, acacia, and other conventionally used base material. Citric acid or any other acidic substance is preferably added to neutralize the alkaline effect of sodium bicarbonate. The two types of components have reverse but complimentary action, and can be given together in the same capsules as independently acting granules having different dissolution characteristics (tablet/capsule/spansule etc) or as separate entities before, during or after meals. It was shown that by giving first component alone enhanced gastric emptying by 40 % and giving second component alone increased it by 30 % while giving the two components together (before and after meals respectively) as a synergistic composition increased the emptying by almost 500 % times confirming the synergistic action of the product. An embodiment of the present invention is to provide first component in the form of a floating preparation to be taken after meals. It consists of low dose calcium salts preferably of citrate or chloride, along with a parasympathomimetic, preferably pilocarpine, or alpha-receptor agonist or beta-receptor antagonist, or a combination thereof. Another embodiment of the invention is to provide second component in the form of a mucoadhesive preparation to be taken before meals. It consists of low dose bicarbonates, particularly of sodium or potassium, and nifedipine or any other calcium channel blocker, alpha-receptor antagonist, beta-receptor agonist or a direct-acting smooth muscle relaxant, or a combination thereof, shown to act locally on the pylorus. Yet another embodiment of the present invention is to provide both the components as a single entity in the form of a capsule. The synergistic effect of both these components result in instantaneous and fast forward propulsion of gastric contents (also called gastric prokinetic action) and help in digestion. The use of such synergistic formulation is not known in the prior art. Another embodiment of the present invention is to provide a prokinetic effect, occurring in minutes. Another embodiment of the present invention is to provide minimum side-effects. The present invention relates to synergistic action of the two components. The action is much more effective and powerful than the existing formulations known in the art used for the purpose. The formulations are helpful in stimulating appetite and in treating gallbladder diseases, stomach-ache, dyspepsia, nausea, pyloric or sphincter of Oddi dysfunction or stenosis, anorexia, uremia, anorexia nervosa or bulimia and associated weight loss such as found in high altitude sickness. The formulations are also useful in the management of gastroparesis due to various diseases like diabetes mellitus, advanced age, autonomic system dysfunctions, abdominal surgeries and during convalescence period. The present invention discloses the use of calcium salts for the localized effect which has never been demonstrated before in gastric disorders. The drugs and related methods known in the art have tremendous side-effects and their mode of action takes days and weeks to relieve the patient. However, the synergistic formulation acts within minutes. The presently disclosed concept of local prokinetic action and gastric acid enhancement is a new concept and the formulations constitute a new invention presently not available commercially but useful in conditions as outlined above and many more. The normal process of digestion which involves forward movement of gastric contents after mixing with the gastric juice and further movement in the small intestine is known in the prior art. The forward propulsion is a result of coordinated muscle movement of the upper gastrointestinal tract (GIT) and relaxation of the pyloric sphincter, termed 'peristalsis'. Normal peristalsis is an automatic activity of the GIT, taking place continuously, and smoothly, without the cognition of the person. In abnormal cases, however, the peristalsis gets slowed down, becomes chaotic, or may even follow reverse direction. The former condition gives rise to symptoms of anorexia, fullness of stomach, sense of bloating and results in abnormally prolonged gastric emptying time. This may cause the feeling of nausea and vomiting. These conditions are associated with a number of acute or chronic diseases like dyspepsia, gastritis, duodenal and gastric ulcer, diabetes mellitus, uremia, mountain sickness, old age, psychosomatic disorders like bulimia and anorexia nervosa, as radiation or drug-induced reaction and a variety of other morbid conditions including gallbladder dysfunctions, post-cholecystectomy syndrome, post-surgery convalescence period. The abnormality of peristalsis and slow gastric emptying results in loss of weight and in the long run leads to reduction in the quality of life. The present invention relates to a novel formulation of combination of both the components which have been made for a novel effect. The synergistic novel effect of both the components have shown to enhance the gastric emptying time. Similarly, the local therapeutic effect of the formulation has been demonstrated for which there was no formulation till now. The present invention relates to a formulation that contains many active components which act at different sites within the stomach resulting in significantly enhanced gastric emptying and therefore have different formulation characteristics. Fast gastric emptying results due to contraction of smooth muscles of the upper portion of the stomach in synchrony with opening of the pylorus of the stomach. This happens by a local action because the concentration of the active ingredients in proximity to the site of action becomes more than what is required for the therapeutic action to set in, the action is almost instantaneous and short-lived (unless changed into a SR formulation) (Fig 1-3). One of the preferred embodiments is the capsule or tablet containing both the components, where different active ingredients are made separately in the form of separate capsules having different dissolution and adhesive properties. Another preferred embodiment is packing of different components in separate capsules or tablets to be taken before or after meals to provide the desired effect. Yet another preferred embodiment is packing of both the components in a single capsule to be administered before the meal. EXAMPLES The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and the description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as there invention nor are they intended to represent that the experiments below are all and only experiments performed. Efforts have been made to ensure accuracy with respect to figures used. Example 1: Process to prepare Oral Formulations a) Preparation of first component: The first component contains the following: (Table Removed) Accurately weigh all the ingredients. Sift HPMC, lactose and glucose through Sieve number 40 and mix in a blender. Sift the calcium carbonate and pilocarpine through mesh number 60 and mix with the mixture containing HPMC, lactose and glucose. The blend is filled in the empty gelatin capsules through a filling machine. For making granules, the blend is passed through a sluggish machine or a compactor. The slug or compact so obtained is passed through an oscillatory granulator using 1 mm screen. The mixture is added to a glident and filled in gelatin capsules. b) Preparation of second component: The second component contains the following: (Table Removed) Accurately weigh all the ingredients. Sift amlodepine and sodium bicarbonate through a Mesh number 60. Sift citric acid and guar gum through mesh number 40. Mix both in a blender for 5 minutes. Dissolve PVP in a sufficient quantity of water and granulate the above mixture. Dry the granules at 60 °C for 2 hours in a tray drier. Sift dried granules through mesh number 20 and mix with cellulose, glident and lubricant (Img stearate and 1% talc). If the granules are to be dispensed as a tablet, compress these using proper tools. Example 2: Process to prepare Oral Formulations a) Preparation of first component: The first component contains the following: (Table Removed) Accurately weigh all the ingredients. Sift HPMC, lactose and glucose through Sieve number 40 and mix in a blender. Sift the calcium citrate through mesh number 60 and mix with the mixture containing HPMC, lactose and glucose. The blend is filled in the empty gelatin capsules through a filling machine. For making granules, the blend is passed through a sluggish machine or a compactor. The slug or compact so obtained is passed through an oscillatory granulator using 1 mm screen. The mixture is added to a glident and filled in gelatin capsules. b) Preparation of second component: The second component contains the following: (Table Removed)Accurately weigh all the ingredients. Sift nifedipine and sodium bicarbonate through a Mesh number 60. Sift citric acid and guar gum through mesh number 40. Mix both in a blender for 5 minutes. Dissolve PVP in a sufficient quantity of water and granulate the above mixture. Dry the granules at 60 °C for 2 hours in a tray drier. Sift dried granules through mesh number 20 and mix with cellulose, glident and lubricant (Img stearate and 1% talc). If the granules are to be dispensed as a tablet, compress these using proper tools. Example 3: Using Examples 1 and 2 first component and second component were manufactured and using the same 24 patients or volunteers were screened with the medication and effects of the formulation were noted objectively by nuclear medicine technique; the method has confirmed contraction of fundus by the first component and relaxation of pylorus by the second component (figure 1).18 of the 24 tested patients demonstrated the effect that gastric emptying increased significantly within minutes of taking the formulation. Nuclear medicine scans are considered as the gold-standard to monitor and quantify changes in gastric emptying in humans. For this, a standard radioactive meal is given to the patient/ volunteer and imaging is started. Imaging for several minutes gives the gastric emptying rate quantitatively. Any drug to be tested for action on gastric emptying can be given thereafter in the same sitting if it is fast-acting, or before a repeat study in the same individual. It was shown that giving the first component alone enhanced gastric emptying by 40 % and giving second component alone increased it by 30 % while giving the two components together (before and after meals respectively) as a synergistic composition increased the emptying by almost 500 % times confirming the synergistic action of the product. The example shown in Figure 1 shows a control study Fig l(a). Each frame is of 1 minute duration obtained after giving a standard oral feed to the patient. The gastric emptying time in the patient found by computer software provided by the Gamma Camera supplier was 78 min. Repeat study with the formulation being given in the 18th minute resulted in a very significant bolus formation leaving the stomach within a few minutes. The gastric emptying increased 400 % in this patient. The example shown in Figure 2 shows graphs generated from the nuclear medicine data. The two patients are serving as self-controls. In the first case Fig 2(a), curve of falling radioactivity depicts normal gastric emptying, which enhances more than 8 times, causing 50 % gastric emptying within 3-4 minutes, with a short-lasting effect (3-4 minutes), after which 'normal1 gastric emptying is resumed. In the second case, the same protocol was followed, but this time the embodiment of the formulation was of sustained-release in nature, ensuring continuity of the effect for a longer duration. Quantification and 'proof of concept' is shown by this example. The example shown in Figure 3 shows a different type of nuclear medicine study called Tc-99m pertechnetate scintigraphy. This radioactive material is given intravenously and is excreted physiologically through gastric juice. In this patient, the upper format shows a dynamic study after injecting pertechentate intravenously. Normal uptake pattern in the stomach is seen. In the second study in the same patient (lower format), the study protocol was repeated after giving the patient a small dose of pilocarpine, a constituent of the present formulation. It is clearly seen that gastric secretion enhances more that 60 % by local action only because the effect occurred within minutes of giving a very low dose of the drug. References: 1. Cohen S., Esophageal motility disorders and their response to calcium channel antagonists; Gastroenterology 93, 201-203, 1987. 2. Snape WJ et al., Metochlopramide to treat gastroparesis due to diabetes mellitus; Ann. Intern. Med. 96, 444-446, 1982. 3. Eastwood GL., Gastritis & other gastric diseases; Internal Medicine {3rd Ed. O'Stein JH (ed.)}, Little & Brown Co., London, 338-343. Wc Claim: 1. A synergistic pharmaceutical formulation for enhancing gastric emptying and sphincter relaxation comprising of: i. a first component selected from the group consisting of calcium salt, α-receptor agonists, ß-receptor antagonists, and parasympathomimetics, or combination thereof in the range of 0.1 mg to 1000 mg; and ii. a second component selected from the group consisting of bicarbonate, calcium channel blockers, α-receptor antagonists, ß-receptor agonists, and anticholinergic drug or combination thereof in the range of 0.1 mg to 2000 mg. 2. The formulation as claimed in claim 1, wherein the first component is in the range of 1 mg to 100 mg. 3. The formulation as claimed in claim 1, wherein the second component is in the range of 1 mg to 200 mg. 4. The formulation as claimed in claim 1, wherein the bicarbonate is selected from the group consisting of sodium bicarbonate, potassium bicarbonate and bicarbonates of mono or bivalent cations. 5. The formulation as claimed in claim 1, wherein the bicarbonate is in the range of 10 mg to 500 mg. 6. The formulation as claimed in claim 1, wherein the calcium salt is selected from the group consisting of gluconate, carbonate, citrate and chloride. 7. The formulation as claimed in claim 1, wherein the calcium salt is in the range of 10 mg to 1000 mg. 8. The formulation as claimed in claim 1, wherein the parasympathomimetics is pilocarpine. 9. The formulation as claimed in claim 1, wherein the parasympathomimetic is in the range of 0.5 mg to 20 mg. 10. The formulation as claimed in claim 1, wherein the calcium channel blocker is nifedipine. 11. The formulation as claimed in claim 1, wherein the calcium channel blocker is in the range of 0.5 mg to 2 mg. 12. The formulation as claimed in claim 1, wherein the calcium salt is citrate which is in the range of 80 mg to 200 mg. 13. The formulation as claimed in claim 1 further comprising an excipient selected from the group consisting of cellulose or its derivative like ethyl cellulose, Hydroxypropyl Methyl cellulose (HPMC), lactose; glucose, Polyvinylpyrrolidone (PVP), carbopole, and guar gum or combination thereof. 14. The formulation as claimed in claim 1 which can be formulated in a form of syrup, a tablet, a capsule or a spansule. 15. The formulation as claimed in claim 1, wherein the first and the second component arc prepared independently or as a combination thereof.

Full Text

Oral formulations for enhancing gastric emptying and sphincter relaxation instantly and a process of preparation thereof FIELD OF INVENTION
The present invention relates to an oral synergistic formulation that acts within minutes of reaching the stomach and acts purely or predominantly by local action, producing a short-lasting potent effect in a low dose. The formulation thus is safe, more cost-effective and more efficacious. BACKGROUND AND PRIOR ART
Gastroparesis (slow gastric emptying) is a very frequently occurring condition, associated with various types of acute dyspepsia, nausea, chronic conditions like diabetes mellitus and renal failure. Group of drugs comprising of gastric prokinetic agents like cisapride, domperidone, metochlopramide and erythromycin are often prescribed for gastroparesis. However, in the long run the use of these drugs leads to lack of appetite, weight loss and chronic dyspepsia. The conventional prokinetic agents act systemically (pharmacological action takes place after therapeutic concentration is achieved in the blood), resulting in slow, prolonged and less potent action. As a result, a higher dose is required which is not just expensive but has higher side effects too.
It is well known that antacids like Digene, Mucain, Gelucil etc (both as tablets or liquids) acts by neutralizing the gastric acid. However, H-2 blockers like ranitidine and omaprazole group of drugs are also given to reduce the production of gastric acid.
Also it is known in the art to correct slow gastric emptying by making dietary adjustments as liquid diet has faster gastric clearance than the solid food. Oral administration of carminatives and effervescent mixtures that act by opening up the gastro-esophageal sphincter (by action of carbon dioxide gas) and release of intragastric pressure. This reduces the feeling of bloating and dyspeptic symptoms.
Also oral administration of spices and herbal extracts that have mild carminative and / or purgative action. These are also expected to reduce the gastric emptying time and the feeling of nausea and vomiting.
By administering drugs such as phenergan, stemetil provides anticholinergic or antihistaminic action.
Administration of prokinetic drugs like cisapride, domperidon, metochlopramide or

erythromycin that have gastric prokinetic action. Domperidon and metochlopramide additionally have anti-vomiting action at central level and are a preferred treatment where gastric prokinetic effect is desired for the benefit of the patient for many years.
All the above stated forms of medical treatment have one or the other lacuna. All the drugs mentioned so far except the prokinetic group deals with the resultant symptoms only and not the actual cause of the symptoms, namely, the slowdown or reversal of the gastrointestinal peristalsis. For example, antacids, H-2 blockers, carminatives, mild purgatives, digestants and anticholinergics do not address the main problem and therefore provide short-term relief while the problem persists. Hence these agents are of no practical value where gastroparesis is chronic, and may actually reduce the gastric emptying further.
Prokinetic agents, therefore, provide the mainstay of medical treatment of diseases and conditions where gastrointestinal motility either slows down or shows dysmotility. However, these are quite slow acting and require prolonged use before any clinical benefit is apparent.
The diseases associated with upper GIT motility disorders are very common and recurrent or chronic in nature, the current management is considered inadequate (though beneficial) by the experts in the art.
Whereas the morbidity caused by gastric motility disorders is widespread and associated with a number of disease conditions, many of these chronic in nature. Moreover, the drugs in prior art are either slow acting or not potent enough, or mainly address the symptoms rather than the cause, and may not be suitable as a long-term solution, it is preferable that a new line of treatment be introduced.
Antacids only provide short-term relief of symptoms pertaining to gastritis and may cause electrolyte imbalance or constipation on prolonged use. Moreover, carminatives, household and herbal concoctions have very mild action for a short interval, their efficacy and is yet to be established in long term or chronic use.
The action of anticholinergic and antihistaminic drugs are limited to slowing down peristalsis and relaxation of upper GIT resulting further enhancement in gastric emptying time, this precludes their use as prokinetic agents. A need is felt both by patients and experts of the Art for a new group of drugs that could enhance the gastric

emptying significantly and promptly mitigating the symptoms using a single or lesser number of formulations. In contrast, the present day management strategy is dependant upon a number of groups of drugs based on different therapeutic concepts, and sometimes acting at cross-purposes rather then synergistically. Many of these groups of drugs have no gastric prokinetic action what so ever but still are frequently used for. want of better alternative.
The inventors have given a great thought in the matter to develop new formulations based on a new concept considering the problems faced by the patients, those conversant with the Art, the lacunae seen and the management of conditions and diseases involving slowing down of gastrointestinal peristalsis (increased gastric emptying time) particularly when occurring frequently or in a recurrent or chronic fashion.
The present invention provides an oral formulation that acts instantly or within minutes of reaching the stomach, which is safe, cost-effective and more efficacious than the treatment options known in the art and is based on an entirely new concept and mechanism of action that has not been used therapeutically till now. Active components of the different embodiments of the formulation are well known drugs that are used independently for different purposes (other than what is intended here) but have been combined for the first time to give very clear synergistic action that is not possible without employing the particular combination of active ingredients and excipients characteristics that have been employed in the present invention.
In the present invention, oral calcium salts are given in higher doses for their systemic effect namely, bone absorption. No floating formulations of the particular calcium salts contained in the present invention have been made before nor has a therapeutic effect of floating preparation of calcium salts on gastric (fundus) musculature been previously described.
Moreover, the carminative action of bicarbonates is well known in the literature (by the action of carbon dioxide on gastro-esophageal sphincter), its action on pyloric sphincter has not been demonstrated before, nor a mucoadhesive preparation for increasing gastric emptying time has been attempted. Still further, we have demonstrated its action on sphincter of Oddi for relieving spasm which has not been demonstrated

before.
An advantage of the new concept is that it is based on synergistic action of contraction of muscles of upper part of stomach (Fundus region) and relaxation of lower portion of stomach and upper GIT (pyloric sphincter and jejunum) that propels the stomach content forward and increase the gastric emptying significantly. The action mimics the physiological process of peristalsis and is equivalent to accelerated peristalsis. The mechanism of this twin relaxation is different to that of the conventional prokinetic drugs (metrochlopramide, domperidon) which acts on central nervous system and on the upper GIT musculature through systemic route. The advantage of the present invention is that it only has a direct local action on the upper GIT musculature as specified above. OBJECTS OF THE INVENTION
The main object of the present invention is to provide a synergistic formulation for enhancing gastric emptying and sphincter relaxation comprising of two components.
Another object of the invention is to provide first component in the form of a floating formulation and second component in the form of a mucoadhesive formulation.
Yet another object of the invention is to provide both components which can be administered either individually or in combination
Another object of the invention is to provide processes for the production of both the components.
Another object of the invention is to provide the synergistic formulation in the form
of syrup, tablet, capsule, spansule, or a granule.
BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS
Figure 1 show contraction of fundus wherein (a) is for control study i.e. liquid gastric
emptying study and (b) after administering the drug to patient shows dramatic fundus
opening.
Figure 2 shows graphs generated from the nuclear medicine data; wherein
a) Curve of falling radioactivity: normal gastric emptying
b) Continuity of the effect for a longer duration.
Figure 3 is a different type of nuclear medicine study called Tc-99m pertechnetate scintigraphy showing instant enhancement of gastric juice secretion after administering the synergistic formulation.

SUMMARY OF THE PRESENT INVENTION
Accordingly, the present invention provides a synergistic pharmaceutical formulation for enhancing gastric emptying and sphincter relaxation comprising of:
i. a first component selected from a group consisting of calcium salt, ex-receptor agonists, /3-receptor antagonists, parasympathoniimetics, and a combination thereof in the range of from 0.1 mg to 1000 mg; and ii. a second component selected from a group consisting of bicarbonate, calcium channel blockers, a-receptor antagonists, /3-receptor agonists, anticholinergic drug and a combination thereof in the range of from 0.1 mg to 2000 mg.
The formulation consists of one or more preferred ingredients and employs an instant contraction of smooth muscles of the gastric fundus and simultaneous relaxation of pyloric sphincter to increase the gastric emptying many folds (by almost 500 %) by the synergistic action. Another aspect of the present invention is to provide a capsule or tablet containing both the components which can be administered either individually or in combination. DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a synergistic formulation containing two types of components: first component and second component, in the form of granules. First component contains a calcium salt, preferably calcium citrate less than 200mg as a floating preparation, while second Component contains preferably 200mg or less of sodium or potassium bicarbonate in a mucoadhesive environment produced by an appropriate combination of excipients. This combination is for mild cases. These two components can also be provided as separate tablets, one to be given before and the other one after the meals.
The synergistic formulation consists of two types of active components: First component contracts the musculature of fundus and body of stomach by local action. These include a-agonists, /3-antagonists, parasympathoniimetics, particularly pilocarpine, or direct acting drugs that contracts smooth muscles, or a combination thereof. These include particularly a salt of Calcium, preferably gluconate, citrate or chloride (0.1-500 mg), while rest of the active ingredients are preferable, particularly to

increase the strength of the contraction. The present invention discloses that pilocarpine (50-5000 microgram) in addition stimulates gastric acid production by local action.
Second component relaxes the musculature of pyloric sphincter and upper jejunum as a result of local action. These include o-antagonists, /3-agonists, anti-cholinergics, or direct acting drugs that relax smooth muscles, or a combination thereof. These particularly include bicarbonates of sodium or potassium (10-2000 mg) and calcium channel blockers, preferably nifedipine (5-3000 microgram). The invariable component of the formulation is bicarbonate, rest being preferable but optional.
First component is given as a floating formulation and second component is given as a mucoadhesive formulation. The excipients preferably include HPMC (Hydroxypropyl Methylcellulose) of different grades, other forms and derivatives of cellulose, lactose or glucose, PVP (Polyvinylpyrrolidone) of various molecular weights, carbopole of various grades, acacia, and other conventionally used base material. Citric acid or any other acidic substance is preferably added to neutralize the alkaline effect of sodium bicarbonate.
The two types of components have reverse but complimentary action, and can be given together in the same capsules as independently acting granules having different dissolution characteristics (tablet/capsule/spansule etc) or as separate entities before, during or after meals. It was shown that by giving first component alone enhanced gastric emptying by 40 % and giving second component alone increased it by 30 % while giving the two components together (before and after meals respectively) as a synergistic composition increased the emptying by almost 500 % times confirming the synergistic action of the product.
An embodiment of the present invention is to provide first component in the form of a floating preparation to be taken after meals. It consists of low dose calcium salts preferably of citrate or chloride, along with a parasympathomimetic, preferably pilocarpine, or alpha-receptor agonist or beta-receptor antagonist, or a combination thereof.
Another embodiment of the invention is to provide second component in the form of a mucoadhesive preparation to be taken before meals. It consists of low dose bicarbonates, particularly of sodium or potassium, and nifedipine or any other calcium

channel blocker, alpha-receptor antagonist, beta-receptor agonist or a direct-acting smooth muscle relaxant, or a combination thereof, shown to act locally on the pylorus.
Yet another embodiment of the present invention is to provide both the components as a single entity in the form of a capsule. The synergistic effect of both these components result in instantaneous and fast forward propulsion of gastric contents (also called gastric prokinetic action) and help in digestion. The use of such synergistic formulation is not known in the prior art.
Another embodiment of the present invention is to provide a prokinetic effect, occurring in minutes.
Another embodiment of the present invention is to provide minimum side-effects. The present invention relates to synergistic action of the two components. The action is much more effective and powerful than the existing formulations known in the art used for the purpose. The formulations are helpful in stimulating appetite and in treating gallbladder diseases, stomach-ache, dyspepsia, nausea, pyloric or sphincter of Oddi dysfunction or stenosis, anorexia, uremia, anorexia nervosa or bulimia and associated weight loss such as found in high altitude sickness. The formulations are also useful in the management of gastroparesis due to various diseases like diabetes mellitus, advanced age, autonomic system dysfunctions, abdominal surgeries and during convalescence period.
The present invention discloses the use of calcium salts for the localized effect which has never been demonstrated before in gastric disorders. The drugs and related methods known in the art have tremendous side-effects and their mode of action takes days and weeks to relieve the patient. However, the synergistic formulation acts within minutes. The presently disclosed concept of local prokinetic action and gastric acid enhancement is a new concept and the formulations constitute a new invention presently not available commercially but useful in conditions as outlined above and many more. The normal process of digestion which involves forward movement of gastric contents after mixing with the gastric juice and further movement in the small intestine is known in the prior art. The forward propulsion is a result of coordinated muscle movement of the upper gastrointestinal tract (GIT) and relaxation of the pyloric sphincter, termed 'peristalsis'.
Normal peristalsis is an automatic activity of the GIT, taking place continuously,

and smoothly, without the cognition of the person. In abnormal cases, however, the peristalsis gets slowed down, becomes chaotic, or may even follow reverse direction. The former condition gives rise to symptoms of anorexia, fullness of stomach, sense of bloating and results in abnormally prolonged gastric emptying time. This may cause the feeling of nausea and vomiting. These conditions are associated with a number of acute or chronic diseases like dyspepsia, gastritis, duodenal and gastric ulcer, diabetes mellitus, uremia, mountain sickness, old age, psychosomatic disorders like bulimia and anorexia nervosa, as radiation or drug-induced reaction and a variety of other morbid conditions including gallbladder dysfunctions, post-cholecystectomy syndrome, post-surgery convalescence period. The abnormality of peristalsis and slow gastric emptying results in loss of weight and in the long run leads to reduction in the quality of life.
The present invention relates to a novel formulation of combination of both the components which have been made for a novel effect. The synergistic novel effect of both the components have shown to enhance the gastric emptying time. Similarly, the local therapeutic effect of the formulation has been demonstrated for which there was no formulation till now.
The present invention relates to a formulation that contains many active components which act at different sites within the stomach resulting in significantly enhanced gastric emptying and therefore have different formulation characteristics. Fast gastric emptying results due to contraction of smooth muscles of the upper portion of the stomach in synchrony with opening of the pylorus of the stomach. This happens by a local action because the concentration of the active ingredients in proximity to the site of action becomes more than what is required for the therapeutic action to set in, the action is almost instantaneous and short-lived (unless changed into a SR formulation) (Fig 1-3).
One of the preferred embodiments is the capsule or tablet containing both the components, where different active ingredients are made separately in the form of separate capsules having different dissolution and adhesive properties.
Another preferred embodiment is packing of different components in separate capsules or tablets to be taken before or after meals to provide the desired effect.
Yet another preferred embodiment is packing of both the components in a single capsule to be administered before the meal.

EXAMPLES
The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and the description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as there invention nor are they intended to represent that the experiments below are all and only experiments performed. Efforts have been made to ensure accuracy with respect to figures used.
Example 1: Process to prepare Oral Formulations a) Preparation of first component:
The first component contains the following:

(Table Removed) Accurately weigh all the ingredients. Sift HPMC, lactose and glucose through Sieve number 40 and mix in a blender. Sift the calcium carbonate and pilocarpine through mesh number 60 and mix with the mixture containing HPMC, lactose and glucose.
The blend is filled in the empty gelatin capsules through a filling machine. For making granules, the blend is passed through a sluggish machine or a compactor. The slug or compact so obtained is passed through an oscillatory granulator using 1 mm screen. The mixture is added to a glident and filled in gelatin capsules. b) Preparation of second component: The second component contains the following:

(Table Removed) Accurately weigh all the ingredients. Sift amlodepine and sodium bicarbonate through a Mesh number 60. Sift citric acid and guar gum through mesh number 40. Mix both in a blender for 5 minutes. Dissolve PVP in a sufficient quantity of water and granulate the above mixture. Dry the granules at 60 °C for 2 hours in a tray drier. Sift dried granules through mesh number 20 and mix with cellulose, glident and lubricant (Img stearate and 1% talc). If the granules are to be dispensed as a tablet, compress these using proper tools.
Example 2: Process to prepare Oral Formulations a) Preparation of first component:
The first component contains the following:

(Table Removed) Accurately weigh all the ingredients. Sift HPMC, lactose and glucose through Sieve number 40 and mix in a blender. Sift the calcium citrate through mesh number 60 and mix with the mixture containing HPMC, lactose and glucose.
The blend is filled in the empty gelatin capsules through a filling machine. For making granules, the blend is passed through a sluggish machine or a compactor. The slug or compact so obtained is passed through an oscillatory granulator using 1 mm screen. The mixture is added to a glident and filled in gelatin capsules. b) Preparation of second component: The second component contains the following:

(Table Removed)Accurately weigh all the ingredients. Sift nifedipine and sodium bicarbonate through a Mesh number 60. Sift citric acid and guar gum through mesh number 40. Mix both in a blender for 5 minutes. Dissolve PVP in a sufficient quantity of water and granulate the above mixture. Dry the granules at 60 °C for 2 hours in a tray drier. Sift dried granules through mesh number 20 and mix with cellulose, glident and lubricant (Img stearate and 1% talc). If the granules are to be dispensed as a tablet, compress these using proper tools.
Example 3:
Using Examples 1 and 2 first component and second component were manufactured and using the same 24 patients or volunteers were screened with the medication and effects of the formulation were noted objectively by nuclear medicine technique; the method has confirmed contraction of fundus by the first component and relaxation of pylorus by the second component (figure 1).18 of the 24 tested patients demonstrated the effect that gastric emptying increased significantly within minutes of taking the formulation. Nuclear medicine scans are considered as the gold-standard to monitor and quantify changes in gastric emptying in humans. For this, a standard radioactive meal is given to the patient/ volunteer and imaging is started. Imaging for several minutes gives the gastric emptying rate quantitatively. Any drug to be tested for action on gastric emptying can be given thereafter in the same sitting if it is fast-acting, or before a repeat study in the same individual. It was shown that giving the first component alone enhanced gastric emptying by 40 % and giving second component alone increased it by 30 % while giving the two components together (before and after meals respectively) as a synergistic composition increased the emptying by almost 500 % times confirming the synergistic action of the product.
The example shown in Figure 1 shows a control study Fig l(a). Each frame is of 1 minute duration obtained after giving a standard oral feed to the patient. The gastric emptying time in the patient found by computer software provided by the Gamma Camera supplier was 78 min. Repeat study with the formulation being given in the 18th minute

resulted in a very significant bolus formation leaving the stomach within a few minutes. The gastric emptying increased 400 % in this patient.
The example shown in Figure 2 shows graphs generated from the nuclear medicine data. The two patients are serving as self-controls. In the first case Fig 2(a), curve of falling radioactivity depicts normal gastric emptying, which enhances more than 8 times, causing 50 % gastric emptying within 3-4 minutes, with a short-lasting effect (3-4 minutes), after which 'normal1 gastric emptying is resumed. In the second case, the same protocol was followed, but this time the embodiment of the formulation was of sustained-release in nature, ensuring continuity of the effect for a longer duration. Quantification and 'proof of concept' is shown by this example.
The example shown in Figure 3 shows a different type of nuclear medicine study called Tc-99m pertechnetate scintigraphy. This radioactive material is given intravenously and is excreted physiologically through gastric juice. In this patient, the upper format shows a dynamic study after injecting pertechentate intravenously. Normal uptake pattern in the stomach is seen. In the second study in the same patient (lower format), the study protocol was repeated after giving the patient a small dose of pilocarpine, a constituent of the present formulation. It is clearly seen that gastric secretion enhances more that 60 % by local action only because the effect occurred within minutes of giving a very low dose of the drug.
References:
1. Cohen S., Esophageal motility disorders and their response to calcium channel
antagonists; Gastroenterology 93, 201-203, 1987.
2. Snape WJ et al., Metochlopramide to treat gastroparesis due to diabetes mellitus; Ann.
Intern. Med. 96, 444-446, 1982.
3. Eastwood GL., Gastritis & other gastric diseases; Internal Medicine {3rd Ed. O'Stein JH
(ed.)}, Little & Brown Co., London, 338-343.

Wc Claim:
1. A synergistic pharmaceutical formulation for enhancing gastric emptying and sphincter
relaxation comprising of:
i. a first component selected from the group consisting of calcium salt, α-receptor agonists, ß-receptor antagonists, and parasympathomimetics, or combination thereof in the range of 0.1 mg to 1000 mg; and
ii. a second component selected from the group consisting of bicarbonate, calcium channel blockers, α-receptor antagonists, ß-receptor agonists, and anticholinergic drug or combination thereof in the range of 0.1 mg to 2000 mg.
2. The formulation as claimed in claim 1, wherein the first component is in the range of 1 mg to 100 mg.
3. The formulation as claimed in claim 1, wherein the second component is in the range of 1 mg to 200 mg.
4. The formulation as claimed in claim 1, wherein the bicarbonate is selected from the group consisting of sodium bicarbonate, potassium bicarbonate and bicarbonates of mono or bivalent cations.
5. The formulation as claimed in claim 1, wherein the bicarbonate is in the range of 10 mg to 500 mg.
6. The formulation as claimed in claim 1, wherein the calcium salt is selected from the group consisting of gluconate, carbonate, citrate and chloride.
7. The formulation as claimed in claim 1, wherein the calcium salt is in the range of 10 mg to 1000 mg.
8. The formulation as claimed in claim 1, wherein the parasympathomimetics is pilocarpine.
9. The formulation as claimed in claim 1, wherein the parasympathomimetic is in the range of 0.5 mg to 20 mg.
10. The formulation as claimed in claim 1, wherein the calcium channel blocker is nifedipine.
11. The formulation as claimed in claim 1, wherein the calcium channel blocker is in the range of 0.5 mg to 2 mg.
12. The formulation as claimed in claim 1, wherein the calcium salt is citrate which is in the range of 80 mg to 200 mg.
13. The formulation as claimed in claim 1 further comprising an excipient selected from the group consisting of cellulose or its derivative like ethyl cellulose, Hydroxypropyl Methyl cellulose (HPMC), lactose; glucose, Polyvinylpyrrolidone (PVP), carbopole, and guar gum or combination thereof.
14. The formulation as claimed in claim 1 which can be formulated in a form of syrup, a tablet, a capsule or a spansule.
15. The formulation as claimed in claim 1, wherein the first and the second component arc prepared independently or as a combination thereof.

Documents:

40-DEL-2006-Abstract-(09-04-2012).pdf

40-del-2006-abstract.pdf

40-DEL-2006-Claims-(09-04-2012).pdf

40-del-2006-claims.pdf

40-DEL-2006-Correspondence Others-(09-04-2012).pdf

40-del-2006-correspondence-others.pdf

40-del-2006-description (complete).pdf

40-del-2006-drawings.pdf

40-del-2006-form-1.pdf

40-del-2006-form-2.pdf

40-del-2006-form-26.pdf

40-del-2006-form-3.pdf

40-del-2006-form-5.pdf

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Patent Number

255262

Indian Patent Application Number

40/DEL/2006

PG Journal Number

06/2013

Publication Date

08-Feb-2013

Grant Date

07-Feb-2013

Date of Filing

04-Jan-2006

Name of Patentee

DIRECTOR GENERAL , DEFENCE RESEARCH & DEVELOPMENT ORGANISATION

Applicant Address

MINISTRY OF DEFENCE, GOVT.OF INDIA WEST BLOCK-VIII, WING-1 SECTOR 1 R.K. PURAM, NEW DELHI-110066

Inventors:

#	Inventor's Name	Inventor's Address
1	FARHAN JALEES AHMED	JAMIA HAMDARD, NEW DELHI
2	ROOP KRISHAN KHAR	JAMIA HAMDARD, NEW DELHI
3	PREMASHISH KAR	LNJP HOSPITAL, NEW DELHI
4	KRISHAN SAWROOP	INMAS, DELHI
5	ASEEM BHATNAGAR	INMAS, DELHI

PCT International Classification Number

A61K 38/26

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA