US20030206873A1

US20030206873A1 - 1,2,3,6-tetrahydropyrimidine-2-one compositions and therapeutic methods therewith for gastrointestinal dysfunction

Info

Publication number: US20030206873A1
Application number: US10/233,126
Authority: US
Inventors: Edward Wei
Original assignee: CRAGMONT PHARMACEUTICALS LLC
Current assignee: CRAGMONT PHARMACEUTICALS LLC
Priority date: 2002-05-02
Filing date: 2002-08-29
Publication date: 2003-11-06
Also published as: ZA200408895B; DE60330333D1; US20030206866A1; US20030207904A1; ATE450260T1; US6933301B2; US6743801B2; US20030207851A1; US6919348B2; US20030207903A1

Abstract

A therapeutic composition is provided that comprises a 1-R1-phenyl, 4-R2-phenyl substituted 1,2,3,6-tetrahydropyrimidine-2-one sensory nerve receptor agonist in a therapeutically effective amount. The sensory nerve receptor agonist may be represented by the general formula 1-[R1-phenyl]-4-[R2-phenyl]-1,2,3,6-tetrahydropyrimidine-2-one wherein: R1 may be -hydroxy, -chloro, -fluoro, -alkyl, -acetoxy, -trifluoromethyl ; and R2 is -nitro, -chloro, -fluoro, -alkyl, -trifluoromethyl. Therapeutic compositions of the invention reduce pain, a sense of abdominal distension, tenesmus, and abnormal bowel function when formulated for oral delivery to human gastrointestinal tract and are useful to alleviate gastrointestinal dysfunction.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of Ser. No. 10/139193, filed May 2, 2002, inventor Wei, entitled “Therapeutic 1,2,3,6-Tetrahydropyrimidine-2-One Compositions and Methods Therewith”, incorporated by reference.[0001]

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not applicable.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention generally relates to a class of chemicals that activate receptors on sensory nerve endings of the human gastrointestinal tract and therapeutic use of these chemicals for gastrointestinal dysfunction. This invention more particularly relates to therapeutic compositions preferably formulated for oral intake and delivery to the luminal surfaces of the human esophagus, ileum, colon and rectum. The particularly preferred embodiment compositions are formulated as chewing gum, tablet or enteric-coated pill or capsule, and comprise “icilin”, a 1,2,3,6-tetrahydropyrimidine-2-one compound.

2. Description of Related Art

Background on icilin. 1,2,3,6-Tetrahydropyrimidine-2-one compounds were described in U.S. Pat. No. 3,821,221(inventors C. Podesva and J. M. Do Nascimento et al, Jun. 28, 1974). These compounds were thought to have depressant and/or stimulant effects on the central nervous system. In 1972, an abstract described a compound in this series called AG-3-5 (1[2-hydroxyphenyl]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyrimidine-2-one). This prototype elicited a syndrome of “wet dog shake behavior” in rats and monkeys accompanied by hyperthermia, hyperactivity and ptosis. Wei (Chemical stimulants of shaking behavior. Journal of Pharmacy and Pharmacology 28: 722-724, 1976) provided the first detailed report of the actions of AG-3-5 in animals and noted that shaking behavior similar to those of a dog when wet could be evoked in various laboratory animals such as the rat, mouse, cat, dog, gerbils, guinea pigs and hamsters.

Subsequently, Wei (Pharmacological aspects of shaking behavior produced by AG-3-5, TRH, and morphine withdrawal. Federation Proceedings 40: 1491-1496, 1981) reported that 0.1 mg of AG-3-5, dissolved in propylene glycol, applied to the dorsum of the tongue elicited prickling sensations of cold and ingestion of 6 mg mixed in orange juice, on one occasion out of three, produced sensations of coolness on the cheeks and on the inner surfaces of the arms and legs. It was hypothesized that AG-3-5 may produce specific activation of receptors for cold, and that stimulation of these receptors accounted for the shaking seen in laboratory animals. In a subsequent publication (E. T. Wei and D. A. Seid. AG-3-5: A chemical producing sensations of cold. Journal of Pharmacy and Pharmacology 35: 110-112, 1983) the effects of AG-3-5 on shaking behavior in the rat were compared to those of menthol and AG-3-5 was shown to be 400 times more potent than menthol on a molar basis on this behavioral endpoint. AG-3-5 was less toxic than menthol, as measured by the oral median lethal dose in rats. AG-3-5 was named icilin because of its cold-producing properties.

Recently, two independent groups simultaneously cloned a biological macromolecule (called a receptor) from trigeminal sensory neurons of the rat. These receptors belong to the transient receptor potential (TRP) family of ion channels and responded to cold temperature and to menthol. Using a sample provided by Wei, McKemy et al. (Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416: 52-58, 2002) showed that icilin was about 200 times more potent than menthol in eliciting ion channel current changes in the cloned and transfected TRP(M8) receptor. The ion permeability changes elicited in transfected cells were more robust with icilin than those elicited by menthol, and the presence of extracellular calcium was required for activity. Menthol currents did not require extracellular calcium.

The chemical structure of icilin bears little similarity to that of menthol; the former chemical being a pyrimidine-2-one attached to two phenyl rings, and the latter a cyclohexanol derivative. Activation of the TRP(M8) receptor on the neuronal membrane may lead to depolarization of the sensory nerve ending and send action potentials towards the spinal cord and brain that are eventually recognized as psychic signals of skin stimulation.

Background on Gastrointestinal Dysfunction. The walls of the digestive tract are organized into four main layers: mucosa, submucosa, muscularis externa, and serosa. The mucosa consists of an epithelium with basement membrane (called the lamina propria), loose connective tissue, blood vessels, and lymph tissues. The submucosa contains loose connective tissue, glands, nerves, and blood vessels. The nerve fibers of the submucosa form a network or plexus called the plexus of Meissner. The muscularis externa consists of two bands of smooth muscle cells, the internal layer is composed of circular smooth muscle and the external layer is composed of longitudinal fibers. Interspersed between the muscle fibers is a nerve plexus called the plexus of Auerbach. The outermost layer of the digestive tube, the serosa, is composed of a membrane of squamous epithelium.

The gut has a simplified “brain”. The complex nerve network in the myenteric and submucosal plexuses has about 100 million neurons (the enteric nervous system). The efferents in the submucosal Meissner plexus regulate secretion by intestinal glands. The efferents in the myenteric Auerbach plexus control the rhythmic contraction of circular and longitudinal muscles that is called peristalsis. Visceral sensory afferent nerve endings are located throughout the submucosa and the Meissner plexus. The cell bodies of the afferents are located either in autonomic ganglia or in dorsal root ganglia. Much of the sensory information from the gut is conveyed via cranial nerves of the parasympathetic nervous system, principally the vagus. Visceral sensations of pain are, however, also transmitted via sympathetic afferent nerves into the spinal cord.

When the gut does not work properly, key elements of dysfunction are usually the mucosa and the intrinsic nervous system. The mucosal lining consists of a single layer of epithelial cells. The epithelium of the small (ileum) and large (colon) intestine have high metabolic activity and a turnover rate of about 5 days, that is, within a period of 5 days, the entire lining is shed and renewed. This is a turnover of about ¼ pounds of cells per day. Many gastrointestinal tract disorders are characterized by depletion of or damage to intestinal mucosa resulting from exposure to environmental agents, from inflammatory responses, and from autoimmune diseases, infections, or physical injuries, and the like.

Sensations, motility, digestion and secretion are controlled by the nervous elements of the gut. The gut submucosa contains sensory afferent nerve fibers that code for pressure, temperature and pain signals. After injury to the gut, especially to the mucosa, inflammation may disrupt the enteric nervous system and contribute to disorders, such as irritable bowel disease. The primary manifestations of gastrointestinal dysfunction are pain, a sense of distension, decreased or increased frequency of bowel movements, intra-luminal bleeding, and flatulence.

Inflammation in the Gut, Visceral Nerves, and Treatment of Visceral Discomfort. The sensations emanating from the gut, and the integration of these sensory signals, are mostly regulated by the visceral nerves of the autonomic nervous system.

Various regions of the intestinal tract, including the esophagus, stomach, ileum, colon, and rectum may be injured by autoimmune disorders, by infections, by psychogenic disorders, and by chemical and physical agents. The discomfort and pain of functional dysphagia (indigestion), gastrointestinal esophageal reflux disease (GERD—also known as heartburn), gastritis (e.g. caused by concentrated alcohol drink), or peptic ulcer disease (stomach and duodenal lining erosion) are caused by stimulation of visceral pain nerve endings located in the mucosa of the esophagus, stomach and duodenum. In the lower bowel, a major functional disorder is the irritable bowel syndrome. Two important organic diseases of the lower bowel are ulcerative colitis and regional enteritis (Crohn's disease). These two organic disorders are collectively referred to as inflammatory bowel disease. Other lower bowel inflammatory conditions are diverticulitis, celiac disease, lactose intolerance, chronic pancreatitis and regional ileitis. The primary clinical manifestations of these disorders are pain, a sense of distension, decreased or increased frequency of bowel movements, intra-luminal bleeding, and flatulence.

Current treatment for inflammatory gut diseases includes antacids, histamine-R2-blocking agents, antibiotics against Helicobacter pylori, anti-inflammatory drugs such as glucocorticosteroids and NSAIDS, anti-spasmodic agents, anti-diarrheal drugs, and, in the case of ulcerative colitis, surgery to remove the affected tissues. In a review, Sheikh and Wright (Irritable Bowel Syndrome: Current Concepts and Future Prospects. Hospital Practice, March 1999, pg. 31-38) describe a new category of “Anti-Afferent” agents designed to reduce intestinal perception by blocking the afferent nerve receptors.

In some patients, certain aromatic oils can relax smooth muscle and relieve pain caused by cramps and gas. Peppermint oil is the most commonly used agent in this class. Enteric-coated capsules containing peppermint oil have beneficial effects on patients with the irritable bowel syndrome. Peppermint oil is 30 to 55% menthol and it is thought that menthol is the active ingredient. In double-blind placebo-controlled studies, the frequency of abdominal pain, discomfort of abdominal distension, bowel movements, borborygmi and flatulence were decreased by encapsulated peppermint oil (Colpermin®). Colpermin® is approved for sale in Europe and in the United Kingdom, but not in the United States perhaps because some of the constituents of the oil, for example, pulgeone may be toxic to the liver. It is thought that the menthol content of peppermint oil may locally diminish smooth muscle contractility as well as reduce afferent discharge of sensory nerve endings in the enteric mucosa. However, menthol is not very potent, can cause local irritation at high concentrations, and has a relatively short duration of action of about 5 to 15 minutes because it is rapidly re-distributed in tissues and is metabolized.

BRIEF SUMMARY OF THE INVENTION

In one embodiment of the present invention, a composition is provided that comprises a 1-R1-phenyl, 4-R2-phenyl substituted 1,2,3,6-tetrahydropyrimidine-2-one visceral sensory nerve endings receptor agonist formulated as chewing gum, tablet or enteric-coated pill or capsule, that is therapeutically effective when delivered to the lining of the human gastrointestinal tract. The visceral sensory nerve endings receptor agonist may be represented by the general formula 1-[R1-phenyl]-4-[R2-phenyl]-1,2,3,6-tetrahydropyrimidine-2-one wherein: R1 is -hydroxy, a derivatized hydroxyl, -chloro, -fluoro, -alkyl (with about 2 to 4 carbons), -acetoxy, -trifluoromethyl; and R2 is -nitro, -chloro, -fluoro, -alkyl, -trifluoromethyl.

A particularly preferred visceral sensory nerve endings receptor agonist embodiment is called “icilin” and a particularly preferred composition has icilin incorporated into chewing gum or as a tablet or an enteric-coated pill or capsule to offer improved therapeutic benefit for the treatment of inflammation of the gastrointestinal lining. Thus, for example, a particularly preferred method of treating gastrointestinal dysfunction in a human comprises orally administering a composition comprising 1-[2-hydroxy]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyridimine-2-one or an analog, wherein the 1-[2-hydroxy]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyridimine-2-one or an analog is preferably in an amount of at least about 5 to 100 mg of the composition, more preferably about 25 mg of the composition, and is adapted to be released in the colon and ileum.

The advantages and aspects of the present invention will be understood by reading the following detailed description and the accompanying claims.

DETAILED DESCRIPTION OF INVENTION

I believe that icilin belongs to the category of novel “Anti-Afferent” therapeutic drugs. In this detailed description I discuss how icilin, formulated for enteric delivery, is useful for the treatment of dysfunction throughout the gastrointestinal tract, that is, from esophagus to rectum.

In the context of this application, “gastrointestinal dysfunction” is meant to describe functional disorders such as dysphagia, irritable bowel syndrome, constipation; inflammatory disorders such as esophagitis, gastritis, enteritis, colitis and proctitis; and specific gastrointestinal disorders such as gastroesophageal reflux disease (GERD), peptic ulcer disease, ulcerative colitis, Crohn's disease, diverticulitis, celiac disease, lactose intolerance, chronic pancreatitis, and regional ileitis. “Gastrointestinal dysfunction,” as used in the context of the instant application, is also meant to include any one or more clinical sign and/or symptoms of the above-mentioned functional disorders. By “clinical sign” is meant an observed biological, physiological, biochemical, or pathophysiological feature of a functional disorder that is an aid in its diagnosis. By “symptom” is meant a particular feature or features of a functional disorder that is “felt” or otherwise experienced by a subject having the functional disorder. For example, GERD often elicits a burning sensation in the esophagus, commonly called “heartburn.” Heartburn is a symptom of the functional disorder GERD. On the other hand, uncontrolled smooth muscle contractions are a clinical sign of enteric neuropathy seen in some diabetic patients and in patients with Crohn's disease.

Compositions and therapeutic methods in accordance with this invention utilize a 1-R1-phenyl, 4-R2-phenyl substituted 1,2,3,6-tetrahydropyrimidine-2-one visceral sensory nerve endings receptor agonist, preferably of the general formula 1-[R1-phenyl]-4-[R2-phenyl]-1,2,3,6-tetrahydropyrimidine-2-one wherein: R1 preferably is -hydroxy, derivatized hydroxyl, -chloro, -fluoro, -alkyl (with about 2 to about 4 carbon atoms) -acetoxy, -trifluoromethyl ; and R2 preferably is -nitro, -chloro, -fluoro, -alkyl (with about 2 to 4 carbons), -trifluoromethyl. I refer to the particularly preferred compound and its analogs as “icilin” and its analogs as “icilin analogs”. Formula 1 illustrates the general formula and icilin is represented by Formula 2.

As later more fully described, where RI is a derivatized hydroxyl, the formula 1 structure can be conjugated with or coupled to another compound, such as a sugar.

Formula. 1: 1-R1, 4-R2, substituted 1,2,3,6-tetrahydropyridimine-2-one

Formula 2: Icilin, 1-[2-hydroxy]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyridimine-2-one.

Icilin is a lemon yellow crystalline powder with a molecular weight of 311 Daltons and a melting point of 229 to 231° C. The powder is without odor and non-irritating, meaning that it does not elicit any smell or unpleasant sensations upon contact with the surfaces of the human body. The compound is stable at room temperature. Icilin is readily soluble in organic solvents such as dimethylsulfoxide, nitromethane, dimethylacetamide and, after warming, in propanediols; slightly soluble in ethanol and acetone; and virtually insoluble in water. Thus, icilin would be considered as a lipophilic, hydrophobic compound that is not easily miscible with aqueous systems. Analogs of icilin, for example, with acetyoxy, ethyl, fluoro, or trifluoromethyl substitutions, retain similar chemical and physical properties and are included within the scope of this invention.

In a previous application (Ser. No. 10/139193, filed May 2, 2002, inventor Wei, entitled “Therapeutic 1,2,3,6-Tetrahydropyrimidine-2-One Compositions and Methods Therewith”), I described evidence that showed icilin and related analogs, targeted at somatosensory nerve endings, have the potential to be useful in reducing pain and itch. These sensory nerve endings are located in the skin and in mucocutaneous structures such as the lips, penis and anus. As experiments progressed, however, I recognized that icilin and related analogs also have effects on visceral nerve endings, that is, on sensory nerve endings of the viscera, such as within the gut. I described how chewing of two wafers of a fruit-flavored gum containing icilin produced generalized sensations of coolness in the thoracic internal structures behind the sternum, in the epigastric area. These cooling effects were pleasant and were sufficient to relieve heartburn from excessive consumption of pizza. Icilin and related analogs appear to decrease sensory input from the gut and to reduce smooth muscle activity of the gut. Thus, these drug effects have potential utility in gastrointestinal dysfunction.

Methods suitable for the preparation of the Formula 1 and Formula 2 compounds are described by Podesva and Do Nascimento, U.S. Pat. No. 3,821,221, issued Jun. 28, 1974, incorporated herein by reference, and are exemplified by Example A hereinafter.

Mechanisms for Icilin Compounds in Treatment of Visceral Discomfort and Inflammation in the Gut. The visceral nerve endings, like the somatosensory nerve endings, contain receptors that recognize signals coding for temperature and for pain. The receptors are coupled to cation channels on the nerve membrane and these receptors, when stimulated, cause afferent neuronal transmission to the spinal cord and brain. Icilin and related analogs, delivered in chewing gum or as a tablet, enteric-coated pill or capsule, produce signals of cold and counteract visceral afferent signals for pain and irritation. These “anti-afferent” actions attenuate the discomforts of stomatitis, mucositis, esophagitis, enteritis, colitis, and proctitis. Major advantages of using icilin and related analogs are the properties of non-irritancy and long duration of action, facts revealed when these compounds were applied to somatosensory nerve endings. For example, icilin applied as an ointment or powder to the lips can produce sensations of cold lasting for several hours. Inhaled as a powder, icilin produces sensations of cold on nasal membranes for up to 8 hours. In addition to its effects on enteric nerve endings, icilin may also have a direct action on smooth muscle cation channels; without wishing to be bound by theory here it appears to act as an inhibitor of cation movement preventing muscle contraction and reducing the irritability of smooth muscle that occurs in inflammatory states. The sensory effects of icilin compounds and local anesthetic action on smooth muscles are the mechanisms for its use in treatment visceral discomfort and inflammation of the lining of the gut.

I have given one example of esophageal discomfort (heartburn) being relieved by ingestion of icilin. The characteristics signs and symptoms of functional dysphagia (indigestion), gastroesophageal reflux disease (GERD), peptic ulcer diseases and various esophagitis are retro-sternal and epigastric pain, a sense of fullness and stomach discomfort, sour or bilious regurgitation, belching and occasional hypersalivation. These effects are reduced when icilin is delivered to the upper gastrointestinal tract. For the lower gastrointestinal tract, use of icilin formulations for the treatment of irritable bowel syndrome (IBS) and irritable bowel disease (IBD) will be better understood from a detailed description of IBS.

Irritable Bowel Syndrome (IBS, also known as Spastic Colon) is a disorder of the entire gastrointestinal tract with certain symptoms similar to those manifested in irritable bowel disease. Unlike IBD, however, no specific anatomic lesion can be found in the gut mucosa of IBS patients. The signs and symptoms of IBS include:

Cramping pain in the lower abdomen

Bloating and gassiness

Changes in bowel habits

Diarrhea or constipation, or both alternately

Immediate need to move the bowels after awakening or during or after meals

Relief of pain after bowel movements

Feeling of incomplete emptying after bowel movements

Mucus in the stool

It is estimated that between 10 and 20 percent of the population has IBS at some time. The syndrome may appear in adolescents or young adults but tends to begin in the second and third decades of life, causing bouts that recur at irregular periods. It affects three times as many women as men and is often associated with stress. The cause of IBS is unknown. Examination of the rectal and colon surface does not reveal any irregular mucosal or vascular pattern; hence the term “functional” is applied to this order and not “organic”. The altered gut activity may, however, be initiated or aggravated by emotional factors, diet, drugs, or hormones.

In IBS, the circular and longitudinal muscles of the small and large intestines become hypo- or hyper-reactive to luminal constituents. There is a failure of the enteric nervous system to integrate the normal signals for contraction and relaxation. Intraluminal pressure studies of the colon show that constipation can occur when there is increased frequency and amplitude of colon muscle contractions and, conversely, diarrhea can be associated with diminished motor function. There may also be excess mucus production, which is not related to epithelial injury, but may be related to hyperactivity of the autonomic nervous system. Hypersensitivity to normal amounts of intraluminal distention exists, as does a heightened perception of pain in the presence of normal quantity and quality of intestinal gas. The pain of IBS seems to be caused by increased visceral nerve sensitivity of the intestine to distention or by abnormal strong contractions of the intestinal smooth muscles.

IBS symptoms usually occur in the awake patient and rarely rouse the sleeping patient. Two major clinical types of 1BS have been described. In constipation-predominant IBS, constipation is common, but bowel habits vary. Most patients have pain over at least one area of the colon, associated with periodic constipation alternating with a more normal stool frequency. Stool often contains clear or white mucus. The pain is either colicky, coming in bouts, or a continuous dull ache; it may be relieved by a bowel movement. Eating commonly triggers symptoms. Bloating, flatulence, nausea, dyspepsia, and heartburn can also occur. Diarrhea-predominant IBS is characterized by precipitous diarrhea that occurs immediately on awakening or during or immediately after eating. Nocturnal diarrhea is unusual. Pain, bloating, and rectal urgency are common, and incontinence may occur.

No specific therapy is available for IBS. A physician's sympathetic understanding and guidance is considered to be of paramount importance in treatment. The physician is expected to explain and demonstrate to the patient that no organic disease is present. Further explanation of normal bowel physiology and the bowel's reaction to stress, food, or drugs may assist the patient in establishing regular bowel routine and coping with irregularities. Anticholinergic drugs (muscarinic-blocking agents), such as atropine, opiate receptor agonists, such as loperamide, and antidepressants, such as imipramine, are prescribed to help the patient cope with diarrhea, abdominal pain and bloating.

Hypothesis Without being limited to theory, I believe icilin compounds are effective for esophageal dysfunction, IBD, IBS, and other forms of gastrointestinal dysfunction because I am convinced that cold receptors exist on visceral nerve afferents of the esophagus, ileum and colon and that these receptors can be activated by icilin compounds. I postulate that stimulation of cold receptors on visceral and somatosensory nerve endings produces sensations that counteract the pain and discomforts of gut inflammation. Icilin and related analogs are superior to peppermint oil and menthol in the treatment of IBS and related disorders because icilin is 200 to 400 times more potent than menthol, does not cause local irritation, is much less toxic than menthol, and has a much longer duration of action.

Formulation and Delivery of Icilin Compounds to Targets. In the working example, infra, icilin powder, admixed with saliva and swallowed relieved heartburn. To be effective for enteritis, colitis, and severe proctitis, however, icilin compounds should preferably be taken orally, in a chemical form designed for release on targets in the intestinal tract. Localized release of icilin molecules on the inflamed gut mucosa is preferred because if there is excessive systemic absorption of the drug en passage to the target, absorbed icilin may stimulate endogenous cold receptors in the body and cause shivering, shaking, and excessive sensations of cold.

Oral formulations of icilin designed for treatment of disorders of the upper alimentary tract can be icilin incorporated into chewing gum, lozenges, lollipops, candy, syrup, mucoadhesive polymers, mucoadhesive formulations, or rapidly dissolving powders or tablets. The goal is to attach the icilin molecule to the nerve receptors in the oral cavity and esophagus as quickly as possible. Standard formulations for gastrointestinal tract drugs are described in “Remington, the science and practice of pharmacy,” Alfonso R. Gennaro, Chairman of the editorial board and editor. 20th ed. Baltimore, Md. Lippincott Williams & Wilkins, 2000, Chpt. 45 Rudnic and Schwartz, Oral Solid Dosage Forms, pg. 858-893, Chpt. 46 Porter, Coating of Pharmaceutical Dosage Forms, pg. 894-902. amd Chpt. 47 Lee and Robinson, Controlled-release drug-delivery systems., pg. 903-929, all herein incorporated by reference. For application of icilin to the oral and esophageal areas, icilin may be incorporated into a mucoadhesive polymer such as polyvinylpyrrolidone, polycarbophil or sodium alginate. The suspensions, syrups, or gels are swallowed as a liquid at room temperature and adhere to the mucous membranes of the oral cavity, esophagus, and stomach lining.

For mucoadhesive pastes to be applied to the lining of the oral cavity, esophagus and stomach one may use Orabase®. Chemically Orabase® consists of plasticized hydrocarbongel, guar gum, carboxymethylcellulose, tragacanth gum and pectin. Orabase® is an adhesive-vehicle preparation and was designed for the purpose of retaining drugs applied on the oral mucous membranes. Studies with this preparation indicate that it adheres to the mucosa for 2 hours or longer after swallowing. Other per oral mucoadhesive compounds are described in U.S. Pat. No. 6,319,513, herein incorporated by reference, and include mucoadhesive adjuncts such as titanium dioxide, silicon dioxide and clays. Remington's Chpt.45 describes the formula for a chewable tablet consisting of: magnesium trisilicate 500 mg, aluminum hydroxide, dried gel 250 mg, mannitol 300 mg, sodium saccharin 2 mg, oil of peppermint 1 mg, magnesium stearate 10 mg, and corn starch 10 mg, into which icilin may incorporated and chewed. Methods for formulating drugs into chewing gum are also commercially available from Fertin Pharma (Denmark), using Medichew® technology. Using this method, the active agent in the gum is solubilized, and various levels release and delivery can be achieved at different parts of upper gastrointestinal tract, e.g. buccal mucosa, throat, or esophagus.

Oral formulations of icilin designed for treatment of disorders and/or their signs and/or symptoms of the lower alimentary tract can be sustained release preparations, enteric-coated icilin tablets or capsules, icilin attached to a glycoside, or icilin-resin complexes. These formulations avoid upper gastrointestinal absorption and permit greater delivery of icilin to the lower bowel mucosa receptors. A sustained-release tablet of icilin, described in Remington's Chpt. 45 may for example, contain icilin compressed with HPMC 2208 (USP) 500 mg, carnauba wax 60 mg, and HPMC 2910 (USP) 30 mg (HPMC refers to hydroxypropylmethylcellulose). An enteric-coated capsule containing icilin, designed to withstand the acidity and digestive juices of the stomach and the small intestine, may be used alone or in combination with menthol or a menthol analog to treat irritable bowel disease. Several methods described in U.S. Pat. No. 5,849,327, U.S. Pat. No. 5,866,619, U.S. Pat. No. 6,140,308 and U.S. Pat. No. 6,166,044, all herein incorporated by reference, give procedures on how such technology can be achieved. Suitable technologies for encapsulation and drug delivery are described by Sandborn et al. (U.S. Pat. No. 6,166,044), incorporated by reference.

In one preferred embodiment, icilin in an enteric coating is administered via oral ingestion. An effective amount of icilin can be delivered to the colon of the patient by oral ingestion of a unit dosage form such as a pill, tablet or capsule, comprising icilin which is enterically coated so as to be released from the unit dosage form in the lower intestinal tract, e.g., in the distal ileum and in the colon of the patient. A preferred unit dose is wherein icilin is present in an amount of about 10 mg to about 100 mg per pill, tablet or capsule. Enteric coatings remain intact in the stomach, but will dissolve and release the contents of the dosage form once it reaches the region where the pH is optimal for dissolution of the coating used. The purpose of an enteric coating is to substantially delay the release of the icilin until it reaches its target site of action in the ileum or colon. Aqueous film-coating technology is employed for the enteric coating of pharmaceutical dosage forms. Delayed-released oral icilin dosage forms have the potential advantage of delivering nearly all the icilin to the ileum or colon in an easily administered form.

Thus, a useful enteric coating is one that remains intact in the low pH environment of the stomach, but readily dissolved when the optimum dissolution pH of the particular coating is reached. This can vary between pH 3 to 7.5 depending upon the chemical composition of the enteric coating, but is preferably between about pH 6.8 and pH 7.2. The thickness of the coating will depend upon the solubility characteristics of the coating material and the site to be treated. The most extensively used polymer for enteric coating is cellulose acetate phthalate (CAP). However, CAP has an optimum dissolution pH greater than 6, thus early drug release may occur. Another useful polymer is polyvinyl acetate phthalate (PVAP), which is less permeable to moisture and gastric fluid, more stable to hydrolysis and able to dissolve at a lower pH, which could also result in early release of icilin in the duodenum. Another available polymer is hydroxypropyl methylcellulose phthalate. This has similar stability to PVAP and dissociates in the same pH range. Further examples of currently used polymers are those based on methacrylic acid, e.g., methacrylic acid ester copolymers with acidic ionizable groups. Dosage forms coated with methacrylic acid polymers dissolve in the ileum at about pH 6.8, and in the terminal ileum and caecum at about pH 7.2. In general coating thicknesses of about 25 to 200 microns, and especially 75 to 150 microns, are preferred using about 3 to 25 mg, preferably 8 to 15 mg of acidic coating material per square centimeter of tablet or capsule surface. The precise coating thickness will however depend upon the solubility characteristics of icilin analogs and the site to be treated.

Methods for preparing a phenol group bound to a sugar are described by Brattsand et al. U.S. Pat. No. 6,140,308, herein incorporated by reference. As earlier described, icilin compounds are described by the general formula 1-R1-phenyl, 4-R2-phenyl substituted 1,2,3,6-tetrahydropyrimidine-2-one. R1 may be a hydroxyl function and this phenol group can be coupled (derivatized) to a sugar, having the general formula icilin-R1-sugar. Icilin-R1-sugar is inactive at the cold receptor located on sensory nerve endings because the free hydroxyl group is essential for receptor stimulation. In the colon, however, bacterial sugar-hydrolyzing enzymes, called glycosidases, can act on the icilin-R1-sugar to produce local release of icilin. Methods for the synthesis of D-glycoside conjugates of drugs were described in detail by Brattsand et al., previously incorporated by reference. The synthesis of an icilin-R1-sugar molecule permits localized delivery to the lower bowel after oral ingestion. Such an icilin-R1-sugar conjugate may be formulated as an enteric-coated tablet, capsule, or pill, to further ensure intact passage through the upper gastrointestinal tract.

Another method for discrete colonic drug delivery is described in U.S. Pat. No. 5,866,619, previously incorporated by reference. Here, using similar chemical synthetic methods as described in U.S. Pat. No. 6,140,308, the free hydroxyl group on icilin compounds may be attached to a saccharide-containing polymer. The chemical-matrix complex is resistant to degradation in the stomach and small intestine, but bacterial enzymatic action, by hydrolyzing the oxy-sugar bond, releases the drug in the colon. Finally, Berliner and Nacht U.S. Pat. No. 5,849,327, herein incorporated by reference, describe the use of porous microscopic beads embedded with an active agent or pro-drug and plugged with a polysaccharide that is only chemically degradable by colon-specific bacteria. The microbeads further contain a coating of an enteric material that remains intact until the dosage form reaches the colon. These formulations may confine release of bioactive icilin such that it only acts locally on inflamed colon mucosa.

It is well understood in the art that the precise dosage and duration of treatment is a function of the tissue being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the age of the individual treated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed formulations.

EXPERIMENTAL

Example A

Chemical Synthesis of Icilin and Analogs. The methods of chemical synthesis are as described by Podesva and Do Nascimento in U.S. Pat. No. 3,821,221, herein incorporated by reference. Briefly, a substituted acetophenone, e.g. 3-nitroacetophenone or 3-trifluoromethylacetophenone, readily obtainable from commercial sources such as Sigma-Aldrich, Co., was mixed with diethylamine or dimethylamine in formaldehyde and refluxed in acidic solutions. After addition of a second substituent (e.g. ortho-aminophenol), the Mannich reaction produced a β-amino-ketone compound (e.g. [β-ortho-hydroxyanilino]-meta-nitropropiophenone) which was isolated. This reagent was then reacted with potassium cyanate or sodium cyanate to produce an unstable urea intermediate that proceeds to cyclize into the tetrahydropyridimine-2-one ring, with the appropriate groups on position 1 (2-hydroxyphenyl) and 4 (3-nitrophenyl) on the 1,2,3,6-tetrahydropyrimidine-2-one ring. The precipitated product was readily collected by filtration (which may be recrystallized using solvents such as ethyl acetate or purified on silica gel columns). The final products are solids stable at room temperature. [0055]

Example 1

A male subject spread 10 mg of icilin with a swab-stick between two sticks of a fruit-flavored chewing gum and chewed the gum for 10 minutes. No sensations of coolness were noted in the mouth or throat. But after 10 minutes general sensations of coolness were felt in the retrostemal and epigastric areas. These cooling effects lasted for about 1 hour. By contrast, the chewing of mentholated gum or mentholated candy produced, after an initial harsh taste, strong cooling of the mouth and throat that lasted only about 10 minutes. The next day the subject consumed a quick meal consisting of a large-size pepperoni-sausage pizza, washed down with coca-cola. The subject reported feelings of satiety, bloating, and severe epigastric discomfort. Consumption of 5 mentholated candies (Mentos) did not affect these symptoms. However, using the icilin-chewing gum reduced all symptoms. [0056]

Example 2

A female subject who met the diagnostic criteria for gastroesophageal reflux disease (GERD) would, on occasions after a big meal, wake in the middle of night with severe epigastric discomfort, eructations, a sour taste in the mouth, and a sense of nausea and pain. Ingestion of Tagamet® would provide some degree of relief from pain, but the other symptoms persisted. The subject was given the icilin-chewing gum wafer and instructed on its use. She reported that using the icilin-chewing gum on two different evenings helped relieve her discomfort and allowed her to go to sleep uneventfully. [0057]

Example 3

A 60-year old female subject who had undergone a Whipple procedure for leiomyosarcoma of the duodenum 13 years previously, frequently had flatulence and abdominal cramps after meals that were not relieved by Phazylne® (simethicone). During one such episode she drank half a cup of barley water containing 10 mg of icilin powder suspended and mixed in the barley water by stirring. She reported within 25 minutes that the sense of abdominal cramping was decreased and she felt much better. [0058]

Example 4

The field-stimulated guinea pig ileum is a standard pharmacological bioassay for studying intestinal smooth muscle contraction. A guinea pig is anesthetized with sodium pentobarbital and a segment of the ileum is cut out and electrodes put into the muscle. The muscle is placed in an oxygenated organ bath and the muscle strip connected to a Grass instrument for stimulation and recording. The rhythmic contractions of the muscle are recorded using a transducer-polygraph. Generally, after a 30 minute stabilization period, muscle contractions of a constant amplitude and frequency is observed. The addition of icilin, dissolved in propylene glycol, to this bath mixture produces a dose-dependent decrease in contractile force. Propylene glycol, the solvent, alone does not produce significant contraction. [0059]
In summary, I believe that no investigations of icilin on the upper and lower gastrointestinal tract have been reported in the scientific literature other than what is discussed or described herein. I point out the unique properties of icilin and describe novel compositions and preferred embodiments for therapeutic methods of use. [0060]
It is to be understood that while the invention has been described above in conjunction with preferred specific embodiments, the description and examples are intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. [0061]

Claims

I claim:

1. A composition for the treatment of upper and lower gastrointestinal dysfunction, comprising:

a therapeutically effective amount of a visceral sensory nerve endings receptor agonist having the formula 1-[R1-phenyl]-4-[R2-phenyl]-1,2,3,6-tetrahydropyrimidine-2-one, wherein RI is hydroxy, a derivatized hydroxyl, chloro, fluoro, an alkyl of about 2 to about 4 carbon atoms, acetoxy, or trifluoromethyl and R2 is nitro, chloro, fluoro, an alkyl or about 2 to 4 carbon atoms or trifluoromethyl; and

an oral preparation in which the a visceral sensory nerve endings receptor agonist is dispersed, the preparation being adapted for delayed release of the agonist.

2. The composition for the treatment of upper and lower gastrointestinal dysfunction as in claim 1 wherein the visceral sensory nerve endings receptor agonist is in an amount of from about 5 to about 100 mg per dose .

3. An enteric-coated tablet, pill or capsule composition comprising:

1-[2-hydroxy]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyridimine-2-one or an analog thereof in an amount of about 5 to about 100 mg per unit.

4. An oral composition, comprising: a 1-[2-hydroxy]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyridimine-2-one or an analog thereof conjugated with a sugar.

5. The oral composition as in claim 4 wherein the sugar conjugate is adapted for substantially intact passage through the upper gastrointestinal tract.

6. A method of treating of upper and lower gastrointestinal dysfunction in a mammal comprising: orally administering a therapeutically effective amount of a sensory nerve endings receptor agonist having the formula 1-[R1-phenyl]-4-[R2-phenyl]-1,2,3,6-tetrahydropyrimidine-2-one, wherein R1 is hydroxy, chloro, fluoro, an alkyl of about 2 to about 4 carbon atoms, acetoxy, or trifluoromethyl and R2 is nitro, chloro, fluoro, an alkyl of about 2 to 4 carbon atoms or trifluoromethyl, to the gastrointestinal tract of the patient.

7. The method as in claim 6, wherein said mammal is a human.

8. The method as in claim 7 wherein the visceral sensory nerve endings receptor agonist is administered as an enteric-coated pill, tablet or capsule.

9. The method as in claim 7 wherein the visceral sensory nerve endings receptor agonist is administered as a lozenge, lollipop, candy, chewing gum, syrup, powder, or paste, or in suspension or in emulsified form.

10. The method as in claim 7 wherein the amount of the visceral sensory nerve receptor agonist administered is in an amount of from about 5 mg to about 100 mg per application.

11. A method of treating upper and lower gastrointestinal dysfunction, comprising:

providing a composition comprising 1-[2-oxy-sugar]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyridimine-2-one or an analog, the 1-[2-oxy-sugar]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyridimine-2-one or an analog being in an amount of 5 mg to 100 mg of the composition; and,

delivering said composition to the gastrointestinal tract via oral administration.

12. The method as in claim 11 wherein the composition is adapted for delayed release.