CZ20003846A3 - Composition for treating inflammatory disease of intestines by dosage of N-acetylglucosamine into large intestine - Google Patents

Abstract

A composition for treating inflammatory bowel disease comprises N-acetylglucosamine (NAG) and a carrier adapted for delivery to the bowel. ACTIVITY : Antiinflammatory; antiulcer. MECHANISM OF ACTION : None given.

Description

The present invention relates to novel compositions and novel methods of treating inflammatory bowel disease (CVD). More particularly, the present invention relates to novel compositions comprising N-acetylglucosamine (NAG) as an active agent for the treatment of ZOS and a pharmacologically and colon suitable NAG carrier, and a method of dosing the composition into the colon for treating ZOS in a person affected by ZOS.

BACKGROUND OF THE INVENTION

Generally speaking, the intestines extend from the stomach to the rectum and include the small and large intestines. The small intestine includes 3 main sections, the duodenum (which is adjacent to the stomach), the jejunum (which is medium), and the ileum (which is distant from the stomach). The large intestine (which is called the colon) is connected to the distal part of the ileum of the small intestine by an ileocecal valve. The colon (colon) comprises 2 major parts, the appendix (which is attached to the ileum of the small intestine), and the rectum, which is a distal part of the colon (colon). The distal end of the rectum is attached to the anus.

The term inflammatory bowel disease (ZOS) is a generic term that includes a number of specific intestinal diseases including ulcerative colitis, chronic rectal inflammation and Crohn's disease. These diseases may or may not overlap to some extent. When this happens, the boundaries between different types of ZOS diseases are blurred. Ulcerative colitis is a chronic, non-specific inflammatory bowel disease that includes an ulcer disease of the large intestine. . Chronic proctitis involves inflammation of the colon and often the rectum. Crohn's disease occurs as several types of intestinal inflammation, but most often this term refers to inflammation of the terminal ileum. The synonyms of Crohn's disease are regional entritis (gut) or regional iletitis, although the latter is not always convenient, since Crohn's disease is not limited to the ileum. Crohn's disease often includes diseases, fistulas (deep coil passages or pathways in the colon), perianal ulceration, and narrowing of the intestinal cross-section (narrowings, strictures). Surgical removal of a diseased part of the intestine (called a colectomy or ilectomy) is reserved for those cases that are most resistant to treatment, as about half of those treated surgically experience the reoccurrence of the disease in another part of the intestine. The most common clinical symptoms of Crohn's disease include lower abdominal pain, fever, anorexia (loss of appetite), weight loss and fullness of the right lower quadrant.

Inflammatory bowel disease (CSD) may include an inflammatory disorder of the vascular and intestinal wall glycosaminglycan (GAG) formation, particularly loss of intestinal wall GAG which results in intestinal fibrosis and loss of functionality (see S. H. Murch et al., Reference 3 in Bibliography). Organ culture shows that this disorder is caused by the presence of intestinal wall breakdown enzymes (see S. L. Pender et al., Reference 6 in Bibliography).

Statistics show that approximately 1% of the North American population suffer from inflammatory bowel disease (CSD) of one form or another. The annual incidence of ulcerative colitis (VC) is estimated to be between 6 and 8 cases per 100,000 inhabitants per year, with the highest incidence of the disease occurring most frequently between the 30s and 50s.

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99999 99 999 · • 9 9 9 9 9 ·· · · 9 9 9 99 9 9 9 · 9 year ago. Since its discovery a few decades ago, Crohn's disease has increased its incidence, and it is estimated to affect between 20 and 70 people per year per 100,000 inhabitants, with 15,000 to 30,000 new cases occurring annually in the United States. At the age of 85, it is estimated that nearly two-thirds of the population have developed a hollow in their colon.

A recent survey in France has found an incidence of 4.9 per 100,000 for Crohn's disease and 3.2 for ulcerative colitis. The highest specific incidence of Crohn's disease with respect to age was in the category of 20 to 29 years, while for ulcerative colitis it was between 20 and 39 years. The incidence of Crohn's disease in France was similar to that in Northern Europe, but the incidence of ulcerative colitis was lower.

Historically, inflammatory bowel disease (CSD) has generally been treated with steroidal anti-inflammatory agents such as cortisone or sulfasalazine, or anti-convulsive agents such as propantheline and dicyclomine, supplemented with laxative or anti-diarrheal agents, as well as agents that reduce bowel movements, as indicated. Recently, it has been found that 5-aminosalicylic acid (5-ASA) and related substances, which are considered to be the active part of sulfasalazine, are effective in the treatment of inflammatory bowel disease. Their effect may be related to their ability to remove the irritating superoxide radicals that are formed in inflamed tissue. In severe, incurable disease, immunosuppressants such as

azathioprine. IN many cases Yippee need surgical remove heavily damaged intestinal tissue. U.S. Pat. Date released Inventor 1,318,592 November 1988 Burton 5,229,374 January 1992 Burton a Freeman

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192 750 5 217 962 March 1993 June 1993

Burton a

Burton a

Gislason

McLean

SUMMARY OF THE INVENTION The invention is directed to a composition for treating inflammatory bowel disease in a patient suffering from inflammatory bowel disease, the composition comprising:

(b) a therapeutic amount of N-acetylglucosamine; and (c) a pharmacologically and intestinal acceptable carrier adapted to deliver N-acetylglucosamine to the intestine of said patient.

N-Acetylglucosamine may be present in the composition in an amount ranging from 0.5 g to 5 g. The carrier may be any substance that delivers N-acetylglucosamine to the diseased intestinal region. The carrier can be distilled or purified water, a rectal foam, a suppository base that can encapsulate N-acetylglucosamine, or some orally non-digestible time-released substance that can withstand gastric acid degradation and can release N-acetylglucosamine in the intestines or colon . Water may be present in sufficient quantity to allow the enema to rectum.

The foam may comprise N-acetylglucosamine, a surfactant, an adjuvant, and a blowing agent. The carrier may comprise one or more ingredients selected from the group consisting of propylene glycol, emulsifying wax, polyoxyethylene-10-stearyl ether, ethoxylated cetyl alcohols and stearyl alcohols, stearate-10, cetyl alcohols, methylparaben, propylparaben, trolamine, purified water, polyethanol alcohols, polyethoxy alcohols. -10-stearyl · · <· ·--st---st------ Ether, methyl and propyl parabens, propylene glycol, anhydrous ethanolamine, deionized water and suitable propellants.

The suppository base may be selected from the group consisting of theobromine oil, glycerinated gelatin, hydrogenated vegetable oil, polyalkyl glycol, polyalkylene glycol fatty acid esters, coconut base, hydrogenated fatty acids, hydrogenated vegetable oil, monoglyceride, cocoa butter, petroleum oil, beeswax, glycerin, polyethylene glycol-600-dilaurate, hydrogenated cocoa glyceride, and polyethylene glycol.

The time-exuding agent may be selected from the group consisting of an acrylic base resin coating, a methacrylic acid copolymer, an acrylic base resin mixed with a suitable non-medicated carrier such as lactose, magnesium stearate, polyethylene glycol, polyvinylpyrrolidone, or sodium starch glycolate, cellulose or ethylcellulose. including a hydrophilic polymer and an enteric polymer, a cellulose derivative, a polyvinyl acetate phthalate or a polyvinyl acetate phthalate mixed with a plasticizer, a gut breakdown polysaccharide, locust bean gum or guar gum, a hydrophilic group-containing film forming polymer, a film forming acrylate polymer film containing from 30 to 100% by weight of at least one monomer selected from the group consisting of lower alkyl esters of acrylic acid and lower alkyl esters of methacrylo acid a hydrocolloid gum obtained from higher plants; and an anionic carboxyl polymer that does not dissolve at a pH of less than about 4, but is soluble at a pH in the range of about 4 to about 7.5.

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The foam may contain 0.5 to 5 g of N-acetylglucosamine as active ingredient and 20 g of a foam containing propylene glycol, emulsifying wax, polyoxyethylene-10-stearyl ether, cetyl alcohol, methylparaben and propylparaben, trolamine, purified water and inert propellants, dichlorodifluoromethane or dichlorotetrafluoroethane.

The composition may comprise between about 0.1% to 90% by weight of N-acetylglycosamine coated with from about 5% to about 29% by weight of the hydrophilic polymer, and from about 0.5% to about 25% by weight of the acrylic polymer that is it dissolves at a pH in the range of about 5.0 to about 7.5.

The invention is also directed to a method of treating a patient suffering from an inflammatory bowel disease comprising administering to the intestines of said patient. compositions comprising therapeutic amounts of N-acetylglucosamine and a bowel-compatible and pharmacologically acceptable carrier. N-Acetylglucosamine may be present in an amount between about 0.5 g and 5 g per enema.

The pharmacologically acceptable carrier can be distilled or purified water, intestinal compatible foam that can coat the colon, a suppository that can be solid at room temperature but melts at body temperature, or an orally non-digestible substance that can withstand gastric acid degradation stomach and release N-acetylglucosamine in the intestines.

The enema may be given to said patient by an enemator.

List of Figures in the Drawings * φφ φφφφφφφφφφφφφφφφφφφφφφ φφφφφφφφφφφφφφφφφφφ φφ φφφ φφφφφφφφφφφ

In the figures which explain typical embodiments of the invention but which should not be construed as limiting the idea or scope of the invention in any way:

Giant. 1 shows a histological section of rectal tissue prior to N-acetylglycosamine treatment.

Giant. 2 shows a histological section of rectal tissue after treatment with N-acetylglucosamine.

Giant. 3 shows a larger magnification of the histological section shown in FIG.

Giant. 4 shows a larger magnification of the histological section shown in FIG.

Description of the invention

We have found that certain forms of inflammatory bowel disease (CSD) can be treated with good results by administering to the affected upper intestine or colon an effective amount of a composition comprising N-acetylglucosamine (NAG) and an intestinal and pharmacologically acceptable carrier, which may be distilled or purified water, a foam enema, a suppository, or a time-secreted carrier that can be taken by mouth and passes largely unstated by the stomach and releases N-acetylglucosamine in the upper intestine or large intestine. The time-deposited coating protecting N-acetylglucosamine from gastric acid attack may be an acrylic-based resin coating that delays the release of N-acetylglucosamine until the Nacetylglucosamine-coated acrylic resin reaches the upper or lower intestine, e • · · · · · · · · · · · · · 9 9 · 9 9 9 9 9 9 9 9

9999 ·· ·· ·· ·· ··· depending on carrier properties. A suitable acrylic acid may be Eudragit S ™, which is a methacrylic acid copolymer. N-Acetylglucosamine, which is coated with an acrylic base resin, may be admixed with a suitable non-medicated carrier such as lactose, magnesium stearate, polyethylene glycol, polyvinylpyrrolidone or sodium starch glycolate. Other suitable coatings that can withstand gastric acid attack may be cellulose or ethylcellulose. The gastric acid resistant coating may also be a base composition which is a hydrophilic polymer and an enteric polymer. The enteric polymer is impermeable to the digestive fluids of the stomach and aids in retarding the release of N-acetylglucosamine in the low pH region, thereby allowing the use of lower concentrations of N-acetylglucosamine. At a higher pH range of intestinal fluids, the hydrophilic and enteric polymer dissolve and thereby release N-acetylglucosamine in the intestine.

A typical formulation may comprise between about 0.1% and about 90% by weight of N-acetylglucosamine coated with about 5% by weight to about 29% by weight of a hydrophilic polymer, and from about 0.5% to about 25% by weight of an acrylic polymer that it dissolves at a pH in the range of about 5.0 to about 7.5.

The acrylic resin is to be treated to resist dissolution and attack at a pH of less than 5, but decomposes at a pH in the range of about 5 to about 8. Another suitable coating may comprise a cellulose derivative such as polyvinyl acetate phthalate or polyvinyl acetate phthalate mixed with plasticizer. The latter normally decomposes at a pH in the range of about 3 to about 6.

Another suitable coating may be a polysaccharide that is degradable in the large intestine, such as a legume gum, such as a legume gum. locust bean or guar gum, and a film-forming polymer preferably containing hydrophilic groups. Such coatings break down in the colon due to glycosidic enzymes. The polysaccharide, which is degradable in the colon, should contain galactose and mannose units. The film-forming acrylic polymer with a polysaccharide addition should contain from about 30 to 100% by weight of at least one monomer selected from the group consisting of lower alkyl esters of acrylic acid and lower alkyl esters of methacrylic acid.

Another suitable coating used in the form of a membrane enveloping an N-acetylglucosamine core, and a suitable non-medicated carrier, may be a pharmaceutically acceptable, film-forming anionic carboxylic polymer that is difficult to dissolve at low pH less than 4 but soluble at higher pH ranging from about 4 to about 7.5. Another suitable gastric acid-resistant coating may be a hydrocolloid gum obtained from higher plants, admixed with a suitable pharmaceutically acceptable binder.

It is understood that, in addition to selecting one or more suitable gastric acid-resistant coatings, it is important to choose the correct thickness of the water-insoluble coating. As is readily understood, a weak coating of gastric acid is easier to penetrate than a thick coating.

The suppository may be a small solid body, shaped for easy penetration into the rectum, consisting of N-acetylglucosamine encased in a carrier substance that is hydrophilic and solid at normal ambient temperatures but melts at body temperature. The suppository may be based on theobromic oil, glycerinated gelatin, hydrogenated vegetable oil, a mixture of polyethylene glycols of different molecular weights, and / or polyethylene glycol fatty acid esters.

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Body temperature melting coatings that coat N-acetylglucosamine can be selected from a wide variety of materials and substances such as coconut oil base, hydrogenated fatty acids or hydrogenated vegetable oils, modified to be solid at ambient / room temperature, but which dissolve at body temperature. Other suitable coatings may be monoglycerides, cocoa butter, vegetable and petroleum oils, beeswax, glycerin, polyethylene glycol-600-dilaurate, hydrogenated cocoa glycerides, polyethylene glycol. The polymeric material should be soluble in body fluids, and preferably be capable of slowly releasing N-acetylglucosamine into the rectum region while the polymeric material dissolves in body fluids. The film may comprise a water-soluble polymer that is biodegradable and contains active N-acetylglucosamine.

The rectal foam may typically consist of 0.5 to 5 g of N-acetylglucosamine as the active ingredient in 20 g of foam containing propylene glycol, emulsifying wax, polyoxyethylene-10-stearyl ether, cetyl alcohol, methylparaben and propylparaben, trolamine, purified water and inert propellants, dichlorodifluoromethane and dichlorotetrafluoroethane.

The foam should be hydrophilic and may consist of propylene glycol, ethoxylated cetyl and stearyl alcohols, stearate-10, cetyl alcohol, methylparaben, propylparaben, trolamine and purified water and dichlorodifluoromethane and dichlorotetrafluoroethane as propellants or blowing agents. Other foam-forming carriers for N-acetylglucosamine containing a mucosal water-miscible mucosa base may be cetyl alcohol, ethoxylated stearyl alcohols, polyethylene-10-stearyl ether, methyl and propylparabens, propylene glycol, anhydrous

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4994 9 I ethanolamine, deinonized water and suitable propellants. In general, the liquid vehicle which may form a foam should comprise at least one surfactant, a foam propellant as an environmentally benign halogenated hydrocarbon, and an adjuvant for the active ingredient, especially N-acetylglucosamine, which is capable of suspending or dissolving N-acetylglucosamine in the foam.

N-Acetylglucosamine, and its precursor, glucosamine, are biochemically classified as aminosaccharides. Aminosaccharides are the basic biochemical compounds produced from blood glucose by most body cells by a series of biochemical reactions that have been elucidated many years ago. Other aminosaccharides include galactosamines and mannosamines and their N-acetylderivatives. N-Acetylglucosamine is a precursor of N-acetylgalactosamine and N-acetylmannosamine and thus, metabolically, N-acetylglucosamine plays an important role in the availability of all aminosaccharides that are incorporated into a functional sugar complex, such as glycosaminoglycans (GAG). However, unlike galactosamine and mannosamine, N-acetylglucosamine is available in industrial quantities at a reasonable cost.

N-Acetylglucosamine and related aminosaccharides are components of a large number of high molecular weight complex polysaccharides, including functionally important glycosaminoglycans and proteoglycans, formerly referred to as mucopolysaccharides. Glycosaminoglycans are composed of repeating disaccharide units of N-acetylglucosamine or related aminosaccharides, and glucuronic and iduronic acids. Examples of glycosaminoglycans include hyaluronic acid (which consists of repeating units of Nacetylglucosamine and glucuronic acid), chondroitin sulphate, chondroitin sulphate, and chondroitin sulphate. Dermatan sulfate, keratan sulfate and heparin, all containing either N-acetylglucosamine or the N-acetylgalactosamine aminosaccharide, which is synthesized from Nacetylglucosamine. Glycosaminoglycans are also present in proteoglycans, which are structures comprising a series of glycosaminoglycan chains attached to polypeptide or protein nuclei.

N-Acetyglucosamine plays an important role in maintaining normal cellular functions, including cell membrane permeability, structural integrity of connective tissues such as skin and cartilage, and joint lubricant. In the intestines, glycosaminoglycans are the basis for the formation of glycocaliches of digestive cells and mucus secreted by intestinal goblet cells. They are also essential components of the intercellular fluid or glue that holds cells together, immunoglobulins, blood group antigens, and a wide range of other biochemically and immunologically important substances.

The extracellular beam, mainly composed of proteoglycans containing N-acetylglucosamine, is present in the basement membrane, as well as lamina propia, and submucosa of the digestive tract. Proteoglycans containing N-acetylglucosamine play an important role in anchoring the cells to the mucopolysaccharide layer on the lining cells filling the digestive tract, as well as in cell renewal and intestinal permeability.

Although N-acetylglucosamine has been detected in all body cells and tissues as part of glycosaminoglycans and proteoglycans, unlike glucose, it has been shown that there are no significant concentrations of free N-acetylglucosamine or its glucosamine precursor in blood or intracellular fluids. Under normal conditions, the body will utilize all available N13 9 9 9 99 99

-acetylglucosamine, which it produces. In disease states, such as diseases involving inflammatory reactions of the digestive tract (ZOS), the body's stores of N-acetylglucosamine may be insufficient to promote cell and function recovery to an optimal level. It has been shown (see Burton et al., Bibliographic reference 1) that the intestinal tissue of patients with inflammatory bowel disease preferentially absorbs the intestinal wall with N-acetylglucosamine rather than glucosamine, causing an additional N-acetylglucosamine in inflammatory bowel disease (ZOS).

When administered to an animal or human, either intravenously or by mouth, N-acetylglucosamine is rapidly distributed throughout the body and incorporated within minutes into glycosaminoglycans and proteoglycans in most tissues and organs, including the intestinal tract and joint cartilage. Free N-acetylglucosamine has a blood half-life of less than 10 minutes, but when incorporated into glycosaminoglycans, the N-acetylglucosamine contained in these complex molecules changes very slowly, with a half-life measured in hours and even days.

N-Acetylglucosamine is a natural aminosaccharide belonging to a class of compounds that are usually very good _; tolerated. In general, monosaccharides and their simple derivatives have widespread use in medicine even at high doses. Even when administered intravenously, N-acetylglucosamine is considered very safe. In particular, no mutagenicity, carcinogenicity or teratogenicity is expected.

Single intravenous or oral doses of N-acetylglucosamine greater than 25 g / kg body weight administered to mice or rats resulted in no observable toxic effect. Intravenous dosage of 20 g N14

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-acetylglucosamine had no people. It does not affect blood glucose or insulin levels and is therefore considered safe for diabetics.

Studies in animals and humans have shown that N-acetylglucosamine is non-toxic at doses substantially higher than those used for most therapeutic purposes. Oral administration at doses up to 3 to 6 g / kg body weight per day for 30 days had no toxic effects and resulted in neither total nor microscopic changes in the various tissues and organs. N-Acetylglucosamine was taken by mouth as a human food supplement at doses up to 3 g per day without adverse effects. For the last few months we have administered children without any adverse effects up to 4.5 g per day orally, or 3 g per day rectally.

In inflammatory bowel tissue, it has been shown by Burton et al (see reference 1 in the bibliography) that there is a preferential incorporation of N-acetylglucosamine over glucosamine. This may result in biochemical deficiency in the process by which glucosamine is converted to N-acetylglucosamine in intestinal cells. The acetylation step of converting glucosamine to N-acetylglucosamine may be insufficient. This may result in a reduction in protective glycocalyx or proteoglycans covering the intestinal cells, as well as a reduction in mucus production and a slower recovery of diseased tissue. As a result of the loss of these protective components, the intestinal wall becomes more susceptible to damage, inflammation and ulceration. Although we do not wish to be adversely bound by any theories, it appears that N-acetylglucosamine is more readily absorbed by cells as a result of its passive diffusion through cell membranes, compared to the apparently active active mechanism (complex, energy-requiring system) required for intracellular distribution.

4 4 4 ·· 4 4 44 • 444 4 44 4 4 4 • 4 4 4444 4 4

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4444 44 44 44 4 · 4 ·· glucosamine. We have observed that in inflammatory bowel disease, N-acetylglucosamine-containing glucosaminoglycans are depleted from the intestinal wall, resulting in the intestinal wall becoming abnormally thick or fibriotic. When this occurs, intestinal permeability and functionality will deteriorate.

Although the symptoms of ulcerative colitis and Crohn's disease are similar and are often barely distinguishable, the gross pathological difference is that Crohn's disease is an inflammatory condition in which inflammation and ulceration can spread along any part of the entire intestine. In Crohn's disease, intestinal fibrosis can be so extensive that it causes a narrowing of the cross-section, resulting in blockage of the intestine. Both ulcerative colitis and Crohn's disease can become serious and may require intensive drug treatment or surgery. Patients with inflammatory bowel disease show major cellular changes in the intestinal wall, often leading to ulceration or fistulae. The chronic nature of these inflammatory conditions, as well as the tendency to affect younger people, with the peak of ulcerative colitis occurring between 15 and 30 years of age, makes inflammatory bowel disease a serious medical problem. The onset of the disease often occurs during puberty or early adulthood.

Diverticulitis is a more common but less severe gastrointestinal condition, often classified as an inflammatory bowel disease. The disorder is inflammation of one or more of the hairs, which are sack-like hairs of the colon wall appearing in weak points. In diverticulitis, cells of the colon wall are initially affected and symptoms range from relatively mild to painful perforation of the intestinal lining. Diet is referred to as a condition or contributing factor in the development of diverticulitis, which is also associated with increasing age, and which is

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ID · ·········· · ··········· Uncommon in individuals under 35 years of age. The disorder is progressive, developing from mild symptoms to painful inflammation. Early stages of diverticulitis may respond to diet adjustment, but later stages require medication or surgery.

In inflammatory bowel disease, including Crohn's disease, there is a significant loss of glycosaminoglycans (GAG) from the intestinal wall, providing further evidence of the involvement of glycosaminoglycans in the pathology of inflammatory bowel disease. The authors do not wish to be bound by any wrong theories. However, the following data is offered as a possible explanation of the invention. The detection of loss of GAG from the intestinal wall well supports considerations of the beneficial effects of N-acetylglucosamine in the treatment of inflammatory bowel disease, since N-acetylglucosamine should supply the necessary substrate or aminosaccharide components needed to replace or prevent loss of glycosaminoglycans. Normal intestinal cell loss and exchange is about half a million cells per minute. This increases up to 3 to 5-fold in inflammatory bowel disease. This may explain the need for additional aminosaccharides to promote cell regeneration since the content of free aminosaccharides in the system is very limited. When the loss of endothelial cells in the intestine exceeds their rate of production, it follows that the cohesion of the mucosa will be reduced. To further support the concept that N-acetylglucosamine prevents the loss or replacement of intestinal wall glycosaminoglycans in inflammatory bowel disease, we have observed that N-acetylglycosamine has a significant effect in stimulating hyaluronic acid synthesis when applied to intestinal lining or human mesothelial cells isolated from intestinal peritoneum.

Examples of Application of the Invention

Example 1

Previous research conducted by the University of British Columbia has shown that N-acetylglucosamine is the preferred precursor in the synthesis of glycosaminoglycan and proteoglycan components in inflamed and damaged tissue occurring in inflammatory bowel disease. This research suggests that oral administration of N-acetylglucosamine complements the body's intake of essential aminosaccharides when the body is under stress due to excessive disorder and tissue loss.

Example 2

The effect of N-acetylglucosamine on digestive tissue has also been shown in a trusted animal model of inflammatory bowel disease developed at the Department of Biology of the Royal University, Kingston, Ontario. Trinitrobenzenesulphonic acid and alcohol instilled interrectally induced a chronic inflammatory bowel disease reaction in rats with ulcers, intestinal wall fibrosis or thickening, and pathological and histological changes similar to those observed in ulcerative coitis. A single interrectal instillation of N-acetylglucosamine (NAG), prior to irritation with trinitrobenzenesulfonic acid (TNB), was found to have a significant dose-dependent effect on reducing the amount and severity of the ulcer as well as reducing the thickness of the intestinal wall (see Table 1 below).

Table 1: Intestinal wall fibrosis in rats exposed to trinitrobenzenesulfonic acid (TNB) -ethanol Ethanol φ φ φ φ φ φ φ φ φ φ φ φ · · · · · · · ·

Colon fibrosis (weight (mg) cm colon)

Intrarectal dosage

Control (20 mg TNB * in 0.25 ml ethanol) 25 mg NAG / kg gross weight 1 hr before TNB / EtOH mg NAG / kg gross weight 1 hr before TNB / EtOH

100 mg NAG / kg gross weight 1 hr before TNB / EtOH

Průměrtchyba

2.301 ± 0.222

1.669 ± 0.142 l, 339 ± 0.155 *

1.150 ± 0.068 * * Statistically significant deviation from control group

Example 3

Additional evidence that N-acetylglucosamine stimulates glycosaminoglycan synthesis has been observed in an ex vivo rat model that maintains blood supply to the stomach, but the stomach is open and placed in a plastic chamber, allowing drugs to be placed in, on the mucosal surface . When N-acetylglucosamine was placed on the surface of the gastric mucosa, it was observed that a large amount of mucus was released from the goblet cells of the stomach. Based on these observations, additional experiments were conducted in which, in the presence of ethanol (which is a gastric irritant), N-acetylglucosamine but not glucosamine were found to cause a substantial reduction in the potential difference between mucotic and serotic surfaces. This phenomenon may result from stimulation of the synthesis of sulfated glycosaminoglycans with N-acetylglycosamine. The effect of N-acetylglycosamine on stimulating the mucus released by the stomach may explain the undisclosed secret claims of clinicians that N-acetylglucosamine is effective in the treatment of non-erosive gastritis.

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In inflammatory bowel disease, glycosaminoglycans of the vascular and intestinal walls also break down. Development of the organ shows that this is due to the intestinal wall degrading enzymes. N-Acetylglucosamine is a substrate for the production of glycosaminoglycans, but in addition to this role serves as a fuel in the synthesis of fibroblasts in the intestinal wall, it has been shown that N-acetylglucosamine can act intracellularly as an O-phosphorylation antagonist and can therefore regulate many inflammatory pathways.

Examples 4 to 23

Clinical evidence of the effect of N-acetylglucosamine in inflammatory bowel disease

Research has been conducted at the Royal Free Hospital in London, (GB), and it has been reported that patients with inflammatory bowel disease lose glycosaminoglycans from the intestinal wall, which is associated with thickening of the intestinal wall or fibrosis. An ethical authorization has been obtained for the treatment of children with severe, untreatable upper or lower inflammatory bowel disease with N-acetylglucosamine. To date, more than 20 children have been treated with N-acetylglucosamine at doses up to 12 g per day. Children were generally resistant to other treatments, including such toxic drugs as azathioprine and intravenous steroids, and N-acetylglucosamine was therefore expected to provide minimal clinical benefit. Of the first 6 patients treated, 3 with inflammatory upper bowel disease responded well, with one child responding better than any previous treatment. Three children with inflammatory bowel disease did not show a significant therapeutic response to orally administered N-acetylglucosamine. This was not unexpected as only a small portion of each orally administered dose could be expected to reach the diseased tissue in the lower intestine.

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In order to expose inflamed colon to higher concentrations of N-acetylglucosamine, patients with inflammatory disease in the lower intestine were administered N-acetylglucosamine by rectal enema at a dose of 1 to 2 g three times a day. Initial 3 patients showed signs of clinical improvement within 48 hours of initiation of treatment. Pre and post colon colon biopsies of several children indicated that after 6 weeks of rectal treatment with Nacetylgucosamine, there was a substantial improvement in gut wall histopathology.

A representative example of this effect is shown in Figures 1 and 2. 1 is part of a biopsy prior to N-acetylglucosamine treatment, and clearly shows that prior to Nacetylglucosamine treatment, atrophic epithelium with severe inflammatory infiltrates and fibrosis occurred. Before complete loss of villi by treatment, the epithelial manifested was almost a membrane actually lacking. A biopsy after N-acetylglucosamine treatment (Fig. 2) showed significantly less inflammatory infiltrates, as well as an increase in villi and a near normal epithelial membrane.

Giant. Figures 3 and 4 are images of the same biopsies shown in Figures 1 and 2, at higher magnification. An important finding is a significant reduction in intestinal wall fibrosis.

Rectal administration of NAG (1.5 to 2 g per day per person), as the only treatment, to nine children with treatment resistant to peripheral colitis inflammation caused clinical resolution in 4 of these children, improvement in 3 children and no effect in 2 children . Biopsies before and after treatment show histological improvement in 4 out of 5 children, with a stunning increase in glycosaminoglycan (GAG) density in the intestines of these children (which φφ φφφ • · • · φ · · φ

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Φ ΦΦ ΦΦΦΦ Φ · Φ was not seen in other treatments) and itraepithelial spots of agglutin (WGA). In particular, epithelial morphology has been improved. Oral NAG (1 to 1.5 g per person per day) was added to treat 11 children with severe small bowel and colon disease, including seven with critical narrowing. 8 out of 11 children showed improvement, while 3 did not and required surgical resection. Six out of seven children with refractory constriction had a marked disappearance of symptoms. Endoscopic and radiological assays confirmed substantial improvement in 4 of 6 children. GAG and WGA spots were again denser in NAG treated children than in children treated with steroids or internal nutrition.

The first uncontrolled trial assumed that NAG was therapeutically effective on resistant ZOS, with a mode of action remote from conventional treatments. Its lack of known side effects has made it particularly suitable for medical use.

Starting in April or about April 1996, an extensive study of the use of prescribed doses of Nacetylglucosamine (NAG) in pediatric patients at Royal Free Hospital suffering from inflammatory bowel disease was conducted.

Since the start of NAG trials in April or about April, 1996, extensive medical history of NAG-tested children has been compiled. Biopsy details and other relevant information selected from such case bibles are reproduced as follows in the summary. The patient is in any case identified by his or her initials.

Rectal administration in ulcerative coitis (VC) and chronic rectal inflammation following colectomy (removal of the large intestine leaving the anus stump) and ileostomy (artificial duct in the ileum to remove feces through the abdomen) • ·

UCs with previous mean colectomy, ileostomy, and fistula on mucous membranes, now with chronic proctitis (chronic rectal inflammation) (presumed due to malfunction and UC support).

1. ZY. Incurable rectal stump proctitis to which metronidazole and corticosteroids have not previously succeeded. Initiation of NAG December 1996, doses of 2 grams rectally daily. Clinical response within 2 days, with blood loss stopped. Biopsy after treatment at 2 months showed significant improvement, especially in epithelial morphology and integrity, with a 30 to 50% reduction in inflammatory infiltrates. It has since been treated continuously with NAG, with only minimal symptoms.

2. SG. Clinical problem, inflammation in the ileoanal sac, with the additional problem of interrupting the growth of the sac with age (so symptoms only partly due to inflammation). Previous treatment with ciclosporin, interferon-α, corticosteroids, enemas containing long-chain fatty acids, metronidazole, codeine phosphate has failed. Beginning of NAG administration in March 1997, dose of 2 grams per day rectally (unfortunate with enema regimen twice daily). A mild clinical response, but histology at 1 month showed a definite improvement compared to pre-treatment biopsy, with an overall reduction in the histological vaccination index from 9/12 to 6/12. Continued rectal administration of NAG for histological response. Subsequent achievement of complete clinical recovery by administration of NAG in combination with antibiotics (metron, diazole and ciprofloxacin).

3. SB. Severe long-term inflammation of the rectal stump, not responsive to corticosteroid enemas, metronidazole and ciprofloxacin. Administered by NAG enemas since April 1997, dose 1 gram twice daily rectally. After 2 months reported only minor

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9999 99 99 99 99 9 clinical improvement but significant histological response compared to pre-treatment biopsy. In this case, inflammatory infiltrates decreased significantly while epithelial changes were less marked.

4. MS. Incurable inflammation of the rectal stump, non-responsive to cyclosporin, corticosteroids and antidiarhotics. Initiation of NAG enemas (1 gram 3 times daily) first in October 1996, with significant improvement. Biopsies were not performed this time. The enemas were discontinued due to good clinical progress in December 1996, and its symptoms gradually returned. NAG enemas were resumed in June 1997 (1 gram twice daily) after pre-treatment biopsy.

5. LE. (possible diagnosis of Crohn's disease but with similar inflammation of the rectal stump after colectomy not responding to corticosteroids and cyclosporin). Launch of NAG enemas (1.5 grams twice a day), June 1997, after pre-treatment biopsy. Subsequent clinical trials and biopsies in August 1997 showed significant improvement.

6. SE-K. Severe persistent inflammation of the rectal stump, resistant to local and systemic steroids, motronidazole, ciprofloxacin. Initiation of rectal administration of NAG (1.5 grams twice daily) in June 1997. The pre-treatment biopsy showed anal mucus, making post-treatment biopsy difficult to explain. However, the clinical response was immediate and striking, and showed complete cessation of bleeding and loss.

7. RM. Persistent inflammation of the rectal stump, with severe perineal inflammation. Treatment (1 gram twice a day) was discontinued at the request of the child after a short period due to pain when inserting an enema catheter.

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Rectal administration in peripheral bowel disease (without surgery involving removal of part of the colon and leaving a rectal stump (colectomy))

8. MI. Chronic distal proctitis, indeterminate histology, resistant to corticosteroids and ciprofloxacin. Proctitis was limited to the first 5 cm of the colon and did not affect the rectum. NAG enemas (1.5 grams per person per day) initiated since February 1997, discontinued after 2 months without effect.

9.. SE. Severe rectal ulcerative colitis, almost requiring crisis surgery in July 1996. During this event, the patient received intravenous azathioprine, heparin, corticosteroids and NAG administration was initiated during the recovery phase. This was administered in doses of 1 g three times a day by mouth and 1 g twice a day rectally. Subsequently, the patient was maintained on azathioprine, various doses of corticosteroids and aminosalicylates. The patient showed an extremely good clinical response, under the circumstances of her severe illness, which would normally be treated surgically, but this was avoided in this case. Although it was not possible to determine the individual benefit of NAG, it is worth noting that its rectal biopsy showed signs of relative histology improvement that were not detectable before NAG enemas were administered. The patient is currently fine and continues to take oral NAG, azathioprine, and low doses of heparin.

Crohn's disease (with or without surgery)

10. AT. This boy had Crohn's disease and a narrow narrowing of the rectum, which, due to the boy's growth, required 9 9 * 9 · _ "9" «9 The last 3 years of regular surgical extension. Because of his illness, it was maintained at low oral doses of prednisolone and aminosalicylates, and NAG enemas (1 g twice daily) were started in December 1996. Since the start of NAG administration, the boy has shown significant clinical improvement, and subsequent tests under anesthesia in March 1997 showed clear improving its anus narrowing with substantially less need for elongation. It was also found that the inflammation of the mucosa was also reduced. Subsequently, he remained completely free of symptoms.

11. HS. A girl with long-term Crohn's disease, previous hemicolectomy and multiple narrowing surgery. Previous treatment with internal nutrition, corticosteroids, azathioprine, cyclosporine and aminosalicylates. Previous barium examination showed multiple narrowing, and the patient became generally insensitive due to steroid treatment. Initiation of NAG administration in July 1996 (1 g three times daily by mouth), and this was associated with a clear improvement in the symptoms associated with narrowing and a reduction in the signs of inflammation. She had only one minor relapse in January 1997, but was subsequently fine. Subsequent barium examination in April 1997 was normal.

12. GC. A boy with severe left-sided Crohn's Colitis (who is clinically known as a potentially refractory disease) resistant to internal nutrition, azathioprine and corticosteroids. In addition, he had associated inflammatory rectal narrowings. NAG (1 g three times daily by mouth and 500 mg twice daily rectally) was started in April 1996, in addition to its intensive treatment regimen. Although subsequent endoscopy showed evidence of a rectal investigation that was previously unclear, its symptoms remained unimportant and underwent partial colectomy in February 1997.

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13. GN. A boy with a medical history similar to GC (above) untreatable left Crohn's colitis. He did not respond to corticosteroids, aminosalycilates, internal nutrition and azathioprine. NAG (1 g three times a day by mouth) was started in April 1996. He minimally responded to this treatment and underwent a partial colectomy in March 1997.

14. LC. Third patient with severe left-sided Crohn's colitis. She was treated with internal nutrition, aminosalicylates, corticosteroids and azathioprine. 4 months after initiation of azathioprine, she remained severely ill with persistent rectal bleeding, severe anemia and a marked increase in inflammatory manifestations. In February 1997, she was given NAG (1 g three times daily by mouth) in addition to azathioprine and steroids. It showed a marked clinical improvement within two weeks after initiation of NAG administration, and subsequently a complete resolution of the disease symptoms occurred. The only factor that complicated the explanation for this case was that azathioprine may show a delayed effect on efficacy, but the timing of improvement with NAG was very striking and the patient avoided the colectomy previously thought to be inevitable. Recently, there was a problem with NAG supplies and its symptoms reappeared.

15. DB. This boy recently had severe Crohn's disease affecting the end of the ileum with a narrowing. He did not respond to corticosteroids, internal nutrition, azathioprine and aminosalicylates. NAG (1 g twice daily by mouth) was started in April 1996. He showed a limited clinical response, and underwent a hemicolectomy in June 1996. The severity of his disease was shown to be a rapid early relapse and is now undergoing an unrelenting course of the disease.

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16th RP. The girl suffered from a narrowing form of Crohn's disease, and had previously removed two small intestinal narrowings where surgeons noticed multiple other small intestinal narrowings (January 1995). She was treated with internal nutrition and aminosalicylates, plus occasionally corticosteroids. In terms of symptoms associated with severe stricture, confirmed by barium monitoring during March 1996, when she had multiple small intestinal narrowings, she was started with NAG in March 1996 (starting dose of 1 g three times daily, increased to 2 g three times daily in August 1996). The barium assay showed a reduction in narrowing after one month of NAG treatment, associated with a very marked clinical improvement. Subsequent barium tests in September and December 1996 did not show the presence of constrictions. Thus, the inventors received radiological and clinical evidence of improvement by administering NAG in the narrowed form of Crohn's small intestine disease.

17. EH. This girl had a long constriction at the end of the ileum, associated with the long-term Crohn's disease. This was confirmed by barium follow-up in December 1996, when it was recorded prior to synoptic prolongation and the patient complained of obstructive pain while receiving solid food. She was treated with internal nutrition, aminosalicylates and steroids. She was initiated with NAG (1 g three times daily by mouth) in November 1996 as a supplement to her current treatment. Within 3 to 4 weeks she became asymptomatic and was able to eat unlimited food. She remained asymptomatic and left out steroids. A subsequent barium test in June 1997 showed a reduction in the constriction, although it still had a radiologically significant constriction. Undoubtedly, without treatment for NAG, her condition would require hemicolectomy and removal of her narrowness, as she was in critical condition in November 1996. Now, the inventors are unsure whether the patient will completely avoid surgery, but will certainly remain on NAG for a long time because of its obvious benefit to her.

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18. ML. This boy had narrowed Crohn's disease, with a history of previous hercolectomy, resection of the narrows, and then the development of stomach blockage due to narrowed duodenal disease. He underwent endoscopic dilatation in May 1996, at which time he was given NAG (1 g twice daily). His additional treatment was based on internal nutrition. Salazopyrine and azathioprine as a supplement to omeprazole (steroid). Underwent re-dilation in July 1996, when the narrowing was improved, this was confirmed by swallowing barium in August 1996. Repeated endoscopy in March 1997 showed a significant improvement with almost no evidence of residual narrowing. However, he was re-admitted with the re-emergence of the narrows, now undergoing surgery. Meanwhile, he continued to treat NAG as a supplement to other treatments. Thus, the early apparent constriction of the constrictions was not maintained, but there is benefit since omeprazole has been omitted in the meantime.

19. IJ. This boy also had multiple small intestine constrictions with a very aggressive Crohn's disease. Previously, internal nutrition, azathioprine, and high doses of corticosteroids had failed, and had also previously experienced a gambling collector. He has been shown to have multiple critical small bowel constrictions that have been a major therapeutic problem. He was initiated with NAG (1.5 g three times a day by mouth) in February 1997, in addition to his continued prior treatment with azathioprine and internal nutrition. He showed a gradual improvement, both in terms of his symptoms associated with narrowing and his inflammatory ideals. The early barium test in March 1997 showed no significant improvement in the narrowing after one month at NAG. The following bar monitoring is likely to be performed in the fall.

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20. NBL. This girl had a narrow Crohn's disease of the small intestine, with a long narrowing at the end of the ileum with pre-synoptic dilatation. She was previously treated with internal nutrition and aminosalicylates. She was started with NAG (1.5 g three times a day) in April 1997, in conjunction with internal nutrition. The patient significantly improved clinically, with no concomitant symptoms associated with strictures when examined in June 1997. The inventors plan to perform a subsequent barium study.

Overall appreciation

Previous evidence confirms that NAG has a decisive therapeutic effect on the treatment of inflammatory bowel disease. There are some clear areas where NAG appears to outperform conventional treatment. NAG clearly proves effective in rectal administration in colitis causing malfunction followed by partial colectomy. Several observed children treated with NAG showed very rapid clinical improvement. Subsequent histological examination of 3 NAG treated children showed a definite improvement. In addition, children who had more extensive colitis developed evidence of rectal thrift that was not there before.

NAG also has been shown to be beneficial in narrowing variants of inflammatory bowel disease (ZOS), especially in narrowing of the upper small intestine. In recent months, there has been only one failure of long-term treatment due to a temporary NAG delivery problem, and all other NAG-treated children suffering from small bowel narrows have shown improvement. Certainly, NAG has been instrumental in avoiding early narrowing surgery in 2 children who had critical narrowing before starting NAG treatment and who are currently symptom free.

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Cases where NAG proved to be less successful were in the treatment of the end of the ileum and upper bowel disease when NAG was administered by mouth. In contrast, rectal treatment with NAG showed a marked improvement. The latter success is probably due to the fact that rectally administered NAG does not have to undergo the intestinal digestion process. Accordingly, administration of NAG with a suitable carrier that can deliver NAG to the ZOS will be successful in treating ZOS. Suitable carriers for rectal administration may be distilled or purified water, a foam suitable for rectal administration, or a suppository. A suitable carrier for oral administration is a coating or double coating in which NAG is protected, a coating or double coating that resists acidic and enzymatic degradation in the stomach and small intestine until the area affected by the CVD is reached. Then the coating is digested and the NAG is delivered intact to the affected area.

As will be apparent to those skilled in the art, in light of the foregoing findings, many alternatives and modifications of the present invention are possible in practice without departing from the spirit of the scope described herein. Accordingly, the scope of the invention is constructed in accordance with the spirit defined by the following claims.

Bibliography

1. Burton, AF and Anderson, FH, Decreased Incorporation of ¹⁴ C-Glucosamine Relative to ³ H-Acetyl Glucosoamine in Intestinal Mucosa of Patients with Inflammatory Bowel Disease., J.Biol.Chem. 78, 19 (1983).

2. Vantrappen, G. and Geboes, K., Glycosaminoglycans and the gut, Lancet, 341, 730 (1993).

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3. Murch, S.H. et al., Disruption of Sulfated Glycosaminoglycans in Intestinal Inflammation, Lancet, 341, 711 (1993).

4. Murch, S.H. et al., Congenital enterocyte heparan sulphate deficiency with massive albumin loss, secretory diarrhea, and malnutrition, Lancet, 347, 1299 (1996).

5. Murch, S. H., Sulfation of Proteoglycans and Intestinal Function, J. Gastroenterol. Hepatol, PO, 210 (1995).

6. Pender, S. L., Gut, 39, 284-290 (1996), J. Immunol.

158, 1582-1590 (1997).

JUDr. P © tr teloosfef attorney • 9 • · · (alternate page)

Claims (9)

A composition for a patient suffering from the treatment of inflammatory bowel disease with inflammatory bowel disease comprising: (a) a therapeutic amount of N-acetylglucosamine; and (b) a pharmacologically and intestinal acceptable carrier adapted for delivery of N-acetylglucosamine to the intestines of said patient and for topical administration to an inflammatory bowel disease site in the intestine of said patient. Composition according to claim 1, characterized in that N-acetylglucosamine is present in the composition in an amount ranging from 0.5 g to 5 g. The composition of claim 1, wherein the carrier is distilled or purified water. The composition of claim 2, wherein the carrier is distilled or purified water. The composition of claim 1, wherein the carrier is a foam suitable for rectal administration. The composition of claim 2, wherein the carrier is a foam suitable for rectal administration. fcfc fcfc fcfc (replacement) 7. The composition according to Claim 1 v y z n a č u .mu.Ci s e by the carrier is suppository basis, who obaluj e N- -acetylglucosamine. 8. The composition according to Claim 2 v y z n a č u .mu.Ci s e by the carrier is suppository basis, who obaluj e N- -acetylglucosamine. 9. The composition according to Claim 1 v y z n a č u .mu.Ci s e in that the carrier is an orally indigestible time release substance that will withstand degradation of the stomach digestive acids and release N-acetylglucosamine in the intestines. The composition of claim 2, wherein the carrier is an orally non-digestible, time-released substance that resists digestion of the stomach digestive acid and releases N-acetylglucosamine in the intestines. The composition of claim 3, wherein the water is present in sufficient quantity to allow the rectum enema. The composition of claim 5, wherein the foam comprises N-acetylglucosamine, a surfactant, an adjuvant, and a blowing agent. The composition of claim 6, wherein the foam comprises N-acetylglucosamine, a surfactant, an adjuvant and a blowing agent. (spare page) Composition according to claim 12, characterized in that the carrier comprises one or more substances selected from the group consisting of propylene glycol, emulsifying wax, polyoxyethylene-10-stearyl ether, ethoxylated cetyl alcohols and stearyl alcohols, stearate-10, cetyl alcohols, methylparaben, propylparaben, trolamine , purified water, cetyl alcohols, ethoxylated stearyl alcohols, polyoxyethylene-10-stearyl ether, methyl and propylparaben, propylene glycol, anhydrous ethanolamine, deionized water and suitable propellants. Composition according to claim 13, characterized in that the carrier comprises one or more substances selected from the group consisting of propylene glycol, emulsifying wax, polyoxyethylene-10-stearyl ether, ethoxylated cetyl alcohols and stearyl alcohols, stearate-10, cetyl alcohols, methylparaben, propylparaben, trolamine , purified water, cetyl alcohols, ethoxylated stearyl alcohols, polyoxyethylene-10-stearyl ether, methyl and propyl parabens, propylene glycol, anhydrous ethanolamine, deionized water and suitable propellants. The composition of claim 7, wherein the suppository base is selected from the group consisting of theobromine oil, glycerinated gelatin, hydrogenated vegetable oil, polyalkyl glycol, polyalkylene glycol fatty esters. acids, coconut oil base, hydrogenated fatty acids, hydrogenated vegetable oil, monoglyceride, cocoa butter, petroleum oil, beeswax, glycerin, polyethylene glycol-600-dilaurate, hydrogenated cocoa glyceride and polyethylene glycol. (spare page) The composition of claim 8, characterized in that the lace base is selected from the group consisting of theobromine oil, glycerinated gelatin, hydrogenated vegetable oil, polyalkyl glycol, polyalkylene glycol fatty acid esters, coconut oil base, hydrogenated fatty acids, hydrogenated vegetable oil, monoglyceride, coconut butter, petroleum oils, beeswax, glycerin, polyethylene glycol-600-dilaurate, hydrogenated cocoa glyceride, and polyethylene glycol. The composition of claim 9, wherein the time-exuding agent is selected from the group consisting of an acrylic-based resin coating, a methacrylic acid copolymer, an acrylic-based resin base admixed with a suitable non-medicated carrier such as lactose, magnesium stearate, polyethylene glycol, polyvinylpyrrolidone. or starch sodium glycolate, cellulose or ethylcellulose, a basic composition comprising a hydrophilic polymer and an enteric polymer, a cellulose derivative, polyvinyl acetate phthalate or polyvinyl acetate phthalate mixed with a plasticizer, polysaccharide that is degradable in the intestines, locust bean gum or guar gum, film-forming a polymer comprising hydrophilic groups, a film-forming acrylic polymer admixed with polysaccharides containing from 30 to 100% by weight of at least one monomer selected from the group consisting of lower alkyl esters of acrylic acid and lower alkyl esters of methacrylic acid, hydrocolloid gum obtained from higher plants, and an anionic carboxyl polymer that does not dissolve at (pH side) · pH · • · * · * · pH · * · less than about 4, but is soluble at a pH in the range of about 4 to about 7.5. Composition according to claim 5, characterized in that the foam contains 0.5 to 5 g of N-acetylglucosamine as active ingredient and 20 g of foam comprising propylene glycol, emulsifying wax, polyoxyethylene-10-stearyl ether, cetyl alcohol, methylparaben and propylparaben, trolamine, purified water and inert propellants, dichlorodifluoromethane or dichlorotetrafluoroethane. 20. The composition of claim 9, wherein the composition comprises between about 0.1% to about 90% by weight of N-acetylglucosamine coated with from about 5% to about 29% by weight of the hydrophilic polymer, and from about 0.5% by weight. % to about 25% by weight of an acrylic polymer that dissolves at a pH in the range of about 5.0 to about 7.5. 21. A method of treating a patient suffering from inflammatory bowel disease comprising administering to the intestine of said patient a composition comprising a therapeutic amount of N-acetylglucosamine and a bowel-compatible pharmacologically acceptable carrier, wherein the composition is administered topically to the inflammatory bowel disease site in the intestines of a patient suffering from an inflammatory bowel disease. * 9 9 9 9 9 9 99 99 * · · · · ···· 9 9 9 9 (replacement page) ··· · ·· 99 9 22nd Way according to claim 21, v y z n a č u .mu.Ci s e t í m that N-acytylglucosamine is present in quantities between about 0.5 g to 5 g per enema. 23. Way according to claim 21, v y z n a č u .mu.Ci s e t í m that pharmacologically acceptable carrier is distilled or purified water. 24. Method according to Claim 22 v y z n a č u j í c í s e t í pharmacologically acceptable carrier Yippee distilled or cleaned water. 25. Method according to Claim 23 v y z n a č u 3 í c í s e in that said enema is administered to said patient by an enemator. 26. The method of claim 21, wherein the carrier is intestinal-compatible foam that covers the inner surface of the colon. The method of claim 22, wherein the carrier is intestinal-compatible foam that covers the inner surface of the colon. The method of claim 21, wherein the carrier is a suppository that is solid at room temperature but melts at body temperature. The method of claim 22, wherein the carrier is a suppository that is solid at room temperature but melts at body temperature. (replacement page) «· 0 0 » 0000 • 0 • 000 • 0 00 0 ·· 9 0 0 00 0 0 0 0 0 0 «0 0 • 0 00 0 » 9 0 • 0 0 0 · 0 0 009 The use according to claim is administered to the patient by an enemator. Use according to claim a compatible foam to cover Use according to claim compatible foam to cover 36, where enema se mentioned 34, wherein the carrier is with the intestines : inner surface of the colon. 35, where carrier Yippee with the intestines the inner surface of the colon. The use of claim 34, wherein the carrier is a suppository that is solid at room temperature but melts at body temperature. The use of claim 35, wherein the carrier is a suppository that is solid at room temperature but melts at body temperature. The use of claim 39, which is indigestible with time-induced digestive acid of the stomach acetylglucosamine. 34, wherein the carrier is an oral substance that will withstand disintegration and release in the colon N44. The use according to claim 35, a non-digestible time excreted substance, stomach digestive acids and acetylglucosamine.