WO1994000476A1 - Use of water-soluble sucroses for the treatment and/or prevention of lesion or inflammation in the digestive tract - Google Patents

Abstract

A method of treating and/or preventing lesion and/or inflammation of non-peptic ulcer nature in the digestive tract of an individual and a method of treating and/or preventing lesion and/or inflammation of the oesophageal, gastric and/or duodenal mucosa of an individual. The method comprises administering to a patient in need thereof a therapeutically or prophylactically effective amount of a salt or complex of a sulfated sucrose, said sucrose salt or sucrose complex being water-soluble at a neutral pH. The sulfated sucrose is at least disulfated and the salt or complex of the sucrose sulfate may be e.g. a salt or a complex with an alkali metal such as sodium or potassium, or an alkaline earth metal. An interesting sucrose sulfate is sodium sucrose octasulfate. The lesion and/or inflammation may e.g. be caused by conditions located in the oesophagus, in the stomach, in the duodenum, in the jejunem or in the ileum, colon or rectum. It may also be conditions caused by fistulae, trauma, enterotoxins, viral infections or microorganisms. Furthermore, the lesion and/or inflammation may be caused by premalignant or malignant diseases.

Description

USE OF WATER-SOLUBLE SUCROSES FOR THE TREATMENT AND/OR PREVENTION OF LESION OR INFLAMMATION IN THE DIGESTIVE TRACT

FIELD OF INVENTION

The present invention relates to the use of a water-soluble salt or water-soluble complex of a sulfated sucrose for the treatment and/or prevention of lesion and/or inflammation in the digestive tract of an individual.

TECHNICAL BACKGROUND

While it is difficult to give an adequate description of inflammatory phenomena in terms of underlying cellular event in the injured tissue, there are certain features of the process that are generally agreed to be characteristic. Thes include fenestration of the microvasculature, leakage of the elements of blood into the interstitial spaces arid migration of leukocytes into the inflamed tissue. On a macroscopic level, this is usually accompanied by the familiar clinical signs of erythema, oedema, tenderness and pain. During this complex response, chemical mediators such as histamine, serotonine, leukotrieneε, prostaglandines, various chemo- tactic factors, bradykinin, lymphokines, kinin and complemen system, lysosomal enzymes and cyclic nucleotides are libe¬ rated locally. Phagocytic cells migrate into the area, and cellular lysosomal membranes may be ruptured, releasing lyti enzymes which in severe cases causes lesions. All these events contribute to the inflammatory response.

Inflammation may also be aggravated by stress. When faced to an stressful situation, the body responds by increasing production of hormones such as adrenaline and cortisol. In addition to this increased production of hormones, stress is known to interfere with the normal immune response in a way not fully elucidated. It is believed that stress af- fects the release of interleukines produced by immunologi- cal active cells. It has been shown that stress decreases the resistance of the body against cancer, and, moreover, many autoimmune diseases progress during stress. Further- more, it is known that surgery is a very powerful stress factor affecting the immune system.

Several drugs are employed to suppress the manifestations of inflammation, including the adrenocorticosteroids, the large group comprising the so called non-steroid anti- inflammatory drugs or NSAIDs, and drugs such as immunosup- pressive agents.

NSAIDs are chemically a heterogeneous group of drugs, mainly constituting aromatic substituted carboxylic acids. Pharmacologically, they have anti-inflammatory, antipyretic and analgetic effects, and they inhibit prostaglandin synthesis and decrease thrombocyte aggregation. The mode of action of NSAIDs is not yet fully understood, although it is known that they inhibit one or more of the mediator substances of inflammation. However, there is no good correlation between inhibition of prostaglandin synthesis and anti-inflammatory effect. The main indication for NSAIDs is rheumatic diseases, particularly where inflam¬ matory processes in supporting tissues give rise to pain and joint-stiffness. Furthermore, the analgetic effects can be used as symptomatic pain relief in cases where the prostaglandin inhibitory effect can be utilized, such as dysmenorrhoea, urolithiasis, etc. Some of the drugs, in¬ cluding indomethacin, have also been used topically on the skin in the treatment of various dermatoses and as a topi- cal anti-inflammatory agent in the eye.

The use of NSAIDs gives rise to a broad spectrum of side effects. Severe and often fatal blood dyscrasias are often seen, notably following the use of phenylbutazone, and gastrointestinal side effects are common with phenylbutazo- ne, salicylates and indomethacin. Allergic reactions are common and may in some cases be due to prostaglandin in¬ hibition with a resulting secondary increase in leucotriene levels. Hepatotoxicity and nephrotoxicity as well as side effects of the central nervous system are also common with these drugs.

Adrenocorticosteroids, and especially glucocorticoids, have potent anti-inflammatory effects when used in pharmacologi¬ cal doses. They specifically inhibit the early vascular phase of the inflammatory process by decreasing the vas- cular permeability and thereby granulocyte migration.

Glucocorticoids also interfere with late inflammatory and reparative processes, in that they inhibit the prolifera¬ tion of mesenchymal cells and the production of intercel¬ lular macromolecules, including proteoglycanes and col- lagen. It has been shown experimentally that glucocorti¬ coids inhibit, for example, macrophage function, production of humoral antibodies, cellular immunity, and possibly the release of lysosomal enzymes. The indications for systemic use of glucocorticoids are apart from substitution therapy very limited, because of side effects, and should be re¬ stricted to severe inflammatory rheumatic diseases, severe cases of allergic diseases such as asthma bronchiale and status asthmaticus and cases of haematological, renal, and gastrointestinal immunological diseases.

Sucralfate which is a sucrose polysulfate-aluminu complex (sucrose octakis(hydrogen sulfate) has been used for the treatment of gastric and duodenal ulcers (cf. US 3,432,489; EP 161816; EP 192640) and for the treatment of emesis and diarrhoea in dogs and cats (cf. EP 133880) . In radio- labelled form, sucralfate has also been used as a diag¬ nostic agent for the imaging of gastrointestinal mucosa, since the substance binds selectively to ulcerated areas in the stomach and upper small intestine (cf. EP 107209) . EP 394333 discloses the topical application of sulfated sugars against inflammation outside the gastrointestinale tract . In fact, sucralfate has been used clinically for more than two decades in the treatment of gastric and duodenal ul¬ cers. Sucralfate is insoluble in water at neutral pH but relatively soluble at normal gastric pH. It is poorly absorbed after oral administration. The exact mode of action of its anti-inflammatory effect has not been re¬ vealed, but one of the following mechanisms may be invol¬ ved:

direct or indirect inhibition of formation of local tissue proinflammatory mediators,

inhibition through regulation of the cyclooxygenase path¬ way,

stimulation of lipocortin production, which in turn in¬ hibits the activity of phospholipase.

Previously, the therapeutic effect of sucralfate on the gastric mucosa has been suggested to be mediated through (i) formation of a protective barrier and thereby reducing pepsin and H⁺ induced injury, (ii) binding of pepsin and bile acids by the aluminum complex, i.e. sucralfate, or

(iii) trophic effects on the mucosa blood flow.

In EP 107 209, Chugai describes sucralfate as an agent which is stated to be characterized by anti-pepsin and anti-acid effects in that it is said to bind to the pepsin and acids in the gastric juice. Pepsin and acids are two agents which attack the ulcer-affected area of the diges¬ tive tract. When binding to pepsin and acid, sucralfate is believed to inhibit their destructive activities directly. Sucralfate is also stated to be characterized by its abil- ity to protect the mucosa in that it is said to form a su¬ cralfate coat on the mucosa of the digestive tract and protects it from attacking factors. These effects combine to provide sucralfate with high anti-ulcer activities. Sucralfate is also believed to be effective in revasculari- zation and accelerating the growth of regenerated mucosa, and is considered to have a great potential for use as an agent to promote the healing of ulcers. Sucralfate is described to have an ability to selectively bind to the ulcer-affected mucosa of the stomach and duodenum rather than the normal mucosa of the digestive tract and forms a protective coating against the invasion of the attacking factors. Sucralfate forms a sticky paste in an acidic solution at a pH below 4.0. When administered orally, sucralfate is believed to react with gastric juice in the stomach to form a sticky paste which binds to the ulcer- affected part of the stomach or duodenum to exhibit a sustained effect to protect the mucosa in that part.

In the American Journal of Gastroenterology, 80(3), 1985, pp. 206-209; "Sucralfate: Nonulcer uses". Brooks, Jr. et al. suggest the use of sucralfate for a variety of non— ulcer applications, including the treatment of post-sclero¬ tic ulcer, reflux oesophagitis and bile reflux oesophagitis as well as for counteracting the ulcerogenic effects of aspirin. However, the suggested applications are all re¬ lated to conditions in which acid is involved or to condi¬ tions in which the sucralfate is believed to adsorb bile.

In US 3,432,489 (Yoshihiro et al.) which disclose sucral- fate as a peptic ulcer inhibiting agent, the effect of sucralfate is compared to the effect of sodium sucrose sulfate. Shay's rat ulcer model was used and from the results as reported in Table III in US 3,432,489 it can be seen that sodium sucrose sulfate in doses of 30, 50 and 100 mg, respectively, (corresponding to about 150 mg/kg, 250 mg/kg and 500 mg/kg, respectively) , has almost no effect against ulcer development, i.e. the study clearly demon¬ strates that only sucralfate has a potential as an ulcer inhibiting agent. Furthermore, it is described that the toxicity of sodium sucrose sulfate is higher than that of sucralfate. The efficacy of sucralfate is believed to be primarily - dependent on an acid environment enabling an aluminum- containing gel to be formed. An acidic environment is necessary for the formation of the aluminum-containing gel. This gel protects the ulcers from the gastric juice and thereby prevents further damage. Thus, for treatment of diseases in the digestive tract, sucralfate has been sug¬ gested for use on sites in which peptic ulcer occurs, i.e. in the lower part of oesophagus, in the stomach and in the upper part of the duodenum. However, Showkat et al. dis¬ close in Dis Colon Rectum, 1991; 34:455-457 in a prelimi¬ nary study that sucralfate administered topically as enemas is effective for treatment of recurrent solitary rectal ulcer. Kochhar et al. disclose in Digestive Diseases and Sciences, 1991; 36:103-107 that sucralfate enemas are effective in treatment of radiation-induced proctosigmoidi- tis.

Sucralfate which is an aluminum-containing compound has been approved by the Food and Drug Administration (FDA) for short-term (up to eight weeks) treatment of duodenal peptic ulcer. However, use of an aluminum-containing compound in human therapy has a potential risk of resulting in elevated levels of aluminum in specific tissues such as brain gray matter, bone and muscle. Elevated aluminum levels in these tissues have been implicated in the etiology of a number of disorders, especially in Alzheimer's disease. Until recent¬ ly, sucralfate was believed to be a safe drug devoid of any side effects, especially aluminum-related side effects. However, Pai et al. (J. Clin. Pharmacol., 27., 1987, 213- 215) have studied serum aluminum concentrations in ten healthy subjects treated with phenytoin 500 mg and with sucralfate and phenytoin in a cross over fashion. Each subject received four 1000 mg sucralfate tablets twice daily before the study and this dosage regimen was repeated during the study day. A total of eight doses of sucralfate was administered over a two-day period. The study shows a statistically significant increase in serum aluminum con¬ centration even after two days of treatment with sucral¬ fate. The areas under the serum aluminum concentration- times curves before and after sucralfate were 496.0 and 770.9 hr ng/ml, respectively, given as mean values. In¬ creases in serum aluminum concentration of the above-men¬ tioned order of magnitude have been implicated in memory- loss related problems and in hyperactivity and learning disorders in children. Increases in plasma aluminum levels in subject taking the usual dosage regimen may be even higher.

Due to the above-mentioned potential aluminum related side effects after administration of sucralfate, there is a need for developing more safe methods of treating and/or preven- ting e.g. peptic ulcers. It should be clear that such methods should involve administration of non-aluminum- containing drug compounds or compounds with a substantially lower load of aluminum in the drug compound than found in sucralfate which contains about 20.7 % w/w aluminum.

Furthermore, there is also a need for developing safe and effective drugs for treatment and/or prevention of lesion and/or inflammation in the digestive tract.

SUMMARY OF THE INVENTION

In one aspect, the invention provides a method of treating and/or preventing lesion and/or inflammation of non-peptic ulcer nature in the digestive tract of an individual, the method comprising administering to a patient in need there¬ of a therapeutically or prophylactically effective amount of a salt or complex of a sulfated sucrose, said sucrose salt or sucrose complex being water-soluble at a neutral pH. In another aspect, the invention provides a method of treating and/or preventing lesion and/or inflammation of the oesophageal, gastric and/or duodenal mucosa of an individual, said method comprising administering to a patient in need thereof a therapeutically or prophylacti¬ cally effective amount of a salt or complex of a sulfated sucrose, said sucrose salt or sucrose complex being water- soluble at a neutral pH and said amount being in a range of about 1-300 μmol per dose.

The present invention further relates to the use of a water-soluble salt or complex of a sulfated sucrose for the manufacturing of a pharmaceutical preparation for the treatment and/or prevention of inflammatory diseases in the digestive tract, in particular inflammatory diseases which are of a non-peptic ulcer nature (as defined below) and inflammatory diseases of the oesophageal, gastric and/or duodenal mucosa.

In the present specification and claims, lesion and/or inflammation of non-pectic nature in the digestive tract is intended to designate lesion and/or inflammation which is not caused by the action of acid gastric juice, and which is located in the digestive tract from uvula to anus.

Based on tests described below, it is contemplated that water-soluble sulfated sucrose is a relatively non-toxic substance exerting anti-inflammatory effects. Water-soluble sucrose sulfates constitute a very interesting alternative and supplement to known drug substances used for the treat¬ ment of diseases in the digestive tract.

Compared to sucralfate, aluminum related side effects can be eliminated, when the water-soluble sulfated sucrose is without any aluminum component. In contrast to sucralfate, the sucrose sulfates used according to the present inven¬ tion are water-soluble at neutral pH. As it is believed that the applied active substance must be present predomi- nantly in dissolved form in order to exert the anti-inflam¬ matory effect, it implicates that a much smaller dose Is necessary when a water-soluble sucrose sulfate is used as the active principle than when sucralfate, which is practi- cally insoluble at neutral pH, is used. Thus, even in cases where the water-soluble sucrose sulfate contains an alumi¬ num component, it is believed that the aluminum related side effects may be dramatically reduced compared to the aluminum related side effects after administration of sucralfate.

In the following is described a number of tests performed by the Applicant in order to demonstrate an anti-inflam¬ matory effect of a water-soluble sucrose salt or complex.

The effect of potassium sucrose octasulfate against the production of interleukin-2 (11-2) and interferon-gamma (INF-gamma) - both spontaneous produced and PHA-induced production - of normal mononuclear human cells was tested in an in vitro model. The concentration of potassium su¬ crose octasulfate was 10, 1 and 0.1 mg/ml. It was demon- strated that potassium sucrose octasulfate exerted a dose- related inhibition of the PHA-activated production of the cytokines interferon-gamma and interleukin-2 from human normal mononuclear cells. The dose-related inhibition was observed at concentrations above 1 mg/ml.

Furthermore, it has been demonstrated in the same model as mentioned above that potassium sucrose octasulfate in concentrations of 1-3 mg/ml gives a 50% inhibition of interleukin-2 and interferon-gamma production from humane T-lymphocytes stimulated with either specific antigen or polyclonal activator. In the test, potassium sucrose oc¬ tasulfate did not seem to be toxic in concentrations up to 10 mg/ml, as judged from vital staining.

In conclusion, the results from the above-mentioned in vitro tests indicate that potassium sucrose octasulfate exerts a potent anti-inflammatory effect. Furthermore, the^' compound is found to be relatively non-toxic.

Another in vitro experiment supports that a water-soluble sucrose sulfate has anti-inflammatory properties. In this in vitro experiment (see Example 1) , the inhibition by sodium sucrose octasulfate of Interleukin-1 alpha induced release of Interleukin-8 from human endothelial cells was determined.

Furthermore, it has been possible to demonstrate experimen- tally in animals that the potassium salt of sucrose oc¬ tasulfate exerts an anti-inflammatory effect which is comparable to that of indomethacin when the drug is ad¬ ministered topically to the skin in order to protect against light-induced erythema (Example 2) . The evaluation of this effect was performed subjectively using a visual scoring scale.

In order to evaluate the effects and possibly reveal the underlying mechanisms of the anti-inflammatory effect of the water-soluble sodium sucrose octasulfate, a double blind, placebo controlled, objectively monitored study has been conducted using a UV-B induced skin inflammation model in human volunteers (Example 3) . From this study, a cream containing 2% sodium sucrose octasulfate was found to inhibit UV-B induced skin inflammation in humans, whereas a cream containing 18% sodium sucrose octasulfate increased UV-B induced inflammation in normal human skin. According¬ ly, no linear dose-effect relationship for sodium sucrose octasulfate could be established. Using the cream vehicle and human skin as a model, the optimal anti-inflammatory effect was produced by sodium sucrose octasulfate cream 2%.

Water-soluble potassium sucrose sulfate has also been tested for acute intravenous toxicity in mice, and the intravenous LD₅₀ dose has been found to be approximately in a range of 250-500 mg/kg body weight (example 4) . In a 11 tolerance study with sodium sucrose octasulfate in rats, it has not been possible to establish a toxic dose of sodium sucrose octasulfate, even using daily intravenous dose as high as 1000 mg/kg body weight (example 5) .

Sodium sucrose octasulfate has also a potent inhibitory effect of the wheel and flare inflammatory response media¬ ted by the intradermal injection of PAF (platelet activa¬ tion factor, a potent inflammatory mediate) , when tested in human volunteers. The inhibitory effect is present both when sodium sucrose octasulfate is mixed with PAF before being intradermally injected, and when sodium sucrose octasulfate is applied on the skin before intradermal injection of PAF (Example 6) .

Interesting embodiments of the aspects of the invention appear from the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The water-soluble salt or complex of the sulfated sucrose used in accordance with the invention is water-soluble salt of the following formula:

wherein R is H, S0₃H or SO₃X, X representing a salt- or complex-forming metal moiety, the groups designated R being the same or different, with the proviso that at least one R represents a sulfate group (S0₃X) .

The salt- or complex-forming metal moiety may be a metal atom or metal atoms (as appropriate with respect to the valency) , possibly associated with other groups involved in the salt or complex formation. Thus, when the metal is aluminum (which, as will be understood, cannot apply to such an extent that the compound is not water-soluble) , the group R in question has the formula S0₃[Al₂(OH)₅] , and when the metal is sodium, which is an interesting embodiment according to the invention, the group R in question has the formula S0₃[Na«H₂0].

A very important property of the sulfated sucroses accor¬ ding to the present invention is their water-solubility at neutral pH. In the present context, the term water-solubi¬ lity at neutral pH is used in the meaning that the water- solubility at a pH in a range of 5.5-8.5 such as 7.0, is higher than 0.05 g/100 ml when determined in an appropriate buffer solution, such as 0.05 M phosphate buffer solution, at 37°C with stirring for 1 hour. Preferably, the water- solubility of a salt or complex of a sulfated sucrose used according to the invention is at least 0.5 g/100 ml, pre- ferably at least 5 g/100 ml, more preferred at least 25 g/100 ml, still more preferred at least 50 g/100 ml, espe¬ cially at least 75 g/100 ml, such as at least 100 g/100 ml when determined at pH 7.0 in a 0.05 M phosphate buffer solution following the method described above (i.e. stir- ring for 1 hour, temperature 37°C) .

Furthermore, the sulfated sucroses used according to the present invention are water-soluble even at pH less than 5.5.

The use of a water-soluble active substance is important from the point of view that a much lower dose can be ad- ministered compared to the practically water-insoluble sucralfate. Accordingly, dose-related side effects can be reduced when using a water-soluble compound which per se is relatively atoxic.

The sulfated sucrose used in accordance with the present invention is at least monosulfated, preferably polysulfated or persulfated, which means that two or more, possible all, sulfur-containing moieties are present as substituents on hydroxy groups of the carbohydrate moiety.

The sulfated sucrose is preferably selected from the group consisting of sucrose pentasulfate, sucrose hexasulfate, sucrose heptasulfate and sucrose octasulfate.

The sulfated sucrose salt or complex is a salt or complex with a metal selected from the group consisting of alkali metals and alkaline earth metals, e.g. Na, K, Ca, Mg, Ba, Al, Zn, Cu, Zr, Ti, Mn or Os or with an organic base (e.g. an amino acid) . The currently preferred salts are sodium and potassium salts, especially the octasulfate salts.

The salt or complex of sucrose sulfate may also be a mixed salt or complex comprising at least two different metals selected from the group consisting of alkali metals and alkaline earth metals as mentioned above, provided that the metal components are selected so that the salt or complex of sulfated sucrose is water soluble.

The sulfated sucroses may be prepared as described in EP 0 230 023. It is believed that the mixed salts or complexes of sulfated sucrose can be prepared essentially as descri¬ bed in EP 0 230 023 involving as a last step precipitation from a mixture of hydroxides in which the counter ions are' the metals in question.

Although there may be cases where the sulfated sucrose may be administered as such, it will typically be formulated with one or more pharmaceutically acceptable carriers or excipients to present it in a form which is suitable for administration to the digestive tract. In other words, it will be present in a form which is suitable for administra¬ tion through the oral or rectal route or via a stoma, such as a solution, emulsion, suspension, dispersion, gel, unit dosage form, multiple unit dosage form, tablet, capsule, powder, controlled release unit dosage form, enema and suppository.

Formulations for oral use include tablets which contain the sulfated sucrose in admixture with non-toxic pharmaceuti¬ cally acceptable excipients. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium chloride, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, potato starch or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example, magnesium stearate, stearic acid or talc. Other pharmaceutically acceptable excipients can be colorants, flavouring agents, plasticizers, humectants etc. The ta- blets may be uncoated or they may be coated by known tech¬ niques, optionally to delay disintegration and absorption in the gastrointestinal tract and thereby provide a su¬ stained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as chewing tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for ex¬ ample, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.

In general, it is known that the degradation of sulfated sugars is catalyzed by acids. Accordigly, formulations for oral use may also be presented in a form which protects the sulfated sucrose from gastric juice. Such formulations may be enteric coated single unit or multiple unit dosage forms. Another contemplated way of protecting the sulfated sucrose from acid catalyzed degradation is to administer the sulfate sucrose in combination with an antacidum such as a H₂ antagonist.

Powders, dispersible powders or granules suitable for preparation of an aqueous suspension by addition of water are also convenient dosage forms of the present invention. Formulation as a suspension provides the sulfated sucrose in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents are, for example, naturally-occurring phos- phatides, as e.g. lecithin, or condensation products of ethylene oxide with e.g. a fatty acid, a long chain alipha¬ tic alcohol or a partial ester derived from fatty acids and a hexitol or a hexitol anhydrides, for example, polyoxye¬ thylene stearate, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitan monooleate etc. Suitable sus- pending agents are, for example, sodium carboxymethylcellu- lose, methylcellulose, sodium alginate etc.

For the rectal application, suitable dosage forms for a composition according to the present invention include suppositories (emulsion or suspension type) , and rectal gelatin capsules (solutions or suspensions) . In a typical suppository formulation, the sulfated sucrose is combined with an appropriate pharmaceutically acceptable suppository base such as cocoa butter, esterified fatty acids, gly- cerinated gelatin, and various water-soluble or dispersible bases like polyethylene glycols and polyoxyethylene sor- bitan fatty acid esters. Various additives like e.g. enhan cers or surfactants may be incorporated.

For administration via a stoma the pharmaceutical composi¬ tion may preferably be presented as a liquid composition, such as a solution, a gel, a dispersion, a suspension, an emulsion or an enema. The pharmaceutically acceptable carriers or excipients may include emulsifying agents, antioxidants, buffering agents, preservatives, humectants, chelating agents, and gelforming agents.

Examples of emulsifying agents are naturally occurring gums, e.g. gum acacia or gum tragacanth, naturally occur¬ ring phosphatides, e.g. soybean lecithin and sorbitan monooleate derivatives.

Examples of antioxidants are butylated hydroxy anisole (BHA) , ascorbic acid and derivatives thereof, tocopherol and derivatives thereof and cysteine.

Examples of preservatives are parabens and benzalkonium chloride.

Examples of humectants are glycerin, propylene glycol, sorbitol and urea.

Examples of chelating agents are sodium EDTA, citric acid and phosporic acid.

Examples of gel forming agents are Carbopol, cellulose derivatives, bentonit, alginates, gelatin and PVP.

The formulation and preparation of the above-mentioned compositions is well-known to those skilled in the art of pharmaceutical formulation. Specific formulation can be found in "Remington's Pharmaceutical Sciences". The pharmaceutical composition of the invention generally comprises the sulfated sucrose in an amount of 0.001-99.% by weight, typically 0.01-75% by weight, more typically 0.1-20% by weight, especially 1-10% by weight of the total composition. In particular, when the sulfated sucrose is sodium sucrose octasulfate, a preferred concentration thereof in the composition is often 0.5-50% by weight, especially 0.5-25% by weight, such as 1-10% by weight. It is suitably administered 1-10 times a day, preferably 1-4 times daily, dependent on the type and severity of the condition to be treated.

The dose of the sulfated sucrose to be used in each par¬ ticular case will of course depend upon the type of com¬ position and the intended use. In cases where the lesion and/or inflammation in the digestive tract is an inflamma¬ tion of non-peptic ulcer nature a therapeutically or pro¬ phylactically effective amount is an amount in a range of about 0.01-10 mmol per dose, especially in a range of about 0.05-5 mmol per dose, preferably in a range of about 0.5-2 mmol per dose. When sodium sucrose octasulfate is used the above-mentioned ranges corresponds to about 0.01- 10 g per dose, about 0.05-5 g per dose and about 0.5-2 g per dose, respectively.

When the sulfated sucrose is used in the treatment and/or prevention of lesion and/or inflammation of the oesopha¬ geal, gastric and/or duodenal mucosa of an individual, the therapeutically or prophylactically effective amount of the salt or complex of a sulfated sucrose is in a range of about 1-300 μmol per dose (corresponding to about 1-300 mg sodium sucrose octasulfate) , preferably in a range of about 10-100 μ ol per dose (corresponding to about 10-100 mg sodium sucrose octasulfate per dose) .

As mentioned above, the water-soluble sulfated sucrose is indicated for use in connection with lesion and/or inflam- mation in the digestive tract caused by conditions such as: Conditions located in the oesophagus such as:

Oesophagitis, defined as inflammation of the oesopha¬ gus.

Reflux oesophagitis, defined as inflammation caused be reflux of irritants from the stomach such as gastric juice and bile.

Conditions located in the stomach such as:

Non-specific acute gastritis, defined as inflammation of the stomach of unknown etiology.

Antral gastritis, defined as inflammation affecting the antrum of the stomach.

Haemorrhagic gastritis, defined as gastritis with haemorrhagic lesions.

Catarrhal gastritis, defined as inflammation of the mucous membrane of the stomach, with hypertrophy of the membrane, secretion of an excessive quantity of mucus, and alteration of the gastric juice.

Non-specific chronic gastritis, defined as chronic inflammation of the stomach of unknown etiology.

Atrophic gastritis, defined as chronic gastritis with atrophy of the mucous membrane and glands.

Alcoholic gastritis, defined as gastritis caused by alcohol.

Erosive gastritis, defined as gastritis in which the surface epithelium is eroded, manifesting as a patchy or a diffuse lesion. 19

Follicular gastritis, defined as inflammation of the glands of the stomach.

Hypertrophic gastritis, defined as proliferation of the gastric mucosa, producing diffuse thickening of the stomach wall and with inflammatory changes.

Phlegmonous gastritis, defined as gastritis charac¬ terized by various abscesses in the stomach wall.

Polypous gastritis, defined as hypertrophic gastritis with polypoid projections into the stomach.

Pseudomembranous gastritis, defined as a variety of gastritis in which a false membrane occurs in patches within the stomach.

NSAID-induced gastritis, defined as gastritis induced by non-steroid anti-inflammatory drugs.

Stress-induced gastritis, defined as gastritis induced by stress.

Steroid-induced gastritis, defined as gastritis in¬ duced by steroid drugs.

Zonal gastritis, defined as gastritis occurring in the vicinity of a gastric lesion.

Conditions located in the duodenum such as:

Duodenitis, defined as inflammation of the duodenum

NSAID-induced duodenitis, defined as duodenitis in- duced by non-steroid anti-inflammatory drugs. Stress-induced duodenitis, defined as duodenitis induced by stress.

Steroid-induced duodenitis, defined as duodenitis induced by steroid drugs.

Zonal duodenitis, defined as duodenitis occurring in the vicinity of a duodenal lesion.

Conditions located in the jejunum, ileum colon and rectum such as:

Jejunitis, defined as inflammation of the jejunum.

Ileitis, defined as inflammation of the ileum.

Colitis, defined as inflammation of the colon.

Diverticulitis, defined as inflammation of a diver- ticulum.

Proctitis, defined as inflammation of the rectum.

Mb.Crohn, defined as chronic granulomatous inflam¬ matory disease involving any part of the gastrointes¬ tinal tract from mouth to anus of autoimmune etiology,

Ulcerative colitis, defined as chronic recurrent ulceration of the colon of autoimmune etiology.

Conditions caused by fistulae, defined as fistulae com¬ municating with the lumen of the digestive tract.

Autoimmune conditions, defined as conditions characterized by a specific humoral or cell-mediated immune response against constituents of the body's own tissues such as: 21 Mb.Crohn, as defined above.

Ulcerative colitis including proctitis, as defined above.

Non tropical sprue or celiac disease, defined as malabsorption syndrome precipitated by ingestion of glutencontaining foods, it is generally believed that autoimmunity plays a major role in the etiology.

Premalignant or malignant diseases such as:

Polypi, defined as solitary of multiple polyps of the digestive tract.

Polyposis familiaris, defined as multiple adenomatouε polyps with high malignant potential, lining the mucous membrane of tfie intestine, particularly the colon.

Cancer oesophagi, defined as cancer located in oeso¬ phagus.

Cancer ventriculi, defined as cancer located in the stomach.

Cancer duodeni, defined as cancer located in duodenum.

Cancer jejuni, defined as cancer located in jenunum.

Cancer ilei, defined as cancer located in ileum.

Cancer coli, defined as cancer located in colon.

Cancer recti defined as cancer located in rectum.

Cancer analis defined as cancer located in anus. Conditions caused by trauma such as radiation, chemicals, toxic agents, surgery and chemotherapy, in particular such conditions as:

Radiation-induced oesophagitis, gastritis, duodenitis, ileitis and proctitis, defined as lesion and/or in¬ flammation following exposure to radiation.

Chemical oesophagitis and gastritis, defined as in¬ flammation and lesions following exposure to chemical agents.

Toxic oesophagitis and gastritis, defined as inflamma¬ tion and lesions following exposure to toxic agents.

Postoperative side effects involving the digestive tract, defined as side effect caused by stress, infec- tion or surgery.

Conditions caused by enterotoxins, defined as toxins speci¬ fically affecting cells of the intestinal mucosa such as enterotoxines from microorganisms including:

Staphylococcus aureus, Shigella dysenteriae, Vibrio cholerae, Bacillus cereus, Escherichia coli, Klebsiel- la, Enterobacter, Bacillus cereus, Clostridium per- fringens and Clostridium difficile.

Conditions caused by invasive infections defined as infec¬ tions in which the microorganism invade the cells of the intestinal mucosa such as infections caused by micro¬ organisms including:

Shigella, Salmonella, Yersenia enterocolitica, Cam- pylobacter jejuni and/or other campylobacters, Vibrio parahemolyticus, Escherichia coli and Mycobacterium tuberculosis. Conditions caused by viral infections involving the diges¬ tive tract, such virus as:

Rotavirus, Norwalk and/or related small round viruses, Enteric adenoviruseε, Reovirus, AIDS, enteroviruses including Poliovirus, Coxackievirus or Echovirus.

Conditions caused by protozoal infections involving the digestive tract, such protozoes as:

Giardia lamblia, Entamoeba histolytica, Schistosoma mansoni, Balantidium coli, Isospora belli or Isospora huminis.

Conditions caused by Traveler's diarrhea.

Conditions caused by infections of the digestive tract, caused by microorganisms such as:

Streptococcus viridans, Streptococcus faecalis and Candida albicans.

Conditions caused by an opportunistic infection defined as an infection caused by a microorganism which is not normal¬ ly pathogenic for man, or an infection caused by a known pathogenic microorganism affecting organs which is normally not involved by infection by that particular microorganism, oppertunistic infections is seen in individuals which are immune suppressed. The microorganisms involved include:

Candida albicans, Cryptococcus neoformans, Coccidiodes immitiε, Hiεtoplas a capsulu , Blastomyces dermatidis, Herpes simplex and/or Herpes genitialis.

The invention is further illustrated by the following non- limiting examples EXAMPLE 1

Inhibition by sodium sucrose octasulfate of 11-1 induced release of 11-8 from human endothelial cells

The amount of Interleukin-1 alpha (11-1) induced release of Interleukin-8 (11-8) from human endothelial cells was investigated. In control cells not stimulated with 11-1, the release of 11-8 was about 5 ng/ml. After stimulation with 11-1, the release of 11-8 was 225 ng/ml. Addition to the cell culture of sodium sucrose octasulfate in the concentration range 1 μg/ml to 1 mg/ml resulted in a dose related inhibition of 11-1 induced release of 11-8 from the endothelial cells. When 1 μg/ml sodium sucrose octasulfate (the lowest concentration investigated in this model) was added to the cell culture, the release of 11-8 was reduced to 75 ng/ml.

It is justified to conclude that sodium sucrose octasulfate has anti-inflammatory properties.

In the following example an investigation on the erythema reduction potential of potassium sucrose octasulfate on UV- B irradiated (sunburned) guinea pig skin is described. The model applied enables a comparison between normal skin, irradiated non-treated skin and irradiated treated skin on the same animal. The study design has been used in order to reveal a possible dose-response relationship. Three concen- trations of potassium sucrose octasulfate were investigated and compared with indometacin as a well as known positive control.

The test showed that potassium sucrose octasulfate has a prophylactic erythema reduction effect on sunburned skin in guinea pigs. A relationship between treatment dose and erythema reduction was found. EXAMPLE 2

Ultraviolet sunburn (erythema) study in guinea pigs

Twelve male SPF albino guinea pigs (6-7 weeks of age, body weight about 350 g) of the Dunkin Hartley strain, from Moellegaard Breeding Centre Ltd. , were used.

The animals were housed in opaque PPL (type IV) cages, two in each cage. They had free accesε to a pellet diet, "3113 Altromin", and vitamin C enriched tap water. The room temperature was set at 21°C ± 2°C and the relative humidity at 55% ± 15%. The air was changed 6 times an hour, and the light was on from 06 to 18 h.

The positive control substance was Indomethacin as a 10% by weight liquid preparation in PEG 400, and the test sub¬ stance was sucrose octasulfate in the form of the potassium salt thereof as a 1, 3 and 10% by weight solution in PEG 400. The vehicle control was PEG 400.

Method

The test was carried out as a dose-response study using three test group of four animals. Both flanks of each guinea pig were used.

Thirty minutes before UV-B light exposure, each group was treated with the test substance, and further three out of four animals in each group was treated with the positive control. The last animal in each group was treated with the vehicle.

Two, four, six and twenty hours after termination of light exposure, the animals were examined and the grade of ery¬ thema reduction was scored. Procedure

The day before treatment, both flanks of the animals were clipped free of hair and shaved with an electric razor. The next day, 0.05 ml of the solutions containing the test substance, positive control substance or vehicle control, respectively, were applied in the centre of the two sites (approximately 5 cm² each) to be exposed to light. After application the substance was massaged into the skin during approximately 30 seconds with the pulp of a finger. To measure prophylactic effectiveness, the application took place 30 minutes before UV-B-exposure.

Thirty minutes later, the unanesthetized animals were restrained on the opposite side to be exposed to the light. A rubber sheet with two openings with a diameter of 4 cm (each about 12.5 cm²), was placed on the clipped and shaved flank of each animal, placing the centre of the openings right over the two treatment sites. The rest of the body was covered in order to protect the animal from the UV- light, except for the two treatment sites. Two guinea pigs at a time were subsequently exposed to ultraviolet light (T

20/12, UV-B, Philip), at a distance of 6 cm for 20 minutes.

Each of the 24 flanks of the 12 animals were treated with both the test substance and either 10% Indomethacin or vehicle. The application of the two substances per flank was performed according to a special system to eliminate variation due to anatomical or structural differences of the epidermis of the flanks and to support the quality of the blind reading.

Two, four, six and twenty-four hours after termination of the UV-B-light exposure, the treatment sites were read and evaluated according to the following scale: Erythema (E) reduction Score

No visible sign of E 0

Barely discernible E 1

Faint non-confluent E 2 Marked non-confluent E 3

Marked non-confluent or confluent zones of E beyond application area 4 Homogeneous E 5

Homogeneous E beyond application area 6

The animals were read blindly, and the erythema reduction scores for each substance were averaged.

A non-parametric distribution-free method, Duncan's Multi¬ ple Range Test, was used to determine statistical signifi¬ cance between different concentrations of the test sub- stance and positive control/vehicle.

The following erythema reduction activity was found:

Vehicle (PEG 400) 0.92

Positive control (Indomethacin 10%) 2.83

Test 1% (sucrose octasulfate) 1.00 Test 3% (sucrose octasulfate) 1.33

Test 10% (sucrose octasulfate) 2.12

Positive effect was seen with the positive control article, indometacin, and with sucrose octasulfate, 10%. The mean score of these two formulations were statistically sig- nificant higher, compared to PEG 400 (and sucrose octasul¬ fate 1% and 3%) .

A dose-response relationship was revealed, ranging from 4% effect for sucrose octasulfate 1% to 63% effect for sucrose octasulfate 10% (the respective mean εcores in percentage of the positive control after the vehicle average score was subtracted. It must be concluded that in this experiment, sucrose octasulfate reduces the erythema on sunburned (UV- B-exposed) skin of guinea pigs to the same extent as in¬ domethacin.

EXAMPLE 3

Modulation of inflammation by sodium sucrose octasulfate

In this study the effect on UV-induced inflammation in humans were evaluated, an anti-inflammatory effect on UV-B induced erythemas might be exerted via a concentration dependent modulation of prostaglandin mediators and leuco- triene production. The increasing number of identified inflammatory mediators and regulators have different tar¬ gets in the skin. Two different methods (Laser Doppler flowmetry and reflectance spectroscopy, respectively) for non-invasive, quantitative detection of inflammatory reac¬ tions in the skin were used. These methods allow a quanti- fication of the effects on the arterial vascular component (skin blood flow) and the capillary and on venous capaci¬ tance vesεels (degree of erythema) .

The study included 10 healthy adult volunteers without any obvious skin disease or prior adverse reactions to sun- light. No medication of any kind was allowed during the study.

Skin inflammation was induced by irradiation by a bank of linear ultraviolet B irradiators (Philips TL 40W/12) . The volunteers were irradiated on a series of test areas on the back, each measuring 2 x 2 cm. The irradiated areas were placed on the back in a manner which avoided the midline (spinal)area and consisted of five columns which were irradiated by different increasing light doses 0, 8.4 m/cm², 33.6 m/cm², 67.2 m/cm², 109.2 m/cm². The median minimal erythema dose (MED) was 33.2 m/cm². A maximum of 3.3 MEDs was given to the most strongly irradiated test areas. The following test substances were applied: sodium sucrose octasulfate cream 2%, 6% and 18%, respectively, and as positive control was used indometacin cream 10%. As vehicle or negative control was used cream base. The vehicle con- trol was identical to the cream bases used for the active compounds, and consisted of lanolin components, poly¬ ethylene glycol, isopropylic myristate, glycerin and de- mineralized water.

The test substance was applied on test areas in horizontal rows. Each of the test substances covered test areas which were irradiated with 0.25, 1, 2 and 3.3 MED UV-B. The test substances were applied in a double-blinded manner and the actual order of application of each test substance was shifted between the volunteers according to a randomized scheme. The test substance were applied at a concentration

Study design

The study design was divided into two separate experiments. In experiment I the test substances were applied on the skin 30 minutes before irradiation. In experiment II the test areas were initially irradiated and the test substan¬ ces applied 6 hours later when local inflammations have developed.

Monitoring of anti-inflammatory effect

The degree of capillary and venous vascular dilatation was quantitated in terms of erythema, monitored objectively and non-invasively by reflectance spectroscopy. In short, reflectance spectroscopy is based on broad banded visible irradiation (white light) of the skin with subsequent monitoring of the reflected light in narrow bands using a monochromator which divides the reflected spectra into 5 nm bands in the spectral area from 350 to 750 nm. Using com- puterized calculations based on prior determinations of the absorption spectra of skin chromophores, it iε possible to determine an index for erythema as an erythema index (El).

Any pro- or anti-inflammatory effect on the arteriolar side of the vascular bed were monitored non-invasively by laser Doppler skin blood flowmetry.

Laser Doppler blood flowmetry is a recognized method for registration of superficial skin blood flow using measure- ments of Doppler shifted reflections of an incoming laser beam due to moving particles in the superficial vascular plexus of the skin. In both experiments the skin reflec¬ tance and skin blood flow were determined on each test area before application of the test compound after 6 hours, and after 24 hours.

Statistics

The statistic evaluation was performed by Wilcoxon's test for paired sample. Statistical significance was accepted at the 5% level (two sided) .

Results

Experiment I - Laser Doppler flowmetry

In this experiment the test substances were applied just before irradiation. Measurements performed 6 hours after application of test subεtances showed that sodium sucrose octasulfate 2% and 6% induced non-significant reductionε of the 33.6 m/cm² UV-B inflammation by 21.1% and 45.0%, re¬ spectively. Sodium sucroεe octaεulfate 18% significantly enhanced the inflammation induced by UV-B. Sodium sucrose octasulfate 18% induced a 201.2% and 211.9% increase of the skin blood flow at the 67.2 m/cm² and 109.2 m/cm² irradia¬ ted test areas. Indo etacin cream 10% (positive control) significantly reduced UV-B inflammation by 61.6% and 64.1% at 67.2 m/cm² and 109.2 m/cm², respectively, indicating, adequate function of the test system.

After 24 hours, the proinflammatory action of sodium su- crose octasulfate 18% was reduced by 84.8% at the 67.2 m/cm² sites compared to the 6 hours measurements, whereaε on the strongest irradiated sites a sustained inflammatory reaction was observed. Contrary, sodium sucrose octasulfate 2% significantly reduced the 67.2 m/cm² and the 109.2 m/cm² erythemas by 19.1% and 15.2%, reεpectively. No significant effects of the intermediate concentrations of sodium su¬ crose octasulfate was detected.

Experiment I - Reflectance spectroscopy

The reflectance spectroscopic monitoring of inflammation revealed significant reduction by sodium εucrose octasul¬ fate 2% on erythemas 67.2 m/cm² after 6 hours (11.6% and 10.4%). Indo etacin 10% significantly reduced skin erythe¬ mas at the more intense degrees of inflammation >33.6 m/cm² (8.6%, 16.6% and 20.7%). Sodium sucrose octasulfate cream 18% significantly increased erythema 11.6%, 25.3% and 35.0% induced by > 33.6 m/cm² UV-B. After 24 hours only the positive control compound (indometacin cream 10%) signifi¬ cantly reduced erythema at 67.2 m/cm² and the 109.2 m/cm² (16.8% and 17.7%), whereas sodium sucrose octasulfate cream 18% significantly increased erythema at 67.2 m/cm² and at 109.2 m/cm² (20.9% and 32.4%).

Experiment II - Laser Doppler flowmetry

In this study all test substances were applied 6 hours after irradiation. Measurements performed 6 hours after application showed no significant effect of any of the test substances. Experiment II - Reflectance spectroscopy

The reflectance spectroscopic evaluation of inflammation revealed no significant reduction of erythema by any of the compounds tested.

Conclusion

In conclusion a cream containing 2% sodium sucrose octasul¬ fate was found to inhibit UV-B induced skin inflammation in humans, whereaε a cream containing 18% sodium sucrose octasulfate increased UV-B induced inflammation in normal human skin. Using the cream vehicle and human skin as a model, the optimal anti-inflammatory effect waε produced by sodium sucroεe octaεulfate cream 2%.

EXAMPLE 4

Acute intravenous toxicity in mice of potasεiu sucrose octasulfate

A total of two mice (female) in each of six groups were dosed with 20 mg potassium sucroεe octasulfate per ml per kg bodyweight. The vehicle was sterile water.

Group 1-3 received a dose of 2000, 1000 and 500 mg/kg, respectively, and the injection period was 30-60 εeconds. All animalε died during doεing. Group 4-6 received a doεe of 250, 100 and 50 mg/kg, respectively, and the injection period was about 10 seconds. No animal died in group 4-6.

In conclusion, the intravenous LD₅₀ dose of potasεium sucrose octasulfate in mice is likely to be about 250-500 mg/kg bodyweight. EXAMPLE 5

Tolerance study with sodium sucrose octasulfate intrave¬ nously into rats

5 groupε of each 6 ratε received the following doεeε of sodium sucrose octasulfate administered intravenously in the tail-vein twice daily for 5 days a week over a two week period (110 treatment days) :

Group 1: 30 mg/kg bodyweight

Group 2: 100 mg/kg bodyweight Group 3: 300 mg/kg bodyweight

Group 4: 1000 mg/kg bodyweight

Group 5: Control (1 ml Ringer solution)

Sodium sucrose octasulfate was given as an isotonic neutral solution in Ringer in a concentration of 100 mg/ml.

A certain local irritation of the tail vein was observed in the high dose groups (3 and 4) with necrosis of the exter¬ nal part of the tails (4 out of 6 rats in group 4, and 3 out of 6 rats in group 3) , necessitating discontinuation of test drug on day 5.

In rats with necrosis of the tail there waε a εlight in¬ crease in spleen weight which most likely was a secondary inflammatory reaction to the tail necrosiε.

Apart from thiε, there were no signs or symptoms of sys¬ temic toxicity in any of the rats, as evaluated from be- haviour, bodyweight or autopsy findings.

In conclusion, it waε not poεsible in this subchronic toxicity study to establish a toxic dose of sodium sucrose octasulfate in rats, titrating the daily intravenous dose as high as 1000 mg/kg bodyweight. There was no signs or symptoms of any systemic adverse reactions in any of the rats.

EXAMPLE 6

Inhibition of sodium sucrose octasulfate in PAF-induced wheel and flare reaction in volunteers

The test was carried out in four healthy volunteers. The volar part of the forearm were divided in an upper and a lower part, defining four test areas.

On a randomized basis, the following experiments were made in each volunteer on the respective four test areaε:

1. Injection intradermally of 200 ng PAF (0.1 ml)

2. Injection intradermally of a mixture of 200 ng PAF plus 200 ng sodium sucrose octasulfate (0.2 ml)

3. Pretreatment of the test area with a 9% (w/w) εodium εucrose octaεulfate gel one hour and 1/2 hour before intradermal injection of 200 ng PAF

4. Pretreatment of the teεt area with a 9% (w/w) sucral¬ fate cream formulation one hour and 1/2 hour before intradermal injection of 200 ng PAF

PAF (platelet activating factor) is a potent inflammatory mediator.

Reεultε

Intradermal injection of 200 ng resulted in an immediate and well defined wheel and flare reaction in all four test persons, visible within 30 εeconds, with a maximum size within median 2.5 minutes and lasting about 10-15 minutes, a mean maximum area of 6.5 cm . Intradermal injection of a mixture of 200 ng PAF plus 200 ng sodium sucrose octasulfate gave no wheel and flare reaction in three of the volunteers and in one there was a minor reaction with a maximum size of 0.5 cm².

Intradermal injection of 200 ng PAF after pre-treatment of the test area with εodium εucrose octasulfate gel formula¬ tion, gave no wheel and flare reaction in two of the test persons and in the other two test personε there waε a minor reaction with a maximum εize of 1 cm².

Intradermal injection of 200 ng PAF after pre-treatment with sucralfate gave an immediate wheel and flare reaction in all four test persons, visible within 30 seconds and with a maximum size of mean 4.5 cm².

Conclusion

Sodium sucrose octasulfate is a potent inhibitor of the wheel and flare inflammatory response mediated by the intradermal injection of PAF, when tested in human volun¬ teers. The inhibitory effect is preεent both when sodium sucrose octasulfate is mixed with PAF before being intra- dermally injected, and when sodium sucrose octasulfate is applied on the skin before intradermal injection of PAF.

The aluminum complex of sucrose sulfate was not effective when applied on the skin before intradermal injection of PAF. It is likely that this effect of sodium sucrose octa- sulfate is due to its inhibition of the inflammatory re¬ sponse induced by PAF, and not only an direct inactivation of PAF.

Claims

1. A method of treating and/or preventing lesion and/or inflammation of non-peptic ulcer nature in the digestive tract of an individual, εaid method compriεing ad ini- stering to a patient in need thereof a therapeutically or prophylactically effective amount of a salt or complex of a sulfated sucrose, said sucroεe salt or sucrose complex being water-soluble at a neutral pH.

2. The method of claim 1, wherein the water-solubility of the salt or complex of εaid εulfated sucrose iε at leaεt

0.05 g/100 ml, when determined at pH 7.0 in a 0.05 M phos- phate buffer solution at 37°C after stirring for 1 hour.

3. The method of claim 1, wherein said εulfated sucrose is at least monosulfated.

4. The method of claim 1, wherein said εulfated εucrose iε at least disulfated, trisulfated or tetrasulfated.

5. The method of claim 1, wherein said εulfated εucrose is at least pentasulfated, hexasulfated, heptasulfated or octasulfated.

6. The method of claim 1, wherein εaid sulfated sucrose is sucrose octasulfate.

7. The method of claim 1, wherein the sulfated sucrose salt or complex is a salt or complex with a metal selected from the group consisting of alkali metals and alkaline earth metals.

8. The method of claim 7, wherein the salt or complex is a Na or K salt or complex.

9. The method of claim 7, wherein the εalt or complex iε a Bi, Ca, Mg, Ba, Al, Zn, Cu, Zr, Ti, Mn or Oε salt or com¬ plex.

10. The method of claim 7, wherein the salt or complex is a mixed salt or complex compriεing at leaεt two different metals selected from the group conεiεting of alkali metals and alkaline earth metals.

11. The method of claim 10, wherein the mixed salt or complex is a salt or complex with a metal selected from the group consisting of Na, K, Bi, Ca, Mg, Ba, Al, Zn, Cu, Zr, Ti, Mn and Os.

12. The method of claim 1, wherein the sulfated sucroεe salt or complex is a salt or complex with an organic base including an amino acid.

13. The method of claim 1, wherein the sulfated sucrose salt is sodium sucrose octasulfate.

14. The method of claim 1, wherein the leεion and/or in¬ flammation of non-peptic ulcer nature in the digeεtive tract is caused by oesophagitis, reflux oesophagitis, acute non-specific gastritis, antral gastritiε, haemorrhagic gastritis, atrophic gastritis, catarrhal gastritiε, non¬ specific chronic gastritis, alcoholic gastritis, erosive gastritiε, follicular gastritis, hypertrophic gastritiε, phlegmonouε gastritis, polypous gastritiε, pεeudomembranouε gastritis, NSAID-induced gastritiε, stress-induced gastri¬ tis, steroid-induced gastritiε, duodenitiε, NSAID-induced duodenitiε, stresε-induced duodenitiε, εteroid-induced duodenitiε, jejunitiε, ileitis, irritable colon, diver- ticulitis, proctitis, Morbuε Crohn, ulcerative colitiε and/or fistulae.

15. The method of claim 1, wherein the lesion and/or in¬ flammation of non-peptic ulcer nature in the digestive tract is caused by an autoimmune disease such as Morbus Crohn, ulcerative colitis, proctitis or non-tropical sprue.

16. The method of claim 1, wherein the lesion and/or in¬ flammation of non-peptic ulcer nature in the digestive tract is caused by a premalignant or malignant diεeaεe εuch aε polypi, polyposis familiaris, cancer oesophagi, cancer ventriculi, cancer duodeni, cancer jejuni, cancer ilei, cancer coli, cancer recti or cancer analis.

17. The method of claim 1, wherein the lesion and/or in- flammation of non-peptic ulcer nature in the digeεtive tract iε cauεed by a traumatic condition such as radiation- induced esophagitis, radiation-induced gastritis, radia¬ tion-induced duodenitis, radiation-induced radiation-in¬ duced jejunitis, radiation-induced ileitis, radiation- induced colitiε or radiation-induced proctitis; chemical esophagitis, chemical gastritis, chemical duodenitis, chemical jejunitis, chemical ileitis, chemical colitis or chemical proctitis; or toxic esophagitis, toxic gastritis, toxic duodenitis, toxic jejunitis, toxic ileitis, toxic colitis or toxic proctitis.

18. The method of claim 1, wherein the lesion and/or in¬ flammation of non-peptic ulcer nature in the digestive tract is a postoperative side effect or εide effectε re¬ lated to chemotherapy or radiation therapy.

19. The method of claim 1, wherein the leεion and/or in¬ flammation of non-peptic ulcer nature in the digeεtive tract is an infectious inflammation caused by enterotoxinε from Staphylococcuε aureuε, Shigella dyεenteriae, Vibrio cholerae, Bacilluε cereuε, Eεcherichia coli, Klebsiella, Enterobacter, Bacillus cereus, Clostridium perfringens or Clostridium difficile.

20. The method of claim 1, wherein the lesion and/or in¬ flammation of non-peptic ulcer nature in the digestive tract iε an infectious inflammation caused by invasive infection of Shigella, Salmonella, Yersenia enterocolitica, Campylobacter jejuni and/or other campylobacterε, Vibrio parahemolyticuε, Escherichia coli or Mycobacterium tuber- culosis.

21. The method of claim 1, wherein the leεion and/or in¬ flammation of non-peptic ulcer nature in the digestive tract is an infectious inflammation caused by viral infec¬ tion of Rotavirus, Norwalk and/or related small round viruses, Enteric adenoviruseε, Reoviruε, AIDS, enteroviru- ses including Poliovirus, Coxackievirus or Echovirus.

22. The method of claim 1, wherein the leεion and/or in¬ flammation of non-peptic ulcer nature in the digestive tract is an infectious inflammation caused by Protozoal infections such as Giardia lamblia, Entamoeba histolytica, Schistosoma mansoni, Balantidiu coli, Isospora belli or Isospora huminis.

23. The method of claim 1, wherein the lesion and/or in¬ flammation of non-peptic ulcer nature in the digeεtive tract iε an infectiouε inflammation caused by Traveler's diarrhea, Streptococcus viridans, Streptococcus faecaliε or Candida albicanε.

24. The method of claim 1, wherein the leεion and/or in¬ flammation of non-peptic ulcer nature in the digestive tract is caused by an opportunistic infection.

25. The method of claim 24, wherein the opportunistic infection is caused by Candida albicans, Cryptococcus neoformanε, Coccidiodeε immitis, Histoplaεma capsulum, Blastomyces dermatidis, Herpes simplex and/or Herpes geni- tialiε.

26. The method of claim 1, wherein said therapeutically or prophylactically effective amount is an amount in a range of about 0.01-10 mmol per dose.

27. The method of claim 1, wherein said therapeutically or prophylactically effective amount is an amount in a range of 0.05-5 mmol per doεe.

28. The method of claim 1, wherein εaid therapeutically or prophylactically effective amount is an amount in a range of 0.5-2 mmol per doεe.

29. The method of claim 1, wherein εaid therapeutically or prophylactically effective amount is administered to the patient at least once daily.

30. The method of claim 29, wherein said therapeutically or prophylactically effective amount is administered to the patient at least three times daily.

31. The method of claim 1, wherein the therapeutically or prophylactically effective amount of εaid sulfated sucroεe iε adminiεtered in form of a pharmaceutical composition suitable for GI administration, the composition being selected from the group consisting of solutions, emulsions, suspenεions, dispersions, gels, unit dosage forms, multiple unit dosage forms, tablets, capsules, powders, controlled release unit dosage forms, enemas and suppoεitorieε.

32. The method of claim 31, wherein εaid compoεition iε adminiεtered through the oral or rectal route or via a stoma.

33. A method of treating and/or preventing lesion and/or inflammation of the oesophageal, gastric and/or duodenal mucosa of an individual, said method comprising administe- ring to a patient in need thereof a therapeutically or prophylactically effective amount of a salt or complex of a sulfated sucrose, said εucroεe εalt or εucrose complex being water-soluble at a neutral pH and said amount being in a range of about 1-300 μmol per dose.

34. The method of claim 33, wherein said therapeutically or prophylactically effective amount is in a range of about 10-100 μmol per dose.

35. The method of claim 33, wherein the water-solubility of the salt or complex of said εulfated εucrose is at least 0.05 g/100 ml, when determined at pH 7.0 in a 0.05 M phoε- phate buffer solution at 37°C after stirring for 1 hour.

36. The method of claim 33, wherein said sulfated sucrose is at least monosulfated.

37. The method of claim 33, wherein said sulfated sucrose is at least disulfated, trisulfated or tetrasulfated.

38. The method of claim 33, wherein said sulfated sucrose is at least pentasulfated, hexasulfated, heptasulfated or octasulfated.

39. The method of claim 33, wherein said sulfated sucrose is sucroεe octasulfate.

40. The method of claim 33, wherein the sulfated sucrose salt or complex is a salt or complex with a metal selected from the group consiεting of alkali metalε and alkaline earth metals.

41. The method of claim 40, wherein the salt or complex is a Na or K salt or complex.

42. The method of claim 40, wherein the salt or complex is a Bi, Ca, Mg, Ba, Al, Zn, Cu, Zr, Ti, Mn or Os salt or complex.

43. The method of claim 40, wherein the salt or complex is a mixed salt or complex comprising at least two different metalε selected from the group consiεting of alkali metalε and alkaline earth metals.

44. The method of claim 43, wherein the mixed salt or complex is a salt or complex with a metal selected from the group consisting of Na, K, Bi, Ca, Mg, Ba, Al, Zn, Cu, Zr, Ti, Mn and Os.

45. The method of claim 33, wherein the sulfated sucrose salt or complex is a salt or complex with an organic base including an amino acid.

46. The method of claim 33, wherein the sulfated sucrose salt is sodium sucrose octasulfate.

47. The method of claim 33, wherein the leεion and/or inflammation of the oeεophageal, gastric and/or duodenal mucosa is caused by reflux oesophagitiε, peptic ulcer, acute non-specific gastritiε, antral gaεtritiε, haemor¬ rhagic gastritis, atrophic gastritis, catarrhal gastritis, non-specific chronic gastritiε, alcoholic gaεtritiε, ero- εive gaεtritiε, follicular gaεtritis, hypertrophic gastri¬ tis, phlegmonous gastritiε, polypous gastritis, pseudo- membranous gastritis, NSAID-induced gastritis, stress- induced gastritis, steroid-induced gastritiε, zonal gaεtri¬ tiε, duodenitis, NSAID-induced duodenitis, εtress-induced duodenitis, steroid-induced duodenitis, zonal duodenitis and/or Morbus Crohn.

48. The method of claim 33, wherein the lesion and/or inflammation of oesophageal, gastric and/or duodenal mucosa is caused by an autoimmune disease such as Morbus Crohn or non-tropical εprue.

49. The method of claim 33, wherein the lesion and/or inflammation of the oesophageal, gastric and/or duodenal mucosa is caused by a premalignant or malignant diseaεe such as polypi, cancer oesophagi, cancer ventriculi or . cancer duodeni.

50. The method of claim 33, wherein the lesion and/or inflammation of the oesophageal, gastric and/or duodenal mucosa is caused by a traumatic condition such as radia¬ tion-induced eεophagitis, radiation-induced gastritis or radiation-induced duodenitis; chemical esophagitis, chemi¬ cal gastritiε or chemical duodenitiε; or toxic eεophagitiε, toxic gaεtritis or toxic duodenitis.

51. The method of claim 33, wherein the lesion and/or inflammation of the oesophageal, gastric and/or duodenal mucosa is a postoperative side effect or side effects related to chemotherapy or radiation therapy.

52. The method of claim 33, wherein the lesion and/or inflammation of the oesophageal, gastric and/or duodenal mucosa is an infectious inflammation caused by viral infec¬ tion of AIDS.

53. The method of claim 33, wherein said therapeutically or prophylactically effective amount is administered to the patient at leaεt once daily.

54. The method of claim 53, wherein εaid therapeutically or prophylactically effective amount iε adminiεtered to the patient at least three times daily.

55. The method of claim 33, wherein the therapeutically or prophylactically effective amount of said sulfated sucrose is administered in form of a pharmaceutical compoεition suitable for GI administration, the composition being εelected from the group consisting of solutionε, emulεions, suspensions, dispersions, gels, unit dosage forms, multiple unit dosage forms, tablets, capsules, powders, controlled release unit dosage forms and enemas.

56. The method of claim 55, wherein said compoεition is, administered through the oral route or via a stoma.

57. Use of a salt or complex of a sulfated sucrose for the manufacture of a pharmaceutical composition for the treat- ment and/or prevention of lesion and/or inflammation of non-peptic ulcer nature in the digestive tract of an in¬ dividual, with the proviso that the salt or complex of the sulfated sucroεe is water-soluble at neutral pH.

58. The use of claim 57, wherein the water-solubility of the salt or complex of said sulfated sucroεe is at least

0.05 g/100 ml, when determined at pH 7.0 in a 0.05 M phos¬ phate buffer solution at 37°C after stirring for 1 hour.

59. The use of claim 57, wherein said sulfated sucrose is at least monosulfated.

60. The use of claim 57, wherein said sulfated sucroεe iε at leaεt disulfated, trisulfated or tetrasulfated.

61. The use of claim 57, wherein said sulfated sucrose is at least pentasulfated, hexasulfated, heptasulfated or octasulfated.

62. The use of claim 57, wherein said sulfated sucroεe iε εucroεe octasulfate.

63. The use of claim 57, wherein the sulfated sucrose salt or complex is a salt or complex with a metal εelected from the group conεiεting of alkali metalε and alkaline earth metalε.

64. The use of claim 63, wherein the salt or complex iε a Na or K salt or complex.

65. The use of claim 63, wherein the salt or complex is a Bi, Ca, Mg, Ba, Al, Zn, Cu, Zr, Ti, Mn or Os salt or com¬ plex.

66. The use of claim 63, wherein the salt or complex is a mixed salt or complex comprising at least two different metals selected from the group consisting of alkali metals and alkaline earth metals.

67. The use of claim 66, wherein the mixed salt or complex is a salt or complex with a metal selected from the group consisting of Na, K, Bi, Ca, Mg, Ba, Al, Zn, Cu, Zr, Ti, Mn and Os.

68. The use of claim 57, wherein the εulfated εucroεe εalt or complex is a salt or complex with an organic base in¬ cluding an amino acid.

69. The use of claim 57, wherein the sulfated sucrose salt is sodium sucrose octasulfate.

70. The use of claim 57, wherein the lesion and/or inflam¬ mation of non-peptic ulcer nature in the digestive tract is caused by oesophagitis, reflux oesophagitiε, acute non- εpecific gastritis, antral gastritis, haemorrhagic gas¬ tritis, atrophic gaεtritis, catarrhal gastritis, non-speci¬ fic chronic gastritis, alcoholic gastritiε, erosive gas¬ tritis, follicular gastritiε, hypertrophic gaεtritiε, phlegmonous gastritiε, polypouε gastritis, pseudomembranous gaεtritis, NSAID-induced gastritis, stress-induced gastri¬ tis, steroid-induced gastritis, duodenitis, NSAID-induced duodenitis, εtress-induced duodenitis, steroid-induced duodenitiε, jejunitiε, ileitiε, irritable colon, diver- ticulitiε, proctitiε, Morbuε Crohn, ulcerative colitis and/or fistulae.

71. The use of claim 57, wherein the lesion and/or inflam¬ mation of non-peptic ulcer nature in the digestive tract is caused by an autoimmune disease such as Morbus Crohn, ulcerative colitis, proctitis or non-tropical εprue.

72. The use of claim 57, wherein the lesion and/or inflam¬ mation of non-peptic ulcer nature in the digestive tract is cauεed by a premalignant or malignant diεeaεe εuch aε polypi, polypoεis familiaris, cancer oeεophagi, cancer ventriculi, cancer duodeni, cancer jejuni, cancer ilei, cancer coli, cancer recti or cancer analiε.

73. The uεe of claim 57, wherein the leεion and/or inflam- mation of non-peptic ulcer nature in the digestive tract is caused by a traumatic condition such as radiation-induced esophagitis, radiation-induced gastritis, radiation-induced duodenitis, radiation-induced radiation-induced jejunitis, radiation-induced ileitis, radiation-induced colitis or radiation-induced proctitis; chemical esophagitis, chemical gastritis, chemical duodenitis, chemical jejunitis, chemi¬ cal ileitis, chemical colitiε or chemical proctitiε; or toxic eεophagitiε, toxic gastritis, toxic duodenitis, toxic jejunitis, toxic ileitis, toxic colitis or toxic proctitis.

74. The use of claim 57, wherein the lesion and/or inflam¬ mation of non-peptic ulcer nature in the digestive tract is a poεtoperative εide effect or εide effectε related to chemotherapy or radiation therapy.

75. The uεe of claim 57, wherein the leεion and/or inflam- mation of non-peptic ulcer nature in the digestive tract is an infectious inflammation caused by enterotoxinε from Staphylococcuε aureus, Shigella dysenteriae, Vibrio cho- lerae. Bacillus cereus, Escherichia coli, Klebsiella, Enterobacter, Bacillus cereus, Clostridium perfringens or Clostridium difficile.

76. The use of claim 57, wherein the lesion and/or inflam¬ mation of non-peptic ulcer nature in the digestive tract is an infectious inflammation caused by invasive infection of Shigella, Salmonella, Yerεenia enterocolitica, Campylobac- ter jejuni and/or other campylobacterε, Vibrio parahemolyt- icuε, Eεcherichia coli or Mycobacterium tuberculoεiε.

77. The use of claim 57, wherein the lesion and/or infla - mation of non-peptic ulcer nature in the digestive tract is an infectious inflammation caused by viral infection of Rotavirus, Norwalk and/or related small round viruses, Enteric adenoviruεes, Reovirus, AIDS, enteroviruεeε includ¬ ing Polioviruε, Coxackievirus or Echovirus.

78. The use of claim 57, wherein the leεion and/or inflam¬ mation of non-peptic ulcer nature in the digestive tract is an infectious inflammation caused by Protozoal infections εuch aε Giardia lamblia, Entamoeba histolytica, Schistoεoma manεoni, Balantidium coli, Iεospora belli or Isoεpora huminiε.

79. The uεe of claim 57, wherein the leεion and/or inflam¬ mation of non-peptic ulcer nature in the digestive tract is an infectious inflammation caused by Traveler's diarrhea, Streptococcus viridans, Streptococcus faecalis or Candida albicanε.

80. The use of claim 57, wherein the lesion and/or inflam¬ mation of non-peptic ulcer nature in the digestive tract iε caused by an opportunistic infection.

81. The use of claim 80, wherein the opportunistic infec- tion is caused by Candida albicans, Cryptococcus neofor- manε, Coccidiodeε immitis, Histoplaεma capεulum, Blaεtomy- ceε dermatidis, Herpes simplex and/or Herpes genitialis.

82. The use of claim 57, wherein said pharmaceutical com¬ position comprises a therapeutically or prophylactically effective amount of the sulfated sucrose, the amount being in a range of about 0.01-10 mmol per doεe.

83. The uεe of claim 82, wherein said therapeutically or prophylactically effective amount is an amount in a range of 0.05-5 mmol per dose.

84. The use of claim 82, wherein said therapeutically or prophylactically effective amount is an amount in a range of 0.5-2 mmol per dose.

85. The uεe of claim 82, wherein εaid therapeutically or prophylactically effective amount iε administered to the patient at least once daily.

86. The uεe of claim 85, wherein εaid therapeutically or prophylactically effective amount is administered to the patient at least three times daily.

87. The use of claim 57, wherein the pharmaceutical com- position is a composition which is suitable for GI admini¬ stration, the composition being selected from the group consisting of solutions, emulsionε, suspensions, disper- εionε, gelε, unit doεage forms, multiple unit dosage forms, tablets, capεules, powderε, controlled releaεe unit dosage forms, enemas and suppositories.

88. The use of claim 87, wherein εaid composition iε in a form which is suitable for administration through the oral or rectal route or via a stoma.

89. Use of a salt or complex of a sulfated εucroεe for the manufacture of a pharmaceutical compoεition for the treat¬ ment and/or prevention of leεion and/or inflammation of the oesophageal, gastric and/or duodenal mucoεa of an indivi¬ dual, with the proviso that the salt or complex of the εulfated εucroεe iε water-εoluble at neutral pH and that the compoεition comprises a therapeutically and/or pro¬ phylactically effective amount of the sulfated εucrose, the amount being in a range of about 1-300 μmol per doεe.

90. The use of claim 89, wherein said therapeutically or prophylactically effective amount is in a range of about 10-100 μmol per dose.

91. The use of claim 89, wherein the water-solubility of the salt or complex of said sulfated sucrose is at least

0.05 g/100 ml, when determined at pH 7.0 in a 0.05 M phos¬ phate buffer εolution at 37°C after εtirring for 1 hour.

92. The use of claim 89, wherein said εulfated εucroεe is at least monosulfated.

93. The use of claim 89, wherein said εulfated εucroεe is at least disulfated, trisulfated or tetrasulfated.

94. The use of claim 89, wherein said sulfated sucrose iε at least pentasulfated, hexaεulfated, heptaεulfated or octaεulfated.

95. The uεe of claim 89, wherein said sulfated sucrose is sucrose octasulfate.

96. The use of claim 89, wherein the sulfated sucrose εalt or complex is a salt or complex with a metal selected from the group consisting of alkali metals and alkaline earth metals.

97. The use of claim 96, wherein the salt or complex is a Na or K salt or complex.

98. The use of claim 96, wherein the salt or complex iε a Bi, Ca, Mg, Ba, Al, Zn, Cu_P Zr, Ti, Mn or Os salt or co - plex.

99. The use of claim 96, wherein the salt or complex is a mixed salt or complex comprising at least two different metals selected from the group consisting of alkali metals and alkaline earth metals.

100. The use of claim 99, wherein the mixed salt or complex is a εalt or complex with a metal εelected from the group consisting of Na, K, Bi, Ca, Mg, Ba, Al, Zn, Cu, Zr, Ti, Mn and Os.

101. The use of claim 89, wherein the εulfated εucrose salt or complex is a salt or complex with an organic base including an amino acid.

102. The use of claim 89, wherein the sulfated εucroεe salt is εodium εucrose octaεulfate.

103. The uεe of claim 89, wherein the leεion and/or inflam¬ mation of the oesophageal, gastric and/or duodenal mucosa is caused by reflux oesophagitiε, peptic ulcer, acute non¬ specific gaεtritis, antral gastritis, haemorrhagic gas¬ tritiε, atrophic gaεtritis, catarrhal gaεtritiε, non-εpeci- fie chronic gastritis, alcoholic gastritis, erosive gas¬ tritis, follicular gastritis, hypertrophic gastritis, phlegmonous gastritis, polypous gastritis, pseudomembranous gastritis, NSAID-induced gastritis, streεs-induced gaε¬ tritiε, εteroid-induced gaεtritis, zonal gastritis, duo- denitis, NSAID-induced duodenitis, stresε-induced duo¬ denitiε, steroid-induced duodenitis, zonal duodenitis and/or Morbuε Crohn.

104. The uεe of claim 89, wherein the leεion and/or inflam¬ mation of oeεophageal, gaεtric and/or duodenal mucoεa iε cauεed by an autoimmune diεease such as Morbus Crohn or non-tropical sprue.

105. The use of claim 89, wherein the leεion and/or inflam¬ mation of the oeεophageal, gaεtric and/or duodenal mucosa is caused by a premalignant or malignant disease such as polypi, cancer oesophagi, cancer ventriculi or cancer duodeni.

106. The uεe of claim 89, wherein the leεion and/or inflam¬ mation of the oeεophageal, gaεtric and/or duodenal mucosa is caused by a traumatic condition such as radiation-in¬ duced esophagitis, radiation-induced gastritiε or radia- tion-induced duodenitis; chemical esophagitiε, chemical gastritis or chemical duodenitis; or toxic esophagitiε, toxic gaεtritiε or toxic duodenitis.

107. The use of claim 89, wherein the leεion and/or inflam¬ mation of the oeεophageal, gastric and/or duodenal mucosa is a poεtoperative εide effect or side effects related to chemotherapy or radiation therapy.

108. The use of claim 89, wherein the lesion and/or inflam¬ mation of the oesophageal, gastric and/or duodenal mucosa is an infectious inflammation caused by viral infection of AIDS.

109. The use of claim 89, wherein said therapeutically or prophylactically effective amount is administered to the patient at least once daily.

110. The uεe of claim 109, wherein εaid therapeutically or prophylactically effective amount iε adminiεtered to the patient at leaεt three timeε daily.

111. The uεe of claim 89, wherein the pharmaceutical com¬ position is a composition which iε suitable for GI admini- εtration, the compoεition being εelected from the group conεiεting of εolutionε, emulεions, suspensions, disper- sions, gels, unit dosage formε, multiple unit dosage forms, tablets, capεuleε, powderε, controlled release unit dosage forms and enemas.

112. The use of claim 111, wherein said compoεition iε in a form which iε suitable for administration through the oral route or via a stoma.