Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/25—Growth hormone-releasing factor [GH-RF] (Somatoliberin)
• • 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
• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/10—Laxatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• Gastrointestinal motility is a coordinated neuromuscular process that transports nutrients through the digestive system.
• C. Scarpignato "Pharmacological Stimulation of Gastrointestinal Motility: Where We Are And Where Are We Going?" Dig. Dis., 15: 112 (1997).
• Impaired (i.e., slowed) motility of the gastrointestinal system which can be involved in gastroesophageal reflux disease, gastroparesis (e.g., diabetic and postsurgical), irritable bowel syndrome, ileus, and constipation (e.g., diet or opioid-induced), is one of the largest health care burdens of industrialized nations.
• S. D. Feighner et al "Receptor for Motilin Identified in the Human Gastrointestinal System," Science, 284: 2184-2188 (Jun. 25, 1999).
• GHS Growth hormone secretagogues
• ghrelin is a 28-amino acid peptide that is produced in the stomach.
• the biologically active form of ghrelin i.e., the acylated form, has a serum half-life of only 9-13 minutes (Akamizu et al. (2004) European Journal of Endocrinology 150:447-55).
• synthetic GHS compounds such as GHRP-6 have been evaluated for the ability to treat GI motility.
• GHRP-6 has a short serum half life that prohibits the use of this compound from being used to treat GI motility disorders.
• Bowers et al. demonstrated that the serum half life of GHRP-6 is only 20 minutes ((1992) Journal of Clinical Endocrinology and Metabolism 74:292-8).
• the present invention relates to a method of stimulating the motility of the gastrointestinal system in a subject in need thereof, wherein the subject suffers from maladies (i.e., disorders, diseases, conditions, or drug- or surgery-induced dysfunction) of the gastrointestinal system.
• the method comprises administering to a subject in need thereof a therapeutically effective amount of a ghrelin mimetic compound or a pharmaceutically acceptable salt, hydrate or solvate thereof.
• the ghrelin mimetic is ipamorelin as represented by Formula I (see below), or a pharmaceutically acceptable salt, hydrate or solvate thereof.
• the instant invention provides methods and therapeutically effective compositions for stimulating the motility of the gastrointestinal system.
• Stimulation of gastrointestinal motility is used in a method of treating opioid-induced gastrointestinal dysfunction, e.g., morphine-induced bowel dysfunction or constipation, in a subject in need thereof comprising administering a therapeutically effective amount of a ghrelin mimetic compound or a pharmaceutically acceptable salt, hydrate or solvate thereof.
• the subject may be using opiates or opioids for post-surgical pain management or for chronic pain management.
• Exemplary opiates and opioids include morphine, codeine, oxycodone, hydromorphone, hydrocodone, methadone, fentanyl, and combinations with anti-inflammatory agents such as acetaminophen or aspirin.
• a preferred ghrelin mimetic is ipamorelin as represented by Formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
• Stimulation of gastrointestinal motility can be used to treat gastroparesis in a subject in need thereof by administering a therapeutically effective amount of a ghrelin mimetic compound.
• a preferred ghrelin mimetic is ipamorelin as represented by Formula I, or a pharmaceutically acceptable salt, hydrate, derivative, acid amide, or solvate thereof.
• stimulation of gastrointestinal motility is used in a method of treating gastroesophageal reflux disease (GERD) in a subject in need thereof comprising administering a therapeutically effective amount of a ghrelin mimetic compound.
• the ghrelin mimetic is ipamorelin as represented by Formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
• the gastroesophageal reflux disease is nocturnal gastroesophageal reflux disease.
• the invention also provides methods for stimulating gastrointestinal motility for the treatment of irritable bowel syndrome (IBS) in a subject in need thereof by administering a therapeutically effective amount of a ghrelin mimetic compound.
• a preferred ghrelin mimetic is ipamorelin as represented by Formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
• the irritable bowel syndrome can be constipation-predominant irritable bowel syndrome or alternating constipation/diarrhea irritable bowel syndrome.
• the invention also provides methods for stimulating gastrointestinal motility to treat constipation in a subject in need thereof by administering a therapeutically effective amount of a ghrelin mimetic compound.
• a preferred ghrelin mimetic is ipamorelin as represented by Formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
• stimulation of gastrointestinal motility is used in a method of treating surgery-induced or related gastrointestinal dysfunction, e.g. post-operative ileus, in a subject in need thereof comprising administering a therapeutically effective amount of a ghrelin mimetic compound.
• the ghrelin mimetic is ipamorelin as represented by Formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
• a preferred ghrelin mimetic is ipamorelin as represented by Formula I ( ⁇ -Methylalanine- L-histidine-D- ⁇ -(2-naphthyl)-alanine-D-phenylalanine-L-lysinamide or H-Aib-His- ⁇ -(2- naphthyl)-D-Ala-D-Phe-Lys-NH 2 ):
• FIG. 1 shows the gastrokinetic efficacy of oral administration of ipamorelin at 10 and 100 mg/kg in a rat model for post-operative ileus.
• FIG. 2 shows the efficacy of i.v. administered ipamorelin at 0.1, 0.25 or 1.0 mg/kg on a rat model of post-operative ileus.
• FIG. 3 shows the efficacy of i.v. administered ipamorelin at 0.01, 0.03 and 0.1 mg/kg in a rat model for post-operative ileus.
• FIG. 4 demonstrates that ghrelin did not accelerate gastric emptying in the rats administered 4 mg/kg of morphine and that rats administered saline or ghrelin displayed the same group mean absorbance of phenol red.
• FIG. 5 shows the gastrokinetic efficacy of intravenous administration of ipamorelin (referred to as 26-0161 in the figure) at 0.25, 1.0, 2.5 mg/kg as compared to 10 mg/kg RC-1139 to treat post-operative ileus in a rat model.
• ipamorelin referred to as 26-0161 in the figure
• FIG. 6 shows the reversal of morphine-induced slowing of gastrointestinal motility in humans by the intravenous administration of a single dose of ipamorelin at doses of 0.01, 0.03 and 0.06 mg/kg.
• FIG. 7 shows a bar graph comparing the effect of various ghrelin mimetics on stomach emptying.
• FIG. 8 shows a bar graph comparing the effect of various ghrelin mimetics on gastrointestinal motility through the small intestine.
• FIG. 9 shows a bar graph comparing the effect of various ghrelin mimetics on stomach emptying.
• FIG. 10 shows a bar graph comparing the effect of various ghrelin mimetics on gastrointestinal motility through the small intestine (distal distance from pyloric sphincter).
• FIG. 11 shows a bar graph comparing the effect of various ghrelin mimetics on gastrointestinal motility through the small intestine (proximal distance from pyloric sphincter).
• FIG. 12A-D show the effect of abdominal surgery on colonic transit time, fecal pellet output, food intake, and body weight gain in rat model of post-operative ileus.
• FIG 13 shows colonic transit time in rats after abdominal surgery after single dose administration of ipamorelin at 0.1 and 1 mg/kg relative to vehicle and a control (GHRP-6).
• FIG. 14 shows cumulative fecal pellet output at 12h, 24h or 48h in rats after abdominal surgery after single dose administration of ipamorelin at 0.1 and 1 mg/kg relative to vehicle and a standard control (GHRP-6).
• FIG. 15 shows cumulative food intake at different time points between 3-48 h in rats after abdominal surgery after single dose administration of ipamorelin at 0.1 and 1 mg/kg relative to vehicle and a standard control (GHRP-6).
• FIG. 16 shows the effect on body weight at 24h and 48h in rats after abdominal surgery after single dose administration of ipamorelin at 0.1 and 1 mg/kg relative to vehicle and a standard control (GHRP-6).
• FIG. 17 shows colonic transit time in rats after abdominal surgery after multiple doses of 0.01 , 0.1 and 1.0 mg/kg ipamorelin relative to vehicle.
• FIG 18 shows the effect of fecal pellet output over a 48h period in rats after abdominal surgery after multiple doses of ipamorelin at 0.01, 0.1 and 1.0 mg/kg ipamorelin relative to vehicle.
• FIG 19 shows the effect on cumulative food intake over a 48h period in rats after abdominal surgery after multiple doses of ipamorelin at 0.01, 0.1 and 1.0 mg/kg ipamorelin relative to vehicle.
• FIG 20 shows the effect on body weight gain over a 48h period in rats after abdominal surgery after multiple doses of ipamorelin at 0.01, 0.1 and 1.0 mg/kg ipamorelin relative to vehicle.
• the present invention relates to a method of stimulating the motility of the gastrointestinal system in a subject in need thereof, wherein the subject suffers from maladies (i.e., disorders or diseases or drug- or surgery-induced dysfunction) of the gastrointestinal system.
• the maladies include opioid-induced gastrointestinal dysfunction, e.g., morphine-induced gastrointestinal dysfunction, constipation, diabetes-related gastroparesis, gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), or drug- or surgery-induced gastrointestinal dysfunction, e.g., post-operative ileus.
• the method comprises administering to a subject in need thereof a therapeutically effective amount of a ghrelin mimetic compound or a pharmaceutically acceptable salt, hydrate or solvate thereof.
• a ghrelin mimetic compound or a pharmaceutically acceptable salt, hydrate or solvate thereof is administered to a subject in need thereof a therapeutically effective amount of a ghrelin mimetic compound or a pharmaceutically acceptable salt, hydrate or solvate thereof.
• the ghrelin mimetic is preferably ipamorelin as represented by Formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
• ghrelin mimetic or “ghrelin mimetic compound” or “ghrelin agonist” are synonymous with the historical terms “growth hormone secretagogue,” or “growth hormone secretagogue compound”.
• a ghrelin mimetic or ghrelin agonist refers to a substance (e.g., a molecule, a compound) which promotes (induces or enhances) at least one function that is characteristic of binding to the ghrelin receptor (GRLN).
• GRLN receptor has been previously reported in the literature as the GHS 13 receptor which reflected its first known attribute — secretion of growth hormone.
• the ghrelin receptor is primarily expressed in the hypothalamus and pituitary.
• the ghrelin mimetics can increase appetite and body weight.
• the ghrelin mimetics are those described in U.S. Patent Nos. 5,767,085, 6,303,620, 6,576,648, 5,977,178, 6,566,337, 6,083,908, 6,274,584 and 6,919,315, the entire content of all of which are incorporated herein by reference.
• the GRLN receptor was identified in locations in the body other than the pituitary and hypothalamus, such as the gastrointestinal tract and the vasculature.
• the binding of ghrelin or ghrelin mimetics to these receptors resulted in pharmacological activity other than, or in addition to, growth hormone release.
• this other pharmacologic activity was an increase in gastrointestinal prokinetic activity as well as changes in cardiac function.
• the growth hormone secretagogue compounds as they were previously named are now more generally called ghrelin mimetics or agonists to represent the wider spectrum of physiological actions resulting from binding to its receptor (GRLN).
• ghrelin mimetics have a core peptide backbone with differing lengths of the backbone (tri-, tetra-, penta-, and hexapeptides, as well as macrocyclic). It is also expected that the different molecular structures will result in differing affinities for the ghrelin receptor and, therefore, could produce differing pharmacological outcomes. A priori one cannot determine which molecule might produce unusual activity or potency relative to others in a general class. It generally emerges from scientific investigation with an unusual result or finding.
• a compound having GRLN receptor agonist activity can be identified and activity assessed by any suitable method.
• the binding affinity of a GRLN receptor agonist to the GRLN receptor can be determined employing receptor binding assays and growth hormone stimulation can be assessed as described in United States Patent No.: 6,919,315, which is incorporated herein by reference.
• the ghrelin mimetics can be obtained from any source, including any commercial source.
• the preferred ghrelin mimetic is ipamorelin as represented by the structural Formula I ( ⁇ -Methylalanine-L-histidine-D- ⁇ -(2-naphthyl)-alanine-D- phenylalanine-L-lysinamide or H- Aib-His- ⁇ -(2-naphthyl)-D-Ala-D-Phe- LyS-NH 2 ):
• the present invention is based in part on the surprising discovery made by the present inventors that certain particular ghrelin mimetics, in particular, ipamorelin, have a surprisingly efficacious and potent stimulatory effect on gastrointestinal motility.
• ipamorelin is a potent growth hormone secretagogue, its binding affinity with the GRLN receptor is about 2-3 logs weaker than many other reported ghrelin mimetics.
• Another aspect of the present invention relates to the co-administration of one or more substances and a ghrelin mimetic, e.g., ipamorelin, to treat a gastrointestinal disorder, disease, or condition.
• Co-administered can mean the administration of two or more substances together as a single pharmaceutical composition, or the administration of two or more substances in a short period of time, e.g., within seconds of each other to within a day of each other.
• Peripherally acting opioid antagonists can mean the administration of two or more substances together as a single pharmaceutical composition, or the administration of two or more substances in a short period of time, e.g., within seconds of each other to within a day of each other.
• peripherally acting opioid receptor antagonists such as, for example, methylnaltrexone, naloxone, naltrexone, nalmefene and alvimopan (ENTEREGTM), which do not cross the blood-brain barrier, to treat opioid-induced side effects without provoking opioid withdrawal symptoms or reverse analgesia.
• opioid receptor antagonists such as, for example, methylnaltrexone, naloxone, naltrexone, nalmefene and alvimopan (ENTEREGTM)
• peripherally acting opioid antagonists refer to opioid antagonists that act peripherally (i.e., not centrally, for example, do not act on the central nervous system).
• Proton pump inhibitors hi another aspect, the present invention provides for co-administration of a ghrelin mimetic, e.g., ipamorelin, and a proton pump inhibitor for the treatment of gastrointestinal conditions or maladies.
• Proton pump inhibitors suppress gastric acid secretion, the final step of acid production, by specific inhibition of the H + K + -ATPase enzyme system at the secretory surface of gastric parietal cells.
• Proton pump inhibitors include benzimidazole compounds, for example, esomeprazole (NEXIUM ® ), omeprazole (PRILOSECTM), lansoprazole (PREV ACIDTM), rabeprazole (ACIPHEXTM). and pantoprazole (ProtonixTM). These proton pump inhibitors contain a sulfmyl group situated between substituted benzimidazole and pyridine rings. At neutral pH, esomeprazole, omeprazole, lansoprazole, and pantoprazole are chemically stable, lipid soluble, weak bases that are devoid of inhibitory activity.
• the present invention provides for the co-administration of a ghrelin mimetic, e.g., ipamorelin, and an H 2 receptor antagonist for the treatment of gastrointestinal conditions or maladies.
• H 2 receptor antagonists competitively inhibit the interaction of histamine with H 2 receptors. They are highly selective and have little or no effect on Hi receptors.
• H 2 receptors are present in numerous tissues, including vascular and bronchial smooth muscle, H 2 receptor antagonists interfere remarkably little with physiological functions other than gastric acid secretion.
• H 2 receptor antagonists include, but are not limited to, nizatidine (AXIDTM), ranitidine (ZANTACTM and TRITECTM), famotidine (PEPCID ACTM), and cimetidine (TAGAMETTM. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th Edition, pp. 901-915 (1996), incorporated herein by reference.
• H 2 receptor antagonists inhibit gastric acid secretion elicited by histamine, other H 2 agonists, gastrin, and, to a lesser extent, muscarinic agonists. H 2 receptor antagonists also inhibit basal and nocturnal acid secretion. Antacids
• Another aspect of the present invention provides a method for the co-administration of a ghrelin mimetic, e.g., ipamorelin, and an antacid for treating a gastrointestinal condition or malady.
• a ghrelin mimetic e.g., ipamorelin
• an antacid for treating a gastrointestinal condition or malady.
• compounds of the invention can be co-administered with antacids to neutralize gastric acid.
• antacids for instance, aluminum and magnesium hydroxide (MAALOXTM and MYLANT ATM) neutralize gastric acidity, resulting in an increase in pH in the stomach and duodenal bulb.
• MAALOXTM and MYLANT ATM neutralize gastric acidity, resulting in an increase in pH in the stomach and duodenal bulb.
• the present invention further provides a method for the co-administration of a ghrelin mimetic, e.g., ipamorelin, and a laxative for treating a gastrointestinal condition or malady.
• Laxatives come in various forms, including, for example, liquids, tablets, suppositories, powders, granules, capsules, chewing gum, chocolate-flavored wafers, and caramels.
• the basic types of laxatives are bulk-forming laxatives, lubricant laxatives, stool softeners (also called emollient laxatives), and stimulant laxatives.
• Bulk-forming laxatives contain materials, such as cellulose and psyllium, that pass through the digestive tract without being digested. In the intestines, these materials absorb liquid and swell, making the stool soft, bulky, and easier to pass. The bulky stool then stimulates the bowel to move.
• Laxatives in this group include such brands as FIBERCON®, FIBERALL®, and METAMUCIL®.
• Lubricant laxatives include, for example, mineral oil. Mineral oil is the most widely used lubricant laxative. Taken by mouth, the oil coats the stool. This keeps the stool moist and soft and makes it easier to pass. Lubricant laxatives are often used for patients who need to avoid straining (e.g., after abdominal surgery). Stool softeners (emollient laxatives) make stools softer and easier to pass by increasing their moisture content. This type of laxative does not really stimulate bowel movements, but it makes it possible to have bowel movements without straining. Stool softeners are best used to prevent constipation in people who need to avoid straining, because of recent surgery, for example.
• Stool-softening agents include, for example, docusate sodium (COLACE®, REGUTOL®, and others), docusate calcium (SURFAK®, DC SOFTGELS®) and docusate potassium (DIALOSE®, DIOCTO-K®).
• Serotonin receptor (5-HT) agonists pure or mixed
• the present invention also provides a method for the co-administration of a ghrelin mimetic, e.g., ipamorelin, and a serotonin receptor agonist, such as a 5-HT 4 agonist, for treating a gastrointestinal condition or malady.
• a ghrelin mimetic e.g., ipamorelin
• a serotonin receptor agonist such as a 5-HT 4 agonist
• the 5-HT 4 agonists speed up movement of bowel contents through the colon and reduce sensitivity to intestinal nerve stimulation.
• Suitable serotonin agonists which can be used in combination with the compounds of the invention include, but not restricted to, rauwolscine, yohimbine, metoclopramide, prucalopride and tegaserod (ZELNORM®).
• SpillerR. "Serotonergic Modulating Drugs for Functional Gastrointestinal Diseases," Br J Clin Pharmacol. 54:11-20 (2002) and U.S. Patent No. 6,413,988, incorporated herein by reference.
• Motilin receptor agonists Motilin receptor agonists
• the present invention further provides a method for the co-administration of a ghrelin mimetic, e.g., ipamorelin, and a motilin receptor agonist for treating a gastrointestinal condition or malady.
• a ghrelin mimetic e.g., ipamorelin
• a motilin receptor agonist for treating a gastrointestinal condition or malady.
• Motilin is a peptide of 22 amino acids which is produced in the gastrointestinal system of a number of species. Motilin induces smooth muscle contractions in the stomach tissue of dogs, rabbits, and humans as well as in the colon of rabbits. Apart from local gastrointestinal intestinal tissues, motilin and its receptors have been found in other tissues.
• motilin In addition to motilin, there are other substances which are agonists of the motilin receptor and which elicit gastrointestinal emptying.
• One of those agents is the antibiotic erythromycin. Studies have shown that erythromycin elicits biological responses that are comparable to motilin itself and therefore can be useful in the treatment of diseases such as chronic idiopathic intestinal pseudo-obstruction and gastroparesis. Weber, F. et al, The American Journal of Gastroenterology, 88:4, 485-90 (1993), incorporated herein by reference.
• Another aspect of the present invention provides a method for the co-administration of a ghrelin mimetic, e.g., ipamorelin, and a dopamine antagonist for treating a gastrointestinal condition or malady.
• a ghrelin mimetic e.g., ipamorelin
• a dopamine antagonist for treating a gastrointestinal condition or malady.
• Dopamine antagonists are drugs that bind to, but do not activate, dopamine receptors thereby blocking the actions of dopamine or exogenous agonists.
• This class of drugs includes, but is not limited to, metoclopramide, domperidone, amisulpride, clebopride, mosapramine, nemonapride, remoxipride, risperidone, sulpiride, sultopride and ziprasidone.
• Cholinesterase inhibitors include, but is not limited to, metoclopramide, domperidone, amisulpride, clebopride, mosapramine, nemonapride, remoxipride, risperidone, sulpiride, sultopride and ziprasidone.
• the present invention also provides a method for the co-administration of a ghrelin mimetic, e.g., ipamorelin, and a cholinesterase inhibitor for treating a gastrointestinal condition or malady.
• a ghrelin mimetic e.g., ipamorelin
• a cholinesterase inhibitor refers to one or more agents that prolong the action of acetylcholine by inhibiting its destruction or hydrolysis by cholinesterase. Cholinesterase inhibitors are also known as acetylcholinesterase inhibitors.
• cholinesterase inhibitors include, but are not limited to, edrophonium, neostigmine, neostigmine methylsulfate, pyridostigmine, tacrine and physostigmine, ambenonium chloride (MYTELASE ® ), edrophonium chloride (TENSILON ® ), neostigmine (PROSTIGMINE ® ), piridogstimina (MESTINON ® ), distigmine bromide, eptastigmine, galanthamine, axeclidine, acetylcholine bromine, acetylcholine chloride, aclatonium napadisilate, ben ⁇ pyrinium bromide, carbachol, carponium chloride, cemecarium bromide, dexpanthenol, diisopropyl paraoxon, echothiophate chloride, eseridine, furtrethonium, methacho
• one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane).
• the Cahn-Inglod-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.
• a compound of the present invention When a compound of the present invention has two or more chiral carbons, it can have more than two optical isomers and can exist in diastereoisomeric forms. For example, when there are two chiral carbons, the compound can have up to 4 optical isomers and 2 pairs of enantiomers ((S,S)/(R,R) and (R,S)/(S,R)).
• the pairs of enantiomers e.g., (S,S)/(R,R)
• the stereoisomers which are not mirror-images e.g., (S 3 S) and (R 5 S) are diastereomers.
• the diastereoisomeric pairs may be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above.
• the present invention includes each diastereoisomer of such compounds and mixtures thereof. Screening
• ghrelin mimetic compounds can be identified, for example, by screening libraries or collections of molecules using suitable methods.
• Another source for the compounds of interest are combinatorial libraries which can comprise many structurally distinct molecular species.
• Combinatorial libraries can be used to identify lead compounds or to optimize a previously identified lead.
• Such libraries can be manufactured by well-known methods of combinatorial chemistry and screened by suitable methods.
• the present invention provides a method of stimulating the motility of the gastrointestinal system in a subject in need thereof, wherein the subject suffers from maladies (i.e., disorders, diseases, conditions, or drug- or surgery-induced dysfunction) of the gastrointestinal system.
• the method comprises administering to a subject in need thereof a therapeutically effective amount of a ghrelin mimetic compound or a pharmaceutically acceptable salt, hydrate or solvate thereof.
• the ghrelin mimetic is ipamorelin as represented by Formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
• gastrointestinal maladies refers to any disease, disorder, condition, or dysfunction resulting in impaired gastrointestinal function.
• the gastrointestinal malady can be opioid-induced gastrointestinal dysfunction, e.g., morphine- induced constipation, post-operative ileus, or gastroparesis. Constipation
• the invention provides a method of treating constipation by administering a therapeutically effective amount of a ghrelin mimetic, e.g., ipamorelin.
• Constipation is a condition in which a person has uncomfortable or infrequent bowel movements. A person with constipation produces hard stools that can be difficult to pass. The person also can feel as though the rectum has not been completely emptied. Acute constipation begins suddenly and noticeably. Chronic constipation, on the other hand, can begin insidiously and persist for months or years.
• the method of treating constipation of the invention can further comprise coadministering a ghrelin mimetic, e.g., ipamorelin, with a therapeutically effective amount of a laxative.
• a laxative include, but are not limited to, bulk forming laxatives, lubricant laxatives, stool softeners, or any combination thereof.
• the invention provides a method of treating opioid-induced constipation by administering a therapeutically effective amount of a ghrelin mimetic, e.g., ipamorelin.
• opioid analgesics to relieve chronic pain can cause effects on organs outside the targets in the central nervous system.
• opioid action can slow stomach emptying and inhibit bowel movement.
• the increased time of fecal contents in the intestines results in excessive absorption of water and sodium from fecal contents, resulting in harder, drier stools and constipation. This effect afflicts approximately 90% of individuals on analgesic pain killers.
• the resulting constipation can be a dose limiting side-effect.
• analgesics used for post-surgical pain management can cause opioid- induced constipation.
• Suitable opioids include, but are not limited to, morphine, codeine, oxycodone, hydromorphone, hydrocodone , methadone, fentanyl, and combinations with antiinflammatory agents such as acetaminophen or aspirin or any combination thereof.
• the method of treating opioid-induced constipation can further comprise coadministering a ghrelin mimetic compound, e.g., ipamorelin, with a therapeutically effective amount of a peripherally acting opioid antagonist, a laxative, or any combination thereof.
• a peripherally acting opioid antagonist include, but are not limited to, methylnaltrexone, naltrexone, nalmefene, naloxone and alvimopan or any combination thereof.
• Suitable laxatives include, but are not limited to bulk forming laxatives, lubricant laxatives, stool softeners, or any combination thereof. Post-operative ileus
• the present invention provides a method of treating post-operative ileus by administering a therapeutically effective amount of a ghrelin mimetic, e.g., ipamorelin.
• a ghrelin mimetic e.g., ipamorelin.
• GI gastrointestinal
• post-operative ileus a term denoting disruption of the normal coordinated movements of the gut, resulting in failure of the propulsion of intestinal contents. Ileus has also been defined as a functional, non-mechanical obstruction of the bowel.
• post-operative ileus refers to delay in normal gastric and colonic emptying.
• the method of treating post-operative ileus can further comprise co-administering a ghrelin mimetic, e.g., ipamorelin, with a therapeutically effective amount of a dopamine antagonist.
• a dopamine antagonist include, but are not limited to, metoclopramide, domperidone, amisulpride, clebopride, mosapramine, nemonapride, remoxipride, risperidone, sulpiride, sultopride and ziprasidone, or any combination thereof. Irritable bowel syndrome
• the present invention provides a method of treating irritable bowel syndrome by administering a therapeutically effective amount of a ghrelin mimetic, e.g., ipamorelin.
• Irritable bowel syndrome is a functional disorder effecting motility of the entire gastrointestinal tract that can produce abdominal pain, constipation, and/or diarrhea.
• the impaired movement of the digestive tract in IBS is not accompanied by a change in physical structure, such as inflammation or tumors.
• the symptoms of IBS are thought to be related to abnormal muscle contractions in any part of the intestines.
• IBS insulin-semiconductor styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene-styrene, bowel - predominant and alternating constipation-predominant/diarrhea-predominant IBS.
• the method of treating IBS may comprise co-administering a ghrelin mimetic compound, e.g., ipamorelin, with a therapeutically effective amount of H 2 receptor antagonist; a serotonin 5- HT agonist; a laxative; or any combination thereof.
• H 2 receptor antagonists include, but are not limited to, nizatidine, ranitidine, famotidine, and cimetidine, or any combination thereof.
• Suitable central nervous system receptor agonists include, but are not limited to, rauwolscine, yohimbine, metoclopramide, tegaserod, or any combination thereof.
• Suitable laxatives include, but are not limited to, bulk forming laxatives, lubricant laxatives, stool softeners, or any combination thereof. Gastroesophageal reflux disorder
• the invention further provides a method of treating gastroesophageal reflux disorder by administering a therapeutically effective amount of a ghrelin mimetic, e.g., ipamorelin.
• Gastroesophageal reflux disease is a condition in which gastric stomach contents (e.g., bile salts) back up into the food pipe (esophagus), causing chronic regurgitation of gastric contents from the stomach into the lower esophagus. Commonly known as heartburn, GERD causes esophageal irritation and inflammation.
• the esophageal sphincter (a ring-shaped muscle located at the lower end of the esophagus to prevent stomach contents from going backwards into the esophagus) can fail to carry out its protective duties. Instead of opening only when a person is eating or swallowing, it relaxes and allows digestive juices to reflux into the esophagus and irritate the esophageal lining.
• the method of treating GERD comprises co-administering a ghrelin mimetic compound, e.g., ipamorelin, with a therapeutically effective amount of H 2 receptor antagonist; an antacid; a proton pump inhibitor; or any combination thereof.
• a ghrelin mimetic compound e.g., ipamorelin
• Suitable H 2 receptor antagonist include, but are not limited to, nizatidine, ranitidine, famotidine, and cimetidine, or any combination thereof.
• Suitable antacids include, but are not limited to, aluminum and magnesium hydroxide and combinations thereof.
• Suitable proton pump inhibitors include, but are not limited to, esomeprazole (NEXIUM ® ), omeprazole, lansoprazole, pantoprazole, or a combination thereof.
• Gastroparesis The present invention provides a method of treating gastroparesis, e.g. diabetic or idiopathic, by administering a therapeutically effective amount of a ghrelin mimetic, e.g., ipamorelin.
• Gastroparesis also referred to as delayed gastric emptying, is a disorder in which the stomach takes too long to empty its contents. It often occurs in people with type 1 diabetes mellitus or type 2 diabetes mellitus. Gastroparesis can occur when nerves to the stomach are damaged or stop working. The vagus nerve controls the movement of food through the digestive tract. If the vagus nerve is damaged, the muscles of the stomach and intestines do not work normally, and the movement of food is slowed or stopped. Diabetes can damage the vagus nerve if blood glucose levels remain high over a long period of time. High blood glucose causes chemical changes in nerves and damages the blood vessels that carry oxygen and nutrients to the nerves.
• the method of treating gastroparesis can comprise co-administering a ghrelin mimetic compound, e.g., ipamorelin, with a therapeutically effective amount of dopamine antagonist.
• a ghrelin mimetic compound e.g., ipamorelin
• dopamine antagonists include, but are not limited to, metoclopramide, domperidone, amisulpride, clebopride, mosapramine, nemonapride, remoxipride, risperidone, sulpiride, sultopride and ziprasidone, or any combination thereof.
• the invention further relates to pharmaceutical compositions useful for stimulating (i.e., inducing) motility of the gastrointestinal system.
• the pharmaceutical composition comprises a ghrelin mimetic and optionally a pharmaceutically acceptable carrier.
• the pharmaceutical composition can comprise a second amount of a suitable therapeutic agent.
• a suitable therapeutic agent can be determined based on the condition being treated in the subject.
• the pharmaceutical composition can comprise a first amount of a ghrelin mimetic, e.g., ipamorelin, and a second amount of a laxative when treating constipation.
• the pharmaceutical composition of the present invention can optionally contain a pharmaceutically acceptable carrier.
• the ghrelin mimetic and laxative can each be present in the pharmaceutical composition in a therapeutically effective amount, hi another aspect, said first and second amount can together comprise a therapeutically effective amount.
• the pharmaceutical composition can comprise a first amount of a ghrelin mimetic and a second amount of a H 2 receptor antagonist.
• the pharmaceutical composition of the present invention can optionally contain a pharmaceutically acceptable carrier.
• the ghrelin mimetic and H 2 receptor antagonist can each be present in the pharmaceutical composition in a therapeutically effective amount.
• said first and second amount can together comprise a therapeutically effective amount.
• the pharmaceutical composition can comprise a first amount of a ghrelin mimetic and a second amount of a serotonin receptor agonist.
• the pharmaceutical composition can optionally contain a pharmaceutically acceptable carrier.
• the ghrelin mimetic and serotonin receptor agonist can each be present in the pharmaceutical composition in a therapeutically effective amount.
• the first and second amount can together comprise a therapeutically effective amount.
• the pharmaceutical composition can comprise a first amount of a ghrelin mimetic, e.g., ipamorelin, and a second amount of an antacid.
• the pharmaceutical composition can optionally contain a pharmaceutically acceptable carrier.
• the ghrelin mimetic and antacid can each be present in the pharmaceutical composition in a therapeutically effective amount, hi another aspect, said first and second amount can together comprise a therapeutically effective amount.
• the pharmaceutical composition can comprise a first amount of a ghrelin mimetic and a second amount of an opioid antagonist.
• the pharmaceutical composition can optionally contain a pharmaceutically acceptable carrier.
• the ghrelin mimetic and opioid antagonist can each be present in the pharmaceutical composition in a therapeutically effective amount.
• the first and second amount can together comprise a therapeutically effective amount.
• the pharmaceutical composition can comprise a first amount of a ghrelin mimetic and a second amount of a proton pump inhibitor.
• the pharmaceutical composition can optionally contain a pharmaceutically acceptable carrier.
• the ghrelin mimetic and proton pump inhibitor can each be present in the pharmaceutical composition in a therapeutically effective amount.
• the first and second amount can together comprise a therapeutically effective amount.
• the pharmaceutical composition can comprise a first amount of a ghrelin mimetic and a second amount of a motilin receptor agonist.
• the pharmaceutical composition can optionally contain a pharmaceutically acceptable carrier.
• the ghrelin mimetic and motilin receptor agonist can each be present in the pharmaceutical composition in a therapeutically effective amount.
• the first and second amount can together comprise a therapeutically effective amount.
• the pharmaceutical composition can comprise a first amount of a ghrelin mimetic and a second amount of a dopamine antagonist.
• the pharmaceutical can optionally contain a pharmaceutically acceptable carrier.
• the ghrelin mimetic and dopamine antagonist can each be present in the pharmaceutical composition in a therapeutically effective amount.
• the first and second amount can together comprise a therapeutically effective amount.
• the pharmaceutical composition can comprise a first amount of a ghrelin mimetic and a second amount of a cholinesterase inhibitor.
• the pharmaceutical composition can optionally contain a pharmaceutically acceptable carrier.
• the ghrelin mimetic and cholinesterase inhibitor can each be present in the pharmaceutical composition in a therapeutically effective amount.
• the first and second amount can together comprise a therapeutically effective amount.
• the pharmaceutical composition can comprise a first amount of a ghrelin mimetic and a second amount of somatostatin.
• the pharmaceutical composition can optionally contain a pharmaceutically acceptable carrier.
• the ghrelin mimetic and somatostatin can each be present in the pharmaceutical composition in a therapeutically effective amount.
• the first and second amount can together comprise a therapeutically effective amount.
• the invention further relates to use of a ghrelin mimetic compound for the manufacture of a medicament for stimulating (i.e., inducing) the motility of the gastrointestinal system.
• Subject refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, pigs, dogs, cats, rabbits, guinea pigs, rats, mice or other bovine, ovine, equine, canine, feline, rodent or murine species.
• the mammal is a human.
• treating and treatment refer to stimulating (e.g., inducing) motility of the gastrointestinal system.
• therapeutically effective amount refers to an amount sufficient to elicit the desired biological response.
• the desired biological response is stimulating (e.g., inducing) motility of the gastrointestinal system.
• the desired biological response is stimulating (e.g., inducing) motility of the gastrointestinal system to treat opioid induced constipation in a subject in need thereof.
• the subject may be using opioids for post-surgical pain management or for chronic pain management.
• the desired biological response is stimulating (e.g., inducing) motility of the gastrointestinal system to treat gastroparesis in a subject in need thereof.
• the desired biological response is stimulating (e.g., inducing) motility of the gastrointestinal system to treat gastroesophageal reflux disease in a subject in need thereof.
• the gastroesophageal reflux disease is nocturnal gastroesophageal reflux disease.
• the desired biological response is stimulating (e.g., inducing) motility of the gastrointestinal system to treat irritable bowel syndrome in a subject in need thereof.
• the irritable bowel syndrome is constipation-predominant irritable bowel syndrome.
• the irritable bowel syndrome is constipation/diarrhea irritable bowel syndrome.
• the desired biological response is stimulating (e.g., inducing) motility of the gastrointestinal system to treat constipation in a subject in need thereof.
• the desired biological response is stimulating (e.g., inducing) motility of the gastrointestinal system to treat post-operative ileus in a subject in need thereof.
• compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in a therapeutically effective amount to achieve its intended purpose. It will be appreciated that the unit content of active ingredient or ingredients contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount can be reached by administration of a plurality of dosage units (such as capsules or tablets or vials or combinations thereof). In addition, it is understood that at some dosage levels, an effective amount may not show any measurable effect until after a week, a month, three months, or six months of usage. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. The specific dose level for any particular user will depend upon a variety of factors including the age, the physical activity level, general health, and the severity of the gastrointestinal malady.
• a therapeutically effective dose also refers to that amount necessary to achieve the desired effect without unwanted or intolerable side effects.
• Toxicity and therapeutic efficacy of a ghrelin mimetic, e.g., ipamorelin, of the invention can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. Using standard methods, the dosage that shows effectiveness in about 50% of the test population, the ED 5O , may be determined. Similarly, the dosage that produces an undesirable side effect to 50% of the population, the SD 50 , can be determined.
• the dose ratio between side effect and therapeutic effects can be expressed as the therapeutic index and it can be expressed as a ratio between SD 5O /ED 5 o Ghrelin mimetics with high therapeutic indexes are preferred, e.g., ipamorelin, i.e., those which are effective at low dosage and which do not have undesirable side effects, if any, until very high doses.
• a preferred therapeutic index is greater than about 3, more preferably, the therapeutic index is greater than 10, most preferably the therapeutic index is greater than 25, such as, for example, greater than 50.
• ghrelin mimetics that do not have side effects at any dosage levels are more preferred.
• ghrelin mimetics that are effective at low dosages and do not have side effects at any dosage levels are most preferred.
• the exact formulation, route of administration and dosage can be chosen depending on the desired effect and can be made by those of skill in the art.
• the ghrelin mimetics are formulated as pharmaceutically acceptable salts.
• pharmaceutically acceptable salt refers to a salt of a compound to be administered prepared from pharmaceutically acceptable non-toxic acids including inorganic acids, organic acids, solvates, hydrates, or clathrates thereof. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, and phosphoric.
• Appropriate organic acids may be selected, for example, from aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, camphorsulfonic, citric, fumaric, gluconic, isethionic, lactic, malic, mucic, tartaric, para- toluenesulfonic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic (besylate), stearic, sulfanilic, alginic, galacturonic, and the like.
• the ghrelin mimetics of the invention can be prepared in the form of their hydrates, such as hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate and the like and as solvates.
• compositions which may be appropriate or suitable for administration.
• suitable pharmaceutical compositions typically comprise an active agent (e.g., a ghrelin mimetic of the invention) and a pharmaceutically acceptable carrier.
• pharmaceutically acceptable carrier is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
• the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated.
• Supplementary active compounds can also be incorporated into the pharmaceutical compositions of the invention. Modifications can be made to any of the pharmaceutical composition components to affect solubility or clearance of the factors of the invention. Peptidic molecules may also be synthesized with D-amino acids to increase resistance to enzymatic degradation. In some cases, the composition can be co-administered with one or more solubilizing agents, preservatives, and permeation enhancing agents.
• Administration of ghrelin mimetics are examples of ghrelin mimetics
• the therapeutically effective amount or dose will depend on the age, sex and weight of the patient, and the current medical condition of the patient. The skilled artisan will be able to determine appropriate dosages depending on these and other factors to achieve the desired - biological response.
• a suitable dose per day for a ghrelin mimetic of the invention can be in the range of from about 1 ng to about 10,000 mg, about 5 ng to about 9,500 mg, about 10 ng to about 9,000 mg, about 20 ng to about 8,500 mg, about 30 ng to about 7,500 mg, about 40 ng to about 7,000 mg, about 50 ng to about 6,500 mg, about 100 ng to about 6,000 mg, about 200 ng to about 5,500 mg, about 300 ng to about 5,000 mg, about 400 ng to about 4,500 mg, about 500 ng to about 4,000 mg, about 1 ⁇ g to about 3,500 mg, about 5 ⁇ g to about 3,000 mg, about 10 ⁇ g to about 2,600 mg, about 20 ⁇ g to about 2,575 mg, about 30 ⁇ g to about 2,550 mg, about 40 ⁇ g to about 2,500 mg, about 50 ⁇ g to about 2,475 mg, about 100 ⁇ g to about 2,450 mg, about 200 ⁇ g to about 2,425 mg, about 300 ⁇ g to about
• Suitable doses per day for a ghrelin mimetic of the invention include doses of about or greater than 1 ng, about 5 ng, about 10 ng, about 20 ng, about 30 ng, about 40 ng, about 50 ng, about 100 ng, about 200 ng, about 300 ng, about 400 ng, about 500 ng, about 1 ⁇ g, about 5 ⁇ g, about 10 ⁇ g, about 20 ⁇ g, about 30 ⁇ g, about 40 ⁇ g, about 50 ⁇ g, about 100 ⁇ g, about 200 ⁇ g, about 300 ⁇ g, about 400 ⁇ g, about 500 ⁇ g (0.5 mg), about 1 mg, about 1.25 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 625
• a suitable dose of the ghrelin mimetic can be in the range of from about 0.20 mg to about 4000 mg per day, such as from about 1 mg to about 4000 mg, for example, from about 5 mg to about 3000 mg, such as about 10 mg to about 2400 mg per day.
• the dose can be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage can be the same or different.
• a suitable dose for an additional therapeutic agent such as, for example, a laxative, can be in same range as described above for the ghrelin mimetic.
• the dose of ghrelin mimetic and additional agent can be the same or different. Suitable doses for the additional agents can be found in the literature.
• the compounds for use in the method of the invention can be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal), vaginal (e.g., trans- and peri vaginally), (intranasal and (trans)rectal), subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, inhalation, and topical administration.
• transdermal e.g., sublingual, lingual, (trans)buccal
• vaginal e.g., trans- and peri vaginally
• intranasal and (trans)rectal subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, inhalation, and topical administration.
• the compounds of the invention are formulated for intravenous delivery.
• the compounds of the invention are formulated for oral delivery.
• Suitable compositions and dosage forms include tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays, dry powders or aerosolized formulations.
• Suitable oral dosage forms include, for example, tablets, capsules or caplets prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrates (e.g., sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate).
• binding agents e.g., polyvinylpyrrolidone or hydroxypropylmethylcellulose
• fillers e.g., lactose, microcrystalline cellulose or calcium phosphate
• lubricants e.g., magnesium stearate, talc or silica
• disintegrates e.g., sodium starch glycolate
• wetting agents e.g., sodium lauryl sulphate
• Liquid preparation for oral administration can be in the form of solutions, syrups or suspensions.
• Liquid preparations e.g., solutions, suspensions and syrups
• can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbic acid).
• suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
• emulsifying agent e.g., lecithin or acacia
• non-aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol
• preservatives e.g.,
• a pharmaceutical composition comprising a ghrelin mimetic of the invention is used to treat a gastrointestinal malady (e.g., a disorder, disease, condition or injury of the gastrointestinal tract which impairs gastrointestinal kinetics) by stimulating gastrointestinal kinetics or motility.
• a gastrointestinal malady e.g., a disorder, disease, condition or injury of the gastrointestinal tract which impairs gastrointestinal kinetics
• the exact formulation, route of administration and dosage can be chosen depending on the desired effect and can be made by those of skill in the art.
• Dosage intervals can be determined by experimental testing.
• One or more ghrelin mimetics of the invention could be administered using a regimen which maintains gastrointestinal motility at about 10% above or below normal, about 20% above or below normal, above 50% above or below normal.
• Another suitable administration method is to provide a ghrelin mimetic of the invention through an implant or a cell line capable of expressing a ghrelin mimetic so that the implant or cell line can provide the ghrelin mimetic to a cell of the gastrointestinal system.
• a pharmaceutical composition of the invention can be formulated to be compatible with its intended route of administration.
• Oral administration refers to the administration of a pharmaceutical composition of the invention via the mouth through ingestion, or via any other part of the gastrointestinal system including the esophagus or through suppository administration.
• Parenteral administration refers to the delivery of a composition, such as a composition comprising a ghrelin mimetic by a route other than through the gastrointestinal tract (e.g., oral delivery).
• parenteral administration may be via intravenous, subcutaneous, intramuscular or intramedullary (i.e., intrathecal) injection.
• the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
• Topical administration refers to the application of a pharmaceutical agent to the external surface of the skin or the mucous membranes (including the surface membranes of the nose, lungs and mouth (in which case it may also be a form of oral administration, such that the agent crosses the external surface of the skin or mucous membrane and enters the underlying tissues.
• Topical administration of a pharmaceutical agent can result in a limited distribution of the agent to the skin and surrounding tissues or, when the agent is removed from the treatment area by the bloodstream, can result in systemic distribution of the agent.
• the ghrelin mimetic is delivered by transdermal delivery.
• Transdermal delivery refers to the diffusion of an agent across the barrier of the skin. Absorption through intact skin can be enhanced by placing the active agent in an oily vehicle before application to the skin (a process known as inunction) and the use of microneedles.
• Passive topical administration may consist of applying the active agent directly to the treatment site in combination with emollients or penetration enhancers.
• Another method of enhancing delivery through the skin is to increase the dosage of the pharmaceutical agent.
• the dosage for topical administration may be increased up to ten, a hundred or a thousand folds more than dosages administered by other routes.
• Penetrants for transdermal delivery are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
• the ghrelin mimetics of the invention can be delivered in the form of an aerosol spray from pressured container or dispenser that contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
• a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
• the ghrelin mimetics of the invention can be formulated into ointments, salves, gels, or creams as generally known in the art.
• the ghrelin mimetics of the invention may be delivered by nasal or pulmonary methods.
• the respiratory delivery of aerosolized medicaments is described in a number of references, beginning with Gansslen (1925) Klin. Weinschr. 4:71 and including Laube et al. (1993) JAMA 269:2106-21-9; Elliott et al. (1987) Aust. Paediatr. J. 23:293-297; Wigley et al. (1971) Diabetes 20:552-556. Corthorpe et al. (1992) Pharm Res 9:764-768; Govinda (1959) Indian J. Physiol. Pharmacol. 3:161-167; Hastings et al. (1992) J. Appl.
• compositions suitable for injectable use include, for example, sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
• physiologically acceptable, suitable carriers include, for example, physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
• Physiologically acceptable carriers maybe any carrier known in the field as suitable for pharmaceutical (i.e., topical, oral, and parenteral) application. Suitable pharmaceutical carriers and formulations are described, for example, in Remington's Pharmaceutical Sciences (19th ed.) (Genarro, ed. (1995) Mack Publishing Co., Easton, Pa.). Oral compositions generally include a physiologically acceptable, inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the ghrelin mimetics of the invention can be incorporated with physiological excipients and used in the form of tablets, troches, or capsules.
• a number of systems that alter the delivery of injectable drugs can be used to change the pharmacodynamic and pharmacokinetic properties of therapeutic agents (see, e.g., K. Reddy, 2000, Annals of Pharmacotherapy 34:915-923).
• Drug delivery can be modified through a change in formulation (e.g., continuous-release products, liposomes) or an addition to the drug molecule (e.g., pegylation).
• Potential advantages of these drug delivery mechanisms include an increased or prolonged duration of pharmacologic activity, a decrease in adverse effects, and increased patient compliance and quality of life.
• Injectable continuous-release systems deliver drugs in a controlled, predetermined fashion and are particularly appropriate when it is important to avoid large fluctuations in plasma drug concentrations.
• Encapsulating a drug within a liposome can produce a prolonged half-life and an increased distribution to tissues with increased capillary permeability (e.g., tumors).
• Pegylation provides a method for modification of therapeutic peptides or proteins to minimize possible limitations (e.g., stability, half-life, immunogenicity) associated with the ghrelin mimetics of the invention.
• one or more ghrelin mimetics can be formulated with lipids or lipid vehicles (e.g., micelles, liposomes, microspheres, protocells, protobionts, liposomes, coacervates, and the like) to allow formation of multimers.
• lipids or lipid vehicles e.g., micelles, liposomes, microspheres, protocells, protobionts, liposomes, coacervates, and the like
• ghrelin mimetics can be multimerized using pegylation, cross-linking, disulfide bond formation, formation of covalent cross-links, glycosylphosphatidylinositol (GPI) anchor formation, or other established methods.
• the multimerized ghrelin mimetics can be formulated into a pharmaceutical composition, and used to increase or enhance their effects.
• the ghrelin mimetics can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.
• suppositories e.g., with conventional suppository bases such as cocoa butter and other glycerides
• retention enemas for rectal delivery.
• ghrelin mimetics of the invention more specifically to local gastrointestinal tissues, such as, but not limited to, the stomach, esophagus, small intestine, or colon.
• the delivery method will depend on factors such as the tissue of interest, the nature of the compound to be delivered, and the duration of the treatment.
• the ghrelin mimetics of the invention are prepared with carriers that will protect the ghrelin mimetics against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
• carriers that will protect the ghrelin mimetics against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
• ipamorelin The gastrokinetic efficacy of ipamorelin was evaluated in a rat model of post-operative ileus.
• ipamorelin was administered either orally (10 mg/kg and 100 mg/kg) or via a single intravenous injection was administered to male rats following abdominal surgery over a dose range of 0.01 mg/kg to 1.0 mg/kg.
• the effect of ipamorelin on gastric emptying relative to control animals was determined by administration of a dose of phenol red via oral gavage followed immediately with the dose of ipamorelin.
• EXAMPLE 1 Gastrokinetic efficacy of ipamorelin (10 or 100 mg/kg) in a rat model of postoperative ileus
• This study evaluated the potential gastrokinetic efficacy of ipamorelin following a single oral administration in a rat model of post-operative ileus at a dose of 10 or 100 mg/kg.
• mice Nine days were allowed between receipt of the animals and the start of treatment to accustom the animals to the laboratory environment. At the start of treatment, animals were approximately 7 weeks of age and were in the weight range of 230 g to 254 g.
• the ipamorelin obtained and used in this study was obtained from Bachem AG (Bubendorf, Switzerland).
• the vehicle used was 0.9% sodium chloride for injection (Baxter).
• the gastrointestinal marker used to evaluate level stomach emptying was phenol red (Sigma Aldrich).
• test article Appropriate amounts of test article were dissolved in 0.9% Sodium Chloride for Injection USP.
• the test article formulations were adjusted between pH 7.4 to 7.5 with 0.1N/1N hydrochloric acid or 0.1 N sodium hydroxide, as required. All dosing formulations were kept at room temperature, protected from light. The phenol red was prepared on the day of dosing as a 5 mg/mL solution in deionized water and was stored at room temperature, protected from light. Catheterization surgery
• Each animal received an antibiotic injection of Benzathine penicillin G and Procaine penicillin G (0.1 mL) intramuscularly on the day of surgery and again 2 days following surgery.
• the animals were anesthetized with isoflurane gas prior to surgery preparation, which included shaving of the femoral and dorsal exteriorization sites.
• the shaved areas were washed with Chlorhexidine gluconate 4% followed by a liberal application of Povidone iodine 10%.
• a bland lubricating ophthalmic agent (Tears Naturale PM) was administered to each eye. Animals were maintained under isoflurane gas anesthesia throughout the surgical procedure.
• a small phlebotomy was made in the vein and a medical grade silicone-based catheter was inserted and the tip of the catheter was placed in the vena cava at approximately the level of the kidneys.
• the catheter was secured in place with an appropriate suture material and then brought subcutaneously to the exteriorization point at the nape of the neck.
• the femoral site was irrigated with warm (approximately 37°C) 0.9% Sodium Chloride Injection, USP.
• the femoral site was closed with interrupted mattress sutures and the exteriorization site with a purse stitch, which was removed in 5-10 days or depending upon healing results.
• a topical antibiotic (Polymyxin B, Bacitracin, Neomycin) was administered to the catheter exteriorization site, daily until termination, and the femoral site until considered unnecessary.
• a jacket was placed on the animal to hold the tether system.
• the catheter prefilled with 0.9% Sodium Chloride Injection, U. S. P., was fed through the tether system and attached to a swivel secured to the outside of the cage.
• the upper portion of the swivel was connected to the infusion pump and all animals were continuously infused with 0.9% Sodium Chloride Injection, U.S.P. at a rate of 0.4 r ⁇ L/h until initiation of treatment.
• Dosing commenced on consecutive days with approximately equal numbers of animals from each group being dosed on each day. Prior to dosing, the animals were water deprived. The test/control articles were administered by oral gavage using a syringe and flexible gavage tube. The animals were dosed immediately following the oral gavage dose of phenol red. The dose volume was 5 ml/kg (for both ipamorelin and phenol red administration) and the actual dose administered was based on the most recent body weight of each animal.
• EXAMPLE 2 Gastrokinetic efficacy of intravenous-administered ipamorelin (0.1, 0.25 or 1.0 mg/kg) in a rat model of post-operative ileus
• ipamorelin was administered as a slow bolus intravenous injection via an indwelling catheter (over a period of ca. 100 seconds).
• mice Male Sprague-Dawley CD® (CrI: CD® (SD)) rats ⁇ Rattus norvegicus) were received from Charles River Canada Inc. St. Constant, Quebec, Canada. Eight days were allowed between receipt of the animals and the surgical implantation of the catheters to allow the animals to become acclimated to the physical and environmental conditions. Dosing of the animals was initiated approximately one week following surgical implantation of the catheters to allow appropriate recovery of the animals prior to treatment. At the start of treatment, animals were approximately between 10 to 12 weeks of age and were in the weight range of 327 g to 397 g.
• the ipamorelin obtained and used in this study was obtained from Bachem AG.
• the vehicle used was 0.9% sodium chloride for injection (Baxter).
• the gastrointestinal marker used to evaluate level stomach emptying was phenol red (Sigma Aldrich). Catheterization surgery
• Each animal received an antibiotic injection of Benzathine penicillin G and Procaine penicillin G (0.1 mL) intramuscularly on the day of surgery and again 2 days following surgery.
• the animals were anesthetized with isoflurane gas prior to surgery preparation, which included shaving of the femoral and dorsal exteriorization sites.
• the shaved areas were washed with Chlorhexidine gluconate 4% followed by a liberal application of Povidone iodine 10%.
• a bland lubricating ophthalmic agent (Tears Naturale PM) was administered to each eye. Animals were maintained under isoflurane gas anesthesia throughout the surgical procedure.
• a small phlebotomy was made in the vein and a medical grade silicone-based catheter was inserted and the tip of the catheter was placed in the vena cava at approximately the level of the kidneys.
• the catheter was secured in place with an appropriate suture material and then brought subcutaneously to the exteriorization point at the nape of the neck.
• the femoral site was irrigated with warm (approximately 37°C) 0.9% Sodium Chloride Injection, USP.
• the femoral site was closed with interrupted mattress sutures and the exteriorization site with a purse stitch, which was removed in 5-10 days or depending upon healing results.
• a topical antibiotic (Polymyxin B, Bacitracin, Neomycin) was administered to the catheter exteriorization site, daily until termination, and the femoral site until considered unnecessary.
• a jacket was placed on the animal to hold the tether system.
• the catheter prefilled with 0.9% Sodium Chloride Injection, U.S.P., was fed through the tether system and attached to a swivel secured to the outside of the cage. The upper portion of the swivel was connected to the infusion pump and all animals were continuously infused with 0.9% Sodium Chloride Injection, U. S. P. at a rate of 0.4 mL/h until initiation of treatment.
• Dosing commenced on consecutive days with approximately equal numbers of animals from each group being dosed on each day.
• the test/control articles were administered as a slow bolus intravenous injection via an indwelling catheter (over a period of ca. 100 seconds).
• the animals were dosed immediately following the oral gavage dose of phenol red.
• the dose volume was 5 mL/kg (for both ipamorelin and phenol red administration) and the actual dose administered was based on the most recent body weight of each animal.
• the animals Prior to dosing of the phenol red, the animals were water deprived. At approximately 30 minutes post-surgery (ileus), animals received 0.4 mL of phenol red by oral gavage. Animals were then dosed and approximately 30 minutes later, were euthanized. Upon euthanasia, the stomach was exposed by laparotomy, quickly ligated at the pylorus and the cardia removed. The stomach was cut open and its contents extracted with 100 mL of 0.1N NaOH. The phenol red content of this extract was assayed colorimetrically at 558 nm in a spectrophotometer. Following collection, samples were stored on wet ice pending transfer for analysis.
• Animals treated with an intravenous dose (0.1, 0.25 or 1.0 mg/kg) of ipamorelin displayed a reduction in stomach phenol red content relative to the vehicle control group (85.7%, 95.6% and 92.2%, respectively). These reductions reached statistical significance at the 0.25 and 1.0 mg/kg dose levels (p ⁇ 0.001 and p ⁇ 0.01 , respectively). See FIG. 2.
• the average stomach phenol red content of the vehicle control group was similar and not statistically different from that of the sham control group and may reflect (unexpected) ileus in the sham control group or an inability to induce detectable ileus in the surgery control group. Consequently, when expressed relative to the sham control group, animals treated with intravenous doses (0.1, 0.25 or 1.0 mg/kg) of ipamorelin displayed reductions in stomach phenol red content (87.1%, 96.0% and 93.1%, respectively) that were statistically significant at all dose levels. See FIG. 2.
• EXAMPLE 3 Gastrokinetic efficacy of intravenous-administered ipamorelin (0.01, 0.03 or 0.1 mg/kg) in a rat model of post-operative ileus
• ipamorelin was administered as a slow bolus intravenous injection via an indwelling catheter (over a period of ca. 100 seconds) at a dose of 0.01 , 0.03 or 0.1 mg/kg.
• a small phlebotomy was made in the vein and a medical grade silicone-based catheter was inserted and the tip of the catheter was placed in the vena cava at approximately the level of the kidneys.
• the catheter was secured in place with an appropriate suture material and then brought subcutaneously to the exteriorization point at the nape of the neck.
• the femoral site was irrigated with warm (approximately 37 0 C) 0.9% Sodium Chloride Injection, USP.
• the femoral site was closed with interrupted mattress sutures and the exteriorization site with a purse stitch, which was removed in 5-10 days or depending upon healing results.
• a topical antibiotic (Polymyxin B, Bacitracin, Neomycin) was administered to the catheter exteriorization site, daily until termination, and the femoral site until considered unnecessary.
• a jacket was placed on the animal to hold the tether system.
• the catheter prefilled with 0.9% Sodium Chloride Injection, U.S.P., was fed through the tether system and attached to a swivel secured to the outside of the cage. The upper portion of the swivel was connected to the infusion pump and all animals were continuously infused with 0.9% Sodium Chloride Injection, U.S.P. at a rate of 0.4 mL/h until initiation of treatment.
• Dosing commenced on consecutive days with approximately equal numbers of animals from each group being dosed on each day.
• the test/control articles were administered as a slow bolus intravenous injection via an indwelling catheter.
• the animals were dosed immediately following the oral gavage dose of phenol red.
• the dose volume was 5 ml/kg for Groups 1, 2 and 5; 0.5 ml/kg for Group 3 and 1.5 ml/kg for Group 4.
• the actual dose administered was based on the most recent body weight of each animal. Gastrointestinal assessment
• the average stomach phenol red content of the vehicle control group was similar and not statistically different from that of the non-operated control group and may reflect an inability to induce detectable ileus in the surgery control group. Consequently, when expressed relative to the non-operated control group, animals treated with intravenous doses (0.01, 0.03 or 0.1 mg/kg) of ipamorelin displayed reductions in stomach phenol red content that were statistically significant at all dose levels.
• Morphine was administered at a dose volume of 0.1 mL/kg for groups 2-3 ** Morphine was administered at a dose volume of 0.4 mL/kg for groups 4-5
• the dose formulations were prepared on the day of dosing.
• the appropriate control was dissolved in the vehicle to achieve the desired concentration.
• the morphine sulfate solution was used as supplied.
• the phenol red was prepared on the day of dosing as a 5 mg/mL solution and stored at room temperature, protected from light pending use.
• Morphine (4 mg/kg or 1 mg/kg) was administered once to the upper dorsum (scapular region) by subcutaneous injection using a hypodermic needle attached to a syringe. Morphine was administered approximately 30 minutes prior to the administration of the control/positive control articles.
• the dose volume was 0.1 mL/kg for Groups 2 and 3 and 0.4 mL/kg for Groups 4 and 5.
• the actual dose administered was based on the most recent practical body weight of each animal. Gastrointestinal assessment
• morphine significantly reduced the stomach emptying by approximately 42% when compared to the control animals, without however attaining statistical significance.
• Ghrelin a potent prokinetic peptide known to reverse gastric ileus, administered intravenously at a dose of 50 ⁇ g/kg following exposure with 1 mg/kg of morphine, accelerated stomach emptying by approximately 37% when compared to the animals treated with 1 mg/kg and saline, and reversed the ileus induced by approximately 11%.
• ghrelin did not accelerate gastric emptying in the rats administered 4 mg/kg of morphine and both groups (saline vs ghrelin) displayed the same group mean absorbance of phenol red (2.99 and 3.01, respectively). See FIG. 4.
• Morphine administered subcutaneously to male albino rats at doses of 1 or 4 mg/kg induced similar level of gastric ileus, in a non dose-dependent manner. Ghrelin accelerated stomach emptying and reversed the gastric ileus induced following exposure with 1 mg/kg of morphine but had no effects on the stomach emptying of the rats administered doses of 4 mg/kg of morphine.
• EXAMPLE 5 Gastrokinetic efficacy of intravenous injection of ipamorelin (1.0, 2.5, 10 mg/kg) as compared to RC-1139 to treat post-operative ileus in a rat model
• Ipamorelin was evaluated in a rat model of post-operative ileus in comparison to RC- 1139, a ghrelin mimetic with known gastrokinetic efficacy.
• each drug was administered as a single intravenous injection as shown in the table below.
• Treatment groups were as follows.
• mice Male Sprague-Dawley CD® (CrI: CD®(SD)) rats (Rattus norvegicus) were randomized to treatment groups At least 5 days was allowed between receipt of the animals and the start of treatment to accustom the animals to the laboratory environment. At the start of treatment, animals were approximately 7 weeks of age and were in the weight range of 205 g to 272 g. Prior to the first dose formulation preparation, a trial preparation was conducted at 2 mg/mL (test article solution) and at 2 mg/mL (reference article solution) to confirm the suitability of the proposed formulation method.
• formulations were prepared by dissolving the appropriate quantity of test or reference article in 0.9% Sodium Chloride for Injection USP. The dosing formulations were then pH adjusted from 7.4 to 7.5 with 0.1N/1N hydrochloric acid or 0.1N sodium hydroxide, as required. All dosing formulations were filtered via 0.2 ⁇ m PVDF filters prior to use and were kept at room temperature, protected from light.
• the phenol red was prepared on the day of dosing as a 5 mg/mL solution in deionized water and was stored at room temperature, protected from light.
• test/control articles and reference article were administered by intravenous injection (given as a slow bolus injection over a period of ca. 100 seconds) into the tail vein using a syringe and appropriate gauge needle.
• the dose volume was 5 mL/kg and the actual dose administered was based on the most recent body weight of each animal.
• EXAMPLE 6 Administration of ipamorelin in healthy volunteers to reverse a morphine- induced slowing of gastric emptying
• Delay in gastric emptying plays an etiologic role in several important target indications including post-operative ileus, opiate-induced bowel dysfunction, and gastroparesis.
• delays in gastric emptying may promote or exacerbate nausea. Consequently, an agent such as ipamorelin, with demonstrated ability to promote gastric emptying in animal models (see above Examples), may serve an important therapeutic role in a variety of GI disorders categorized by reduced motility.
• Ipamorelin is a ghrelin mimetic.
• Ghrelin a 28-amino acid peptide hormone
• Ghrelin a 28-amino acid peptide hormone
• GI prokinetic effect
• ghrelin has been shown to resolve gastric postoperative ileus. See Trudel 2002.
• ghrelin The prokinetic activity of ghrelin is likely mediated either by direct effect on the gut or indirectly by the vagal-cholinergic-muscarinic pathway. It acts locally in the stomach to stimulate the firing of vagal afferent neurons and stimulate gastric motility. See Peeters 2003. Efforts have been underway for many years to exploit the positive effects of ghrelin in a variety of disorders via the identification and development of pharmaceutical agents that mimic ghrelin. Ghrelin has an exceptionally short half-life (approximately 10 minutes) in humans and consequently has a limited therapeutic potential. Ipamorelin is a ghrelin mimetic with a half-life of approximately six hours in humans, available as an intravenous treatment and thus, is suitable for therapeutic use.
• the present study was designed to employ a well-validated, clinical pharmacology model (acetaminophen AUC) for assessment of the effect of ipamorelin on gastric emptying.
• Ipamorelin was demonstrated in the examples described above to have potent, stimulating effects on gastric emptying in a rat model. This study was intended to extend these findings into humans.
• Ipamorelin selected for this study (0.06 mg/kg IV infused over 15 minutes), was a dose that has been demonstrated to be safe and well-tolerated in prior Phase 1 studies.
• Ipamorelin was formulated as a 0.5 mg/mL sterile solution with 2 equivalents of acetic acid in normal saline. The sterile solution was further diluted with normal saline to an appropriate volume for administration prior to use.
• the dose of morphine selected for this study was a dose that is both clinically relevant as an analgesic dose and has been demonstrated previously to significantly delay gastric emptying in normal volunteers [Yuan 1998].
• acetaminophen dose selected for this study is a standard Over-the-Counter dose of acetaminophen. This dose has been employed successfully in prior gastric emptying studies and produces plasma concentrations which are readily measured (>0.2 ⁇ g/mL).
• the study design was a standard, three-period, randomized, single-dose crossover study.
• the study was conducted as a single-center, double-blind, randomized, single-dose, three-way crossover investigation. The study compared the following treatments:
• the primary parameter of interest is the early absorption of acetaminophen as reflected in the plasma AUC over the first hour following acetaminophen administration (AUCo -60 ). Parameters of additional interest include AUCo-isc CMAX, and TMAX-
• the study drug was administered via a well-calibrated infusion pump (e.g., Harvard pump or similar) over a 15 minute period. Each subject's dose was calculated based on body weight to a maximum of 100 kg (6 mg). The dosing volume was then diluted to a total volume of 15 mL using normal saline for injection as the diluent. The syringe was drawn up with an air bubble (to facilitate agitation) and the syringe was mixed by gently inverting six times. Morphine administration
• Morphine (1.0 mg/mL)/placebo was administered by slow bolus (over 30-60 seconds). The infusion catheter was then flushed immediately with 3-5 mL normal saline. Acetaminophen administration
• Example 6a This study was the same design as that of Example 6a but evaluated lower doses of IV ipamorelin to reverse opiate-induced delay in gastric emptying. Data are presented for the twenty three subjects who completed all treatments. The study treatments were: (1) untreated (saline) control; (2) morphine 0.05 mg/kg IV; and (3) morphine 0.05 mg/kg + ipamorelin 0.01 mg/kg IV and (4) morphine 0.05 mg/kg + ipamorelin 0.03 mg/kg IV. Acetaminophen elixir was administered orally in each treatment cycle to permit assessment of gastric emptying. The treatments were administered in a single-blind, placebo-controlled, 3 -way crossover study with a washout of 5-8 days between treatments.
• EXAMPLE 8 Comparison of the effects of various ghrelin mimetics, including ipamorelin, on gastrointestinal motility in rats
• the objective of this study was to evaluate the pharmacological effects of a series of ghrelin mimetics on gastrointestinal motility in rats, as measured by charcoal transit, relative to a commonly used prokinetic agent, metoclopramide, and control, following a single intravenous infusion of the experimental agent.
• Each dosing formulation was prepared on the day of dosing.
• the reference article formulations were also prepared on the day of dosing by mixing the appropriate amount of reference article with the appropriate volume of vehicle to achieve the desired final concentration.
• the saline and metoclopramide (1 mg/mL) were used as supplied. Dosing was performed on consecutive days with approximately equal numbers of animals being dosed on each day. The animals were deprived of food overnight prior to treatment. Each formulation was administered by intravenous injection into the tail vein using a syringe and appropriate gauge needle. The dose volume was 5 mL/kg or 10 mL/kg (in the case of metoclopramide only).
• Ipamorelin significantly increased stomach emptying relative to the control group, reducing the amount of charcoal remaining in the stomach by 66%.
• Ghrelin and GHRP-6 also significantly reduced the amount of charcoal remaining in the stomach, by 57% and 64%, respectively, relative to the control group, but their effects did not differ significantly from that of ipamorelin.
• Ipamorelin clearly produced a highly significant (P ⁇ 0.001) increase in stomach emptying and a tendency towards an increase in intestinal motility compared to saline-treated control group animals, supporting the view that ipamorelin is a potent gastroprokinetic agent.
• the results of these experiments are set forth in Figures 7 and 8.
• EXAMPLE 9 Comparison of the effects of various ghrelin mimetics, including ipamorelin, on gastrointestinal motility in rats
• the objective of this study was to evaluate the pharmacological effects of a series of ghrelin mimetics on gastrointestinal motility in rats, as measured by charcoal transit, relative to control, following a single intravenous infusion of the experimental agent.
• Treatment groups were as follows:
• Dosing commenced on consecutive days with approximately equal numbers of animals from each group being dosed on each day.
• the animals were food deprived overnight prior to treatment. Prior to dosing, the animals were water deprived.
• the test/reference/positive control articles were administered by intravenous injection into the tail vein using a syringe and appropriate gauge needle.
• the dose volume was 5 mL/kg and the actual dose administered was based on the most recent practical body weight of each animal.
• the rats were euthanized and the abdominal cavity was opened and the stomach and intestines were removed.
• the presence or absence of charcoal in the stomach was documented.
• the stomachs were weighed (with and without contents) and this was recorded to give an indication of gastric emptying.
• the intestines were opened and extended to their full length.
• the charcoal was located and the distances from the pyloric sphincter to the most proximal and distal traces of charcoal were measured and recorded, as well as the total distance from the pyloric sphincter to the cecum (all distances were measured in mm).
• ghrelin and the three ghrelin mimetics tested in this study displayed disparate effects on gastric emptying and intestinal transit in the male albino rat when administered independently. Only ipamorelin displayed similar prokinetic effects to ghrelin on gastric emptying and both measurements of intestinal transit (proximal and distal distances traveled by the charcoal from the pyloric sphincter).
• Ghrelin, GHRP-6, and ipamorelin resulted in gastric emptying by one of the two measures (proximal distance traveled by the charcoal from the pyloric sphincter) of intestinal transit. See Figures 9, 10 and 11.
• EXAMPLE 10 Efficacy of ipamorelin for the treatment of postoperative ileus in rats
• Rats Male male Sprague-Dawley rats with indwelling catheters implanted in the right jugular vein were obtained from Charles River (Wilmington, MA). The initial body weight of the animals was 250-270 g. The catheters were maintained patent during the acclimation and were used for the dosing of ipamorelin or vehicle. An additional group of control rats, not subjected to surgery and drug or vehicle treatment, were purchased with an indwelling catheter implanted into the proximal colon (1-2 cm from the cecum) used for infusion of a dye marker measuring colonic transit. All rats were single-housed under controlled conditions (25 0 C, 12 h light/dark cycle) with free access to food and water.
• POI post-operative ileus
• Cumulative fecal output, food intake and body weight Fecal pellets were counted and weighed at 3-h intervals and 12-h intervals during the first 48 post-surgery (see experimental design). The cumulative fecal output was evaluated by adding the number of pellets throughout a 48-h postsurgical period. Food intake was recorded at 3-h interval or 12-h intervals according to the experimental design and was normalized as g/lOOg body weight. The cumulative food intake was calculated for 48 h post-surgery in both series of experiments. Body weight was measured daily at 8:00-9:00 AM before fasting the animals, on the day of experiment before the surgery and at 24 h and 48 h post-surgery. Changes in body weight are expressed as body weight gain compared to the weight of the fasted animal taken before the surgery.
• Test and control articles The test compound ipamorelin (free base) was converted to the diacetate salt by mixing with 2 molar equivalents of glacial acetic acid. Stock solutions of 0.5 mg/ml were prepared daily in sterile saline plus glacial acetic acid (0.1 ⁇ l per ml) to bring ipamorelin into solution (pH 3-4). Then the solution was titrated with NaOH to pH 7.0-7.2. Additional dilutions were made in saline. Sterile saline was used in the vehicle control experiments. The positive control [D-Lys 3 ]-GHRP-6 was purchased from Sigma- Aldrich (St. Louis, MO) and dissolved in sterile saline. Both the test and control articles were administered as a bolus i.v. infusion via the jugular catheter at a volume of 0.2 ml /10Og body weight.
• Experimental Series 1 Determine the acute effects induced by a single dose of ipamorelin in a rat model of POI.
• Naive rats were fasted but not subjected to surgery. Body weight, colonic transit, fecal pellet output and food intake were measured at the same time points as in rats with POI. Note that the naive animals remained in their home cage and were not handled in contrast to the rats with POI, which were handled multiple times during the dosing of ipamorelin or vehicle.
• POI in the rat Effect of abdominal surgery on colonic transit time, fecal pellet output, food intake and body weight.
• Experimental series 1 Determine the acute effects induced by a single dose treatment with ipamorelin in a rat model of POI.
• Experimental series 1 demonstrate that a single-dose treatment with 1 mg/kg ipamorelin given at the end of surgery decreased the time to the first bowel movement, but did not induce effects on fecal output and food intake during the 48-h course of recovery in rats with POI. However, these results are consistent with those expected based on the reported half-life of ipamorelin in the rat of 30-60 minutes. (Johansen et. al., 1998).
• Experimental series 2 Determine the efficacy of multiple doses of ipamorelin in a rat model of POI.
• the dose-response effect of multiple doses of ipamorelin (0.01, 0.1 or 1 mg/kg i.v.) was investigated in rats with POI.
• the results showed that the multiple dosing of 0.1 mg/kg or 1 mg/kg ipamorelin caused a significant acceleration of colonic transit compared to the effect of the vehicle (Fig. 17).
• Fig. 18 The effects of multiple doses of ipamorelin on fecal pellet output are presented in Fig. 18. Multiple doses of ipamorelin induced an increase in cumulative fecal pellet output compared to the vehicle. The effect reached significance at doses of 0.1 mg/kg or 1 mg/kg (Fig. 18). Fecal output increased at a higher rate (lower 1 /slope values) in the rats receiving ipamorelin at doses of 0.1 or lmg/kg i.v. compared to rats treated with vehicle. At a dose of 0.01 mg/kg, ipamorelin showed no significant effect. In addition, ipamorelin induced an increase food intake (Figs. 19).
• Ghrelin is an appetitestimulatory signal from stomach with structural resemblance to motilin. Gastroenterology, 2001 Feb;120(2):337-45.
• Trudel L Tomasetto C, Rio MC, Bouin M, Plourde V, Eberling P, et al.
• Ghrelin/motilinrelated peptide is a potent prokinetic to reverse gastric postoperative ileus in rat.

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