WO2020056036A1 - Compositions for treating gastroesophageal reflux and barrett's esophagus - Google Patents
Compositions for treating gastroesophageal reflux and barrett's esophagus Download PDFInfo
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- WO2020056036A1 WO2020056036A1 PCT/US2019/050670 US2019050670W WO2020056036A1 WO 2020056036 A1 WO2020056036 A1 WO 2020056036A1 US 2019050670 W US2019050670 W US 2019050670W WO 2020056036 A1 WO2020056036 A1 WO 2020056036A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
- A61K9/0058—Chewing gums
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
Definitions
- the present disclosure consists of therapeutically-active compositions for treating pain, irritation, and inflammation associated with gastroesophageal reflux and Barrett’s esophagus that combines strontium either in salt or complex form, at least one acid neutralizing or acid reducing agent, and chlorogenic acid.
- Optional therapeutic agents include (but not limited to): at least one amino acid derivative or metabolite, at least one methoxyflavonoid, at least one vitamin, and at least one polymer.
- Gastroesophageal reflux commonly referred to as heartburn, is the movement of acidic material from the stomach back into the esophagus.
- Common symptoms of GER include, but are not limited to, burning-type pain in the lower part of the mid-chest, behind the breast bone, and in the mid-abdomen, sore throat, coughing, and water brash, the sensation of a bitter taste in the mouth.
- GER is usually a temporary condition that causes no lasting damage to the affected tissues.
- chronic bouts of GER leads to severe damage to the esophageal lining, a condition referred to as gastroesophageal reflux disease (GERD). If GERD is left untreated, the continual damage to the esophageal lining can develop into Barrett’s esophagus, a precancerous condition that can lead to esophageal cancer.
- SAGES The American Gastrointestinal Endoscopic Surgeons
- Barrett’s esophagus sometimes called Barrett’s syndrome or columnar epithelium lined lower esophagus (CELLO) refers to an abnormal change (metaplasia) in the cells of the lower portion of the esophagus. Specifically, the esophageal tissue changes into tissue that is similar to intestinal lining. The main cause of Barrett’s esophagus is believed to be an adaptation to chronic acid exposure from acid reflux. Barrett’s esophagus is found in 5-10% of patients who seek medical care for GER. People with Barrett’s esophagus are at an increased risk for developing esophageal adenocarcinoma.
- GER over the counter
- H2RA histamine H2 receptor antagonists
- An additional class of treatment seeks to physically block acid reflux by using a seaweed-derived carbohydrate polymer, alginic acid that floats on the surface of stomach contents and physically blocks their passage into the esophagus.
- compositions and formulation disclosed herein provide a new therapeutic approach to treating GER, GERD, and Barrett’s esophagus by using a combination of ingredients that reduce the pain and inflammation by blocking the acid and inflammation-inducing biochemical pathways at multiple points and thereby provide and overall therapeutic benefit far greater than any individual ingredient.
- a particularly advantageous property of this invention is that each of the ingredients that provide therapeutic benefits in the present invention (e.g.
- strontium, chlorogenic acid, agmatine, ascorbic acid, and calcium carbonate as one exemplary ingredient combination are found in foods that are consumed every day in typical meals and for this reason lack the potential adverse reactions that can occur with the use of synthetic ingredients like histamine H2 receptor antagonists and proton pump inhibitors. Since most GER patients consume a GER treatment one or more times daily and for many patients, for their lifetime, the inherent safety of the ingredients used in the present invention provide a substantial medical benefit over the most commonly used conventional GER treatments.
- the present disclosure relates generally to compositions of a strontium salt and at least one additional ingredient such as chlorogenic acid, a vitamin, an amino acid derivative or metabolite, or a methoxyflavonoid.
- the strontium salt is strontium carbonate, strontium bicarbonate, strontium hydroxide, strontium phosphate, strontium lactate, strontium citrate, strontium chloride, strontium sulfate, strontium nitrate, strontium hydrosulfide, strontium oxide, strontium acetate, strontium glutamate, strontium aspartate, strontium malonate, strontium maleate, strontium threonate, strontium lactate, strontium pyruvate, strontium ascorbate, strontium alpha-ketoglutarate or strontium succinate.
- the at least one vitamin is ascorbic acid.
- the at least one amino acid derivative or metabolite is kynurenic acid and/or agmatine.
- the at least one methoxyflavonoid is tangeretin or nobiletin.
- the additional ingredient is chlorogenic acid.
- the additional ingredient is agmatine.
- the additional ingredient is kynurenic acid.
- the present disclosure also relates generally to complexes of a divalent cationic strontium and at least two counter compounds.
- the at least two counter compounds are selected from chlorogenic acid, a vitamin, an amino acid derivative or metabolite, or a methoxyflavonoid.
- the strontium ion is from a strontium salt.
- the strontium salt is strontium carbonate, strontium bicarbonate, strontium hydroxide, strontium phosphate, strontium lactate, strontium citrate, strontium chloride, strontium sulfate, strontium nitrate, strontium hydrosulfide, strontium oxide, strontium acetate, strontium glutamate, strontium aspartate, strontium malonate, strontium maleate, strontium threonate, strontium lactate, strontium pyruvate, strontium ascorbate, strontium alpha- ketoglutarate or strontium succinate.
- the at least one vitamin is ascorbic acid.
- the at least one amino acid is kynurenic acid and/or agmatine. In one embodiment, the at least one methoxyflavonoid is tangeretin or nobiletin.
- the strontium is complexed to two chlorogenic acid molecules. In another embodiment the strontium is complexed to two kynurenic acid molecules. In another embodiment the strontium is complexed to two agmatine molecules. In another embodiment the strontium is complexed to two ascorbic acid molecules. In another embodiment, three strontium ions are complexed to two citrate molecules. In another embodiment the strontium is complexed to chlorogenic acid and agmatine. In another embodiment the strontium is complexed to chlorogenic acid and kynurenic acid. In another embodiment the strontium is complexed to chlorogenic acid and ascorbic acid.
- the strontium is complexed to kynurenic acid and ascorbic acid. In another embodiment the strontium is complexed to agmatine and ascorbic acid. In another embodiment the strontium is complexed to agmatine and kynurenic acid.
- the foregoing compositions also include an acid neutralizing agent.
- the acid neutralizing agent is aluminum carbonate, aluminum hydroxide, dihydroxyaluminum aminoacetate, aluminum phosphate, di hydroxy alumium sodium carbonate, magnesium carbonate, sodium bicarbonate, bismuth aluminate, bismuth carbonate, bismuth subcarbonate, bismuth subgallate, bismuth submitate, calcium carbonate, calcium phosphate, tricalcium phosphate, citric acid, trisodium citrate, glycine, magnesium aluminate, magaldrate, magnesium aluminosilicates, magnesium carbonate, magnesium glycinate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, milk solids, potassium bicarbonate, sodium potassium tartrate, tartaric acid, potassium bitartrate, magaldrate, almagate, or hydrotalcite.
- the acid neutralizing agent is aluminum carbonate.
- the acid neutralizing agent is aluminum
- the acid neutralizing agent is dihydroxyaluminum aminoacetate. In another embodiment, the acid neutralizing agent is aluminum phosphate. In another embodiment, the acid neutralizing agent is dihydroxyalumium sodium carbonate. In another embodiment, the acid neutralizing agent is magnesium carbonate. In another embodiment, the acid neutralizing agent is sodium bicarbonate. In another embodiment, the acid neutralizing agent is bismuth aluminate. In another embodiment, the acid neutralizing agent is bismuth carbonate. In another
- the acid neutralizing agent is bismuth subcarbonate. In another embodiment, the acid neutralizing agent is bismuth subgallate. In another embodiment, the acid neutralizing agent is bismuth submitate. In another embodiment, the acid neutralizing agent is calcium carbonate.
- the acid neutralizing agent is calcium phosphate.
- the acid neutralizing agent is tricalcium phosphate. In another embodiment, the acid neutralizing agent is citric acid. In another embodiment, the acid neutralizing agent is trisodium citrate. In another embodiment, the acid neutralizing agent is glycine. In another embodiment, the acid neutralizing agent is magnesium aluminate. In another embodiment, the acid neutralizing agent is magaldrate. In another embodiment, the acid neutralizing agent is magnesium aluminosilicates. In another embodiment, the acid neutralizing agent is magnesium carbonate. In another embodiment, the acid neutralizing agent is magnesium glycinate, magnesium hydroxide. In another embodiment, the acid neutralizing agent is magnesium oxide. In another embodiment, the acid neutralizing agent is magnesium trisilicate. In another embodiment, the acid neutralizing agent is milk solids.
- the acid neutralizing agent is potassium bicarbonate. In another embodiment, the acid neutralizing agent is sodium potassium tartrate. In another embodiment, the acid neutralizing agent is tartaric acid. In another embodiment, the acid neutralizing agent is potassium bitartrate. In another embodiment, the acid neutralizing agent is magaldrate. In another embodiment, the acid neutralizing agent is almagate. In another embodiment, the acid neutralizing agent is
- the foregoing composition also includes an acid reducing agent.
- the acid reducing agent is cimetidine, famotidine, nizatidine, rantidine, omeprazole, lansoprazole, rabeprazole, pantoprazole, or esomeprazole.
- the acid reducing agent is cimetidine.
- the acid reducing agent is famotidine.
- the acid reducing agent is nizatidine.
- the acid reducing agent is rantidine.
- the acid reducing agent is omeprazole.
- the acid reducing agent is lansoprazole.
- the acid reducing agent is rabeprazole.
- the acid reducing agent is pantoprazole.
- the acid reducing agent is esomeprazole.
- the foregoing compositions also include at least one polymer.
- the polymer is alginic acid, polyvinylpyrrolidone (PVP), or xanthan gum.
- the polymer is alginic acid.
- the polymer is PVP.
- the polymer is xanthan gum.
- the foregoing compositions also include excipients needed to formulate the compositions into a final dosage form.
- additional excipients are added to formulate the foregoing compositions into a chewable tablet.
- additional excipients are added to formulate the foregoing compositions into a gummy dosage form to enable the ingredients to be released into the esophagus not as a bolus but instead in an extended release manner.
- additional excipients are added to formulate the foregoing compositions into a chewy tablet.
- additional excipients are added to formulate the foregoing compositions into a chewing gum.
- additional excipients are added to formulate the foregoing compositions into a lozenge.
- additional excipients are added to formulate the foregoing compositions into a spray.
- compositions and formulations can be used to treat or prevent the symptoms associated with GER, GERD, or Barrett’s esophagus in a patient.
- the patient is treated by consuming the above described compositions and formulations.
- the patient is treated by taking the compositions and formulations after eating but before the onset of symptoms, for example, taking the compositions and formulation within an hour or within 30 minutes after a meal.
- the patient is treated by taking the compositions and formulations after the onset of symptoms.
- the patient is treated by taking the compositions and formulations up to an hour before eating.
- the compositions and formulations are taken sequentially to maximize the exposure of the compositions and formulations to the esophagus.
- the present disclosure relates to compounds for use in treating symptoms associated with gastroesophageal reflux (GER), gastroesophageal reflux disease (GERD), Barrett’s esophagus and other related conditions (all referred to as“GER” herein unless otherwise indicated).
- GER gastroesophageal reflux
- GERD gastroesophageal reflux disease
- Barrett’s esophagus and other related conditions (all referred to as“GER” herein unless otherwise indicated).
- GER, GERD, and Barrett’s esophagus are caused by reflux of acidic stomach contents through the lower esophageal sphincter (LES) that activate Type C nociceptors in the esophageal mucosa that transmit burning pain signals to the brain.
- Acid-induced pain is triggered by activation of a family of acid-sensitive ion channels (ASIC) that are present on the surface of nociceptors, immune white blood cells and on epithelial cells in the esophagus, and on fibroblasts, keratinocytes and vascular endothelial cells throughout the body.
- ASIC acid-sensitive ion channels
- the pain sensation of GER is characterized as a diffuse burning sensation in the chest and most often occurs when a person is in a recumbent position that facilitates the‘reflux passage’ of hydrochloric acid in the stomach contents through the LES in to the esophagus that is highly sensitive to acidic pH and partially disgusted food.
- the rapid pain relief that occurs by neutralization of stomach acid by ‘antacids’ demonstrated that GER pain is predominantly triggered by acid contacting the nociceptors of the esophagus.
- many food ingredients with a spicy taste also exacerbate pain by activating ion channels that are sensitive to both acid and certain chemically reactive ingredients such as capsaicin.
- Type C nociceptors are strongly activated as occurs in acid reflux, multiple powerful inflammatory molecules are released that further activate nociceptor pain signals and activate inflammatory cells such as mast cells, neutrophils and other immune white blood cells including monocytes, macrophages and lympocytes.
- These inflammatory substances released by Type C nociceptors included Substance P, Neurokinin A, Calcitonin Gene-Related Peptide (CGRP), glutamic acid and ATP.
- Glutamic acid is the predominant excitatory neurotransmitter in the peripheral and central nervous system and binds to and activates multiple receptors including the NMD A, AMPA and Kinate receptors that directly and indirectly trigger further activation of pain and inflammation in nociceptors and multiple immune cells and‘structural cells’ including fibroblasts, mucosal cells, vascular endothelial cells and other cells that are damaged by inflammation.
- Antacids that elevate the pH of the naturally acidic stomach fluid.
- the pH of an empty stomach is typically between 1.5 and 3 and is entirely due to the hydrochloric acid secreted by the parietal cells in the stomach.
- Antacid ingredients are inherently basic and thus acid-neutralizing and include calcium carbonate, salts of bicarbonate and magnesium and aluminum hydroxides.
- PPI Proton pump inhibitors
- a third class of commonly used acid- blocking drugs are the histamine-2 receptor antagonists or ⁇ -2 Blockers.’ After oral ingestion these drugs are absorbed into the blood and bind to and block the histamine-2 receptor of the acid-secreting parietal cells, thus inhibiting baseline and stimulated acid secretion into the stomach.
- H-2 Blockers include; cimetidine, famotidine, nizatidine and ranitidine.
- a fourth class of GER medication uses the natural ingredient, alginic acid, that is a negatively charged carbohydrate polymer extracted from brown seaweed. It has a unique, non acid neutralizing or acid blocking mechanism unlike any other treatment. When exposed to acid in the stomach, alginic acid forms a gel that floats on the surface of the stomach contents and creates a physical gel barrier that blocks the lower entry of the LES and physically prevents reflux of the stomach contents into the sensitive esophagus. While alginic acid has no acid neutralizing activity and has no effect on acid secretion, it has been shown to be effective in treating symptoms of GER.
- alginic acid Due to its polyanionic carbohydrate structure, alginic acid is an effective carrier for carbonate and bicarbonate antacids that, in combination, provide a more effective treatment.
- Each of the above treatments represent the‘state-of-the-therapeutic-art’ approaches for treating GER.
- the therapeutic targets are components of the stomach.
- Antacids target stomach acid and act in the stomach by neutralizing hydrochloric acid
- PPFs and H-2 blockers act directly on the acid-secreting parietal cells of the stomach to inhibit acid secretion
- alginic acid acts in the stomach to physically block reflex of stomach acid and food content. Consequently, each of the four treatment approaches only target stomach acid that only indirectly treat the mechanisms within the esophagus that trigger GER that may lead to Barrett’s Esophagus.
- the present disclosure provides a unique therapeutic strategy unlike any other GER treatment. None of these approaches target the actual‘shock organ’ that directly cause the signs and symptoms of GER, the cellular lining of the esophagus. Nor do any of these treatment approaches target the chronic inflammatory changes that lead to Barrett’s Esophagus, a pre- cancerous condition caused by chronic esophageal inflammation. While the indirect treatment in the stomach that reduces stomach acid or blocks its reflux can significantly reduce GER symptoms, the effect has only a limited duration. Furthermore, chronic GER increases the sensitivity of the inflamed esophageal mucosa to acid-induced pain and increases the severity of GER.
- the approach of the present disclosure is distinct from any current treatment.
- the present disclosure directly targets the esophageal mucosa to reduce pain and inflammation by inhibiting the most important known biochemical pathways and inflammatory mediators and cytokines that cause inflammation and pain.
- the chemical properties of the compound of the present disclosure can be combined with one or more of the above conventional treatments to provide an unprecedented level of efficacy and safety.
- the advantage of the present disclosure is the fact that each of the compounds used are naturally occurring in the body and/or some are ingested on a daily basis in foods or in nutritional supplements, frequently at high levels that exceed those used in the present disclosure. These ingredients not only have pleiotropic and potent anti-pain and anti-inflammatory activities but, in combination have anti cancer activities as well.
- H2RA histamine H2 receptor antagonists
- the present disclosure presents a different pharmacological approach that can achieve both high efficacy and substantially reduce adverse reactions. Instead of using a single highly potent drug to block acid secretion that will indirectly reduce pain and inflammation, the present disclosure uses several relatively low potency ingredients that block critical pain and
- inflammation pathway regulatory proteins and multiple points in each pathway.
- the result is partial inhibition of a particular regulatory protein, thus allowing it to function at a reduced level and continue to regulate other parallel pathways that are not inflammation and pain generators.
- the net effect on the pathway will be substantially greater due to the multiple levels of inhibition.
- By preserving the activity of partially blocked regulatory protein it can continue to participate in the regulation of other pathways and thereby reduce the potential for toxic or adverse reactions. In a metaphoric sense, this is akin to turning down the volume of a radio instead of shutting it off completely.
- the Present disclosure also reduces the increased sensitivity of nociceptors that are the first trigger of pain and inflammation.
- Type C nociceptors When Type C nociceptors are strongly activated as occurs in acid reflux, they rapidly become sensitized and thus an activation stimulus that would normally only cause minimal pain will produce a much higher level of pain and increased release of the aforementioned inflammatory mediators including Substance P.
- Two forms of sensitization occur: (1) immediate peripheral sensitization of the endings of the nociceptors that reach to the highest levels of a viable mucous membrane. This immediate sensitization can occur within minutes and may last for many hours.
- central sensitization occurs in the Dorsal Root Ganglia (DRG) within which peripheral nociceptors synapse and pain signals are retransmitted to the spinal cord and to the brain.
- DRG Dorsal Root Ganglia
- the transition of acute pain into chronic pain occurs due to such central sensitization and is the proximate cause of chronic pain conditions, including pain that occurs from GERD.
- Such chronic pain and the associated release of multiple inflammation mediators produces a long-term pain-triggering‘set-point’ that is very difficult, if not impossible to effectively treat with conventional GERD treatments.
- the present disclosure provides ingredients that are known to be able to prevent and reverse central sensitization of nociceptors and thus prevent and reverse chronic pain states and related inflammation.
- the Present disclosure optimally uses multiple ingredients that each reduce acid-induced pain and inflammation by different mechanisms. Additionally each ingredient partially inhibits the pathways inhibited by of each of the other ingredients, thus providing a unique synergy of therapeutic activity.
- the compounds consist of therapeutically-active compositions that combine strontium either in salt or complex form with at least one acid neutralizing or acid reducing agent and chlorogenic acid.
- the compounds optionally include additional therapeutic agents including, but not limited to at least one amino acid derivative, in particular agmatine and/or kynurenic acid, at least one methoxyflavonoid, at least one vitamin, in particular ascorbic acid, and at least one polymer.
- additional therapeutic agents including, but not limited to at least one amino acid derivative, in particular agmatine and/or kynurenic acid, at least one methoxyflavonoid, at least one vitamin, in particular ascorbic acid, and at least one polymer.
- the combination increases the overall therapeutic potency of the combination beyond the potency of any of the separate constituents. Specifically, the
- invention or“present invention” as used herein are intended to be non limiting and are not intended to refer to any single embodiment of the particular invention but encompasses all possible embodiments as described in the specification and the claims.
- the term“and/or” may mean“and,” it may mean“or,” it may mean “exclusive-or,” it may mean“one,” it may mean“some, but not all,” it may mean“neither,” and/or it may mean“both.”
- treatment means any manner in which the symptoms of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also
- GER gastroesophageal reflux
- GORD gastro-esophageal reflux disease
- acid neutralizing refers to a chemical agent that is capable of reducing the acidity of a liquid. The chemical does not need to be able to bring the acid to a complete neutral state.
- acid neutralizing agents include salts of carbonates, bicarbonates, hydroxides, phosphates, and citrates.
- acid reducing refers to a chemical agent that is capable to reducing the production of stomach acid.
- acid reducing agents include histamine H2 receptor antagonists and proton pump inhibitors.
- each center may independently be of R-configuration or S-configuration or a mixture thereof.
- the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture.
- each double bond may independently be E or Z a mixture thereof.
- the term ‘including’ should be read to mean‘including, without limitation,’‘including but not limited to,’ or the like;
- the term‘comprising’ as used herein is synonymous with‘including,’‘containing,’ or‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps;
- the term‘having’ should be interpreted as‘having at least;’ the term ‘includes’ should be interpreted as‘includes but is not limited to;’ the term‘example’ is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; adjectives such as‘known’,‘normal’,‘standard’, and terms of similar meaning should not be construed as limiting the item described to a given time period or to an item available as of a given time, but instead should be read to encompass known, normal, or standard technologies that may be available or known now or at any time in the future; and use of terms like ‘preferably,’‘preferred,’‘desi
- a group of items linked with the conjunction‘and’ should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as ‘and/or’ unless expressly stated otherwise.
- a group of items linked with the conjunction‘or’ should not be read as requiring mutual exclusivity among that group, but rather should be read as‘and/or’ unless expressly stated otherwise.
- the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates.
- the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, or the like.
- the compounds described herein exist in unsolvated form.
- Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
- the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
- Nociception is the neural processes of encoding and processing stimuli that have the potential to damage tissue.
- Nociceptors are specialized nerves located throughout the body that detect mechanical, thermal or chemical changes. There are two classes of nociceptors, the first class is“A-delta” nerves, which respond to physical trauma by transmitting a pain sensation with a sharp, pricking quality. The second class is“Type C” nerves (TCN), which are chemical sensors that respond to irritants from our environment, such as microbes, temperature extremes, and ionizing radiation and transmit diffuse sensations of burning pain, stinging pain or itching (“irritation”).
- TCN Type C nerves
- TCN When excessively stimulated, TCN can also release neuropeptides (e.g Substance P) that directly activate histamine-containing mast cells and attract and activate other immune system cells such as neutrophils that cause redness, swelling and even local tissue damage.
- neuropeptides e.g Substance P
- nociceptors After activation by a stimuli, nociceptors synapse near the spinal cord in the dorsal root ganglia (DRG) and release neurotransmitters that activate nerve pathways that relay signals to the brain.
- DRG dorsal root ganglia
- the brain interprets the signals as various types of pain or itch.
- Exposure to stimuli activates nociceptors.
- both types of nociceptors may be activated or in many instances either the A-delta or TCN are preferentially activated.
- TCNs extend to the outermost portions of the body, such as the skin, mouth, nose, throat, eyes, etc. (herein referred to as“epithelium”) and may be activated by virtually any process that changes the local biochemistry of the epithelium, TCNs are preferentially activated in response to most irritating stimuli.
- the TCNs Upon activation of TCNs, the TCNs transmit a signal to the spinal cord and trigger neurotransmitter release in the DRG that activate nerves in the spinal cord that relay the pain and itch signals to the brain.
- TCNs Acute activation of TCNs that is caused by exposure to a chemical irritant, such as stomach acid, typically causes painful or pruritic sensations that last only several days and is termed “nociceptive pain”. When the stimulus is prolonged or excessively severe, painful sensations or pruritus can continue for many years. Such chronic pain or pruritus caused by excessive nociceptor activation or damage is termed“neuropathic” and is among one of the most difficult conditions to treat.
- Nociceptive Signals are Typically Encoded as Precisely-Timed Changes of Intracellular Calcium Concentration that Travel as“Calcium Waves” within Nociceptors
- the intensity of the signal (e.g the severity of pain or pruritus) is encoded as a change in frequency of calcium waves that trigger neurotransmitters that are released into the synapse and activate post-synaptic nerves that relay the information ultimately to the brain.
- the calcium signal is transmitted through multiple biochemical pathways, many of which operate in sequence such that the output of one pathway becomes the input of the next.
- nociceptors In order for a neuropathic condition to develop, nociceptors must be continuously activated by a potent stimulus. The duration of the activation required may substantially vary depending on the specific nerve injury or stimulant. When such activation occurs, the peripheral nociceptors that innervate the epithelium and mucous membranes such as those of the esophagus may become sensitized within hours and may continue to increase their sensitivity to irritants and may even be activated by stimuli that are normally not irritating. Release of multiple inflammatory mediators that accompany any trauma or inflammation are also important contributors to sensitization.
- neuropathic state In order to establish a neuropathic state, sensory nerves in the DRG that receive sensory input from the TCN must also become sensitized. As for the peripheral TCN, the central neurons require sustained, high intensity activation for an extended period of time that may be as short as several weeks or much longer. The presence of inflammation, infectious agents, or trauma can accelerate the sensitized, neuropathic state. Due to neuronal“cross-talk,” it is common for an initially small painful portion of sensitized tissue, for example, as occurs in post-herpetic neuralgia, to expand to the adjacent tissue via nociceptors that were uninjured, including A-delta nociceptors. Sensitized neuropathic tissue may also generate painful stimuli in response to mechanical pressure, e.g. coughing or swallowing, or temperature changes, a condition known as allodynia.
- the sensitized state in both the peripheral nociceptors and their central counterparts is a form of activity-dependent plasticity that is very similar to the neurons in the CNS that form memories.
- the nociceptive response produces a “memory of pain or itching.”
- the molecules and pathways that produce the long-lasting neuronal sensitization are reasonably well defined.
- the activation of intracellular kinases Of particular importance are protein kinase A and C (PKA and PKC, respectively), each of which exist in several different forms and the mitogen activated protein kinases (MAPK) that include the p38 MAPK, ERK1/2 MAPK and the JNK MAPK.
- PKA and PKC protein kinase A and C
- MAPK mitogen activated protein kinases
- kinases are activated by a broad range of environmental“danger signals” and internal cytokines and growth factors exposures including ionizing radiation, reactive oxygen species (ROS) always accompany infection and trauma.
- ROS reactive oxygen species
- these kinases are activated in multiple pathways and give rise to sequential cascades that result in regulation and activation of genes that regulate well over 100 different molecules that activate immune cells, produce inflammation and molecules that influence ion channels, and molecular sensors that cause the peripheral and central nociceptor sensitization that causes neuropathic pain and pruritus.
- NF-Kappa B the“Master Gene Regulator of Inflammation.”
- some of these kinases like PKC can directly sensitize and activate nociceptors that cause calcium influx and interfere with strontium’s ability to alter the calcium dynamics that occur in neuropathic states.
- the redox state of a nociceptor can produce some of the most potent acute and chronic nociceptor activating stimuli that exist.
- One of the most important regulatory signals that cause a cell to convert to a defensive state in which multiple inflammatory and cell protective immune activators are activated is the intracellular ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG).
- Glutathione is the most plentiful intracellular thiol antioxidant, and is among the most important signal generators that trigger a cell to synthesize powerful inflammatory mediators and activate genes that, in turn, activate virtually every immune system inflammatory cell.
- the ratio of reduced glutathione, GSH, to the oxidized form, GSSG, is normally 9 to 1 or more.
- GSH reduced glutathione
- GSSG oxidized form
- pro-inflammatory cytokines e.g TNF-alpha, IL-l, IL-6 and many others
- cytokines that attract and active inflammatory immune cells, all of which sensitize and activate nociceptors that transmit pain and pruritic signals, and in turn amplify these inflammatory cascades by neurogenic inflammatory pathways.
- Many of a cell’s most important regulators of inflammation and immune defense are highly sensitive to a reduction in a cell’s GSH concentration, and are directly activated by a low
- NF-Kappa B the most important of these redox-sensitive regulatory pathways is NF-Kappa B. This molecule is responsible for that directly or indirectly inducing the synthesis of among the most important and powerful inflammation activators, including TNF-alpha and many of the inflammatory interleukins and chemokines that attract inflammatory cells that secrete mediators that directly activate nociceptors and thus increase their long-term sensitization and conversion to a neuropathic state.
- NF-Kappa B acts as a“final common pathway” for activation of multiple inflammatory pathways, substances that reduce or block NF-Kappa B activation will have substantial and broad anti-inflammatory activity and will block many forms of immune system- mediated activation of inflammatory pathways.
- NF-Kappa B is also one of the many regulatory molecules that is directly activated by an oxidative intracellular environment - one in which the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) is minimized. This oxidative environment directly activates NF-Kappa B that greatly increases the synthesis of nociceptor activating mediators and cytokines.
- NF- Kappa B Since both peripheral nociceptors with endings in the epithelium and central nociceptors in the DRG and spinal cord become sensitized upon continuous activation, activation of NF- Kappa B is an important and critical stimulator of neuropathic sensitization.
- TLRs Toll -Like Receptors
- NF-Kappa B One of the most important consequences of NF-Kappa B is to stimulate the production of chemokines, including IL-8, that attract and activate neutrophils, a blood-borne white blood cell (WBC) that typically constitutes over 50% of all WBCs in the blood.
- chemokines including IL-8, that attract and activate neutrophils, a blood-borne white blood cell (WBC) that typically constitutes over 50% of all WBCs in the blood.
- WBC blood-borne white blood cell
- ROS reactive oxygen species
- NF -Kappa B oxidative activation of NF -Kappa B
- many kinases including protein kinase A, protein kinase C and mitogen-activated protein kinases that act to amplify virtually all inflammatory pathways that directly activate nociceptors.
- Such activation of nociceptors also causes them to release Substance P that directly triggers mast cell activation and release of histamine, TNF -alpha, IL-l, IL-6, IL-8 and many more inflammatory substances that further activate nociceptors. Due to the simultaneous activation of multiple inflammatory and nociceptor-activating pathways, there is a net amplification of nociceptor activation that is known to directly lead no neuropathic pain and pruritus.
- the esophageal mucosa lacks such protection and is easily damaged by reflux of the stomach contents. Such damage allows both hydrochloric acid and the stomach-derived protease, pepsin, to penetrate the esophageal mucosa in high quantities and directly trigger multiple inflammatory and pain-producing pathways. Among these, acid-induced neurogenic inflammation is among the most important.
- Biochemical pathways function by the sequential transmission of signals between multiple molecules until a particular endpoint is achieved.
- stomach acid secretion the presence of food molecules in in the stomach activate nutrient sensors in stomach cells that trigger a cascade of biochemical events in multiple cells that ultimately lead to acid secretion.
- mast cells and other inflammatory cells that trigger mucosal inflammation in the esophagus and contribute to its pathogenesis.
- Mast cells populate the mucosa of the esophagus and contribute significantly to the inflammation caused by reflux of the acidic stomach contents into the esophagus.
- stomach acid When activated by stomach acid, mast cells release over 50 distinct inflammatory and pain-inducing mediators that trigger activation of other inflammatory cells and directly activate pain sensations in nociceptors, which in turn, release additional mediators that amplify the overall painful inflammatory reaction that is known to cause the signs and symptoms of GER, GERD, and Barrett’s esophagus.
- Protons produce pain and inflammation, in part, by activating acid sensitive ion channels (ASIC) and transient receptor potential vanilloid receptor-l (TRPV-l) ion channel, also known as the capsaicin receptor. Both ASIC and TRPV-l are present on Type C nociceptors. Upon activation, these receptors depolarize the nociceptors that cause two distinct activities: (1) transmission of calcium coded pain signals to the brain, and (2) Release of substance P, neurokinin A, calcitonin gene-related peptide (CGRP) and other neuropeptides and
- substance P is among the most important since in directly activates mast cells and other inflammatory cells to release a myriad of inflammation mediators. Substance P also causes blood vessels to become permeable causing leakage of plasma from the vessels and allowing inflammatory white blood cells to accumulate at the site of inflammation.
- ASIC ASIC that open and allow a burst of calcium influx that triggers multiple cascades of pathways, each of which have multiple sequential‘molecular steps’ that amplify the calcium signal and ultimately result in inflammatory mediator release.
- Many of these mediators directly activate adjacent sensory neurons, Type C nociceptors, by activating multiple receptors and ion channels that allow calcium influx that are ultimately transduced into the pain sensation of GER.
- Strontium’s unique therapeutic properties are due to its chemical resemblance to calcium, the most important and universal“second messenger” in nerves and in all other cells that regulate virtually all cellular functions.
- the calcium ion always has two positive charges and its ionic radius is 0.99 angstroms, about the size of a hydrogen atom.
- strontium most closely resembles calcium, since it also only exists as a divalent positively- charged ion and has an ionic radius of 1.13 angstroms. For this reason, strontium typically binds to calcium-binding sites and mimics calcium’s activity.
- strontium-induced response is less potent and may be as low as about l/lOOOth as active as calcium, but for certain calcium- dependent activities, strontium has activity that is nearly the same as calcium or in the range of l/lOth to 1/30th as active as calcium. In other calcium-dependent activities, strontium can be more active than calcium. It is strontium’s calcium-mimetic activity that enables strontium to produce its many and varied activities. Since calcium is critical for so many cellular functions, if it were strongly inhibited the effects would be toxic to a cell. In contrast, since strontium can typically substitute for calcium, albeit with lower activity, the activity of the calcium-dependent pathway will not be shut down.
- prostaglandins e.g PGE2
- leukotrienes e.g, LTB4, C4, D4, and E4
- ROS reactive oxygen species
- Strontium thus significantly alters the pain and itch sensations encoded within calcium waves present in painful and pruritic neuropathic conditions, and has the effect of garbling the signal and reducing its perceived intensity by the brain. Due to strontium binding to multiple calcium-dependent signaling pathways, strontium significantly alters calcium-encoded signals by multiple independent mechanisms. Some of the calcium-dependent kinases are known to be essential for the development of neuropathic conditions, since their inhibition in animal models can prevent and or reverse established neuropathic conditions.
- Strontium is not able to bind effectively to the calcium binding proteins within the cytoplasmic interior of nociceptors that normally remove calcium within less than a millisecond after calcium enters the nociceptor, thus producing a transient increase in calcium concentration that contributes to the precisely-timed calcium waves. Strontium is also much less effectively pumped into and released from a nociceptor’s primary calcium storage site, the endoplasmic reticulum (ER).
- ER endoplasmic reticulum
- strontium When a nociceptor-activating signal is received, strontium inhibits the calcium- induced calcium release (CICR) pathway that amplifies the calcium signal, and strontium does not have the ability to regulate inositol triphosphate (rP 3 )-induced calcium release by acting to inhibit additional calcium release if the concentration of calcium in the cytoplasm is too high.
- CICR calcium- induced calcium release
- strontium reaches a concentration of more than 150% greater than calcium and displaces calcium from performing its amplifying function during CICR.
- Strontium is also much less active then calcium in regulating a second important calcium amplifying mechanism triggered by IP 3 , a ubiquitous substance that also activates calcium release from the ER by an IP 3 - specific receptor.
- IP 3 acts as a potent stimulator of calcium release that acts to amplify the much smaller calcium influx during depolarization. When the calcium concentration is sufficiently elevated, calcium acts to inhibit further calcium release thus maintaining the calcium concentration within a limited concentration range.
- strontium When strontium is present, it can mimic calcium in its ability to activate IP 3 - induced calcium release, but strontium is not able to inhibit excessive calcium release causing both calcium and strontium to reach higher concentrations over an extended time. Strontium’s ability to substantially inhibit calcium-induced release due to IP 3 is particularly important, since IP 3 - induced calcium release is known to be responsible for generation of calcium waves. These types of strontium effects significantly change the calcium dynamics and calcium waveforms associated with neuropathic conditions, and thus contribute to strontium’s suppressive effects on pain and pruritus.
- strontium While strontium also affects additional pathways that control the dynamics of calcium within nociceptors, there is one strontium-induced interference with calcium-dependent transmission of pain and itch-encoded calcium waves that is critically important for suppression of acute, chronic, and neuropathic conditions. That is, the ability of strontium to bind and inactivate synaptotagmin-l, a molecule that is principally responsible for neurotransmitter release peripheral Type C nociceptors in the esophageal mucosa and in the DRG. Of particular importance is the ability to suppress the release of glutamic acid and ATP from nociceptors.
- Glutamic acid binds to specific receptors including the NMDA receptors located on peripheral nociceptors, inflammatory white blood cells and structural cells including fibroblasts and mucosal cells. When activated the NMDA receptor activates calcium influx and triggers pain and multiple inflammatory pathways. Blockade of NMDA receptors, in addition to strontium’s suppressive activity on neurotransmitter release will provide a greatly increased suppressive effect on pain and inflammation. Other members of the synaptotagmin molecular superfamily and related calcium-regulated molecules regulate the release of inflammatory neuropeptides, including substance P from the peripheral portion of a TCN in the epithelium.
- Substance P is known to be the most important inflammatory neuropeptide released from TCNs that activates virtually every inflammatory immune“white blood cell” (WBC), including mast cells that contain histamine and over 50 different inflammatory chemicals, including tumor necrosis factor-alpha (TNF-alpha), interleukin 1 alpha and beta (IL-l alpha and beta) and IL-6.
- WBC white blood cell
- TNF-alpha tumor necrosis factor-alpha
- IL-l alpha and beta interleukin 1 alpha and beta
- IL-6 interleukin 1 alpha and beta
- These three pro-inflammatory cytokines are believed to be the“first responders” that directly activate TCNs to cause pain and/or itching and are thought to be significant contributors to the development and maintenance of neuropathic conditions, as well as most skin conditions that are associated with inflammation, pain or itching.
- Synaptotagmin-l is a protein present on the surface of vesicles that contain and ultimately release neurotransmitters that bind to the post-synaptic neurons in the DRG and the peripheral TCN endings in the epithelium that relay the pain and itch-encoded signals to the brain.
- the frequency of the presynaptic neurotransmitter release from nociceptors are precisely matched so that the intensity, timing and other properties of the original pain or itch signal encoded in the calcium wave is accurately transmitted to the brain.
- the delay between the arrival of the calcium wave, neurotransmitter release and post-synaptic activation is usually about 1/1000 th of a second and the amount released is related to the intensity of the original TCN signal.
- This type of neurotransmission is termed“synchronous release,” since the timing of the arrival of the calcium wave is tightly synchronized to the release of neurotransmitters that triggers post-synaptic activation of the DRG nerve. Without this precise coupling, the frequency encoded pain or itch signal becomes distorted and garbled.
- asynchronous release When strontium substitutes for calcium, the amplitude of synchronous neurotransmitter release in response to TCN activation is typically reduced by more than 90%. Strontium has an additional signal distorting effect that significantly distorts the timing of neurotransmitter release called“asynchronous release.” In contrast to synchronous release that is tightly coupled to the stimulating signal, asynchronous release may extend to several hundred milliseconds. With strontium, the total amount of neurotransmitter that is released may be the same as with calcium, however the strength of the synchronous release that contains the encoded pain or itch intensity information is strongly reduced, and the critical timing information is essentially destroyed.
- This strontium mechanism not only reduces the perceived severity of a pain or itch signal, but it also suppresses the release of substance P at the proximal end of the TCN in the epithelium at the original site of TCN activation.
- Strontium s ability to inhibit the release of TNF-alpha, IL-alpha and IL-6 from cells is thought to be due to strontium’s inhibition of Store Operated Calcium Entry (SOCE) that amplifies the initial calcium signal from calcium influx through NMD A, ASIC, TRPV1 & TRPA1 and other calcium permeable ion channels that are activated by pain and inflammation-inducing stimuli. Suppression of synchronous
- neurotransmitter release also has an important therapeutic benefit for neuropathic pain or pruritus treatment.
- strontium ranelate is the only known osteoporosis drug that has two independent osteoporosis therapeutic mechanisms - strontium inhibits bone loss by inhibiting bone-resorbing osteoclasts, and simultaneously stimulates osteoblasts that produce new bone.
- Nociceptors also have a CaSR that inhibits nociceptor activation when the extracellular concentration of calcium is raised above normal, or if a similar concentration of strontium is administered. This mechanism is believed to contribute to the ability of strontium to rapidly inhibit TCN activation by, for example, highly acidic chemical peels such as 70% glycolic acid, pH 0.6, that cause burning pain within seconds after application. When strontium is mixed with the acid, burning pain and stinging is suppressed by 80% or more so that any remaining sensory irritation is not bothersome.
- Activation of the CaSR also causes activation of several pathways that are known to increase both acute, chronic and neuropathic pain and pruritus and inflammation. Since in real world use, strontium typically inhibits pain and pruritus, it is likely that the pain and itch enhancing effect caused by activation of the CaSR by strontium is, in effect, negated by other strontium anti-irritant mechanisms. None the less, even a low level,“subclinicar pain and itch enhancing effect reduces the ability of strontium to effectively treat, prevent or reverse neuropathic conditions for which any excess TCN activation is known to promote the neuropathic condition.
- strontium reported ability to bind to the CaSR and rapidly activate two of the MAPK molecules, p38 and ERK1/2, that are known to be among the primary contributors to peripheral and central nociceptor sensitization. Strontium binding to the CaSR is also reported to activate an important enzyme, phospholipase C, that produces two important regulatory molecules, the aforementioned IP, and diacylglycerol (DAG), both of which contribute to nociceptor activation and sensitization and inflammation.
- SR 3 is one of the most important and potent calcium releasing molecules that directly triggers calcium release from ER stores.
- DAG is the principle activator of protein kinase C, a family of molecules that directly activates nociceptors and many of the pathways that produce pain and itch and inflammatory mediators.
- PKC is also known to be an important nociceptor sensitizer, since PKC inhibition can prevent or reverse neuropathic pain in animal models.
- PKC also activates NF-Kappa B, one of the most important stimulators of molecules that triggers pain, pruritus and inflammation and are thought to be able to directly cause neuropathic sensitization.
- strontium produces its osteoporosis therapeutic benefits by binding to the CaSR is very recent and additional strontium- sensitive pathways will likely be identified.
- human nociceptors have the CaSR that regulate nociceptor activation suggests that the CaSR activation by topically-applied strontium may be working at a reduced level due to strontium’s ability to inhibit important pain and itch pathways while simultaneously activating pathways via the CaSR that are known to trigger pain and itch pathways.
- strontium’s therapeutic potential may be substantially compromised.
- Strontium also blocks rapid endocytosis of vesicles that are used to release both neurotransmitters and inflammation -induced molecules by blocking dynamin-l, a calcium- dependent GTPase. While not being bound by this or any particular mechanisms, it is believed that strontium’s ability to block substance P release from Type C nociceptors and the pro- inflammatory cytokines TNF-alpha, IL-l alpha and IL-6 is related to strontium’s interference with such calcium-dependent release processes.
- strontium has been surprisingly discovered that the reason strontium is frequently unable to completely block pain, itching or inflammation is due to two factors: (1) the limited amount of strontium that can be topically applied, after which the hyperosmotic effects of the strontium salts themselves start to cause pain, itching or inflammation; and (2) the ability of strontium to stimulate pathways that may act to negate strontium’s inherent anti -irritant activities, thus reducing the overall therapeutic benefit.
- this is due to the fact that strontium has a relatively low potency in its ability to suppress pain, itching and inflammation compared to many other drugs with similar therapeutic goals. It is this low potency of strontium that prevents it from blocking pain when it is orally ingested in the form of the prescription drug, strontium ranelate that is approved for treatment of osteoporosis in over 100 countries.
- neuropathic condition to develop e.g., viral infection, physical trauma such as amputation or nerve compression, metabolic nerve damage as occurs in diabetes, coexisting inflammation and other factors.
- non-steroidal anti-inflammatory drugs like aspirin, ibuprofen and naproxen are typically used at oral doses of several hundred milligrams and provide an effective reduction of many types of inflammation-associated pain.
- Opioid pain relievers such as levorphanol, oxymorphone, oxycodone and hydrocodone are
- strontium salts such as strontium ranelate, an oral drug approved for the treatment and prevention of osteoporosis, is approved in over 100 countries, and is administered at a dose of 2,000 mg per day. Since strontium ranelate is a simple salt of strontium, it yields 680 mg of elemental strontium upon contact with water or gastric fluids. However, even at this high dose of pure elemental strontium, there are no reports of the ability to reduce pain or inflammatory reactions.
- topical strontium has the ability to reduce pain, pruritus and inflammation due to the fact that topical formulations can deliver thousands of times higher strontium concentrations then can be achieved by oral, systemic administration. Even at the relatively high local concentrations that can be achieved topically when administered to the epithelium, the effect of strontium on key biochemical pathways that cause pain, pruritus and inflammation is only partial. For example, if the activity of a hypothetical pain or itch-producing pathway is inhibited by 90% to 100%, a patient reports that their pain or itching was completely stopped. In contrast, topically-applied strontium may only inhibit that pathway by 40% to 50%, sufficient inhibition for a patient to observe that the pain or itching was clearly reduced, but still present and still bothersome.
- strontium acts directly on Type C nociceptors and reduces their sensitivity to acid-induced nerve depolarization that directly produces the sensation of GER-associated burning pain and also triggering inflammatory neuropeptide and pro-inflammatory cytokine release that is known to increase painful sensations by sensitizing Type C nociceptors.
- Strontium can inhibit acid-induced inflammation by at least two independent anti inflammatory mechanisms.
- strontium can inhibit inflammation caused by a broad range of chemically and biologically-unrelated inflammation irritating stimuli. Given the fact that the refluxed gastric juices and partly digested food contain many potentially irritating chemicals in addition to acid, strontium should provide a broad protective benefit to the esophagus.
- IL-8 levels are associated with GER and may be pathogenically important as an inducer of chronic inflammatory damage to the esophagus found in GER.
- Substance P increases production of IL-8, a potent stimulator of neutrophil activation and a major contributor to the formation of reactive oxygen species (e.g. superoxide, hydrogen peroxide, hydroxyl radical, singlet oxygen) that are highly toxic and powerful inflammation inducers.
- reactive oxygen species e.g. superoxide, hydrogen peroxide, hydroxyl radical, singlet oxygen
- TNF- alpha, IL-l alpha and IL-6 are important regulators and promoters of cancer metastasis. If these cytokines have a similar stimulatory effect on metastasis of esophageal adenocarcinoma, then strontium treatment may reduce metastatic disease from esophageal carcinoma, a frequently lethal result of chronic GER.
- strontium has been shown to inhibit substance P release by Type C nociceptors, thus confirming human studies in which topical strontium application inhibited acid-induced pain and neurogenic inflammation. While the precise molecular mechanism by which strontium inhibits substance P release is unknown, it is believed that the release of substance P, neurokinin A and CGRP occur together and by the same or similar trigger mechanism. Thus, the fact that strontium inhibits substance P is a good indicator that strontium will also inhibited neurokinin A and CGRP.
- Capsaicin is the component of chili peppers that causes the burning sensation when it comes in contact with mucous membranes.
- Capsaicin is a member of the vanilloid family and binds the vanilloid receptor subtype 1 (TRPV1).
- TRPV1 is an ion channel type receptor and can also be activated with heat, protons, and physical abrasions.
- strontium has limited affect against capsaicin induced pain and inflammation. In these studies, strontium was only able to reduce the pain and inflammation by about 40%. Without wishing to be bound by any one theory, it is believed that activation of TRPV1 activates G-protein coupled receptors, which in turn activate numerous other pain and inflammation pathways, some of which are less calcium dependent.
- strontium The activation of less calcium dependent pathways reduces the overall effect of strontium.
- protons e.g. stomach acid
- strontium has limited affect against TRPV1 activation, additional compounds are needed that either target different pain and inflammation pathways or target different places along the same pain and inflammation pathways that strontium targets.
- the combination of strontium and the additional compounds creates a synergistic affect that is greater that the individual components alone.
- Osteoporosis is a chronic condition that results in bone weakening and loss of bone mass and density and results in increased fractures, especially in post-menopausal women, people over 70 and those taking certain drugs like oral anti-inflammatory glucocorticoids like prednisone, barbiturates, some antiepileptic drugs, L-thyroxine, cancer drugs like methotrexate, depot progesterone, anticoagulants like Heparin, warfarin and related coumarins,
- thiazolidinediones used for diabetes treatment lithium therapy for psychiatric disorders and proton pump inhibitors, the most commonly used GER treatment drugs.
- Unfortunately the population that is most likely to use many of the above drugs are those most at risk for osteoporosis, older people.
- the strontium in the present invention can provide a substantial anti -osteoporosis benefit since strontium is the only substance known to stimulate new bone formation while suppressing bone loss.
- the prescription drug strontium ranelate is the only strontium drug approved for osteoporosis treatment and at its recommended daily dose delivers 680 mg of elemental strontium per day, of which approximately 25% is absorbed by the GI tract into the blood.
- Simple orally-administered strontium salts including those used in the present invention deliver the same rate of strontium absorption as strontium ranelate and for this reason strontium dietary supplements are widely available without a prescription in the United States.
- stomach typically contains between 20 to 100 ml of fluid primarily composed of hydrochloric acid, potassium chloride and sodium chloride at a pH between 1.5 and 3.5.
- the volume of the stomach after a meal can easily reach 1000 ml without expanding, however after a large meal the stomach volume can expand to 4000 ml.
- the average volume of saliva in the human mouth that is typically swallowed is approximately 1 ml. Therefore an ingredient in an oral product of the present invention that was present at, for example, 100 mg/product would present a
- concentration of lOOmg/ml at the surface of the esophageal mucosa In sharp contrast, if an antacid is self-administered for Heartburn treatment according to the recommendation of the US National Library of Medicine’s public health database, MedlinePlus, approximately 1 hour after a meal, the concentration in the stomach of the above ingredient would typically range from l/lOOOth to l/4000th of the original 100 mg/ml concentration resulting in a concentration from 0.1 mg/ml to 0.025 mg/ml.
- Molecules that enter the stomach may also be subject to degradation by the acid or by enzymatic transformation by stomach or food-derived substances. Such degradation would not be expected in the esophageal lumen.
- ingredients of the present invention can produce a high-level therapeutic within several seconds and thus even the transient exposure of the esophagus dissolved a small volume of saliva may exhibit a high-level therapeutic activity. Such high activity would not be possible if treatment depended on reflux of the ingredients of the present invention to reach the esophageal mucosa.
- compositions and formulations disclosed herein target key pain and inflammation pathways.
- Glutamic acid is the principle excitatory neurotransmitter of the peripheral and central nervous system. Release of Glu from Type C Nociceptors in the skin is among the most important activators of pain and itch signals that, in turn, activate multiple biochemical pathways that trigger both acute and chronic pain and itch conditions. Sufficiently strong Glu-indepuced activation also triggers release of powerful pain, itch and inflammatory peptide
- neurotransmitters including Substance P, Calcitonin Gene-Related Peptide (CGRP) and others that activate multiple immune white blood cells including Neutrophils, Monocytes,
- Macrophages, Lymphocytes and Mast Cells that can release over 50 inflammatory molecules including histamine that directly trigger pain, itching and inflammation.
- Blockade of Glu- mediated activation can block sensory irritation and inflammation in both animal models and in humans. Each of these many pain and inflammation-triggering activities are dependent on the influx of calcium that alters intracellular concentrations and overall calcium dynamics.
- the combination of blocking Glu receptors, in particular the NMD A Glu receptor and the pluripotential activity of strontium to greatly alter calcium dynamics provides a strong synergy that reduces pain and inflammation.
- TNF-alpha Proinflammatory Cytokines including TNF-alpha, IL-l alpha, IL1 beta, IL-6, and IL-8.
- TNF and IL-cytokines are among the earliest pain, itch and inflammatory molecules that are released in inflammatory conditions and directly activate nociceptors and trigger multiple cascades that amplify pain and itch signals.
- Some of the most recent FDA-approved prescription drugs to treat chronic skin inflammatory diseases like Psoriasis that has itching as the principle symptom have been successfully treated by blocking TNF-alpha.
- Protein Kinases including Protein Kinase A, (PKA), Protein Kinase C (PKC), and the Mitogen-Activated Protein Kinases (MAPK) (1) p38, (2) Janus N-Terminal Kinase (JNK) and (3) Extracellular Signal Receptor Kinases (ERK 1/2). These molecules and related kinases transduce and amplify Glu-induced receptor activation and transmit sensory irritation signals via nociceptor activation to the Dorsal Root Ganglia (DRG) in the spinal cord and to the brain where the noxious quality of pain and itching is consciously appreciated.
- DDG Dorsal Root Ganglia
- Such nociceptor sensitization in the skin’s periphery and in the‘central’ nervous pathways like the DRG is known to be critical for the maintenance of chronic and neuropathic pain and itch conditions.
- These transcription factors include NF -Kappa, known as the Master Immune System regulator that can trigger increased synthesis of over 300 molecules that cause inflammation, pain and itching. Other critical transcription factors such as AP-l amplify these effects.
- HD AC Histone Deacetylase
- Histone Deacetylase (HD AC) Inhibitors & DNA Methylase Inhibitors are a second class of gene translation regulators. These molecules have powerful regulatory effects on the expression of pain, itch and inflammation pathways and can prevent and potentially reverse chronic and neuropathic pain conditions in animal models and in humans.
- compositions and formulations disclosed herein to treat the symptoms associated with GER are:
- Potent anti-inflammatory activities that inhibit the most important inflammation pathways known to contribute to esophageal inflammation including (a) Inhibition of NF- Kappa B, the‘master inflammatory gene regulator’; (b) Inhibition of TNF-alpha, IL-l alpha & beta & IL-8; (c) Inhibition of Nitric Oxide, a potent sensitizer of nociceptors and
- ROS Reactive Oxygen Species
- Each of the ingredients of the present invention take advantage of the multiple activities of each ingredient that amplify the fundamental anti-pain and anti-inflammatory activities of strontium.
- some of strontium’s activities inhibit important pain and inflammation pathways while other of strontium’s activities stimulate other pathways that indirectly inhibit pain and inflammation pathways.
- a hard comb that has 20 teeth, half of which point upwards and half that point downward in a random manner. Each of these teeth represents a biochemical pathway that is stimulated by strontium (teeth pointing up) while teeth that point down represent inhibition of other pathways.
- the particular pattern of distinct pathways that are simultaneously stimulated or inhibited is responsible for the unique therapeutic benefits of strontium.
- an amplifying molecule would have to have an identical pattern of‘biochemical teeth’ to amplify strontium’s activities without also inhibiting some of the pathways.
- Chlorogenic acid acts at different steps in the same inflammatory pathways inhibited by strontium, and thus in effect amplify the basic anti-irritant activity and nociceptor-protective activities of strontium.
- Chlorogenic acid is a powerful anti-oxidant that inhibits the considerable oxidative damage from neutrophil extravasation and extravasation into an inflamed esophageal mucosa.
- Substantial anti-oxidant synergy is expected in combination with the powerful anti-oxidant activity of ascorbic acid and its stimulation of the synthesis of intracellular glutathione.
- Chlorogenic acid also inhibits many inflammatory mediators including High Mobility Box 1 release, Toll-Like Receptor 4 (TLR4), Nitric Oxide synthesis,
- cyclooxygenase 2 the enzyme that synthesizes PGE2, an important contributor to pain and inflammation pathways, NF-Kappa B, TNF-alpha, IL-l and IL-8.
- Chlorogenic acid to potently inhibit two enzymes that are critical inducing sensitization of nociceptors, Histone Deacetylase (HD AC) and DNA methylase.
- HD AC Histone Deacetylase
- HDAC Histone Deacetylase
- DNA methylase inhibitors were shown to inhibit the transition from acute to chronic pain and to reverse nociceptor sensitization in chronic and neuropathic pain conditions.
- agmatine that can similarly prevent and reverse sensitization, there is a high likelihood that the chronic pain of GERD can be reversed.
- Ascorbic acid (Vitamin C) has several important activities that contribute to the inhibition of pain, inflammation and that stimulates healing of inflammation damaged tissues. Ascorbic acid is a powerful anti -oxidant and can inhibit the production of highly toxic oxidants and free radicals including hydrogen peroxide, nitric oxide, superoxide and the hydroxyl radical. At relatively high local concentrations that can only be achieved by topical application, ascorbic acid inhibits the potentially severe oxidative damage produced by neutrophils that are rapidly attracted to sites of inflammation and by release of oxidants greatly stimulate oxidative damage and pain-triggering pathways.
- Ascorbic also stimulates intracellular concentrations of the major water soluble anti oxidant, reduced glutathione (GSH) that is a powerful anti-oxidant protector. Reduced GSH also directly inhibits activation of NF -Kappa B, the most important gene regulatory of inflammation. Additionally ascorbic acid is a necessary cofactor for the synthesis of collagen and when topically applied stimulates collagen synthesis, an important repair function for damaged esophageal mucosa. Ascorbic acid also inhibits TNF-alpha induced activation of NF-Kappa B, the‘master gene regulatory of inflammation’ . In combination with strontium and the other molecules of the Present invention, ascorbic acid will provide added pain and inflammation suppression.
- GSH reduced glutathione
- Citric acid is a 6 carbon molecule with three negatively charged carboxyl groups that is a central molecule of the energy-producing Citric Acid Cycle. Citric acid has multiple anti inflammatory activities including inhibitor of neutrophil degranulation, the process by which neutrophils release multiple toxic enzymes and oxidants into their local environment.
- Neutrophils are among the most important cellular mediators of acute inflammation and constitute about 50% of all the white blood cells in circulation.
- Citric acid also inhibits neutrophil secretion of IL-l beta, and TNF-alpha,
- myeloperoxidase and platelet factor 4 all potent stimulators of pain and inflammation pathways.
- the three carboxyl groups of citric acid also serve as ideal binding sites for strontium to form a strontium complex, thus eliminating the need for a negatively-charged strontium counter ions like chloride or nitrate that can greatly increase the osmolarity of a solution and thereby stimulate pain and inflammation-inducing osmotic sensors.
- Each of the above anti-inflammatory activities are protective of esophageal mucosa and also inhibit inflammation-induced pain, a major contributor to GERD pain.
- Kynurenic acid acts at different steps in the same inflammatory pathways inhibited by strontium, and thus in effect amplify the basic anti-irritant activity and nociceptor-protective activities of strontium.
- Kynurenic acid is a metabolite of tryptophan and has neuroprotective, anti-inflammatory, and antiproliferative properties.
- Kynurenic acid is an endogenous antagonist of the N-methyl-D-aspartate (NMD A) receptors. By blocking calcium entry of through the NMDA receptors, the intracellular calcium concentration will be reduced and the necessary calcium transients that would further activate glutamic acid release are suppressed.
- NMD A N-methyl-D-aspartate
- Kynurenic acid is also a potent activation of the G protein-Coupled Receptor, GPR-35 that has multiple suppressive activities on the release of pain and inflammation pathways in nociceptors, immune cells, keratinocytes and other cells. Additionally kynurenic acid inhibits neutrophil and monocyte extravasation from the blood into sites of inflammation, thus suppressing
- Kynurenic acid is also an agonist of the alpha-7 nicotinic acetylcholine receptor which exerts a suppressive effect on neurons to produce an anticonvulsant and neuroprotective activity.
- Agmatine acts at different steps in the same inflammatory pathways inhibited by strontium, and thus in effect amplify the basic anti-irritant activity and nociceptor-protective activities of strontium.
- Agmatine is a potent inhibitor of NMDA receptors that are critical for the generation of pain signals and for activation of many inflammatory pathways on a variety of cells.
- Synchronous release of Glu by nociceptors at high levels of stimulation triggers substance P release and activation of mast cells and many other inflammatory cells important in GER.
- strontium that strongly inhibits synchronous Glu release and other of the ingredients of the present invention blockade of NMDA receptors will produce a synergistic suppression of pain and inflammation.
- Acid-sensitive ion channels are acid sensitive cationic channels present on Type C nociceptor and inflammatory cells. ASICs are activated by protons (H+). In GER, members of the ASIC superfamily are believed to trigger the pain and contribute to the subsequent neurogenic inflammation. Agmatine also opens strontium permeable ASICs and in the presence of strontium allows increased strontium to enter cells and inhibit its multiple pain and inflammation targets. Agmatine also directly inhibits acid secretion in the stomach and thus has activity that resembles that of Proton Pump Inhibitors and H2 antagonists. Agmatine also strongly inhibits that powerful pain inducer, Nitric Oxide (NO) that greatly sensitizes pain pathways present in GER.
- Nitric Oxide Nitric Oxide
- Agmatine is also a strong agonist of the Alpha-2 Adrenergic receptor and imidazoline receptors that are capable of reversing the sensitization of nociceptors that contributes to the chronicity of pain from GERD.
- agmatine also inhibits matrix metaloprotease activity that directly mediates esophageal mucosal damage
- compositions and formulas of the present disclosure were formulated to perform several functions: (1) treat acute pain associated with GER; (2) desensitize nociceptors thus reducing the risk of developing chronic or neuropathic pain associated with GER; (3) inhibit inflammatory pathways; (4) reduce esophageal mucosal damage; (5) increase protective collagen production in esophageal mucosa.
- the composition and formulations achieve the above objectives by interacting on several different molecular pathways, thus creating a synergistic effect that greatly outperforms the actions of each component alone. The main components of the compositions and formulations are discussed below.
- Strontium is present as a divalent cation. Strontium is designated by its commonly used atomic symbol,‘Sr’ and is depicted below.
- Strontium mimics the ability of calcium to pass through voltage dependent calcium channels and once inside cells, it competes with calcium for binding to calcium-dependent receptors.
- Strontium has four broad classes of pharmacological activities that reduce GER associated pain and inflammation: (1) disruption of intracellular calcium dynamics and calcium wave propagation, (2) inhibition of neurotransmitter release, (3) inhibition of substance P release and resultant neurogenic inflammation, and (4) inhibition of pro-inflammatory cytokine release, each of which was discussed in detail above.
- compounds of the present disclosure use a strontium salt.
- strontium salts include strontium carbonate, strontium bicarbonate, strontium hydroxide, strontium phosphate, strontium lactate, strontium citrate, strontium chloride, strontium sulfate, strontium nitrate, strontium hydrosulfide, strontium oxide, strontium acetate, strontium glutamate, strontium aspartate, strontium malonate, strontium maleate, strontium threonate, strontium lactate, strontium pyruvate, strontium ascorbate, strontium alpha- ketoglutarate or strontium succinate.
- compounds of the present disclosure use a strontium complex.
- strontium complexed to strontium complex include chlorogenic acid, at least on amino acid derivative or metabolite, at least one methoxyflavonoid, or at least one vitamin.
- the strontium salt is strontium carbonate, which acts to neutralize acid in a manner similar to calcium carbonate, the commonly used antacid in many products. This molecule has two distinct pharmacological activities.
- the carbonate portion or other acid neutralizing salt component serves as a conventional acid neutralizing agent and in the acid environment of the stomach it combines with acid to form water.
- the strontium ion unlike calcium used in conventional antacids, inhibits multiple pain and inflammation pathways that are known to be significant contributors to GER pain and inflammation.
- the strontium salt is strontium citrate.
- Chlorogenic acid (IUPAC name: (lS,3R,4R,5R)-3- ⁇ [(2E)-3-(3,4-dihydroxyphenyl)prop- 2-enoyl]oxy ⁇ -l,4,5-trihydroxycyclohexanecarboxylic acid) is a compound present in high concentrations in coffee and other foods.
- Vitamins have diverse biochemical functions, ranging from regulators of cell and tissue growth and differentiation, to coenzymes, to hormone-like functions, to antioxidants.
- Vitamins contemplated in the present disclosure include, but are not limited to vitamin A, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin C, vitamin D, and vitamin E. In particular, vitamin C and vitamin E.
- Vitamin C also known as ascorbic acid, is an essential nutrient involved in the repair of tissue and the enzymatic production of certain neurotransmitters. Vitamin C is a cofactor in at least eight enzymatic reactions in humans important in many essential functions, including wound healing. More generally, the biochemical role of vitamin C is to act as an antioxidant (a reducing agent) by donating electrons to various enzymatic and non-enzymatic reactions. Doing so converts vitamin C to an oxidized state - either as semidehydroascorbic acid or dehydroascorbic acid. These compounds can be restored to a reduced state by glutathione and NADPH-dependent enzymatic mechanisms.
- Vitamin E is a group of eight compounds that include four tocopherols and four tocotrienols. Vitamin E has many biological functions, including its role as a fat-soluble antioxidant, protecting cell membrane from oxidative damage. Vitamin E is an enzyme activity regulator, such as for protein kinase C (PKC) - which plays a role in smooth muscle growth - vitamin E participates in deactivation of PKC to inhibit smooth muscle growth.
- PKC protein kinase C
- Kynurenic acid (IUPAC name: 4-hydroxyquinoline-2-carboxylic acid) is a metabolite of the amino acid L-tryptophan that has been shown to have neuro activity. It is an antagonist of ionotropic AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, NMDA (N-Methyl- D-aspartic acid or N-Methyl-D-aspartate), and Kainate glutamate receptors; a noncompetitive antagonist at the glycine site of the NMDA receptor; an antagonist of the a7 nicotinic acetylcholine receptor; and a ligand for the orphan G protein-coupled receptor GPR35.
- AMPA a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- NMDA N-Methyl- D-aspartic acid or N-Methyl-D-aspartate
- Agmatine (IUPAC name: l-(4-Aminobutyl)guanidine) is a metabolite of L-arginine that acts on multiple molecular targets. It is acts on neurotransmitter receptor ionophores; ion channels; membrane transporters, nitric oxide synthesis inhibition; polyamine metabolism; protein-ADP-ribosylation; matrix metalloproteases; advanced glycation end product formation; and NADPH oxidase. Of particular importance is the ability of agmatine to open ASIC without the need for acid conditions that allows external strontium to flow into the channels and exert its multiple anti-pain and anti-inflammatory activities.
- Tangeretin (IUPAC name: 5,6,7,8-tetramethoxy-2-(4-methoxyphenyl)-4H-l- benzopyran-4-one) is an O-polumethoxylated flavone that is found in citrus peels and citrus juice like tangerine juice.
- Nobiletin (IUPAC name: 2-(3,4-Dimethoxyphenyl)-5,6,7,8-tetramethoxychromen-4-one) is a flavonoid found in citrus peels.
- Both of these similar compounds have potent suppressive activities on mast cell activation that results in the release of approximately 60 distinct pain, itch and inflammatory mediators. Extensive studies in animals and humans show that mast cell inhibition can produce broad and potent anti-inflammatory activities. Both compounds are potent inhibitors of NF- Kappa and multiple pro-inflammatory cytokines [0131] Additionally both compounds have anti -proliferative effects in various cancer cell lines and will be of benefit to prevent the development of the pre-cancerous condition Barrett's Esophagus that develops from chronic GER
- the present disclosure also contemplates the use of strontium-containing complexes.
- the complexes are bipartite or tripartite in nature, in that they include at least one or two different components: divalent cationic strontium, and at least one of the
- the complexes are strontium di-chlorogenic acid. In another embodiment, the complexes are strontium di -agmatine. In another embodiment, the complexes are strontium di-kynurenic acid. In another embodiment, the complexes are strontium, chlorogenic acid, and agmatine. In another embodiment, the complexes are strontium, chlorogenic acid, and kynurenic acid. In another embodiment, the complexes are strontium agmatine and kynurenic acid. In another embodiment, the complexes are strontium, chlorogenic acid, and ascorbic acid.
- the complexes are strontium, kynurenic acid, and ascorbic acid. In another embodiment, the complexes are strontium, agmatine, and ascorbic acid. In another embodiment, the complexes are strontium, chlorogenic acid, agmatine, kynurenic acid, and citric acid.
- the complexes may also be complexed with a polymer, such as a polyanionic polymer such as polyvinylpyrrolidone (PVP), cyclodextrins, carragenans, alginic acid, xanthan gum, sulfated polysaccharides, pentosan polysulfate, chondroitin sulfate, dextran sulfate and heparin sulfate.
- PVP polyvinylpyrrolidone
- cyclodextrins carragenans
- alginic acid xanthan gum
- sulfated polysaccharides pentosan polysulfate
- chondroitin sulfate chondroitin sulfate
- dextran sulfate and heparin sulfate.
- the polymer also has extended release capabilities.
- Alginic acid is naturally-occurring polysaccharide obtained from brown seaweed.
- alginic acid is a polyanionic linear copolymer of (l-4)-linked beta-D-mannuronic acid and alpha-L-glucuronic acid. Due to its repeated carboxyl groups, alginic acid electrostatically binds to positively charged atoms, such as strontium and calcium, when the pH of the vehicle is above the pKa of the carboxyl groups (approximately 3-4) causing them to be negatively charged and able to bind to strontium and calcium. As the pH is decreased and approaches the pH of an empty stomach (1 or less), hydrogen ions will compete with strontium and calcium and will displace and free strontium and calcium. Alginic acid thus acts as a typical ion exchange column matrix. By using various mixtures of naturally occurring alginic acid polymers, the rate of strontium and calcium release as a function of pH and ionic strength of the vehicle can be adjusted to achieve release over an extended period of time.
- Alginic acid and its salts are widely used in foods, cosmetics and in medical devices.
- the FDA has declared alginic acid GRAS (Generally Recognized as Safe). A similar safety classification exists in the European Union and other countries.
- alginic acid When consumed after a meal, alginic acid forms a“raft” that floats on the surface of the gastric pool, providing a physical barrier to the irritating and inflammation-producing effects of gastric acid, proteases and other chemical irritants that is unrelated to any acid neutralizing activity that may be present.
- Alginic acid has been recognized by the FDA as a safe ingredient for GER therapy and is currently available in an OTC antacid in the US and it is available as an OTC Drug in the European Union for GER treatment and esophageal protection.
- Alginic acid also has bioadhesive properties when applied to mucosal membranes.
- the bioadhesive properties “coat” the esophagus, which protects the esophagus from exposure to the acidic contents of the stomach.
- alginic acid compounds that are compressible into tablets.
- Polyvinylpyrrolidone is commonly used as an inert carrier of therapeutically active molecules. Due to the varying polar structure of the PVP polymer, it presents multiple, repeating sites to which atoms and molecules may bind via ionic forces. Upon subsequent exposure to ionic media, such as water, the bound substance may be released into the media over an extended period of time. Thus facilitating gradual release of the substance as a function of pH and other adjustable conditions, such as temperature, etc. As such, the PVP acts as a“molecular reservoir” providing for sustained release of therapeutic substances.
- the PVP polymer may be in its native form, or it may be chemically modified by derivatization and/or crosslinking to adjust the“releasing” properties of the polymer. In one embodiment, PVP is used as a carrier for disclosed compositions.
- PVP is used in foods, cosmetics and in medical devices. It is used as an excipient in FDA approved oral prescription drugs as a tablet binder.
- Xanthan Gum is a polysaccharide that is commonly used as a food additive and can provide a chewy base for sustained release of the ingredients of the present disclosure.
- Gum base is a non-nutritive, non-digestible, water-insoluble delivery system used to carry sweeteners, flavors, and any other substances in chewing gum and bubble gum. It provides all the basic textural and chewing properties of gum.
- Components of gum base can include, but are not limited to, natural coagulated or concentrated lattices of vegetable origin, synthetic coagulated or concentrated lattices, plasticizing materials, terpene resins, and antioxidants.
- Additional acid neutralizing agents may be added.
- acid neutralizing agents include calcium carbonate, sodium bicarbonate, sodium citrate, aluminum hydroxide, aluminum phosphate, magnesium hydroxide, magnesium carbonate, magaldrate, almagate, and hydrotalcite.
- calcium carbonate is one of the most widely used acid neutralizing agents in OTC GER treatment drugs, calcium actually causes an increase in acid production in the stomach after repeated use and over time may exacerbate acid secretion if antacid treatment is temporarily stopped. Thus, using calcium actually causes a dependency on antacid use.
- Acid reducing agents are compound that reduce the production of acid in the stomach.
- H2RA Histamine H2 Receptor antagonists
- H2RA include cimetidine, ranitidine, famotidine, and nizatidine.
- Proton pump inhibitors are the most potent acid blocking treatment available and are among the most frequently used drugs in the world. They work by blocking the hydrogen ion pump of the stomach’s parietal cells and prevent hydrochloric acid secretion into the stomach’s lumen.
- PPI Proton pump inhibitors
- One of the most serious adverse reactions of PPI is their ability to cause osteoporosis, especially when they are used over many years in older patient who have a uniquely high risk of developing osteoporosis.
- the strontium based compounds of the present disclosure with a PPI could help prevent the development of osteoporosis.
- strontium ranelate a salt of ranelic acid that contains two strontium atoms as the“active ingredient,” is reported to be the most effective osteoporosis treatment to date.
- Strontium ranelate has been shown to stimulate new bone formation and inhibit bone loss.
- compositions of the present disclosure containing PPIs are formulated to deliver as much strontium as strontium ranelate.
- the compounds of the present disclose may also be formulated with additional ingredients known in the pharmaceutical art to increase stability, increase disintegration of solid tablets, or increase customer appeal.
- additional ingredients known in the pharmaceutical art to increase stability, increase disintegration of solid tablets, or increase customer appeal.
- excipients include binders, bulking agents, diluents, sweeteners, flavorants, lubricants, gum base, and colorants.
- Suitable binders include but are not limited to starches (com starch, wheat starch, modified corn or wheat starch, Starch 1500, or pregelatinized starch), polymers (polaxomer, polyethylene glycol, polymethacrylate, polyethylene oxide, sodium carboxymethylcellulose, polyvinyl alcohol, calcium polycarbophil, or combinations thereof), natural gums (pectin, gelatin, gum Arabic, acacia, carrageenan, guar gum or tragacanth), and low or medium viscosity cellulose derivatives (carbomer, hydroxypropylmethylcellulose, hydroxypropylcellulose, microcrystalline cellulose, carboxymethylcellulose, hydroxyethylcellulose, methylcellulose or combinations thereof).
- starches com starch, wheat starch, modified corn or wheat starch, Starch 1500, or pregelatinized starch
- polymers polymers (polaxomer, polyethylene glycol, polymethacrylate, polyethylene oxide, sodium carboxymethylcellulose, polyvinyl alcohol, calcium polycar
- Suitable sweeteners include but are not limited to those derived from natural sources such as sugar, confectionary sugar, powdered sugar, sucrose, dextrose, glucose, lactose, fructose, maltodextrin, sorbitol, mannitol, xylitol, polydextrose, erythritol, or combinations thereof.
- sweeteners also include but are not limited to artificial sweeteners such as aspartame, sucralose, acesulfamine K, saccharin derivatives, or mixtures thereof.
- compositions disclosed herein can be formulated into an easy to consume dose.
- the compositions disclosed herein are formulated as a solid.
- solids includes lozenges, chewable tablets, gummies, effervescent tablets, sprays, and chewing gum.
- the tablets are manufactured using conventional techniques in the pharmaceutical industry such as wet granulation, spray drying, or roller compaction.
- wet granulation is a method in which the active ingredient is mixed with a binder and other excipients in a suitable granulator.
- a granulating solution such as water or a solution containing dissolved binder is added to the powder blend while mixing it thoroughly. This process allows the powder blend to become wet and agglomerate to form granules.
- These granules are then dried in a conventional tray drier or a fluid bed drier to obtain dry granules, which are then milled and screened to obtain granules with desirable particle size distribution.
- These granules are then mixed with additional ingredients such as diluents, bulk sweeteners, intense sweeteners, flavors, disintegrants, lubricants, anti-adherents, glidants etc., and compressed in to tablets.
- Spray drying is another method to granulate powders to obtain spherical free flowing powders, which can be blended with various other excipients and compressed in to tablets.
- the active ingredient, binder and other desired excipients are suspended in water and sprayed using an atomizer in to the spray drier.
- the droplets so generated by the atomizer are dried to form granules, which can be screened and milled to obtain desired particle size.
- the granules can be further processed to obtain tablets as explained above.
- Roller compaction is another method to manufacture granules.
- dry blend of active ingredient(s), binder and other desired excipients are forced through a pair of rollers held under high pressure, where the powder compacts to form thin wafer like sheets, which are then milled and screened to obtain free flowing granules.
- Small amounts of water can be sprayed on to the powder blend prior to feeding in to the rollers, to enhance binding properties of ingredients in this process.
- the granules so obtained can be further processed to obtain tablets as explained above.
- compositions disclosed herein are formulated as a liquid.
- compositions and formulations disclosed herein are designed to (1) target the Type C nociceptors in the esophagus and (2) reduce the acidity of the stomach contents.
- the compositions and formulations disclosed herein are designed to be taken after eating, for example, up to three hours post meat, up to two hours post meal, up to one hour post meal, or up to 30 minutes post meal.
- the compositions are formulated in a final product that maximizes exposure of the composition to the esophagus.
- Non-limiting examples include chewy tablets, gummies, lozenges, lollipops, gums, and the like where the continuous chewing and/or swallowing delivers the composition to the esophagus over a longer period of time than conventional chewable tablets.
- the full dose may be broken up into smaller sub-doses and taken sequentially, that is, the first sub-dose is fully consumed before the second sub-dose is taken and so forth.
- compositions and formulations disclosed herein are designed to be taken after the onset of GER symptoms.
- the compositions are formulated in a final product that maximizes exposure of the composition to the esophagus.
- Non-limiting examples include chewy tablets, gummies, lozenges, lollipops, gums, and the like where the continuous chewing and/or swallowing delivers the composition to the esophagus over a longer period of time than conventional chewable tablets.
- the full dose may be broken up into smaller sub-doses and taken sequentially, that is, the first sub-dose is fully consumed before the second sub-dose is taken and so forth.
- compositions and formulations disclosed herein are designed to be taken before eating. Taking the compositions and formulations before eating essentially pre-treats the esophagus before exposure to the stomach acid content. The pre-treatment can reduce or prevent GER symptoms.
- the compositions may not include the acid neutralizing agent or acid reducing agent.
- the compositions are formulated in a final product that maximizes exposure of the composition to the esophagus. Non-limiting examples include sprays, chewy tablets, gummies, lozenges, lollipops, gums, and the like where the continuous chewing and/or swallowing delivers the composition to the esophagus over a longer period of time than conventional chewable tablets.
- the full dose may be broken up into smaller sub-doses and taken sequentially, that is, the first sub-dose is fully consumed before the second sub-dose is taken and so forth.
- the exemplary formulations that follow describe combinations of strontium, chlorogenic acid, and an acid neutralizing agent that can be used to treat symptoms associated with GER, GERD, or Barrett’s esophagus.
- the final formulation amount for each compound are those commonly used in the art for formulating OTC and prescription treatments for patients suffering from symptoms associated with GER, GERD, or Barrett’s esophagus.
- the strontium can optionally be used in similar concentration as used in strontium ranelate.
- the GER formulations combine the base formulation with at least one acid neutralizing or acid reducing agent.
- a polymer can be added to either the base formulations or the GER formulations.
- Table 1 For Table 1, the following numbers correspond to the listed ingredient: (1) strontium carbonate; (2) strontium bicarbonate; (3) strontium hydroxide; (4) strontium phosphate; (5) strontium citrate; (6) strontium lactate; (7) chlorogenic acid and its salts; (8) ascorbic acid and its salts; (9) citric acid and its salts; (10) kynurenic acid and its salts; (11) agmatine; (12) tangeretin; and (13) nobiletin. Table 1 below lists the specific combinations for formulations A-D30 (on the vertical axis) using ingredients 1-13 (on the horizontal axis).
- each of the formulations disclosed in Table 1 includes calcium carbonate, sodium bicarbonate, sodium citrate, aluminum hydroxide, aluminum phosphate, magnesium hydroxide, magnesium carbonate, magaldrate, almagate, and hydrotalcite.
- Each of the formulations disclosed in Table 1 further includes calcium carbonate.
- Each of the formulations disclosed in Table 1 further includes sodium bicarbonate.
- Each of the formulations disclosed in Table 1 further includes sodium citrate.
- Each of the formulations disclosed in Table 1 further includes aluminum hydroxide.
- Each of the formulations disclosed in Table 1 further includes aluminum phosphate.
- Each of the formulations disclosed in Table 1 further includes magnesium hydroxide.
- Each of the formulations disclosed in Table 1 further includes magnesium carbonate.
- Each of the formulations disclosed in Table 1 further includes magldrate. Each of the formulations disclosed in Table 1 further includes almagate. Each of the formulations disclosed in Table 1 further includes hydrotalcite. Each of the formulations disclosed in Table 1 further includes aluminum hydroxide and magnesium hydroxide. [0165] To each of the formulations disclosed in Table 1, one or more of the following histamine H2 receptor antagonists can optionally be added: cimetidine, famotidine, nizatidine, and rantidine. Each of the formulations disclosed in Table 1 further includes cimetidine. Each of the formulations disclosed in Table 1 further includes famotidine. Each of the formulations disclosed in Table 1 further includes nizatidine. Each of the formulations disclosed in Table 1 further includes rantidine
- omeprazole lansoprazole
- rabeprazole pantoprazole
- esomeprazole esomeprazole
- one or more of the following acid neutralizing agents can optionally be added: calcium carbonate, sodium bicarbonate, sodium citrate, aluminum hydroxide, aluminum phosphate, magnesium hydroxide, magnesium carbonate, magaldrate, almagate, and hydrotalcite.
- one or more of the following histamine H2 receptor antagonists can optionally be added: cimetidine, famotidine, nizatidine, and rantidine.
- one or more of the following acid neutralizing agents can optionally be added: calcium carbonate, sodium bicarbonate, sodium citrate, aluminum hydroxide, aluminum phosphate, magnesium hydroxide, magnesium carbonate, magaldrate, almagate, and hydrotalcite. Additionally, one or more of the following proton pump inhibitors can be added: omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole.
- alginic aid PVP
- xanthan gum To each of the formulations disclosed in Table 1, one or more of the following polymers can optionally be added: alginic aid, PVP, and xanthan gum.
- alginic acid Each of the formulations disclosed in Table 1 further includes PVP.
- xanthan gum Each of the formulations disclosed in Table 1 further includes xanthan gum.
- the acid neutralizing agents are used in the amounts set out is the Code of Federal Regulations (CFR), Title 21, Section 331.
- 21CFR331 sets a maximum daily dosage limit of 8 grams for calcium carbonate.
- the maximum daily dosage for PPFs is set by the FDA and is based on the indication.
- omeprazole has a maximum daily dosage of 20 mg for heartburn.
- the maximum daily dosage for H2 blockers is set by the FDA and is based on the indication.
- famotidine has a maximum daily dosage of 20mg for heartburn.
- Chlorogenic acid is present in coffee. Coffee drinkers consume up to 1 gram of chlorogenic acid a day.
- Chlorogenic acid is also available as a dietary supplement with a recommended daily dose of 400-600 milligrams per day.
- Agmatine is available as a dietary supplement with a recommended daily dose between 500 milligrams to 2.5 grams per day.
- Ascorbic acid is available as a dietary supplement with a recommended daily dose of up to 2 grams per day.
- the formulations disclosed herein are evaluated for their ability to suppress acid induced pain and irritation. Briefly, a participant’s inner forearms are divided into six sections labeled 1- 12. Each section is swabbed with a 25% glycolic acid solution. A second solution is swabbed in each quadrant as shown in Table 2, below.
- the pain level is assessed at time of application and every minute thereafter for 10 minutes. Participants rated the pain levels on a 0-4 scale where 0 was no pain; 1 is slight pain; 2 is mild pain; 3 is moderate pain; and 4 is unbearable pain.
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Abstract
The present disclosure consists of therapeutically-active compositions for treating pain, irritation, and inflammation associated with gastroesophageal reflux and Barretts esophagus that combines strontium either in salt or complex form, at least one acid neutralizing or acid reducing agent, chlorogenic acid. Optional therapeutic agents include (but not limited to): at least one amino acid derivative, at least one methoxyflavonoid, at least one vitamin, and at least one polymer.
Description
COMPOSITIONS FOR TREATING GASTROESOPHAGEAL REFLUX AND
BARRETT’S ESOPHAGUS
CROSS-REFERENCE TO RELATED APPLICATIONS
[001] This application claims the benefit of U.S. Provisional Patent Application No.
62/730,472 filed on September 12, 2018. Priority is claimed pursuant to 35 U.S.C. § 119. The above noted patent application is incorporated by reference as if set forth fully herein.
TECHNICAL FIELD
[002] The present disclosure consists of therapeutically-active compositions for treating pain, irritation, and inflammation associated with gastroesophageal reflux and Barrett’s esophagus that combines strontium either in salt or complex form, at least one acid neutralizing or acid reducing agent, and chlorogenic acid. Optional therapeutic agents include (but not limited to): at least one amino acid derivative or metabolite, at least one methoxyflavonoid, at least one vitamin, and at least one polymer.
BACKGROUND
[003] Gastroesophageal reflux (GER), commonly referred to as heartburn, is the movement of acidic material from the stomach back into the esophagus. Common symptoms of GER include, but are not limited to, burning-type pain in the lower part of the mid-chest, behind the breast bone, and in the mid-abdomen, sore throat, coughing, and water brash, the sensation of a bitter taste in the mouth. GER is usually a temporary condition that causes no lasting damage to the affected tissues. However, in some individuals, chronic bouts of GER leads to severe damage to the esophageal lining, a condition referred to as gastroesophageal reflux disease (GERD). If GERD is left untreated, the continual damage to the esophageal lining can develop into Barrett’s esophagus, a precancerous condition that can lead to esophageal cancer.
[004] The American Gastrointestinal Endoscopic Surgeons (SAGES) estimates that 36-77 % of men and women have symptoms of GERD. Of this population, between 15-50% have heartburn symptoms every month, 14-20% have symptoms weekly and 7% have heartburn symptoms daily.
[005] Barrett’s esophagus, sometimes called Barrett’s syndrome or columnar epithelium lined lower esophagus (CELLO), refers to an abnormal change (metaplasia) in the cells of the lower portion of the esophagus. Specifically, the esophageal tissue changes into tissue that is similar to intestinal lining. The main cause of Barrett’s esophagus is believed to be an adaptation to
chronic acid exposure from acid reflux. Barrett’s esophagus is found in 5-10% of patients who seek medical care for GER. People with Barrett’s esophagus are at an increased risk for developing esophageal adenocarcinoma.
[006] The high prevalence of GER has resulted in the development of a multibillion treatment industry in which prescription and over the counter (OTC) drugs are among the world’s largest selling category. The majority of drugs approved for GER treatment are designed to reduce the acidity of the stomach’s contents either by reducing hydrochloric acid secretion by the stomach’s parietal cells via histamine H2 receptor antagonists (H2RA) and proton pump inhibitors or by chemically neutralizing the acid by using carbonate or hydroxide-containing antacids. An additional class of treatment seeks to physically block acid reflux by using a seaweed-derived carbohydrate polymer, alginic acid that floats on the surface of stomach contents and physically blocks their passage into the esophagus.
[007] All of these treatment modalities have one important therapeutic commonality - they all target only the stomach acid, either by neutralizing it, by inhibiting its synthesis or by physically blocking its reflux. None of these treatments target the actual“shock organ,” the esophageal mucosa and its pain and inflammation-producing nociceptors that directly trigger the signs and symptoms of heartburn, GER, and GERD. Nor do any conventional treatments have any direct suppressive effects on nociceptor-induced pain or esophageal inflammation. It would therefore be desirable to have the therapeutic approach of the present invention combined with
conventional therapies that reduce the pain and inflammation effects of stomach acid to achieve maximal pain relief and anti-inflammatory benefits
SUMMARY
[008] The compositions and formulation disclosed herein provide a new therapeutic approach to treating GER, GERD, and Barrett’s esophagus by using a combination of ingredients that reduce the pain and inflammation by blocking the acid and inflammation-inducing biochemical pathways at multiple points and thereby provide and overall therapeutic benefit far greater than any individual ingredient. Of particular importance is the ability of the ingredients of the present invention to directly suppress the pain and inflammation-inducing nociceptive nerves that represent the earliest step of the pain and inflammation-triggering biochemical pathways. A particularly advantageous property of this invention is that each of the ingredients that provide therapeutic benefits in the present invention (e.g. strontium, chlorogenic acid, agmatine, ascorbic acid, and calcium carbonate as one exemplary ingredient combination) are found in foods that
are consumed every day in typical meals and for this reason lack the potential adverse reactions that can occur with the use of synthetic ingredients like histamine H2 receptor antagonists and proton pump inhibitors. Since most GER patients consume a GER treatment one or more times daily and for many patients, for their lifetime, the inherent safety of the ingredients used in the present invention provide a substantial medical benefit over the most commonly used conventional GER treatments.
[009] In accordance with the teachings herein, the present disclosure relates generally to compositions of a strontium salt and at least one additional ingredient such as chlorogenic acid, a vitamin, an amino acid derivative or metabolite, or a methoxyflavonoid. In one embodiment, the strontium salt is strontium carbonate, strontium bicarbonate, strontium hydroxide, strontium phosphate, strontium lactate, strontium citrate, strontium chloride, strontium sulfate, strontium nitrate, strontium hydrosulfide, strontium oxide, strontium acetate, strontium glutamate, strontium aspartate, strontium malonate, strontium maleate, strontium threonate, strontium lactate, strontium pyruvate, strontium ascorbate, strontium alpha-ketoglutarate or strontium succinate. In one embodiment, the at least one vitamin is ascorbic acid. In one embodiment, the at least one amino acid derivative or metabolite is kynurenic acid and/or agmatine. In one embodiment, the at least one methoxyflavonoid is tangeretin or nobiletin. In one embodiment, the additional ingredient is chlorogenic acid. In another embodiment, the additional ingredient is agmatine. In another embodiment, the additional ingredient is kynurenic acid.
[010] The present disclosure also relates generally to complexes of a divalent cationic strontium and at least two counter compounds. In one embodiment, the at least two counter compounds are selected from chlorogenic acid, a vitamin, an amino acid derivative or metabolite, or a methoxyflavonoid. In one embodiment, the strontium ion is from a strontium salt. In this embodiment, the strontium salt is strontium carbonate, strontium bicarbonate, strontium hydroxide, strontium phosphate, strontium lactate, strontium citrate, strontium chloride, strontium sulfate, strontium nitrate, strontium hydrosulfide, strontium oxide, strontium acetate, strontium glutamate, strontium aspartate, strontium malonate, strontium maleate, strontium threonate, strontium lactate, strontium pyruvate, strontium ascorbate, strontium alpha- ketoglutarate or strontium succinate. In one embodiment, the at least one vitamin is ascorbic acid. In one embodiment, the at least one amino acid is kynurenic acid and/or agmatine. In one embodiment, the at least one methoxyflavonoid is tangeretin or nobiletin. In one embodiment the strontium is complexed to two chlorogenic acid molecules. In another embodiment the strontium is complexed to two kynurenic acid molecules. In another embodiment the strontium is complexed to two agmatine molecules. In another embodiment the strontium is complexed to
two ascorbic acid molecules. In another embodiment, three strontium ions are complexed to two citrate molecules. In another embodiment the strontium is complexed to chlorogenic acid and agmatine. In another embodiment the strontium is complexed to chlorogenic acid and kynurenic acid. In another embodiment the strontium is complexed to chlorogenic acid and ascorbic acid.
In another embodiment the strontium is complexed to kynurenic acid and ascorbic acid. In another embodiment the strontium is complexed to agmatine and ascorbic acid. In another embodiment the strontium is complexed to agmatine and kynurenic acid.
[011] In some embodiments, the foregoing compositions also include an acid neutralizing agent. In these embodiments, the acid neutralizing agent is aluminum carbonate, aluminum hydroxide, dihydroxyaluminum aminoacetate, aluminum phosphate, di hydroxy alumium sodium carbonate, magnesium carbonate, sodium bicarbonate, bismuth aluminate, bismuth carbonate, bismuth subcarbonate, bismuth subgallate, bismuth submitate, calcium carbonate, calcium phosphate, tricalcium phosphate, citric acid, trisodium citrate, glycine, magnesium aluminate, magaldrate, magnesium aluminosilicates, magnesium carbonate, magnesium glycinate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, milk solids, potassium bicarbonate, sodium potassium tartrate, tartaric acid, potassium bitartrate, magaldrate, almagate, or hydrotalcite. In one embodiment, the acid neutralizing agent is aluminum carbonate. In another embodiment, the acid neutralizing agent is aluminum hydroxide. In another
embodiment, the acid neutralizing agent is dihydroxyaluminum aminoacetate. In another embodiment, the acid neutralizing agent is aluminum phosphate. In another embodiment, the acid neutralizing agent is dihydroxyalumium sodium carbonate. In another embodiment, the acid neutralizing agent is magnesium carbonate. In another embodiment, the acid neutralizing agent is sodium bicarbonate. In another embodiment, the acid neutralizing agent is bismuth aluminate. In another embodiment, the acid neutralizing agent is bismuth carbonate. In another
embodiment, the acid neutralizing agent is bismuth subcarbonate. In another embodiment, the acid neutralizing agent is bismuth subgallate. In another embodiment, the acid neutralizing agent is bismuth submitate. In another embodiment, the acid neutralizing agent is calcium carbonate.
In another embodiment, the acid neutralizing agent is calcium phosphate. In another
embodiment, the acid neutralizing agent is tricalcium phosphate. In another embodiment, the acid neutralizing agent is citric acid. In another embodiment, the acid neutralizing agent is trisodium citrate. In another embodiment, the acid neutralizing agent is glycine. In another embodiment, the acid neutralizing agent is magnesium aluminate. In another embodiment, the acid neutralizing agent is magaldrate. In another embodiment, the acid neutralizing agent is magnesium aluminosilicates. In another embodiment, the acid neutralizing agent is magnesium
carbonate. In another embodiment, the acid neutralizing agent is magnesium glycinate, magnesium hydroxide. In another embodiment, the acid neutralizing agent is magnesium oxide. In another embodiment, the acid neutralizing agent is magnesium trisilicate. In another embodiment, the acid neutralizing agent is milk solids. In another embodiment, the acid neutralizing agent is potassium bicarbonate. In another embodiment, the acid neutralizing agent is sodium potassium tartrate. In another embodiment, the acid neutralizing agent is tartaric acid. In another embodiment, the acid neutralizing agent is potassium bitartrate. In another embodiment, the acid neutralizing agent is magaldrate. In another embodiment, the acid neutralizing agent is almagate. In another embodiment, the acid neutralizing agent is
hydrotalcite
[012] In some embodiments, the foregoing composition also includes an acid reducing agent.
In these embodiments, the acid reducing agent is cimetidine, famotidine, nizatidine, rantidine, omeprazole, lansoprazole, rabeprazole, pantoprazole, or esomeprazole. In one embodiment the acid reducing agent is cimetidine. In another embodiment the acid reducing agent is famotidine. In another embodiment the acid reducing agent is nizatidine. In another embodiment the acid reducing agent is rantidine. In another embodiment the acid reducing agent is omeprazole. In another embodiment the acid reducing agent is lansoprazole. In another embodiment the acid reducing agent is rabeprazole. In another embodiment the acid reducing agent is pantoprazole. In another embodiment the acid reducing agent is esomeprazole.
[013] In some embodiments, the foregoing compositions also include at least one polymer. In these embodiments, the polymer is alginic acid, polyvinylpyrrolidone (PVP), or xanthan gum. In one embodiment, the polymer is alginic acid. In another embodiment, the polymer is PVP. In another embodiment, the polymer is xanthan gum.
[014] In some embodiments, the foregoing compositions also include excipients needed to formulate the compositions into a final dosage form. In one embodiment, additional excipients are added to formulate the foregoing compositions into a chewable tablet. In another
embodiment, additional excipients are added to formulate the foregoing compositions into a gummy dosage form to enable the ingredients to be released into the esophagus not as a bolus but instead in an extended release manner. In another embodiment, additional excipients are added to formulate the foregoing compositions into a chewy tablet. In another embodiment, additional excipients are added to formulate the foregoing compositions into a chewing gum. In another embodiment, additional excipients are added to formulate the foregoing compositions into a lozenge. In another embodiment, additional excipients are added to formulate the foregoing compositions into a spray.
[015] The foregoing compositions and formulations can be used to treat or prevent the symptoms associated with GER, GERD, or Barrett’s esophagus in a patient. The patient is treated by consuming the above described compositions and formulations. In one embodiment, the patient is treated by taking the compositions and formulations after eating but before the onset of symptoms, for example, taking the compositions and formulation within an hour or within 30 minutes after a meal. In another embodiment, the patient is treated by taking the compositions and formulations after the onset of symptoms. In another embodiment, the patient is treated by taking the compositions and formulations up to an hour before eating. In another embodiment, the compositions and formulations are taken sequentially to maximize the exposure of the compositions and formulations to the esophagus.
DETAILED DESCRIPTION
[016] The present disclosure relates to compounds for use in treating symptoms associated with gastroesophageal reflux (GER), gastroesophageal reflux disease (GERD), Barrett’s esophagus and other related conditions (all referred to as“GER” herein unless otherwise indicated).
[017] GER, GERD, and Barrett’s esophagus are caused by reflux of acidic stomach contents through the lower esophageal sphincter (LES) that activate Type C nociceptors in the esophageal mucosa that transmit burning pain signals to the brain. Acid-induced pain is triggered by activation of a family of acid-sensitive ion channels (ASIC) that are present on the surface of nociceptors, immune white blood cells and on epithelial cells in the esophagus, and on fibroblasts, keratinocytes and vascular endothelial cells throughout the body. The pain sensation of GER is characterized as a diffuse burning sensation in the chest and most often occurs when a person is in a recumbent position that facilitates the‘reflux passage’ of hydrochloric acid in the stomach contents through the LES in to the esophagus that is highly sensitive to acidic pH and partially disgusted food. The rapid pain relief that occurs by neutralization of stomach acid by ‘antacids’ demonstrated that GER pain is predominantly triggered by acid contacting the nociceptors of the esophagus. In addition to acidic reflux, many food ingredients with a spicy taste also exacerbate pain by activating ion channels that are sensitive to both acid and certain chemically reactive ingredients such as capsaicin. Of additional therapeutic importance is the fact that when Type C nociceptors are strongly activated as occurs in acid reflux, multiple powerful inflammatory molecules are released that further activate nociceptor pain signals and activate inflammatory cells such as mast cells, neutrophils and other immune white blood cells
including monocytes, macrophages and lympocytes. These inflammatory substances released by Type C nociceptors included Substance P, Neurokinin A, Calcitonin Gene-Related Peptide (CGRP), glutamic acid and ATP. Glutamic acid is the predominant excitatory neurotransmitter in the peripheral and central nervous system and binds to and activates multiple receptors including the NMD A, AMPA and Kinate receptors that directly and indirectly trigger further activation of pain and inflammation in nociceptors and multiple immune cells and‘structural cells’ including fibroblasts, mucosal cells, vascular endothelial cells and other cells that are damaged by inflammation.
[018] There are multiple OTC and prescription drugs with different pharmacological mechanisms that have been used for many years to treat and prevent GER pain and the associated inflammation that directly amplifies nociceptor activation and pain intensity and contributes to its chronicity. The most commonly used drugs to treat GER are antacids that elevate the pH of the naturally acidic stomach fluid. The pH of an empty stomach is typically between 1.5 and 3 and is entirely due to the hydrochloric acid secreted by the parietal cells in the stomach. Antacid ingredients are inherently basic and thus acid-neutralizing and include calcium carbonate, salts of bicarbonate and magnesium and aluminum hydroxides. Within seconds of ingestion they greatly raise the pH of stomach fluid and thus partially or completely‘neutralize’ the acid to a non-pain inducing pH of approximately 7. After antacid ingestion, most people experience cessation of pain within seconds. However the neutralizing benefits of antacids have a short duration and the continued secretion of acid in the stomach will rapidly reduce the pH to a pain-inducing level. Since food ingestion stimulates acid secretion that can trigger pain, antacids must be repeatedly used throughout the day, especially if the LES has been damaged by chronic inflammation and especially if the user is in a recumbent position in a chair or sleeping. While antacids are acutely effective at reducing or eliminating acid-induced pain, they do not have inherent anti-inflammatory activity and thus have only very limited effectiveness at treating the chronic inflammation of GER. Proton pump inhibitors (PPI) are a second class of treatments that reduce the‘baseline’ rate of acid secretion and also reduce the level of food- stimulated acid secretion. After they are orally ingested PPI are absorbed into the bloodstream and act on the acid- secreting parietal cells of the stomach and inhibit the enzyme responsible for acid secretion. Commonly available PPI include omeprazole, lansoprazole, dexlansoprazole, rabeprazole, pantoprazole, esomeprazole. While they are relatively safe, they all have a potentially severe side effect of contributing to osteoporosis, especially in post-menopausal women that reduces bone density and can lead to fractures. Since GER is typically a lifelong condition, PPI may be used for many years and in post-menopausal women and older men, they
can contribute to an already serious age-related condition. A third class of commonly used acid- blocking drugs are the histamine-2 receptor antagonists or Ή-2 Blockers.’ After oral ingestion these drugs are absorbed into the blood and bind to and block the histamine-2 receptor of the acid-secreting parietal cells, thus inhibiting baseline and stimulated acid secretion into the stomach. Commonly available H-2 Blockers include; cimetidine, famotidine, nizatidine and ranitidine. A fourth class of GER medication uses the natural ingredient, alginic acid, that is a negatively charged carbohydrate polymer extracted from brown seaweed. It has a unique, non acid neutralizing or acid blocking mechanism unlike any other treatment. When exposed to acid in the stomach, alginic acid forms a gel that floats on the surface of the stomach contents and creates a physical gel barrier that blocks the lower entry of the LES and physically prevents reflux of the stomach contents into the sensitive esophagus. While alginic acid has no acid neutralizing activity and has no effect on acid secretion, it has been shown to be effective in treating symptoms of GER. Due to its polyanionic carbohydrate structure, alginic acid is an effective carrier for carbonate and bicarbonate antacids that, in combination, provide a more effective treatment. Each of the above treatments represent the‘state-of-the-therapeutic-art’ approaches for treating GER.
[019] For each of the above drug classes, the therapeutic targets are components of the stomach. Antacids target stomach acid and act in the stomach by neutralizing hydrochloric acid, PPFs and H-2 blockers act directly on the acid-secreting parietal cells of the stomach to inhibit acid secretion, and alginic acid acts in the stomach to physically block reflex of stomach acid and food content. Consequently, each of the four treatment approaches only target stomach acid that only indirectly treat the mechanisms within the esophagus that trigger GER that may lead to Barrett’s Esophagus.
[020] The present disclosure provides a unique therapeutic strategy unlike any other GER treatment. None of these approaches target the actual‘shock organ’ that directly cause the signs and symptoms of GER, the cellular lining of the esophagus. Nor do any of these treatment approaches target the chronic inflammatory changes that lead to Barrett’s Esophagus, a pre- cancerous condition caused by chronic esophageal inflammation. While the indirect treatment in the stomach that reduces stomach acid or blocks its reflux can significantly reduce GER symptoms, the effect has only a limited duration. Furthermore, chronic GER increases the sensitivity of the inflamed esophageal mucosa to acid-induced pain and increases the severity of GER.
[021] The approach of the present disclosure is distinct from any current treatment. The present disclosure directly targets the esophageal mucosa to reduce pain and inflammation by inhibiting
the most important known biochemical pathways and inflammatory mediators and cytokines that cause inflammation and pain. Furthermore, the chemical properties of the compound of the present disclosure can be combined with one or more of the above conventional treatments to provide an unprecedented level of efficacy and safety. Additionally, the advantage of the present disclosure is the fact that each of the compounds used are naturally occurring in the body and/or some are ingested on a daily basis in foods or in nutritional supplements, frequently at high levels that exceed those used in the present disclosure. These ingredients not only have pleiotropic and potent anti-pain and anti-inflammatory activities but, in combination have anti cancer activities as well.
[022] To block the pain and inflammation associated with GER, conventional treatments use a single active ingredient that blocks a single biochemical pathway. For example, proton pump inhibitors selectively block the hydrogen/potassium ATPase that uses the energy of ATP to translocate protons into the stomach and thus reduce the pH of its contents. Similarly, histamine H2 receptor antagonists (H2RA) selectively block the H2 histamine receptor that must be activated by histamine to stimulate proton secretion into the stomach. Such single receptor targeting approach typically requires that the regulatory molecule being used be very potent and have the ability to block most of the target’s biochemical activity in order to achieve the desired pharmacological benefits. While blockade of the target receptor in the target organ, the hydrogen/potassium ATPase in the case of a proton pump inhibitor in the acid-secreting parietal cell of the stomach, it is not uncommon to have blockade of the same or similar molecular target in other organs that produces adverse reactions. Such is the case with proton pump inhibitors since they also block a similar target receptor in bones that causes bone weakening and ultimately osteoporosis.
[023] The present disclosure presents a different pharmacological approach that can achieve both high efficacy and substantially reduce adverse reactions. Instead of using a single highly potent drug to block acid secretion that will indirectly reduce pain and inflammation, the present disclosure uses several relatively low potency ingredients that block critical pain and
inflammation pathway regulatory proteins and multiple points in each pathway. The result is partial inhibition of a particular regulatory protein, thus allowing it to function at a reduced level and continue to regulate other parallel pathways that are not inflammation and pain generators. The net effect on the pathway will be substantially greater due to the multiple levels of inhibition. By preserving the activity of partially blocked regulatory protein, it can continue to participate in the regulation of other pathways and thereby reduce the potential for toxic or adverse reactions. In a metaphoric sense, this is akin to turning down the volume of a radio
instead of shutting it off completely.
[024] The Present disclosure also reduces the increased sensitivity of nociceptors that are the first trigger of pain and inflammation. When Type C nociceptors are strongly activated as occurs in acid reflux, they rapidly become sensitized and thus an activation stimulus that would normally only cause minimal pain will produce a much higher level of pain and increased release of the aforementioned inflammatory mediators including Substance P. Two forms of sensitization occur: (1) immediate peripheral sensitization of the endings of the nociceptors that reach to the highest levels of a viable mucous membrane. This immediate sensitization can occur within minutes and may last for many hours. And (2) after repeated peripheral sensitization, ‘central’ sensitization occurs in the Dorsal Root Ganglia (DRG) within which peripheral nociceptors synapse and pain signals are retransmitted to the spinal cord and to the brain. The transition of acute pain into chronic pain occurs due to such central sensitization and is the proximate cause of chronic pain conditions, including pain that occurs from GERD. Such chronic pain and the associated release of multiple inflammation mediators produces a long-term pain-triggering‘set-point’ that is very difficult, if not impossible to effectively treat with conventional GERD treatments. The present disclosure provides ingredients that are known to be able to prevent and reverse central sensitization of nociceptors and thus prevent and reverse chronic pain states and related inflammation.
[025] The Present disclosure optimally uses multiple ingredients that each reduce acid-induced pain and inflammation by different mechanisms. Additionally each ingredient partially inhibits the pathways inhibited by of each of the other ingredients, thus providing a unique synergy of therapeutic activity.
[026] In one embodiment, the compounds consist of therapeutically-active compositions that combine strontium either in salt or complex form with at least one acid neutralizing or acid reducing agent and chlorogenic acid. The compounds optionally include additional therapeutic agents including, but not limited to at least one amino acid derivative, in particular agmatine and/or kynurenic acid, at least one methoxyflavonoid, at least one vitamin, in particular ascorbic acid, and at least one polymer. The combination increases the overall therapeutic potency of the combination beyond the potency of any of the separate constituents. Specifically, the
combinations described herein perform several functions over an extended period of time: (1) increase the pH of the stomach contents, (2) block stomach acid production, (3) reduce pain, (4) prevent and reverse nociceptor sensitization, (5) reduce inflammation, and (6) promotes bone health. The compounds and their effects on pain, inflammation, and acid production pathways are discussed in greater detail below.
[027] In the description that follows, a number of terms are extensively utilized. In order to provide a clear and consistent understanding of the specification and claims, including the scope to be given such terms, the following non-limiting definitions are provided.
[028] When the terms“one,”“a,” or“an” are used in this disclosure, they mean“at least one” or“one or more,” unless otherwise indicated.
[029] The terms“invention” or“present invention” as used herein are intended to be non limiting and are not intended to refer to any single embodiment of the particular invention but encompasses all possible embodiments as described in the specification and the claims.
[030] As used herein, the term“and/or” may mean“and,” it may mean“or,” it may mean “exclusive-or,” it may mean“one,” it may mean“some, but not all,” it may mean“neither,” and/or it may mean“both.”
[031] As used herein,“treatment” means any manner in which the symptoms of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also
encompasses any pharmaceutical use of the compositions herein
[032] The term“gastroesophageal reflux” or“GER” refers to the movement of contents from the stomach back into the esophagus and mouth. The term also includes other names such as pyrosis, dyspepsia, heartburn, acid reflux, and acid indigestion. Unless otherwise indicated, the use of GER in the present disclosure includes GERD (defined below) and Barrett’s esophagus.
[033] The term“gastroesophageal reflux disease” or“GERD” refers to acute and chronic inflammation and damage to the esophagus due to repetitive exposure to stomach contents. The term also includes other names such as gastro-esophageal reflux disease (GORD), gastric reflux disease, and acid reflux disease.
[034] The term“acid neutralizing” as used herein refers to a chemical agent that is capable of reducing the acidity of a liquid. The chemical does not need to be able to bring the acid to a complete neutral state. Non-limiting examples of acid neutralizing agents include salts of carbonates, bicarbonates, hydroxides, phosphates, and citrates.
[035] The term“acid reducing” as used herein refers to a chemical agent that is capable to reducing the production of stomach acid. Non-limiting examples of acid reducing agents include histamine H2 receptor antagonists and proton pump inhibitors.
[036] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In
addition it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof.
[037] Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included. For example all tautomers of phosphate groups are intended to be included. Furthermore, all tautomers of heterocyclic bases known in the art are intended to be included, including tautomers of natural and non-natural purine-bases and pyrimidine-bases.
[038] ETnless otherwise defined, all terms (including technical and scientific terms) are to be given their ordinary and customary meaning to a person of ordinary skill in the art, and are not to be limited to a special or customized meaning unless expressly so defined herein. It should be noted that the use of particular terminology when describing certain features or aspects of the disclosure should not be taken to imply that the terminology is being re-defined herein to be restricted to include any specific characteristics of the features or aspects of the disclosure with which that terminology is associated. Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term ‘including’ should be read to mean‘including, without limitation,’‘including but not limited to,’ or the like; the term‘comprising’ as used herein is synonymous with‘including,’‘containing,’ or‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term‘having’ should be interpreted as‘having at least;’ the term ‘includes’ should be interpreted as‘includes but is not limited to;’ the term‘example’ is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; adjectives such as‘known’,‘normal’,‘standard’, and terms of similar meaning should not be construed as limiting the item described to a given time period or to an item available as of a given time, but instead should be read to encompass known, normal, or standard technologies that may be available or known now or at any time in the future; and use of terms like ‘preferably,’‘preferred,’‘desired,’ or‘desirable,’ and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function of the invention, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the invention. Likewise, a group of items linked with the conjunction‘and’ should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as ‘and/or’ unless expressly stated otherwise. Similarly, a group of items linked with the
conjunction‘or’ should not be read as requiring mutual exclusivity among that group, but rather should be read as‘and/or’ unless expressly stated otherwise.
[039] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article“a” or “an” does not exclude a plurality. A single processor or other unit may fulfill the functions of several items recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.
[040] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments.
[041] It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to
understanding, the following appended claims may contain usage of the introductory phrases“at least one” and“one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles“a” or“an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases“one or more” or“at least one” and indefinite articles such as“a” or“an” (e.g.,“a” and/or“an” should typically be interpreted to mean“at least one” or“one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should typically be interpreted to mean at least the recited number (e.g., the bare recitation of“two recitations,” without other modifiers, typically means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to“at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g.,“a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). In those instances where a convention analogous to
“at least one of A, B, or C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g.,“a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and/or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase“A or B” will be understood to include the possibilities of“A” or“B” or“A and B.”
[042] All numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification are to be understood as being modified in all instances by the term‘about.’ Accordingly, unless indicated to the contrary, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority to the present application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.
[043] It is understood that the compounds described herein can be labeled isotopically.
Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element in a compound may be any isotope of said element. Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
[044] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated
forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
Nociception and Inflammation Pathways
[045] Nociception is the neural processes of encoding and processing stimuli that have the potential to damage tissue. Nociceptors are specialized nerves located throughout the body that detect mechanical, thermal or chemical changes. There are two classes of nociceptors, the first class is“A-delta” nerves, which respond to physical trauma by transmitting a pain sensation with a sharp, pricking quality. The second class is“Type C” nerves (TCN), which are chemical sensors that respond to irritants from our environment, such as microbes, temperature extremes, and ionizing radiation and transmit diffuse sensations of burning pain, stinging pain or itching (“irritation”). When excessively stimulated, TCN can also release neuropeptides ( e.g Substance P) that directly activate histamine-containing mast cells and attract and activate other immune system cells such as neutrophils that cause redness, swelling and even local tissue damage. After activation by a stimuli, nociceptors synapse near the spinal cord in the dorsal root ganglia (DRG) and release neurotransmitters that activate nerve pathways that relay signals to the brain. The brain interprets the signals as various types of pain or itch.
A. Acute, Chronic, and Neuropathic Pain and Pruritus Occur Upon Nociceptor Activation
[046] Exposure to stimuli activates nociceptors. Depending on the stimuli, both types of nociceptors may be activated or in many instances either the A-delta or TCN are preferentially activated. Since only the TCNs extend to the outermost portions of the body, such as the skin, mouth, nose, throat, eyes, etc. (herein referred to as“epithelium”) and may be activated by virtually any process that changes the local biochemistry of the epithelium, TCNs are preferentially activated in response to most irritating stimuli. Upon activation of TCNs, the TCNs transmit a signal to the spinal cord and trigger neurotransmitter release in the DRG that activate nerves in the spinal cord that relay the pain and itch signals to the brain. Acute activation of TCNs that is caused by exposure to a chemical irritant, such as stomach acid, typically causes painful or pruritic sensations that last only several days and is termed “nociceptive pain”. When the stimulus is prolonged or excessively severe, painful sensations or pruritus can continue for many years. Such chronic pain or pruritus caused by excessive nociceptor activation or damage is termed“neuropathic” and is among one of the most difficult conditions to treat.
B. Nociceptive Signals are Typically Encoded as Precisely-Timed Changes of Intracellular Calcium Concentration that Travel as“Calcium Waves” within Nociceptors
[047] No matter what causes nociceptor activation, the event is encoded into a universal code; a complex change in the intracellular calcium concentration that, in turn, is transmitted throughout the nociceptor. Calcium thus acts as a universal“second messenger” and information transmitted by a nociceptor, including the intensity and quality of pain or pruritus is converted into a language made up of rapidly changing calcium concentrations. Since nerves in general and nociceptors in particular transmit their calcium code typically within about l/lOOO*11 of a second, the timing and spatial distribution of calcium must be exquisitely regulated to accurately transmit the encoded information. In virtually all nerves, including nociceptors, the intensity of the signal ( e.g the severity of pain or pruritus) is encoded as a change in frequency of calcium waves that trigger neurotransmitters that are released into the synapse and activate post-synaptic nerves that relay the information ultimately to the brain. The higher the frequency, the more intense the perceived sensation. When a nociceptor is activated, the calcium signal is transmitted through multiple biochemical pathways, many of which operate in sequence such that the output of one pathway becomes the input of the next.
C. Nociceptive Signals and the Biochemical Pathways that Encode Signals Have an Output that is Logarithmically Related to the Input
[048] The many nociceptor pathways as well as the overall neurotransmitter release by a nociceptor is typically logarithmically related to the intensity of the stimulus. For example, if the irritant caused the nociceptor activation to increase its frequency of activation, also called depolarization, from 10 to 50 per second, the frequency of the resultant neurotransmitter release may only increase by a factor of 1.7 (Log 10=1.0; Log 50=1.7). This fact is particularly relevant since it suggests that a relatively small amount of inhibition of a nociceptor’s activation can cause a large reduction in the perceived severity of the painful or pruritic stimulus. Since their are many separate pathways in nociceptors that act in sequence to encode and transmit the irritant stimulus, inhibiting each of the sequential pathways at one or more of a pathway’s steps has the potential to produce a very large cumulative reduction of the painful or pruritic sensation.
[049] Recent research has demonstrated that high osmolarity formulations activate specific osmotic sensors present on nociceptors, keratinocytes and immune or inflammatory cells. An
example of this is the“salt in the wound” effect that causes stinging and burning if a concentrated solution of a simple salt is poured into wound. In addition to causing discomfort, high osmolarity solutions can directly activate inflammatory cells and cause them to release chemicals that cause nociceptor activation.
D. The Development and Maintenance of Neuropathic Pain or Pruritus Requires Excessive and Continuous Nociceptor Activation
[050] In order for a neuropathic condition to develop, nociceptors must be continuously activated by a potent stimulus. The duration of the activation required may substantially vary depending on the specific nerve injury or stimulant. When such activation occurs, the peripheral nociceptors that innervate the epithelium and mucous membranes such as those of the esophagus may become sensitized within hours and may continue to increase their sensitivity to irritants and may even be activated by stimuli that are normally not irritating. Release of multiple inflammatory mediators that accompany any trauma or inflammation are also important contributors to sensitization.
[051] In order to establish a neuropathic state, sensory nerves in the DRG that receive sensory input from the TCN must also become sensitized. As for the peripheral TCN, the central neurons require sustained, high intensity activation for an extended period of time that may be as short as several weeks or much longer. The presence of inflammation, infectious agents, or trauma can accelerate the sensitized, neuropathic state. Due to neuronal“cross-talk,” it is common for an initially small painful portion of sensitized tissue, for example, as occurs in post-herpetic neuralgia, to expand to the adjacent tissue via nociceptors that were uninjured, including A-delta nociceptors. Sensitized neuropathic tissue may also generate painful stimuli in response to mechanical pressure, e.g. coughing or swallowing, or temperature changes, a condition known as allodynia.
[052] The sensitized state in both the peripheral nociceptors and their central counterparts is a form of activity-dependent plasticity that is very similar to the neurons in the CNS that form memories. In the case of neuropathic pain or pruritus, the nociceptive response produces a “memory of pain or itching.” The molecules and pathways that produce the long-lasting neuronal sensitization are reasonably well defined. In particular, the activation of intracellular kinases. Of particular importance are protein kinase A and C (PKA and PKC, respectively), each of which exist in several different forms and the mitogen activated protein kinases (MAPK) that include the p38 MAPK, ERK1/2 MAPK and the JNK MAPK. These kinases are activated by a broad range of environmental“danger signals” and internal cytokines and growth factors
exposures including ionizing radiation, reactive oxygen species (ROS) always accompany infection and trauma. When activated, these kinases are activated in multiple pathways and give rise to sequential cascades that result in regulation and activation of genes that regulate well over 100 different molecules that activate immune cells, produce inflammation and molecules that influence ion channels, and molecular sensors that cause the peripheral and central nociceptor sensitization that causes neuropathic pain and pruritus. Among these inflammation and immune- system activating genes, the most important is called Nuclear Factor, Immunoglobulin Light Chain Kappa, Enhancer of B Cells, abbreviated NF-Kappa B, called the“Master Gene Regulator of Inflammation.” Additionally, some of these kinases like PKC can directly sensitize and activate nociceptors that cause calcium influx and interfere with strontium’s ability to alter the calcium dynamics that occur in neuropathic states.
E. Stimuli that Oxidize Intracellular Glutathione Trigger Multiple Nociceptor- Activating Pathways
[053] Of the many conditions that may cause nociceptor activation during the development of neuropathic conditions, the redox state of a nociceptor can produce some of the most potent acute and chronic nociceptor activating stimuli that exist. One of the most important regulatory signals that cause a cell to convert to a defensive state in which multiple inflammatory and cell protective immune activators are activated is the intracellular ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG). Glutathione is the most plentiful intracellular thiol antioxidant, and is among the most important signal generators that trigger a cell to synthesize powerful inflammatory mediators and activate genes that, in turn, activate virtually every immune system inflammatory cell. The ratio of reduced glutathione, GSH, to the oxidized form, GSSG, is normally 9 to 1 or more. When cells are exposed to trauma, infection, inflammation or inflammatory mediators, ionizing radiation or general’’cellular stress,” the amount of reduced glutathione plummets and directly trigger multiple cascades of gene activation that ultimately lead to the synthesis of well over 100 inflammatory mediators, pro-inflammatory cytokines ( e.g TNF-alpha, IL-l, IL-6 and many others), and cytokines that attract and active inflammatory immune cells, all of which sensitize and activate nociceptors that transmit pain and pruritic signals, and in turn amplify these inflammatory cascades by neurogenic inflammatory pathways. Many of a cell’s most important regulators of inflammation and immune defense are highly sensitive to a reduction in a cell’s GSH concentration, and are directly activated by a low
GSH/GSSG ratio indicating that a cell is in an oxidative redox state.
[054] Perhaps the most important of these redox-sensitive regulatory pathways is NF-Kappa B. This molecule is responsible for that directly or indirectly inducing the synthesis of among the most important and powerful inflammation activators, including TNF-alpha and many of the inflammatory interleukins and chemokines that attract inflammatory cells that secrete mediators that directly activate nociceptors and thus increase their long-term sensitization and conversion to a neuropathic state.
[055] Since NF-Kappa B acts as a“final common pathway” for activation of multiple inflammatory pathways, substances that reduce or block NF-Kappa B activation will have substantial and broad anti-inflammatory activity and will block many forms of immune system- mediated activation of inflammatory pathways. NF-Kappa B is also one of the many regulatory molecules that is directly activated by an oxidative intracellular environment - one in which the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) is minimized. This oxidative environment directly activates NF-Kappa B that greatly increases the synthesis of nociceptor activating mediators and cytokines.
[056] Since both peripheral nociceptors with endings in the epithelium and central nociceptors in the DRG and spinal cord become sensitized upon continuous activation, activation of NF- Kappa B is an important and critical stimulator of neuropathic sensitization.
F. Activation of Toll-Like Receptors by Microbes Activate Gene Transcription by NF-Kappa B That Sensitizes Activate Nociceptors
[057] Epidermal cells, mucosal cells and virtually all inflammatory immune cells have many receptors that that can cause nociceptor activation. Among the most important are Toll -Like Receptors (TLRs), molecules that recognize conserved molecular structures of bacteria, fungi and viruses. Upon activation, TLRs trigger multiple inflammatory and nociceptor activating pathways, all of which lead to NF-Kappa B activation.
G. Activation of NF-Kappa B Produces Chemokines that Attract Inflammatory Cells
[058] One of the most important consequences of NF-Kappa B is to stimulate the production of chemokines, including IL-8, that attract and activate neutrophils, a blood-borne white blood cell (WBC) that typically constitutes over 50% of all WBCs in the blood. Neutrophils are the first responders to any type of trauma, infection or inflammatory process and accumulate at the triggering site in massive quantities. Upon activation by IL-8 and other inflammatory mediators, neutrophils produce massive levels of powerful oxidants, reactive oxygen species (ROS; e.g.,
superoxide, hydrogen peroxide, nitric oxide and hypochlorous acid) that rapidly deplete GSH from cells, including nociceptors, thus promoting oxidative activation of NF -Kappa B and activation of many kinases, including protein kinase A, protein kinase C and mitogen-activated protein kinases that act to amplify virtually all inflammatory pathways that directly activate nociceptors.
[059] Activation of these multiple independent inflammatory pathways and inflammatory cells result in intense activation of nociceptors that contribute to the development of neuropathic sensitization and neuropathic pain and pruritus.
[060] Such activation of nociceptors also causes them to release Substance P that directly triggers mast cell activation and release of histamine, TNF -alpha, IL-l, IL-6, IL-8 and many more inflammatory substances that further activate nociceptors. Due to the simultaneous activation of multiple inflammatory and nociceptor-activating pathways, there is a net amplification of nociceptor activation that is known to directly lead no neuropathic pain and pruritus.
Cellular and Molecular Pathways Triggered By Stomach Acid Secretion
[061] Unlike the gastric mucosa that is protected from the acid and protease-rich contents of the stomach by multiple levels of cellular and physical barriers, the esophageal mucosa lacks such protection and is easily damaged by reflux of the stomach contents. Such damage allows both hydrochloric acid and the stomach-derived protease, pepsin, to penetrate the esophageal mucosa in high quantities and directly trigger multiple inflammatory and pain-producing pathways. Among these, acid-induced neurogenic inflammation is among the most important.
[062] Biochemical pathways function by the sequential transmission of signals between multiple molecules until a particular endpoint is achieved. In the case of stomach acid secretion, the presence of food molecules in in the stomach activate nutrient sensors in stomach cells that trigger a cascade of biochemical events in multiple cells that ultimately lead to acid secretion.
[063] Similar multi-molecular cascades are mast cells and other inflammatory cells that trigger mucosal inflammation in the esophagus and contribute to its pathogenesis. Mast cells populate the mucosa of the esophagus and contribute significantly to the inflammation caused by reflux of the acidic stomach contents into the esophagus. When activated by stomach acid, mast cells release over 50 distinct inflammatory and pain-inducing mediators that trigger activation of other inflammatory cells and directly activate pain sensations in nociceptors, which in turn, release additional mediators that amplify the overall painful inflammatory reaction that is known to cause the signs and symptoms of GER, GERD, and Barrett’s esophagus.
A. Acid Activation of Pain and Inflammatory Mediators
[064] Protons produce pain and inflammation, in part, by activating acid sensitive ion channels (ASIC) and transient receptor potential vanilloid receptor-l (TRPV-l) ion channel, also known as the capsaicin receptor. Both ASIC and TRPV-l are present on Type C nociceptors. Upon activation, these receptors depolarize the nociceptors that cause two distinct activities: (1) transmission of calcium coded pain signals to the brain, and (2) Release of substance P, neurokinin A, calcitonin gene-related peptide (CGRP) and other neuropeptides and
inflammatory mediators that, in turn, initiate multiple inflammatory and pain-triggering cascades in a process called“neurogenic inflammation.” Of these released neuropeptides, substance P is among the most important since in directly activates mast cells and other inflammatory cells to release a myriad of inflammation mediators. Substance P also causes blood vessels to become permeable causing leakage of plasma from the vessels and allowing inflammatory white blood cells to accumulate at the site of inflammation.
B. Mast Cell Activation
[065] Within the mast cell, acid activates ASIC that open and allow a burst of calcium influx that triggers multiple cascades of pathways, each of which have multiple sequential‘molecular steps’ that amplify the calcium signal and ultimately result in inflammatory mediator release. Many of these mediators directly activate adjacent sensory neurons, Type C nociceptors, by activating multiple receptors and ion channels that allow calcium influx that are ultimately transduced into the pain sensation of GER.
Strontium Affects Nociception and Inflammation Pathways
[066] Strontium’s unique therapeutic properties are due to its chemical resemblance to calcium, the most important and universal“second messenger” in nerves and in all other cells that regulate virtually all cellular functions. The calcium ion always has two positive charges and its ionic radius is 0.99 angstroms, about the size of a hydrogen atom. Of all the elements, strontium most closely resembles calcium, since it also only exists as a divalent positively- charged ion and has an ionic radius of 1.13 angstroms. For this reason, strontium typically binds to calcium-binding sites and mimics calcium’s activity. Most often a strontium-induced response is less potent and may be as low as about l/lOOOth as active as calcium, but for certain calcium- dependent activities, strontium has activity that is nearly the same as calcium or in the range of l/lOth to 1/30th as active as calcium. In other calcium-dependent activities, strontium can be
more active than calcium. It is strontium’s calcium-mimetic activity that enables strontium to produce its many and varied activities. Since calcium is critical for so many cellular functions, if it were strongly inhibited the effects would be toxic to a cell. In contrast, since strontium can typically substitute for calcium, albeit with lower activity, the activity of the calcium-dependent pathway will not be shut down. Instead, the pathway activity will be reduced, similar to turning down the volume control of a radio. Since strontium, in a metaphoric sense, only turns down the volume control of calcium-dependent pathways rather than shutting down such pathways, the chances of significant adverse reactions or toxicity is much reduced compared to a drug that completely blocks a pathway.
A. Strontium Alters the Dynamics and Spatial Distribution of Calcium
Waves
[067] When irritants from chemicals, disease, trauma or other exposures activate receptors on the surface of TCNs that encode the intensity of their response as rapid changes in intracellular calcium concentrations, these changes can occur in less than l/lOOOth of a second and produce highly complex“waves” of changing calcium concentration that propagate through the nerve and triggered most, if not all, of the pathways that cause acute, chronic and neuropathic irritation. In addition to the frequency of calcium waves, alterations in the dynamics of calcium concentration change the duration, magnitude and the precise shape of the calcium waveform that alters the coexisting electrostatic field that is a critical regulator of TCN activity. These changes independently activate the release of multiple inflammatory mediators, including prostaglandins ( e.g PGE2), leukotrienes (e.g, LTB4, C4, D4, and E4) and reactive oxygen species (ROS) including superoxide, hydrogen peroxide, hydroxyl radicals, hypochlorous acid and peroxyni trite.
[068] Strontium thus significantly alters the pain and itch sensations encoded within calcium waves present in painful and pruritic neuropathic conditions, and has the effect of garbling the signal and reducing its perceived intensity by the brain. Due to strontium binding to multiple calcium-dependent signaling pathways, strontium significantly alters calcium-encoded signals by multiple independent mechanisms. Some of the calcium-dependent kinases are known to be essential for the development of neuropathic conditions, since their inhibition in animal models can prevent and or reverse established neuropathic conditions.
[069] Strontium is not able to bind effectively to the calcium binding proteins within the cytoplasmic interior of nociceptors that normally remove calcium within less than a millisecond after calcium enters the nociceptor, thus producing a transient increase in calcium concentration
that contributes to the precisely-timed calcium waves. Strontium is also much less effectively pumped into and released from a nociceptor’s primary calcium storage site, the endoplasmic reticulum (ER). When a nociceptor-activating signal is received, strontium inhibits the calcium- induced calcium release (CICR) pathway that amplifies the calcium signal, and strontium does not have the ability to regulate inositol triphosphate (rP3)-induced calcium release by acting to inhibit additional calcium release if the concentration of calcium in the cytoplasm is too high.
[070] Once calcium enters a nociceptor during its activation and depolarization, it activates the release of a massive amount of calcium that is stored in the ER by the CICR pathway. This mechanism has the effect of greatly amplifying the amount of calcium that is available to form a wave and to regulate calcium-dependent pathways. Strontium is over a hundred-fold less active than calcium in its ability to induce CICR and thus significantly alters the calcium concentration changes that normally occur in response to irritants. When in the ER, strontium also binds much less avidly to the ER calcium binding proteins that act as buffers and sequester the free calcium until it is released by CICR or other similar mechanisms. As a result, strontium reaches a concentration of more than 150% greater than calcium and displaces calcium from performing its amplifying function during CICR. Strontium is also much less active then calcium in regulating a second important calcium amplifying mechanism triggered by IP3, a ubiquitous substance that also activates calcium release from the ER by an IP3 - specific receptor. At low concentrations of calcium, IP3 acts as a potent stimulator of calcium release that acts to amplify the much smaller calcium influx during depolarization. When the calcium concentration is sufficiently elevated, calcium acts to inhibit further calcium release thus maintaining the calcium concentration within a limited concentration range. When strontium is present, it can mimic calcium in its ability to activate IP3 - induced calcium release, but strontium is not able to inhibit excessive calcium release causing both calcium and strontium to reach higher concentrations over an extended time. Strontium’s ability to substantially inhibit calcium-induced release due to IP3 is particularly important, since IP3 - induced calcium release is known to be responsible for generation of calcium waves. These types of strontium effects significantly change the calcium dynamics and calcium waveforms associated with neuropathic conditions, and thus contribute to strontium’s suppressive effects on pain and pruritus.
B. Strontium Inhibits Calcium-Dependent Neurotransmitter Release
[071] While strontium also affects additional pathways that control the dynamics of calcium within nociceptors, there is one strontium-induced interference with calcium-dependent transmission of pain and itch-encoded calcium waves that is critically important for suppression
of acute, chronic, and neuropathic conditions. That is, the ability of strontium to bind and inactivate synaptotagmin-l, a molecule that is principally responsible for neurotransmitter release peripheral Type C nociceptors in the esophageal mucosa and in the DRG. Of particular importance is the ability to suppress the release of glutamic acid and ATP from nociceptors. Glutamic acid binds to specific receptors including the NMDA receptors located on peripheral nociceptors, inflammatory white blood cells and structural cells including fibroblasts and mucosal cells. When activated the NMDA receptor activates calcium influx and triggers pain and multiple inflammatory pathways. Blockade of NMDA receptors, in addition to strontium’s suppressive activity on neurotransmitter release will provide a greatly increased suppressive effect on pain and inflammation. Other members of the synaptotagmin molecular superfamily and related calcium-regulated molecules regulate the release of inflammatory neuropeptides, including substance P from the peripheral portion of a TCN in the epithelium. Substance P is known to be the most important inflammatory neuropeptide released from TCNs that activates virtually every inflammatory immune“white blood cell” (WBC), including mast cells that contain histamine and over 50 different inflammatory chemicals, including tumor necrosis factor-alpha (TNF-alpha), interleukin 1 alpha and beta (IL-l alpha and beta) and IL-6. These three pro-inflammatory cytokines are believed to be the“first responders” that directly activate TCNs to cause pain and/or itching and are thought to be significant contributors to the development and maintenance of neuropathic conditions, as well as most skin conditions that are associated with inflammation, pain or itching.
[072] Synaptotagmin-l is a protein present on the surface of vesicles that contain and ultimately release neurotransmitters that bind to the post-synaptic neurons in the DRG and the peripheral TCN endings in the epithelium that relay the pain and itch-encoded signals to the brain. Normally, the frequency of the presynaptic neurotransmitter release from nociceptors are precisely matched so that the intensity, timing and other properties of the original pain or itch signal encoded in the calcium wave is accurately transmitted to the brain. The delay between the arrival of the calcium wave, neurotransmitter release and post-synaptic activation is usually about 1/1000th of a second and the amount released is related to the intensity of the original TCN signal. This type of neurotransmission is termed“synchronous release,” since the timing of the arrival of the calcium wave is tightly synchronized to the release of neurotransmitters that triggers post-synaptic activation of the DRG nerve. Without this precise coupling, the frequency encoded pain or itch signal becomes distorted and garbled.
[073] When strontium substitutes for calcium, the amplitude of synchronous neurotransmitter release in response to TCN activation is typically reduced by more than 90%. Strontium has an
additional signal distorting effect that significantly distorts the timing of neurotransmitter release called“asynchronous release.” In contrast to synchronous release that is tightly coupled to the stimulating signal, asynchronous release may extend to several hundred milliseconds. With strontium, the total amount of neurotransmitter that is released may be the same as with calcium, however the strength of the synchronous release that contains the encoded pain or itch intensity information is strongly reduced, and the critical timing information is essentially destroyed. This strontium mechanism not only reduces the perceived severity of a pain or itch signal, but it also suppresses the release of substance P at the proximal end of the TCN in the epithelium at the original site of TCN activation. Strontium’s ability to inhibit the release of TNF-alpha, IL-alpha and IL-6 from cells is thought to be due to strontium’s inhibition of Store Operated Calcium Entry (SOCE) that amplifies the initial calcium signal from calcium influx through NMD A, ASIC, TRPV1 & TRPA1 and other calcium permeable ion channels that are activated by pain and inflammation-inducing stimuli. Suppression of synchronous
neurotransmitter release also has an important therapeutic benefit for neuropathic pain or pruritus treatment.
[074] Accordingly, in one embodiment, it is therefore desirable to further alter the calcium dynamics of nociceptors by further suppressing calcium release or by interfering with critical calcium-dependent pathways that are partially inhibited by strontium.
C. Strontium Binds to a Calcium-Sensing Receptor on Nociceptors that
Suppresses Nociceptor Activation
[075] Most, if not all, cells have a recently-identified surface receptor that detects the extracellular calcium concentration. Strontium also binds and activates the calcium-sensing receptor (CaSR) as efficiently as calcium, but triggers additional activities. This knowledge resulted in the commercial development of a simple strontium salt, strontium ranelate, an orally administered prescription drug for osteoporosis treatment in over 100 countries. Due to strontium’s unique ability to mimic calcium’s ability to activate the CaSR and, additionally, to activate additional pathways linked to the CaSR, strontium ranelate is the only known osteoporosis drug that has two independent osteoporosis therapeutic mechanisms - strontium inhibits bone loss by inhibiting bone-resorbing osteoclasts, and simultaneously stimulates osteoblasts that produce new bone.
[076] Nociceptors also have a CaSR that inhibits nociceptor activation when the extracellular concentration of calcium is raised above normal, or if a similar concentration of strontium is administered. This mechanism is believed to contribute to the ability of strontium to rapidly
inhibit TCN activation by, for example, highly acidic chemical peels such as 70% glycolic acid, pH 0.6, that cause burning pain within seconds after application. When strontium is mixed with the acid, burning pain and stinging is suppressed by 80% or more so that any remaining sensory irritation is not bothersome.
[077] Activation of the CaSR also causes activation of several pathways that are known to increase both acute, chronic and neuropathic pain and pruritus and inflammation. Since in real world use, strontium typically inhibits pain and pruritus, it is likely that the pain and itch enhancing effect caused by activation of the CaSR by strontium is, in effect, negated by other strontium anti-irritant mechanisms. None the less, even a low level,“subclinicar pain and itch enhancing effect reduces the ability of strontium to effectively treat, prevent or reverse neuropathic conditions for which any excess TCN activation is known to promote the neuropathic condition.
[078] Of particular concern is strontium’s reported ability to bind to the CaSR and rapidly activate two of the MAPK molecules, p38 and ERK1/2, that are known to be among the primary contributors to peripheral and central nociceptor sensitization. Strontium binding to the CaSR is also reported to activate an important enzyme, phospholipase C, that produces two important regulatory molecules, the aforementioned IP, and diacylglycerol (DAG), both of which contribute to nociceptor activation and sensitization and inflammation. SR3 is one of the most important and potent calcium releasing molecules that directly triggers calcium release from ER stores. Many of the pain and itch producing chemicals that are produced during inflammation, infection or trauma use the IP3 pathway to activate nociceptors and produce the calcium waves that transmit pain and itch sensations. DAG is the principle activator of protein kinase C, a family of molecules that directly activates nociceptors and many of the pathways that produce pain and itch and inflammatory mediators. PKC is also known to be an important nociceptor sensitizer, since PKC inhibition can prevent or reverse neuropathic pain in animal models. PKC also activates NF-Kappa B, one of the most important stimulators of molecules that triggers pain, pruritus and inflammation and are thought to be able to directly cause neuropathic sensitization. It should be emphasized that the recognition that strontium produces its osteoporosis therapeutic benefits by binding to the CaSR is very recent and additional strontium- sensitive pathways will likely be identified. The fact that human nociceptors have the CaSR that regulate nociceptor activation suggests that the CaSR activation by topically-applied strontium may be working at a reduced level due to strontium’s ability to inhibit important pain and itch pathways while simultaneously activating pathways via the CaSR that are known to trigger pain and itch pathways. Most importantly, since activation of these CaSR pathways are known
to be important contributors to the development of neuropathic conditions, strontium’s therapeutic potential may be substantially compromised.
D. Strontium Blocks Endocytosis of Vesicles
[079] Strontium also blocks rapid endocytosis of vesicles that are used to release both neurotransmitters and inflammation -induced molecules by blocking dynamin-l, a calcium- dependent GTPase. While not being bound by this or any particular mechanisms, it is believed that strontium’s ability to block substance P release from Type C nociceptors and the pro- inflammatory cytokines TNF-alpha, IL-l alpha and IL-6 is related to strontium’s interference with such calcium-dependent release processes.
E. Limitations of Strontium on Nociception and Inflammatory Pathways
[080] It has been surprisingly discovered that the reason strontium is frequently unable to completely block pain, itching or inflammation is due to two factors: (1) the limited amount of strontium that can be topically applied, after which the hyperosmotic effects of the strontium salts themselves start to cause pain, itching or inflammation; and (2) the ability of strontium to stimulate pathways that may act to negate strontium’s inherent anti -irritant activities, thus reducing the overall therapeutic benefit. Regarding the first factor, this is due to the fact that strontium has a relatively low potency in its ability to suppress pain, itching and inflammation compared to many other drugs with similar therapeutic goals. It is this low potency of strontium that prevents it from blocking pain when it is orally ingested in the form of the prescription drug, strontium ranelate that is approved for treatment of osteoporosis in over 100 countries.
[081] Regarding the second factor, the degree to which strontium will negate its anti -irritant benefits depends on many factors related to the type of nerve damage that caused the
neuropathic condition to develop (e.g., viral infection, physical trauma such as amputation or nerve compression, metabolic nerve damage as occurs in diabetes, coexisting inflammation and other factors.
[082] For example, commonly used non-steroidal anti-inflammatory drugs (NS AID) like aspirin, ibuprofen and naproxen are typically used at oral doses of several hundred milligrams and provide an effective reduction of many types of inflammation-associated pain. Opioid pain relievers such as levorphanol, oxymorphone, oxycodone and hydrocodone are
pharmacologically related to codeine, morphine and heroin and provide effective pain relief at oral doses in the range of 2 mg to about 10 mg per dose. In contrast, orally administered strontium salts such as strontium ranelate, an oral drug approved for the treatment and
prevention of osteoporosis, is approved in over 100 countries, and is administered at a dose of 2,000 mg per day. Since strontium ranelate is a simple salt of strontium, it yields 680 mg of elemental strontium upon contact with water or gastric fluids. However, even at this high dose of pure elemental strontium, there are no reports of the ability to reduce pain or inflammatory reactions.
[083] It has been determined that topical strontium has the ability to reduce pain, pruritus and inflammation due to the fact that topical formulations can deliver thousands of times higher strontium concentrations then can be achieved by oral, systemic administration. Even at the relatively high local concentrations that can be achieved topically when administered to the epithelium, the effect of strontium on key biochemical pathways that cause pain, pruritus and inflammation is only partial. For example, if the activity of a hypothetical pain or itch-producing pathway is inhibited by 90% to 100%, a patient reports that their pain or itching was completely stopped. In contrast, topically-applied strontium may only inhibit that pathway by 40% to 50%, sufficient inhibition for a patient to observe that the pain or itching was clearly reduced, but still present and still bothersome.
Strontium Affects Pathways Directly Associated with Gastroesophageal Reflux and Barrett’s Esophagus
[084] Previous studies have demonstrated that topically applied strontium can virtually abolish the intense burning pain caused by application of 70% glycolic acid, pH 0.6 to the skin. Similar pilot studies in humans also demonstrate strontium can inhibit burning pain due to installation of 1% lactic acid to the conjunctiva of the eye. Other published studies demonstrate that topically- applied strontium can inhibit pain and inflammation caused by a wide range of chemically and biologically-unrelated chemical irritants found in the environment, the workplace and the home and in foods.
[085] Clinical observations also demonstrate that the pain of“sore throat” can be greatly relieved, if not eliminated within several minutes after gargling with a strontium chloride solution. Since acidic material from the stomach is what causes the burning pain and
inflammation in GER, it is hypothesized that strontium would be effective in treating GER.
[086] Unlike most antacids, which use acid neutralizing effects to reduce the acid-induced pain and inflammation, strontium acts directly on Type C nociceptors and reduces their sensitivity to acid-induced nerve depolarization that directly produces the sensation of GER-associated burning pain and also triggering inflammatory neuropeptide and pro-inflammatory cytokine release that is known to increase painful sensations by sensitizing Type C nociceptors.
[087] Strontium can inhibit acid-induced inflammation by at least two independent anti inflammatory mechanisms. In addition to acid-induced inflammation, strontium can inhibit inflammation caused by a broad range of chemically and biologically-unrelated inflammation irritating stimuli. Given the fact that the refluxed gastric juices and partly digested food contain many potentially irritating chemicals in addition to acid, strontium should provide a broad protective benefit to the esophagus.
A. Strontium Inhibits Neurogenic Inflammation
[088] Multiple studies have demonstrated that elevated IL-8 levels are associated with GER and may be pathogenically important as an inducer of chronic inflammatory damage to the esophagus found in GER. Substance P increases production of IL-8, a potent stimulator of neutrophil activation and a major contributor to the formation of reactive oxygen species (e.g. superoxide, hydrogen peroxide, hydroxyl radical, singlet oxygen) that are highly toxic and powerful inflammation inducers. Strontium’s abilities to block substance P would prevent the elevation of IL-8 levels.
[089] Additionally, recent studies recent studies suggest that elevated production of TNF- alpha, IL-l alpha and IL-6 are important regulators and promoters of cancer metastasis. If these cytokines have a similar stimulatory effect on metastasis of esophageal adenocarcinoma, then strontium treatment may reduce metastatic disease from esophageal carcinoma, a frequently lethal result of chronic GER.
B. Strontium Inhibits Acid Activated Inflammatory Pathways
[090] As mentioned above, acid from the stomach activates many pathways that trigger pain and inflammation such as the release of substance P, neurokinin A, and CGRP. In unpublished animal studies, strontium has been shown to inhibit substance P release by Type C nociceptors, thus confirming human studies in which topical strontium application inhibited acid-induced pain and neurogenic inflammation. While the precise molecular mechanism by which strontium inhibits substance P release is unknown, it is believed that the release of substance P, neurokinin A and CGRP occur together and by the same or similar trigger mechanism. Thus, the fact that strontium inhibits substance P is a good indicator that strontium will also inhibited neurokinin A and CGRP.
C. Limitations of Strontium
[091] Capsaicin is the component of chili peppers that causes the burning sensation when it comes in contact with mucous membranes. Capsaicin is a member of the vanilloid family and
binds the vanilloid receptor subtype 1 (TRPV1). TRPV1 is an ion channel type receptor and can also be activated with heat, protons, and physical abrasions. Previous studies have shown that strontium has limited affect against capsaicin induced pain and inflammation. In these studies, strontium was only able to reduce the pain and inflammation by about 40%. Without wishing to be bound by any one theory, it is believed that activation of TRPV1 activates G-protein coupled receptors, which in turn activate numerous other pain and inflammation pathways, some of which are less calcium dependent. The activation of less calcium dependent pathways reduces the overall effect of strontium. As noted above, protons (e.g. stomach acid) can activate the TRPV1 receptors. Since strontium has limited affect against TRPV1 activation, additional compounds are needed that either target different pain and inflammation pathways or target different places along the same pain and inflammation pathways that strontium targets. The combination of strontium and the additional compounds creates a synergistic affect that is greater that the individual components alone.
D. Additional Medical Benefit of Strontium
[092] Osteoporosis is a chronic condition that results in bone weakening and loss of bone mass and density and results in increased fractures, especially in post-menopausal women, people over 70 and those taking certain drugs like oral anti-inflammatory glucocorticoids like prednisone, barbiturates, some antiepileptic drugs, L-thyroxine, cancer drugs like methotrexate, depot progesterone, anticoagulants like Heparin, warfarin and related coumarins,
thiazolidinediones used for diabetes treatment, lithium therapy for psychiatric disorders and proton pump inhibitors, the most commonly used GER treatment drugs. Unfortunately the population that is most likely to use many of the above drugs are those most at risk for osteoporosis, older people.
[093] In addition to a variety of prescription drug used to treat osteoporosis, calcium supplementation is widely recommended to help reduce bone loss. Since calcium
supplementation provides limited benefits, additional non-toxic treatments or supplements would be of great benefit.
[094] The strontium in the present invention can provide a substantial anti -osteoporosis benefit since strontium is the only substance known to stimulate new bone formation while suppressing bone loss. The prescription drug strontium ranelate is the only strontium drug approved for osteoporosis treatment and at its recommended daily dose delivers 680 mg of elemental strontium per day, of which approximately 25% is absorbed by the GI tract into the blood. Simple orally-administered strontium salts including those used in the present invention deliver
the same rate of strontium absorption as strontium ranelate and for this reason strontium dietary supplements are widely available without a prescription in the United States. It is one object of the present invention to deliver a protective amount of elemental strontium, up to about 680 mg of elemental strontium per day to help prevent osteoporosis-induced bone loss. It is another object of the present invention to deliver additional calcium in the form of a calcium salt along with strontium to provide further osteoporosis protection, especially for older patients and those who ingest drugs that promote bone loss.
Therapeutic Strategy
[095] By directly treating the esophageal mucosa, exceptionally high local concentrations of the ingredients of the present invention can be achieved that would be difficult, if not impossible of they were diluted in the relatively large volume of the stomach. An empty stomach typically contains between 20 to 100 ml of fluid primarily composed of hydrochloric acid, potassium chloride and sodium chloride at a pH between 1.5 and 3.5. The volume of the stomach after a meal can easily reach 1000 ml without expanding, however after a large meal the stomach volume can expand to 4000 ml. The average volume of saliva in the human mouth that is typically swallowed is approximately 1 ml. Therefore an ingredient in an oral product of the present invention that was present at, for example, 100 mg/product would present a
concentration of lOOmg/ml at the surface of the esophageal mucosa. In sharp contrast, if an antacid is self-administered for Heartburn treatment according to the recommendation of the US National Library of Medicine’s public health database, MedlinePlus, approximately 1 hour after a meal, the concentration in the stomach of the above ingredient would typically range from l/lOOOth to l/4000th of the original 100 mg/ml concentration resulting in a concentration from 0.1 mg/ml to 0.025 mg/ml.
[096] Molecules that enter the stomach may also be subject to degradation by the acid or by enzymatic transformation by stomach or food-derived substances. Such degradation would not be expected in the esophageal lumen. Unlike many biologically active molecules that may require sustained application to an organ that may extend from many minutes or much longer in order for them to produce their therapeutic activity, ingredients of the present invention can produce a high-level therapeutic within several seconds and thus even the transient exposure of the esophagus dissolved a small volume of saliva may exhibit a high-level therapeutic activity. Such high activity would not be possible if treatment depended on reflux of the ingredients of the present invention to reach the esophageal mucosa.
Key Pain and Inflammation Targets
[097] The compositions and formulations disclosed herein target key pain and inflammation pathways.
A. Release and Receptor Activation by Glutamic Acid
[098] Glutamic acid (Glu) is the principle excitatory neurotransmitter of the peripheral and central nervous system. Release of Glu from Type C Nociceptors in the skin is among the most important activators of pain and itch signals that, in turn, activate multiple biochemical pathways that trigger both acute and chronic pain and itch conditions. Sufficiently strong Glu-indepuced activation also triggers release of powerful pain, itch and inflammatory peptide
neurotransmitters including Substance P, Calcitonin Gene-Related Peptide (CGRP) and others that activate multiple immune white blood cells including Neutrophils, Monocytes,
Macrophages, Lymphocytes and Mast Cells that can release over 50 inflammatory molecules including histamine that directly trigger pain, itching and inflammation. Blockade of Glu- mediated activation can block sensory irritation and inflammation in both animal models and in humans. Each of these many pain and inflammation-triggering activities are dependent on the influx of calcium that alters intracellular concentrations and overall calcium dynamics. The combination of blocking Glu receptors, in particular the NMD A Glu receptor and the pluripotential activity of strontium to greatly alter calcium dynamics provides a strong synergy that reduces pain and inflammation.
B. Proinflammatory Cytokines
[099] Proinflammatory Cytokines including TNF-alpha, IL-l alpha, IL1 beta, IL-6, and IL-8. TNF and IL-cytokines are among the earliest pain, itch and inflammatory molecules that are released in inflammatory conditions and directly activate nociceptors and trigger multiple cascades that amplify pain and itch signals. Some of the most recent FDA-approved prescription drugs to treat chronic skin inflammatory diseases like Psoriasis that has itching as the principle symptom have been successfully treated by blocking TNF-alpha.
C. Protein Kinases
[0100] Protein Kinases including Protein Kinase A, (PKA), Protein Kinase C (PKC), and the Mitogen-Activated Protein Kinases (MAPK) (1) p38, (2) Janus N-Terminal Kinase (JNK) and (3) Extracellular Signal Receptor Kinases (ERK 1/2). These molecules and related kinases transduce and amplify Glu-induced receptor activation and transmit sensory irritation signals via
nociceptor activation to the Dorsal Root Ganglia (DRG) in the spinal cord and to the brain where the noxious quality of pain and itching is consciously appreciated.
D. Transcription Factors and Gene Expression Regulators
[0101] Transcription Factors and Gene Expression Regulators that trigger increased synthesis of Glu and other receptors and nociceptor sensitivity regulators that increase nociceptor sensitivity and causes a normally non-irritating trigger to be highly irritating. Such nociceptor sensitization in the skin’s periphery and in the‘central’ nervous pathways like the DRG is known to be critical for the maintenance of chronic and neuropathic pain and itch conditions. These transcription factors include NF -Kappa, known as the Master Immune System regulator that can trigger increased synthesis of over 300 molecules that cause inflammation, pain and itching. Other critical transcription factors such as AP-l amplify these effects.
E. Histone Deacetylase (HD AC) Inhibitors & DNA Methylaes Inhibitors
[0102] Histone Deacetylase (HD AC) Inhibitors & DNA Methylase Inhibitors are a second class of gene translation regulators. These molecules have powerful regulatory effects on the expression of pain, itch and inflammation pathways and can prevent and potentially reverse chronic and neuropathic pain conditions in animal models and in humans.
Therapeutic Goals
[0103] The compositions and formulations disclosed herein to treat the symptoms associated with GER are:
1. Potent and acute and chronic suppression of acid-induced pain by multiple independent mechanisms.
2. Potent anti-inflammatory activities that inhibit the most important inflammation pathways known to contribute to esophageal inflammation including (a) Inhibition of NF- Kappa B, the‘master inflammatory gene regulator’; (b) Inhibition of TNF-alpha, IL-l alpha & beta & IL-8; (c) Inhibition of Nitric Oxide, a potent sensitizer of nociceptors and
inflammation; and (d) inhibition of PGE2, a potent inflammation mediator.
3. Reduction of Reactive Oxygen Species (ROS) that directly contribute to inflammation, pain and cancer development.
4. Stimulation of esophageal mucosal repair by stimulation of collagen and glycosaminoglycan synthesis.
5. Reduction of mucosal infiltration of inflammatory and pain producing white blood cells, including Neutrophils, most plentiful of all white blood cells that may constitute 50% of all white cells in the blood. Neutrophils are the‘first-responders’ to cellular damage by trauma, ROS, acid exposure or infection and can greatly increase pain and inflammation in minutes.
6. Protection from and Reduction of osteoporosis in women and men due to chronic use of Proton Pump Inhibitors or to age-related osteoporosis.
7. Desensitization of the pain sensitivity of esophageal pain-producing nociceptors that cause increased pain for a fixed level of acid exposure. (Chlorogenic Acid), including (a) inhibition of HD AC; (b) inhibition of DNA Methylase; (c) both of the above activities can prevent or reverse the chronic sensitization of; and (d) nociceptors that greatly increase pain and inflammation.
8. Anti-proliferative effects on chronically inflamed esophageal cells that leads to Barrett’s esophagus, a pre-cancerous condition.
[0104] Each of the ingredients of the present invention take advantage of the multiple activities of each ingredient that amplify the fundamental anti-pain and anti-inflammatory activities of strontium. There are thousands of chemicals that share one or more of strontium’s activities but also have activities that negate or inhibit key strontium activities. For example, some of strontium’s activities inhibit important pain and inflammation pathways while other of strontium’s activities stimulate other pathways that indirectly inhibit pain and inflammation pathways. To visualize these unusual properties, imagine a hard comb that has 20 teeth, half of which point upwards and half that point downward in a random manner. Each of these teeth represents a biochemical pathway that is stimulated by strontium (teeth pointing up) while teeth that point down represent inhibition of other pathways. The particular pattern of distinct pathways that are simultaneously stimulated or inhibited is responsible for the unique therapeutic benefits of strontium.
[0105] In order to amplify strontium’s overall anti-pain and anti-inflammatory benefits, a molecule that would amplify strontium’s activity would have to have‘teeth’ that align with those of strontium and point up and down with the same pattern. It is not necessary that all of strontium’s activities are replicated, but it is critically important that whatever teeth the additional molecule has replicate the teeth of strontium. Some of these amplifying molecules many have only a few teeth similar to those of strontium, but they must be identically aligned.
For example, if strontium’s teeth # 1, 4, 5, 10 and 12 point up and the downward pointing teeth # 2, 3, 6, 11 and 17 point down, an amplifying molecule would have to have an identical pattern of‘biochemical teeth’ to amplify strontium’s activities without also inhibiting some of the pathways.
[0106] The following descriptions of the key strontium-amplifying molecules in the present invention will illustrate the unique therapeutic benefits of the combination of strontium with the ingredients of the present invention.
A. Chlorogenic Acid Affects Nociception and Inflammation Pathways
[0107] Chlorogenic acid acts at different steps in the same inflammatory pathways inhibited by strontium, and thus in effect amplify the basic anti-irritant activity and nociceptor-protective activities of strontium. The effects of Chlorogenic acid on some of the key nociception and inflammatory pathways are discussed below. Chlorogenic acid is a powerful anti-oxidant that inhibits the considerable oxidative damage from neutrophil extravasation and extravasation into an inflamed esophageal mucosa. Substantial anti-oxidant synergy is expected in combination with the powerful anti-oxidant activity of ascorbic acid and its stimulation of the synthesis of intracellular glutathione. Chlorogenic acid also inhibits many inflammatory mediators including High Mobility Box 1 release, Toll-Like Receptor 4 (TLR4), Nitric Oxide synthesis,
cyclooxygenase 2, the enzyme that synthesizes PGE2, an important contributor to pain and inflammation pathways, NF-Kappa B, TNF-alpha, IL-l and IL-8.
[0108] Of particular importance is the ability of Chlorogenic acid to potently inhibit two enzymes that are critical inducing sensitization of nociceptors, Histone Deacetylase (HD AC) and DNA methylase. In animal studies of acute, chronic and neuropathic pain, HDAC and separately DNA methylase inhibitors were shown to inhibit the transition from acute to chronic pain and to reverse nociceptor sensitization in chronic and neuropathic pain conditions. In combination with agmatine that can similarly prevent and reverse sensitization, there is a high likelihood that the chronic pain of GERD can be reversed.
B. Ascorbic Acid Affects Pathways Directly Associated with Gastroesophageal
Reflux and Barrett’s Esophagus
[0109] Ascorbic acid (Vitamin C) has several important activities that contribute to the inhibition of pain, inflammation and that stimulates healing of inflammation damaged tissues. Ascorbic acid is a powerful anti -oxidant and can inhibit the production of highly toxic oxidants and free radicals including hydrogen peroxide, nitric oxide, superoxide and the hydroxyl radical.
At relatively high local concentrations that can only be achieved by topical application, ascorbic acid inhibits the potentially severe oxidative damage produced by neutrophils that are rapidly attracted to sites of inflammation and by release of oxidants greatly stimulate oxidative damage and pain-triggering pathways.
[0110] Ascorbic also stimulates intracellular concentrations of the major water soluble anti oxidant, reduced glutathione (GSH) that is a powerful anti-oxidant protector. Reduced GSH also directly inhibits activation of NF -Kappa B, the most important gene regulatory of inflammation. Additionally ascorbic acid is a necessary cofactor for the synthesis of collagen and when topically applied stimulates collagen synthesis, an important repair function for damaged esophageal mucosa. Ascorbic acid also inhibits TNF-alpha induced activation of NF-Kappa B, the‘master gene regulatory of inflammation’ . In combination with strontium and the other molecules of the Present invention, ascorbic acid will provide added pain and inflammation suppression.
C. Citric Acid Affects Nociception and Inflammation Pathways
[0111] Citric acid is a 6 carbon molecule with three negatively charged carboxyl groups that is a central molecule of the energy-producing Citric Acid Cycle. Citric acid has multiple anti inflammatory activities including inhibitor of neutrophil degranulation, the process by which neutrophils release multiple toxic enzymes and oxidants into their local environment.
Neutrophils are among the most important cellular mediators of acute inflammation and constitute about 50% of all the white blood cells in circulation.
[0112] Citric acid also inhibits neutrophil secretion of IL-l beta, and TNF-alpha,
myeloperoxidase and platelet factor 4, all potent stimulators of pain and inflammation pathways. The three carboxyl groups of citric acid also serve as ideal binding sites for strontium to form a strontium complex, thus eliminating the need for a negatively-charged strontium counter ions like chloride or nitrate that can greatly increase the osmolarity of a solution and thereby stimulate pain and inflammation-inducing osmotic sensors. Each of the above anti-inflammatory activities are protective of esophageal mucosa and also inhibit inflammation-induced pain, a major contributor to GERD pain.
D. Kynurenic Acid Affects Nociception and Inflammation Pathways Important in GER
[0113] Kynurenic acid acts at different steps in the same inflammatory pathways inhibited by strontium, and thus in effect amplify the basic anti-irritant activity and nociceptor-protective
activities of strontium. The effects of Kynurenic acid on some of the key nociception and inflammatory pathways are discussed below. Kynurenic acid is a metabolite of tryptophan and has neuroprotective, anti-inflammatory, and antiproliferative properties. Kynurenic acid is an endogenous antagonist of the N-methyl-D-aspartate (NMD A) receptors. By blocking calcium entry of through the NMDA receptors, the intracellular calcium concentration will be reduced and the necessary calcium transients that would further activate glutamic acid release are suppressed. The combination of the suppression of kynurenic acid induced suppression of calcium dynamics with the suppressive effects of strontium, chlorogenic acid and agmatine on intracellular calcium dynamics will greatly reduce glutamic acid-induced pain and inflammation. Kynurenic acid is also a potent activation of the G protein-Coupled Receptor, GPR-35 that has multiple suppressive activities on the release of pain and inflammation pathways in nociceptors, immune cells, keratinocytes and other cells. Additionally kynurenic acid inhibits neutrophil and monocyte extravasation from the blood into sites of inflammation, thus suppressing
inflammation and pain. Kynurenic acid is also an agonist of the alpha-7 nicotinic acetylcholine receptor which exerts a suppressive effect on neurons to produce an anticonvulsant and neuroprotective activity.
E. Agmatine Affects Nociception and Inflammation Pathways that Amplify
Strontium and Contribute to Pain and GER Inflammation
[0114] Agmatine acts at different steps in the same inflammatory pathways inhibited by strontium, and thus in effect amplify the basic anti-irritant activity and nociceptor-protective activities of strontium. The effects of agmatine on some of the key nociception and
inflammatory pathways are discussed below. Each of these pathways are strong contributors to pain and GER.
[0115] Agmatine is a potent inhibitor of NMDA receptors that are critical for the generation of pain signals and for activation of many inflammatory pathways on a variety of cells.
Synchronous release of Glu by nociceptors at high levels of stimulation triggers substance P release and activation of mast cells and many other inflammatory cells important in GER. In combination of with strontium that strongly inhibits synchronous Glu release and other of the ingredients of the present invention, blockade of NMDA receptors will produce a synergistic suppression of pain and inflammation.
[0116] Acid-sensitive ion channels (ASIC) are acid sensitive cationic channels present on Type C nociceptor and inflammatory cells. ASICs are activated by protons (H+). In GER, members of the ASIC superfamily are believed to trigger the pain and contribute to the subsequent
neurogenic inflammation. Agmatine also opens strontium permeable ASICs and in the presence of strontium allows increased strontium to enter cells and inhibit its multiple pain and inflammation targets. Agmatine also directly inhibits acid secretion in the stomach and thus has activity that resembles that of Proton Pump Inhibitors and H2 antagonists. Agmatine also strongly inhibits that powerful pain inducer, Nitric Oxide (NO) that greatly sensitizes pain pathways present in GER. Agmatine is also a strong agonist of the Alpha-2 Adrenergic receptor and imidazoline receptors that are capable of reversing the sensitization of nociceptors that contributes to the chronicity of pain from GERD. In combination with the HD AC and DNA methylase inhibitory activity of chlorogenic acid, a synergistic nociceptor desensitization effect in expected. Finally agmatine also inhibits matrix metaloprotease activity that directly mediates esophageal mucosal damage
The Components of the Present Disclosure
[0117] The compositions and formulas of the present disclosure were formulated to perform several functions: (1) treat acute pain associated with GER; (2) desensitize nociceptors thus reducing the risk of developing chronic or neuropathic pain associated with GER; (3) inhibit inflammatory pathways; (4) reduce esophageal mucosal damage; (5) increase protective collagen production in esophageal mucosa. The composition and formulations achieve the above objectives by interacting on several different molecular pathways, thus creating a synergistic effect that greatly outperforms the actions of each component alone. The main components of the compositions and formulations are discussed below.
A. Strontium
[0118] Strontium is present as a divalent cation. Strontium is designated by its commonly used atomic symbol,‘Sr’ and is depicted below.
[0119] Strontium mimics the ability of calcium to pass through voltage dependent calcium channels and once inside cells, it competes with calcium for binding to calcium-dependent receptors. Strontium has four broad classes of pharmacological activities that reduce GER associated pain and inflammation: (1) disruption of intracellular calcium dynamics and calcium wave propagation, (2) inhibition of neurotransmitter release, (3) inhibition of substance P release and resultant neurogenic inflammation, and (4) inhibition of pro-inflammatory cytokine release, each of which was discussed in detail above.
[0120] In one embodiment, compounds of the present disclosure use a strontium salt. Non limiting examples of strontium salts include strontium carbonate, strontium bicarbonate, strontium hydroxide, strontium phosphate, strontium lactate, strontium citrate, strontium
chloride, strontium sulfate, strontium nitrate, strontium hydrosulfide, strontium oxide, strontium acetate, strontium glutamate, strontium aspartate, strontium malonate, strontium maleate, strontium threonate, strontium lactate, strontium pyruvate, strontium ascorbate, strontium alpha- ketoglutarate or strontium succinate. In another embodiment, compounds of the present disclosure use a strontium complex. Non-limiting examples of compounds complexed to strontium complex include chlorogenic acid, at least on amino acid derivative or metabolite, at least one methoxyflavonoid, or at least one vitamin.
[0121] In another embodiment the strontium salt is strontium carbonate, which acts to neutralize acid in a manner similar to calcium carbonate, the commonly used antacid in many products. This molecule has two distinct pharmacological activities. The carbonate portion or other acid neutralizing salt component serves as a conventional acid neutralizing agent and in the acid environment of the stomach it combines with acid to form water. The strontium ion, unlike calcium used in conventional antacids, inhibits multiple pain and inflammation pathways that are known to be significant contributors to GER pain and inflammation. In another embodiment, the strontium salt is strontium citrate.
B. Chlorogenic acid
[0122] Chlorogenic acid (IUPAC name: (lS,3R,4R,5R)-3-{[(2E)-3-(3,4-dihydroxyphenyl)prop- 2-enoyl]oxy}-l,4,5-trihydroxycyclohexanecarboxylic acid) is a compound present in high concentrations in coffee and other foods.
C. Vitamins
[0123] Vitamins have diverse biochemical functions, ranging from regulators of cell and tissue growth and differentiation, to coenzymes, to hormone-like functions, to antioxidants. Vitamins contemplated in the present disclosure include, but are not limited to vitamin A, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin C, vitamin D, and vitamin E. In particular, vitamin C and vitamin E.
[0124] Vitamin C, also known as ascorbic acid, is an essential nutrient involved in the repair of tissue and the enzymatic production of certain neurotransmitters. Vitamin C is a cofactor in at least eight enzymatic reactions in humans important in many essential functions, including wound healing. More generally, the biochemical role of vitamin C is to act as an antioxidant (a reducing agent) by donating electrons to various enzymatic and non-enzymatic reactions. Doing so converts vitamin C to an oxidized state - either as semidehydroascorbic acid or
dehydroascorbic acid. These compounds can be restored to a reduced state by glutathione and NADPH-dependent enzymatic mechanisms.
[0125] Vitamin E is a group of eight compounds that include four tocopherols and four tocotrienols. Vitamin E has many biological functions, including its role as a fat-soluble antioxidant, protecting cell membrane from oxidative damage. Vitamin E is an enzyme activity regulator, such as for protein kinase C (PKC) - which plays a role in smooth muscle growth - vitamin E participates in deactivation of PKC to inhibit smooth muscle growth.
D. Amino Acid Derivatives or Metabolites
[0126] Kynurenic acid (IUPAC name: 4-hydroxyquinoline-2-carboxylic acid) is a metabolite of the amino acid L-tryptophan that has been shown to have neuro activity. It is an antagonist of ionotropic AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, NMDA (N-Methyl- D-aspartic acid or N-Methyl-D-aspartate), and Kainate glutamate receptors; a noncompetitive antagonist at the glycine site of the NMDA receptor; an antagonist of the a7 nicotinic acetylcholine receptor; and a ligand for the orphan G protein-coupled receptor GPR35.
[0127] Agmatine (IUPAC name: l-(4-Aminobutyl)guanidine) is a metabolite of L-arginine that acts on multiple molecular targets. It is acts on neurotransmitter receptor ionophores; ion channels; membrane transporters, nitric oxide synthesis inhibition; polyamine metabolism; protein-ADP-ribosylation; matrix metalloproteases; advanced glycation end product formation; and NADPH oxidase. Of particular importance is the ability of agmatine to open ASIC without the need for acid conditions that allows external strontium to flow into the channels and exert its multiple anti-pain and anti-inflammatory activities.
E. Methoxyflavonoids
[0128] Tangeretin (IUPAC name: 5,6,7,8-tetramethoxy-2-(4-methoxyphenyl)-4H-l- benzopyran-4-one) is an O-polumethoxylated flavone that is found in citrus peels and citrus juice like tangerine juice.
[0129] Nobiletin (IUPAC name: 2-(3,4-Dimethoxyphenyl)-5,6,7,8-tetramethoxychromen-4-one) is a flavonoid found in citrus peels.
[0130] Both of these similar compounds have potent suppressive activities on mast cell activation that results in the release of approximately 60 distinct pain, itch and inflammatory mediators. Extensive studies in animals and humans show that mast cell inhibition can produce broad and potent anti-inflammatory activities. Both compounds are potent inhibitors of NF- Kappa and multiple pro-inflammatory cytokines
[0131] Additionally both compounds have anti -proliferative effects in various cancer cell lines and will be of benefit to prevent the development of the pre-cancerous condition Barrett's Esophagus that develops from chronic GER
F. Strontium Based Complexes
[0132] The present disclosure also contemplates the use of strontium-containing complexes. In one embodiment, the complexes are bipartite or tripartite in nature, in that they include at least one or two different components: divalent cationic strontium, and at least one of the
aforementioned components such as chlorogenic acid, agmatine, kynurenic acid, ascorbic acid, or citric acid. In one embodiment, the complexes are strontium di-chlorogenic acid. In another embodiment, the complexes are strontium di -agmatine. In another embodiment, the complexes are strontium di-kynurenic acid. In another embodiment, the complexes are strontium, chlorogenic acid, and agmatine. In another embodiment, the complexes are strontium, chlorogenic acid, and kynurenic acid. In another embodiment, the complexes are strontium agmatine and kynurenic acid. In another embodiment, the complexes are strontium, chlorogenic acid, and ascorbic acid. In another embodiment, the complexes are strontium, kynurenic acid, and ascorbic acid. In another embodiment, the complexes are strontium, agmatine, and ascorbic acid. In another embodiment, the complexes are strontium, chlorogenic acid, agmatine, kynurenic acid, and citric acid.
[0133] In other embodiments, the complexes may also be complexed with a polymer, such as a polyanionic polymer such as polyvinylpyrrolidone (PVP), cyclodextrins, carragenans, alginic acid, xanthan gum, sulfated polysaccharides, pentosan polysulfate, chondroitin sulfate, dextran sulfate and heparin sulfate. In some embodiments, the polymer also has extended release capabilities.
G. Polymers
1. Alginic Acid
[0134] Alginic acid is naturally-occurring polysaccharide obtained from brown seaweed.
Structurally, it is a polyanionic linear copolymer of (l-4)-linked beta-D-mannuronic acid and alpha-L-glucuronic acid. Due to its repeated carboxyl groups, alginic acid electrostatically binds to positively charged atoms, such as strontium and calcium, when the pH of the vehicle is above the pKa of the carboxyl groups (approximately 3-4) causing them to be negatively charged and able to bind to strontium and calcium. As the pH is decreased and approaches the pH of an empty stomach (1 or less), hydrogen ions will compete with strontium and calcium and will
displace and free strontium and calcium. Alginic acid thus acts as a typical ion exchange column matrix. By using various mixtures of naturally occurring alginic acid polymers, the rate of strontium and calcium release as a function of pH and ionic strength of the vehicle can be adjusted to achieve release over an extended period of time.
[0135] Alginic acid and its salts are widely used in foods, cosmetics and in medical devices. The FDA has declared alginic acid GRAS (Generally Recognized as Safe). A similar safety classification exists in the European Union and other countries.
[0136] When consumed after a meal, alginic acid forms a“raft” that floats on the surface of the gastric pool, providing a physical barrier to the irritating and inflammation-producing effects of gastric acid, proteases and other chemical irritants that is unrelated to any acid neutralizing activity that may be present. Alginic acid has been recognized by the FDA as a safe ingredient for GER therapy and is currently available in an OTC antacid in the US and it is available as an OTC Drug in the European Union for GER treatment and esophageal protection.
[0137] Alginic acid also has bioadhesive properties when applied to mucosal membranes. When a patient consumes alginic acid, the bioadhesive properties“coat” the esophagus, which protects the esophagus from exposure to the acidic contents of the stomach. Of particular interest are alginic acid compounds that are compressible into tablets.
2. Polyvinylpyrrolidone
[0138] Polyvinylpyrrolidone (PVP) is commonly used as an inert carrier of therapeutically active molecules. Due to the varying polar structure of the PVP polymer, it presents multiple, repeating sites to which atoms and molecules may bind via ionic forces. Upon subsequent exposure to ionic media, such as water, the bound substance may be released into the media over an extended period of time. Thus facilitating gradual release of the substance as a function of pH and other adjustable conditions, such as temperature, etc. As such, the PVP acts as a“molecular reservoir” providing for sustained release of therapeutic substances. The PVP polymer may be in its native form, or it may be chemically modified by derivatization and/or crosslinking to adjust the“releasing” properties of the polymer. In one embodiment, PVP is used as a carrier for disclosed compositions.
[0139] PVP is used in foods, cosmetics and in medical devices. It is used as an excipient in FDA approved oral prescription drugs as a tablet binder.
3. Xanthan Gum
[0140] Xanhan gum is a polysaccharide that is commonly used as a food additive and can provide a chewy base for sustained release of the ingredients of the present disclosure.
4. Gum Base
[0141] Gum base is a non-nutritive, non-digestible, water-insoluble delivery system used to carry sweeteners, flavors, and any other substances in chewing gum and bubble gum. It provides all the basic textural and chewing properties of gum. Components of gum base can include, but are not limited to, natural coagulated or concentrated lattices of vegetable origin, synthetic coagulated or concentrated lattices, plasticizing materials, terpene resins, and antioxidants.
H. Acid Neutralizing Agents
[0142] Additional acid neutralizing agents may be added. Non-limiting examples of such acid neutralizing agents include calcium carbonate, sodium bicarbonate, sodium citrate, aluminum hydroxide, aluminum phosphate, magnesium hydroxide, magnesium carbonate, magaldrate, almagate, and hydrotalcite.
[0143] Although calcium carbonate is one of the most widely used acid neutralizing agents in OTC GER treatment drugs, calcium actually causes an increase in acid production in the stomach after repeated use and over time may exacerbate acid secretion if antacid treatment is temporarily stopped. Thus, using calcium actually causes a dependency on antacid use.
I. Acid Reducing Agents
[0144] Acid reducing agents are compound that reduce the production of acid in the stomach.
1. Histamine H2 Receptor Antagonists
[0145] Histamine H2 Receptor antagonists (H2RA) are a class of drugs used to block the action of histamine on parietal cells, specifically the histamine H2 receptors, thus decreasing the production of acid by these cells. Non-limiting examples of H2RA include cimetidine, ranitidine, famotidine, and nizatidine.
2. Proton Pump Inhibitors
[0146] Proton pump inhibitors (PPI) are the most potent acid blocking treatment available and are among the most frequently used drugs in the world. They work by blocking the hydrogen ion pump of the stomach’s parietal cells and prevent hydrochloric acid secretion into the stomach’s lumen.
[0147] One of the most serious adverse reactions of PPI is their ability to cause osteoporosis, especially when they are used over many years in older patient who have a uniquely high risk of developing osteoporosis. The strontium based compounds of the present disclosure with a PPI could help prevent the development of osteoporosis. Specifically, strontium ranelate, a salt of ranelic acid that contains two strontium atoms as the“active ingredient,” is reported to be the most effective osteoporosis treatment to date. Strontium ranelate has been shown to stimulate new bone formation and inhibit bone loss.
[0148] The recommended dose of strontium ranelate is 2 grams orally per day, which delivers 680 mg of elemental strontium. Clinical studies show that approximately 25% of ingested strontium is absorbed into the blood and is entirely responsible for the observed improvement of osteoporosis. In one embodiment, compositions of the present disclosure containing PPIs are formulated to deliver as much strontium as strontium ranelate.
J. Excipients
[0149] The compounds of the present disclose may also be formulated with additional ingredients known in the pharmaceutical art to increase stability, increase disintegration of solid tablets, or increase customer appeal. Non-limiting examples possible excipients include binders, bulking agents, diluents, sweeteners, flavorants, lubricants, gum base, and colorants.
[0150] Suitable binders include but are not limited to starches (com starch, wheat starch, modified corn or wheat starch, Starch 1500, or pregelatinized starch), polymers (polaxomer, polyethylene glycol, polymethacrylate, polyethylene oxide, sodium carboxymethylcellulose, polyvinyl alcohol, calcium polycarbophil, or combinations thereof), natural gums (pectin, gelatin, gum Arabic, acacia, carrageenan, guar gum or tragacanth), and low or medium viscosity cellulose derivatives (carbomer, hydroxypropylmethylcellulose, hydroxypropylcellulose, microcrystalline cellulose, carboxymethylcellulose, hydroxyethylcellulose, methylcellulose or combinations thereof).
[0151] Suitable sweeteners include but are not limited to those derived from natural sources such as sugar, confectionary sugar, powdered sugar, sucrose, dextrose, glucose, lactose, fructose, maltodextrin, sorbitol, mannitol, xylitol, polydextrose, erythritol, or combinations thereof.
Additionally, sweeteners also include but are not limited to artificial sweeteners such as aspartame, sucralose, acesulfamine K, saccharin derivatives, or mixtures thereof.
Formulations
[0152] The compositions disclosed herein can be formulated into an easy to consume dose. In the one embodiment, the compositions disclosed herein are formulated as a solid. Non-limiting examples of solids includes lozenges, chewable tablets, gummies, effervescent tablets, sprays, and chewing gum. The tablets are manufactured using conventional techniques in the pharmaceutical industry such as wet granulation, spray drying, or roller compaction.
[0153] Wet granulation is a method in which the active ingredient is mixed with a binder and other excipients in a suitable granulator. A granulating solution such as water or a solution containing dissolved binder is added to the powder blend while mixing it thoroughly. This process allows the powder blend to become wet and agglomerate to form granules. These granules are then dried in a conventional tray drier or a fluid bed drier to obtain dry granules, which are then milled and screened to obtain granules with desirable particle size distribution. These granules are then mixed with additional ingredients such as diluents, bulk sweeteners, intense sweeteners, flavors, disintegrants, lubricants, anti-adherents, glidants etc., and compressed in to tablets.
[0154] Spray drying is another method to granulate powders to obtain spherical free flowing powders, which can be blended with various other excipients and compressed in to tablets. Typically in a spray drying operation, the active ingredient, binder and other desired excipients are suspended in water and sprayed using an atomizer in to the spray drier. The droplets so generated by the atomizer are dried to form granules, which can be screened and milled to obtain desired particle size. The granules can be further processed to obtain tablets as explained above.
[0155] Roller compaction is another method to manufacture granules. In this method dry blend of active ingredient(s), binder and other desired excipients are forced through a pair of rollers held under high pressure, where the powder compacts to form thin wafer like sheets, which are then milled and screened to obtain free flowing granules. Small amounts of water can be sprayed on to the powder blend prior to feeding in to the rollers, to enhance binding properties of ingredients in this process. The granules so obtained can be further processed to obtain tablets as explained above.
[0156] In another embodiment, the compositions disclosed herein are formulated as a liquid.
Treatment and Administration
[0157] The compositions and formulations disclosed herein are designed to (1) target the Type C nociceptors in the esophagus and (2) reduce the acidity of the stomach contents.
[0158] In one embodiment, the compositions and formulations disclosed herein are designed to be taken after eating, for example, up to three hours post meat, up to two hours post meal, up to
one hour post meal, or up to 30 minutes post meal. In this embodiment, the compositions are formulated in a final product that maximizes exposure of the composition to the esophagus. Non-limiting examples include chewy tablets, gummies, lozenges, lollipops, gums, and the like where the continuous chewing and/or swallowing delivers the composition to the esophagus over a longer period of time than conventional chewable tablets. In this embodiment, the full dose may be broken up into smaller sub-doses and taken sequentially, that is, the first sub-dose is fully consumed before the second sub-dose is taken and so forth.
[0159] In another embodiment, the compositions and formulations disclosed herein are designed to be taken after the onset of GER symptoms. In this embodiment, the compositions are formulated in a final product that maximizes exposure of the composition to the esophagus. Non-limiting examples include chewy tablets, gummies, lozenges, lollipops, gums, and the like where the continuous chewing and/or swallowing delivers the composition to the esophagus over a longer period of time than conventional chewable tablets. In this embodiment, the full dose may be broken up into smaller sub-doses and taken sequentially, that is, the first sub-dose is fully consumed before the second sub-dose is taken and so forth.
[0160] In another embodiment, the compositions and formulations disclosed herein are designed to be taken before eating. Taking the compositions and formulations before eating essentially pre-treats the esophagus before exposure to the stomach acid content. The pre-treatment can reduce or prevent GER symptoms. In this embodiment, the compositions may not include the acid neutralizing agent or acid reducing agent. In this embodiment, the compositions are formulated in a final product that maximizes exposure of the composition to the esophagus. Non-limiting examples include sprays, chewy tablets, gummies, lozenges, lollipops, gums, and the like where the continuous chewing and/or swallowing delivers the composition to the esophagus over a longer period of time than conventional chewable tablets. In this embodiment, the full dose may be broken up into smaller sub-doses and taken sequentially, that is, the first sub-dose is fully consumed before the second sub-dose is taken and so forth.
EXAMPLES
[0161] The exemplary formulations that follow describe combinations of strontium, chlorogenic acid, and an acid neutralizing agent that can be used to treat symptoms associated with GER, GERD, or Barrett’s esophagus. The final formulation amount for each compound are those commonly used in the art for formulating OTC and prescription treatments for patients suffering
from symptoms associated with GER, GERD, or Barrett’s esophagus. The strontium can optionally be used in similar concentration as used in strontium ranelate.
A. Exemplary Formulations
[0162] Tables 1 below lists the specific compounds that make up the following base
formulations containing at least one strontium salt and at least one additional ingredient such as a chlorogenic acid, a vitamin, an amino acid derivative or metabolites, or a methoxyflavonoid. The GER formulations combine the base formulation with at least one acid neutralizing or acid reducing agent. Optionally a polymer can be added to either the base formulations or the GER formulations.
[0163] For Table 1, the following numbers correspond to the listed ingredient: (1) strontium carbonate; (2) strontium bicarbonate; (3) strontium hydroxide; (4) strontium phosphate; (5) strontium citrate; (6) strontium lactate; (7) chlorogenic acid and its salts; (8) ascorbic acid and its salts; (9) citric acid and its salts; (10) kynurenic acid and its salts; (11) agmatine; (12) tangeretin; and (13) nobiletin. Table 1 below lists the specific combinations for formulations A-D30 (on the vertical axis) using ingredients 1-13 (on the horizontal axis).
Table 1
[0164] To each of the formulations disclosed in Table 1, one or more of the following acid neutralizing agents can optionally be added: calcium carbonate, sodium bicarbonate, sodium citrate, aluminum hydroxide, aluminum phosphate, magnesium hydroxide, magnesium carbonate, magaldrate, almagate, and hydrotalcite. Each of the formulations disclosed in Table 1 further includes calcium carbonate. Each of the formulations disclosed in Table 1 further includes sodium bicarbonate. Each of the formulations disclosed in Table 1 further includes sodium citrate. Each of the formulations disclosed in Table 1 further includes aluminum hydroxide. Each of the formulations disclosed in Table 1 further includes aluminum phosphate. Each of the formulations disclosed in Table 1 further includes magnesium hydroxide. Each of the formulations disclosed in Table 1 further includes magnesium carbonate. Each of the formulations disclosed in Table 1 further includes magldrate. Each of the formulations disclosed in Table 1 further includes almagate. Each of the formulations disclosed in Table 1 further includes hydrotalcite. Each of the formulations disclosed in Table 1 further includes aluminum hydroxide and magnesium hydroxide.
[0165] To each of the formulations disclosed in Table 1, one or more of the following histamine H2 receptor antagonists can optionally be added: cimetidine, famotidine, nizatidine, and rantidine. Each of the formulations disclosed in Table 1 further includes cimetidine. Each of the formulations disclosed in Table 1 further includes famotidine. Each of the formulations disclosed in Table 1 further includes nizatidine. Each of the formulations disclosed in Table 1 further includes rantidine
[0166] To each of the formulations disclosed in Table 1, one or more of the following proton pump inhibitors can optionally be added: omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole. Each of the formulations disclosed in Table 1 further includes omeprazole. Each of the formulations disclosed in Table 1 further includes lansoprazole. Each of the formulations disclosed in Table 1 further includes rabeprazole. Each of the formulations disclosed in Table 1 further includes pantoprazole. Each of the formulations disclosed in Table 1 further includes esomeprazole
[0167] To each of the formulations disclosed in Table 1, one or more of the following acid neutralizing agents can optionally be added: calcium carbonate, sodium bicarbonate, sodium citrate, aluminum hydroxide, aluminum phosphate, magnesium hydroxide, magnesium carbonate, magaldrate, almagate, and hydrotalcite. Additionally, one or more of the following histamine H2 receptor antagonists can optionally be added: cimetidine, famotidine, nizatidine, and rantidine.
[0168] To each of the formulations disclosed in Table 1, one or more of the following acid neutralizing agents can optionally be added: calcium carbonate, sodium bicarbonate, sodium citrate, aluminum hydroxide, aluminum phosphate, magnesium hydroxide, magnesium carbonate, magaldrate, almagate, and hydrotalcite. Additionally, one or more of the following proton pump inhibitors can be added: omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole.
[0169] To each of the formulations disclosed in Table 1, one or more of the following polymers can optionally be added: alginic aid, PVP, and xanthan gum. Each of the formulations disclosed in Table 1 further includes alginic acid. Each of the formulations disclosed in Table 1 further includes PVP. Each of the formulations disclosed in Table 1 further includes xanthan gum.
[0170] To each of the formulations disclosed in Table 1, additional excipients can be added to make a chewable tablet.
[0171] To each of the formulations disclosed in Table 1, additional excipients can be added to make a gummy.
[0172] To each of the formulations disclosed in Table 1, additional excipients can be added to make a chewing gum.
[0173] To each of the formulations disclosed in Table 1, additional excipients can be added to make a lozenge.
[0174] To each of the formulations disclosed in Table 1, additional excipients can be added to make a lollipop.
[0175] To each of the formulations disclosed in Table 1, additional excipients can be added to make a spray.
B. Exemplary Dose Amounts
[0176] The acid neutralizing agents are used in the amounts set out is the Code of Federal Regulations (CFR), Title 21, Section 331. For example, 21CFR331 sets a maximum daily dosage limit of 8 grams for calcium carbonate. The maximum daily dosage for PPFs is set by the FDA and is based on the indication. For example, omeprazole has a maximum daily dosage of 20 mg for heartburn. The maximum daily dosage for H2 blockers is set by the FDA and is based on the indication. For example, for example, famotidine has a maximum daily dosage of 20mg for heartburn. Chlorogenic acid is present in coffee. Coffee drinkers consume up to 1 gram of chlorogenic acid a day. Chlorogenic acid is also available as a dietary supplement with a recommended daily dose of 400-600 milligrams per day. Agmatine is available as a dietary supplement with a recommended daily dose between 500 milligrams to 2.5 grams per day. Ascorbic acid is available as a dietary supplement with a recommended daily dose of up to 2 grams per day.
C. Comparative Testing
[0177] The formulations disclosed herein are evaluated for their ability to suppress acid induced pain and irritation. Briefly, a participant’s inner forearms are divided into six sections labeled 1- 12. Each section is swabbed with a 25% glycolic acid solution. A second solution is swabbed in each quadrant as shown in Table 2, below.
Table 2
[0178] The pain level is assessed at time of application and every minute thereafter for 10 minutes. Participants rated the pain levels on a 0-4 scale where 0 was no pain; 1 is slight pain; 2 is mild pain; 3 is moderate pain; and 4 is unbearable pain.
[0179] The embodiments discussed above are provided to give those of ordinary skill in the art a complete disclosure and description of how to make and use the embodiments of the methods, and are not intended to limit the scope of what the inventor regards as his invention.
Modifications of the above-described modes (for carrying out the invention that are obvious to persons of skill in the art) are intended to be within the scope of the following claims. All publications, patents, and patent applications cited in this specification are incorporated herein by reference as if each such publication, patent or patent application were specifically and individually indicated to be incorporated herein by reference.
Claims
1. A composition for treating gastroesophageal reflux comprising: at least one strontium salt and chlorogenic acid.
2. A composition for treating gastroesophageal reflux comprising: at least one strontium salt and agmatine.
3. The composition of claim 1 or 2, wherein the at least one strontium salt is strontium carbonate, strontium bicarbonate, strontium hydroxide, strontium phosphate, strontium lactate, strontium citrate, strontium chloride, strontium sulfate, strontium nitrate, strontium hydrosulfide, strontium oxide, strontium acetate, strontium glutamate, strontium aspartate, strontium malonate, strontium maleate, strontium threonate, strontium lactate, strontium pyruvate, strontium ascorbate, strontium alpha-ketoglutarate or strontium succinate.
4. The composition of claim 1, 2, or 3, further comprising at least one acid neutralizing agent.
5. The composition of claim 4, wherein the at least one acid neutralizing agent is aluminum carbonate, aluminum hydroxide, dihydroxyaluminum aminoacetate, aluminum phosphate, dihydroxyalumium sodium carbonate, magnesium carbonate, sodium bicarbonate, bismuth aluminate, bismuth carbonate, bismuth subcarbonate, bismuth subgallate, bismuth submitate, calcium carbonate, calcium phosphate, tricalcium phosphate, citric acid, trisodium citrate, glycine, magnesium aluminate, magaldrate, magnesium aluminosilicates, magnesium carbonate, magnesium glycinate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, milk solids, potassium bicarbonate, sodium potassium tartrate, tartaric acid, potassium bitartrate, magaldrate, almagate, or hydrotalcite.
6. The composition of any one of the previous claims, further comprising at least one acid reducing agent.
7. The composition of claim 6, wherein the at least one acid reducing agent is cimetidine, famotidine, nizatidine, rantidine, omeprazole, lansoprazole, rabeprazole, pantoprazole, or esomeprazole.
8. The composition of any one of the preceding claims, further comprising at least one vitamin.
9. The composition of claim 8, wherein the at least one vitamin is ascorbic acid or vitamin E.
10. The composition of any one of the preceding claims, further comprising at least one amino acid derivative or metabolite.
11. The composition of claim 10, wherein the at least one amino acid is kynurenic acid or agmatine.
12. The composition of any one of the preceding claims, further comprising at least one methoxyfl avonoi d .
13. The composition of claim 12, wherein the at least one methoxyflavonoid is tangeretin or nobiletin.
14. The composition of any one of the preceding claims, further comprising at least one polymer.
15. The composition of claim 14, wherein the at least one polymer is alginic acid, PVP, or xanthan gum.
16. The composition of any one of the preceding claim, wherein composition is formulated as a chewable tablet.
17. The composition of any one of claims 1-15, wherein the composition is formulated as a chewing gum.
18. The composition of any one of claims 1-15, wherein the composition is formulated as a gummy.
19. The composition of any one of claims 1-15, wherein the composition is formulated as a lozenge.
20. The composition of any one of claims 1-15, wherein the composition is formulated as a spray.
21. A composition for treating gastroesophageal reflux comprising a complex of a divalent cationic strontium and at least two counter compounds.
22. The composition of claim 21, wherein the at least two counter compounds are selected from the group consisting of chlorogenic acid, kynurenic acid, agamtine, and ascorbic acid.
23. The composition of claim 22, wherein the at least two counter compounds are chlorogenic acid.
24. The composition of claim 22, wherein the at least two counter compounds are kynurenic acid.
25. The composition of claim 22, wherein the at least two counter compounds are agmatine.
26. The composition of claim 22, wherein the at least two counter compounds are ascorbic acid.
27. The composition of claim 22, wherein the at least two counter compounds are chlorogenic acid and agmatine.
28. The composition of claim 22, wherein the at least two counter compounds are chlorogenic acid and kynurenic acid.
29. The composition of claim 22, wherein the at least two counter compounds are chlorogenic acid; and ascorbic acid.
30. The composition of claim 22, wherein the at least two counter compounds are kynurenic acid; and ascorbic acid.
31. The composition of claim 22, wherein the at least two counter compounds are agmatine and ascorbic acid.
32. The composition of claim 22, wherein the at least two counter compounds are agmatine and kynurenic acid.
33. A composition for treating gastroesophageal reflux comprising a complex of a divalent cationic strontium; a chlorogenic acid; a kynurenic acid; an agmatine; and a citric acid.
34. The composition of any one of claims 21-33, wherein the divalaent cationic strontium is from a strontium salt.
35. The composition of claim 34, wherein the strontium salt is strontium carbonate, strontium bicarbonate, strontium hydroxide, strontium phosphate, strontium lactate, strontium citrate, strontium chloride, strontium sulfate, strontium nitrate, strontium hydrosulfide, strontium oxide, strontium acetate, strontium glutamate, strontium aspartate, strontium malonate, strontium maleate, strontium threonate, strontium lactate, strontium pyruvate, strontium ascorbate, strontium alpha-ketoglutarate or strontium succinate.
36. The composition of any one of claims 21-35, further comprising at least one acid neutralizing agent.
37. The composition of claim 36, wherein the at least one acid neutralizing agent is aluminum carbonate, aluminum hydroxide, dihydroxyaluminum aminoacetate, aluminum phosphate, dihydroxyalumium sodium carbonate, magnesium carbonate, sodium bicarbonate, bismuth aluminate, bismuth carbonate, bismuth subcarbonate, bismuth subgallate, bismuth submitate, calcium carbonate, calcium phosphate, tricalcium phosphate, citric acid, trisodium citrate, glycine, magnesium aluminate, magaldrate, magnesium aluminosilicates, magnesium carbonate, magnesium glycinate, magnesium hydroxide, magnesium oxide, magnesium
trisilicate, milk solids, potassium bicarbonate, sodium potassium tartrate, tartaric acid, potassium bitartrate, magaldrate, almagate, or hydrotalcite.
38. The composition of any one of claims 21-37, further comprising at least one acid reducing agent.
39. The composition of claim 38, wherein the at least one acid reducing agent is cimetidine, famotidine, nizatidine, rantidine, omeprazole, lansoprazole, rabeprazole, pantoprazole, or esomeprazole.
40. The composition of any one of claims 20-39, further comprising at least one
methoxyfl avonoi d .
41. The composition of claim 40, wherein the at least one methoxyfl avonoi d is tangeretin or nobiletin.
42. The composition of any one of claims 20-41 further comprising at least one polymer.
43. The composition of claim 42, wherein the at least one polymer is alginic acid; PVP; or xanthan gum.
44. The composition of any one of claims 20-43, wherein the composition if formulated as a chewable tablet.
45. The composition of any one of claims 20-43, wherein the composition is formulated as a chewing gum.
46. The composition of any one of claims 20-43, wherein the composition is formulated as a gummy.
47. The composition of any one of claims 20-43, wherein the composition is formulated as a lozenge.
48. The composition of any one of claims 20-43, wherein the composition is formulated as a spray.
49. A composition comprising strontium citrate, calcium carbonate, chlorogenic acid, and ascorbic acid.
50. A composition comprising strontium citrate, calcium carbonate, agmatine, and ascorbic acid.
51. The composition of claim 49 or 50 further comprising strontium carbonate.
52. The composition of any one of claims 49-51 further comprising a polymer.
53. The composition of claim 52, wherein the at least one polymer is alginic acid; PVP; or xanthan gum.
54. The composition of any one of claims 49-53, wherein the composition if formulated as a chewable tablet.
55. The composition of any one of claims 49-53, wherein the composition is formulated as a chewing gum.
56. The composition of any one of claims 49-53, wherein the composition is formulated as a gummy.
57. The composition of any one of claims 49-53, wherein the composition is formulated as a lozenge.
58. The composition of any one of claims 49-53, wherein the composition is formulated as a spray.
59. A method of treating gastroesophageal reflux comprising administering the compound of any one of the previous claims to a subject.
60. The method of claim 59, wherein the compound is administered to the patient after eating but before onset of gastroesophageal reflux symptoms.
61. The method of claim 59, wherein the compound is administered to the patient within one hour after eating.
62. The method of claim 59 wherein the compound is administered to the patient within thirty minutes after eating.
63. The method of claim 59, wherein the compound is administered to the patient upon presentation of gastroesophageal reflux symptoms.
64. The method of claim 59, wherein the compound is administered to the patient before eating.
65. The method of claim 59, wherein the compound is administered in a sequential manner.
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