CN1627948A - compositions and kits for treating inflammatory bowel disease - Google Patents
compositions and kits for treating inflammatory bowel disease Download PDFInfo
- Publication number
- CN1627948A CN1627948A CN02828982.XA CN02828982A CN1627948A CN 1627948 A CN1627948 A CN 1627948A CN 02828982 A CN02828982 A CN 02828982A CN 1627948 A CN1627948 A CN 1627948A
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- heparin
- chitosan
- sulfate
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Classifications
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/727—Heparin; Heparan
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/745—Polymers of hydrocarbons
- A61K31/75—Polymers of hydrocarbons of ethene
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0031—Rectum, anus
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Abstract
The use of an aqueous composition comprising chitosan in combination with a biologically active polysaccharide, such as heparin, in the rectal treatment of inflammatory bowel disease is disclosed.
Description
Technical field
The present invention relates to suppress gastrointestinal tract inflammation and infection, and quicken, stimulate or promote the application of the new pharmaceutical compositions of gastrointestinal tract wound healing.The present invention also comprises the preparation method of said preparation.
Background technology
Dan Baijutang and glucosaminoglycan (GAG) are carried out many critical functions in vivo.This glucosaminoglycan is heparin, Heparan sulfate, chondroitin sulfate, hyaluronic acid, dermatan sulfate and keratan sulfate.Other has similar bioactive semi-synthetic glycocalix and is called heparinoid, for example dextran sulfate.
Free heparin and Heparan sulfate activate the plasma protein antithrombase, and it then suppresses the serine protease of coagulation cascade in the blood (coagulation cascade).Utilize this phenomenon clinically and make heparin become the most widely used blood-anticoagulant clinically.Other glucosaminoglycan and heparinoid of great majority also shown anticoagulant active, but theirs is active and imprecise also not obvious.The glucosaminoglycan of other report and the biological function of heparinoid are the abilities that they stop inflammatory reaction.
Heparin stops the ability of inflammation also to be used to clinical.For example,, not only play blood coagulation resisting function, also play antiinflammatory action if use the heparin therapy dvt to form; Lump has also reduced.The antiinflammatory action of heparin and GAGs may be most important but it be unclear that any owing to some mechanism.Because the sulfate radical and/or the intensive anion attribute of carboxyl functional group of polysaccharide, electronegative polysaccharide can with a large amount of protein binding.In these albumen some relate to inflammation system, for example complement factor.Researcher supposition endothelium or blood vessel wall inner membrance work in inflammatory reaction.Particularly, with Heparan sulfate (similar) molecule parcel with heparin endotheliocyte and leukocyte---outgrowth leukocyte combines in inflammatory process.Excretory chemical substance in inflammatory process---cytokine can promote this relation.
Researcher proposes heparin with the behavior of several mode inflammation-inhibiting.Because the structure of heparin is similar to heparin sulfate, it has disturbed the adhesion of inflammatory cell and endotheliocyte.In addition, think that heparin can promote the cytokine of inflammation such as tumor necrosis factor (TNF) to interact with some.
Researcher is also to determining that interest has taken place in the effect of heparin in repairing mucous membrane of colon (enteral film) damage.Heparin has improved the albumen irritation cell to be upgraded and outgrowth effect.This effect impels blood vessel wall and colonic film healing.Other function of the GAGs of bibliographical information and heparinoid suppresses the ability of infected by microbes in addition.
Many microorganisms, the antibacterial of herpes-like virus and Colibacter, staphylococcus and Streptococcus for example is a receptor with the GAGs of mammalian cell surface.These microorganisms combine with the GAGs high degree of specificity, begin infection cell then.Conjugated protein with GAGs or heparinoid is pulsating combines by the GAGs-on blocking-up microorganism surface, just can protect from infection.
The helicobacter pylori pathogen that for example can cause acute, chronic Type B gastritis and peptic ulcer disease, it combines with heparin sample GAG and Heparan sulfate on the epithelial cell.Be heparin/Heparan sulfate conjugated protein (HSBP) in conjunction with what be correlated with therewith.It may be the reason that causes by bacterial gastric mucosa clonal expansion that these agglutinins interact, and can stop with combining of HSBP owing to unbound heparin.
Inflammatory bowel (IBD)
Term IBD is meant two kinds of intestinal tract diseases: segmental enteritis and ulcerative colitis.These diseases seem similar but significant difference.
These two kinds of diseases all are enteritiies.Do not know to cause the factor that causes inflammation among the IBD at present; Therefore the cause of disease of these diseases it be unclear that.
Modal IBD symptom is a diarrhoea.In ulcerative colitis, the heavy absorption function of normal water is impaired, causes many liquefaction just.Because the inner membrance of colon has also formed ulcer, therefore often comprise blood in the diarrhoea.
In the late period of this disease, colon narrows down usually and shortens, and follows water to absorb to weaken, rectal urgency (urgency) and the control of intestinal function died down.Segmental enteritis can prevent the normal absorption of food, causes diarrhoea and fat (steatorrhea) and the excretory increase of other food, thereby causes losing weight.In addition, in segmental enteritis, intestinal may narrow down and be obstructed.
Ulcerative colitis
Ulcerative colitis (UC) comprises the inflammation of colon and rectum inner membrance, and it causes hemorrhage of rectum and diarrhoea.Ulcerative colitis is usually directed to the end (terminal ileum) of ileum, also relates to large intestine among about 30-50% patient.When ulcerative colitis only influences the lowermost portion of colon, during rectum, be called as proctitis ulcerosa (UP) this moment.
Segmental enteritis
In segmental enteritis (CD), inflammation extends to muscle even serous coat always.This inflammatory process causes blood vessel Yin Wendu to increase and expands, and liquid infiltrates tissue, the infiltration of inflammatory cell, and mucosa forms ulcer.
For many years, given segmental enteritis many titles, it can be called as Crohn disease, distal ileitis, granulomatous colitis or ileocolitis.But these title mutual alternative are used.
The treatment of enteritis
When the cause of disease is unknown, be difficult to obtain effective treatment.Yet, with regard to IBD, but can study control disease or inductive therapy, induce medically being meant alleviation to mean stable disease.Therapeutic scheme to patient's success might not prove effective to other people.
Confirmed that corticosteroid is the most effective medicine of treatment ulcerative colitis acute attack, uniform release/improvement rate is near 70%.Yet, the patient of about 20-30% acute stage to the reaction of corticosteroid a little less than or reactionless.Although the effect to the ulcerative colitis acute stage is limited, be favourable with sulfasalazine (sulphasalazine) or 5-aminosalicylic acid treatment, and its main advantage that has is the long term maintenance mitigation.Immunosuppressant, for example azathioprine and Ciclosporin A have inducing action and the effect of keeping alleviation subsequently, particularly in even more serious case, but may follow dangerous side effect.Yet all these treatments all can cause unwanted side effect.Therefore, need research replaceable, the enteritis therapy that the lower curative effect of toxicity is higher.
Use heparin therapy inflammatory bowel (IBD)
As if at first view, use the heparin therapy inflammatory bowel---to comprise hemorrhage disease in the symptom---illogical.Yet, discovery will be arranged in addition to IBD and heparin in-depth analysis.Following is the research overview that heparin is used for therapeutic trial IBD.This feature is based on Dr.Joshua R.Korzenik and is published in paper in the CCFA science periodical, and inflammatory bowel (InflammatoryBowel Diseases) (Vol.3, No.2).
Use the case of heparin therapy IBD to start from Ireland at first.Dr.Peter Gaffney, a surgeon gives the patient that a shank has thrombosis with heparin, and this patient also suffers from ulcerative colitis.The colitis that he notices this patient 10 days internal diabetes except.Subsequently, Dr.Gaffney does not have the patient of thrombosis to try out heparin to two, and obtains same success.
So far carried out other small sample research several times, wherein 51 among 60 IBD patients produce useful reaction to heparin therapy.Although these results are encouraging, but the not safety of definite heparin, and the optimal dose and the course of treatment of treatment IBD.
Nearest IBD studies show that heparin has even even more important effect in treatment IBD.In the further research that Karolinska Institute carries out,, obtained challenging result by injection Fragmin (reaching heparin (dalteparin), a kind of low molecular weight heparin) treatment patient.
If medicine is directly applied to the inflammation tissue, just can obtain more effectively heparin administration, but because heparin when being used for the treatment of IBD, therefore degraded rapidly in vivo needs the appropriate drug induction system.
Summary of the invention
According to the present invention, we provide a kind of chitosan waterborne compositions that combines with bioactive polysaccharide that comprises, it is used for the rectal treatment of IBD, and this bioactive polysaccharide is selected from heparin, Heparan sulfate, chondroitin sulfate, hyaluronic acid, dermatan sulfate, keratan sulfate and dextran sulfate.
Chitosan is a linear polysaccharide, and is deacetylated and prepare through chitosan alkalescence usually.Chitosan itself is naturally occurring polysaccharide, its wide material sources, but common plant-scale source is a Crustaceans, for example Eriocheir sinensis or shrimp, shellfish.Chitosan is by 1, and the D-glycosamine of 4-β-connection and N-acetyl-D-glycosamine residue is formed.The chitosan of alkali form and particularly high molecular and/or the deacetylated chitosan of height N-are water-soluble hardly.The average pKa of glycosamine residue is about 6.8 in the chitosan, chitosan and acid, and for example HCl and acetic acid form salt.The salt that forms with monobasic acid tends to dissolving in water.Chitosan can with the strong combination of deleterious and bad (weight) metal (for example Hg, Cd and Pb) and transition metal (for example Cr, Ni, Mn and Cu) to environment.
These chitosans comprise chitosan salts, for example with salt, especially organic acid with pharmaceutically acceptable anionic acid formation, for example more rudimentary alkanoic acid such as acetic acid, formic acid, propanoic acid and butanoic acid.Other suitable organic acid comprises lactic acid, glycolic, citric acid, ascorbic acid and aminoacid.Suitable mineral acid for example is a hydrochloric acid.Also comprise chitosan derivative, for example alkylating, N is carboxymethylated, N, the chitosan that O-is carboxymethylated and crosslinked.Crosslinked chitosan can be through covalent bond or ionic crosslinking.
Chitosan can be any chitosan; But we are higher than 50% by preferred chitosan deacetylation, more preferably are higher than approximately 55%, especially are higher than 60%.Deacetylation preferably is lower than 100%, especially is lower than 90% more preferably less than 95%.Preferred especially deacetylation is between 85% to 95%.
We have up to 15 by also preferred chitosan, the viscosity of 000mPas, preferably from 2 to 10,000, more preferably from 2 to 2,000, and most preferably from 2 to 1000mPas, this viscosity is to measure in the 1%w/v solution of 1%v/v acetic acid aqueous solution preparation under 25 ℃ of temperature.Solution viscosity is the indication of chitosan mean molecule quantity, can be understood that chitosan is to have the polymer that the variable chains length molecule distributes.
This waterborne compositions can be for example solution, dispersion liquid or suspension.The pH of this waterborne compositions is preferably 4.0 to 6.8, between 4.5 to 5.5.
The viscosity of waterborne compositions depends on the viscosity of chitosan and bioactive polysaccharide composition; Yet preferably be lower than 50mPas, more preferably less than 10mPas.
Weight ratio between chitosan and the bioactive polysaccharide is preferably 100: 1 to 1: 1, more preferably 20: 1 to 1: 1.Concrete ratio will depend on the performance of performance, its deacetylation and the polysaccharide of chitosan.Preferably, chitosan combines the complex of formation with clean positive charge with bioactive polysaccharide; Therefore, common ratio will make that whole complex of chitosan and polysaccharide are positively charged, particularly in the slightly acidic water medium, for example pH is from 4.0 to 6.8 aqueous medium.
Particularly preferred bioactive polysaccharide is a heparin.Low molecular weight heparin for example reaches heparin, also can be mentioned especially.
For example deacetylation is that 86% chitosan and the compound particularly preferred ratio of heparin are between 100: 1 to 1: 1.By using pharmaceutically acceptable mineral acid or organic acid such as HCl, suitably keep the pH of waterborne compositions.
Use heparin-chitosan complex treatment IBD
As mentioned above, found that heparin can be used to suffer from some inflammatory bowel valuably, and for example the lower limb dvt forms or the patient of lung embolus with thrombosis-thromboembolism disease.Find in relatively at random in the controlled of quiet notes heparin and quiet notes corticosteroid treatment serious acute IBD, same effective in treatment UC as the heparin and the corticosteroid of first-line treatment.And, also find in some uncontrolled clinical trials, further to obtain the evidence of heparin therapy activeness UC patient's beneficial effect.And, in all these researchs, do not record serious adverse.Although be considered to anticoagulant effect, the main mechanism of action of heparin in UC is still unknown.In addition, proof effects of heparin leukocyte recruitment in the report, but can not get rid of the protective effect that this mechanism also relates to heparin.Because the possible microorganism pathology of IBD, ability that heparin combines with multiple microorganism and anti-inflammatory efficacy thereof also are useful.
In our bench-scale testing, heparin-enema is used as the ancillary drug of the patients of ulcerative colitis with tip disease or UP or selects medicine for use.
Heparin-chitosan complex directly is applied to ill site, and the many problems in the time of can avoiding quiet notes heparin to be administered systemically take place.For example, natural heparin is degraded fast in vivo, and is delayed with this process of the compound back of chitosan.And because its clean positive charge, therefore heparin-chitosan complex and living tissue adhesion also are fixed in intestinal portion.
And vein gives heparin and also must be implemented by doctor or nurse.On the contrary, heparin-chitosan complex but can be taken at home easily by the patient.
Usually, can use the waterborne compositions of above-mentioned enema, suppository or rectum doleiform formula effectively to treat inflammatory bowel.
Said composition can prepare by the aqueous formulation of a kind of chitosan of mixing and a kind of aqueous formulation of bioactive polysaccharide.Necessary or when needing, in the suitable container of resulting composition can being packed into, rectum bottle for example is as enema.
Chitosan and bioactive polysaccharide can be contained in the form of separation component in the test kit, contain the solution of each composition in the test kit, mix immediately before rectally.
According to a further aspect of the invention, the rectal treatment method of inflammatory bowel is provided, it comprises the chitosan waterborne compositions that combines with bioactive polysaccharide that comprises of the patient treatment effective dose of suffering from this disease, and this bioactive polysaccharide is selected from heparin, Heparan sulfate, chondroitin sulfate, hyaluronic acid, dermatan sulfate, keratan sulfate and dextran sulfate.
The present invention sets forth by following embodiment.
Embodiment 1
The preparation of heparin-chitosan suspending agent
Material
Heparin is available from Pharmacia Hepar Inc., Franklin, and Ohio, USA, anti-xa activity are 185IU/mg.
Chitosan (Chitech ), by Medicarb AB, StockholmSweden provides.
Preparation
Preparation be equivalent to respectively 500,2500 and 5000IU (anti-Xa factor) comprise 0.054,0.27 and three kinds of aqueous solutions (Aqua steril ad) of 0.54mg heparin/mL.By in water, adding 0.12,0.61 and three kinds of solution of 1.23mg/mL (Aqua steril ad) preparation chitosan power.The HCl maintenance pH value that adds 4M is 4.7.
In mixing, will comprise 500,2500 and the heparin solution of 5000IU add respectively comprise 0.123,0.614 and the solution of 1.227mg/mL chitosan in.Continue to mix again and looked like " homogenizing " until complex in 5 minutes.
This suspending agent is gone in the plastic H DPE rectum bottle with every part of branch of 50mL, 135mL PLMLangeskov, and Denmark, and as table 1 labelling.
Table I chitosan-heparin compostions enema IBD preparation
| The IBD preparation | Volume | Chitosan | Heparin |
| The 500IU heparin | 50ml | ?0.12mg/ml | ?10IU/0.054mg/ml |
| The 2500IU heparin | 50ml | ?0.61mg/ml | ?50IU/0.27mg/ml |
| The 5000IU heparin | 50ml | ?1.23mg/ml | ?100IU/0.54mg/ml |
Embodiment 2
Clinical research
Research purpose is different heparin of screening and chitosan compositions are suitable for IBD/ proctitis patient is carried out initial research with discovery a preparation.The important parameter of preparation and selection principle are amount, viscosity, dosage and the administering mode of heparin.The medicine of research can be from single dose 50ml rectum with obtaining the flexible plastic tube (enema).Selection comprises 500,2500, the heparin (table 1) of three kinds of variable concentrations of 5000IU (anti-Xa factor).
The patient accepts heparin-enema twice with every day, around continuing to reach.If conditions of patients is alleviated when following up a case by regular visits to 2 (treating for 2 weeks), this patient withdraws from from research, estimates at the treatment end.
At 0 day, carry out Clinical Follow-up after 2 weeks (± 2 days) and after 4 weeks.1 week back research nurse carries out phone and checks.
To patient inquiry about the processing of enema, possible hemorrhage, compliance and Subjective Sense of Happiness.When treatment beginning and end, fill in quality of life application form (IBD-Q) by the patient.
The patient is treated by random assortment, and with the probability that equates with the dosage set of dispense to test center.
The main various dose bag of individual patient is by labelling similarly.
Keep the patient of treatment (5-ASA, SASP, Olsalazine), dose maintenance is constant.The not good or patient that do not have reaction or worsen in the dosage of successively decreasing of oral administration steroid therapy but reaction can be with the consumption of prednisolone by reducing to zero 5mg/ week gradually, and dosage is recorded among the CRF.
In this research process, do not allow the acute treatment of other IBD.
The required other medicines that are used to improve patient's Subjective Sense of Happiness are given cautiously by researcher, and are recorded among the CRF.If desired, acetaminophen can be used but aspirin can not be used.
Basic clinical usefulness variable is to the inductivity of alleviating, as measured rough whole remission rates and remission time.Safety is measured by the untoward reaction of report with to visiting of vital sign.
Alleviate and to be defined as,, and macroscopicly have blood in stool and be higher than patient's normal defecation average＜2 not having according to used scoring system endoscope mark＜1 such as L fberg.
Compare with baseline, the patient that the situation that showed is improved (endoscope's mark and/or clinical activity are divided minimizing) is construed to the respondent.All patients are divided into the respondent or week 2 and weeks 4 respondent not.
Be used to estimate clinical activity by the clinical symptoms index that comprises stool, continuity, hemorrhage of rectum, rectum or abdominal pain and the multiple different variablees of urgent micturition.The evaluation phase is first three day of Clinical Follow-up.
When following up a case by regular visits to, measure the conventional Subjective Sense of Happiness evaluation of body weight, pulse and blood pressure (5 minutes tranquillization, sitting posture) and patient at every turn.Check that skin is to survey for example hematoma of hemorrhage complication.
Begin to carry out flexible video image endoscopy (colonoscopy or sigmoidoscopy) or rigidity sigmoidoscopy in research, after 2 weeks of treatment, carry out the rigidity sigmoidoscopy.When 4 weeks that research finishes, carry out flexible video image endoscopy or rigidity sigmoidoscopy.Adopt routine clinical scope pattern.
0 minute=non-inflammatory mucosa
1 minute=graininess, edema lacked vascular pattern
2 minutes=hyperemia, fragility, petechia
3 minutes=ulcer
When following up a case by regular visits to, four conventional biopsies are carried out in the most serious place of inflammation part of non-inflammatory mucosa (under the situation of less popularity UC) and colon and rectum in beginning and end.
Two living tissue samples place formalin, through comprising conventional H﹠amp; After E dyeing is handled, carry out the double blinding evaluation by same pathologist.Adopt the grading scale of Selendrijk to determine mucosal inflammation.
Will be from one to two living tissue sample in each site immediately-70 ℃ of coolings, in order to analyze the expression of activity of myeloperoxidase and immuning tissue's leukocyte adhesion molecule.
Use the quality of life of simple quality of life application form to estimate beginning and to alleviate or treat the patient in latter stage as IBD patient's research.
Five laboratory efficacy variable of conventional clinically employing:
Platelet count (TPK)
Erythrocyte sedimentation rate (ESR)
Proteins C reactive (CRP)
Albumin and hoptoglobin.
Extracting blood when each Clinical Follow-up analyzes.
When following up a case by regular visits to, gather at every turn and be used for hemoglobin, leukocyte and protein (if U-dipstick---the blood demonstration positive: the urine sample of analysis and U-leukotriene E4 analysis urinary sediment).
Monitor the efficacy variable of each individual patients baseline.With first three day of beginning one's study be baseline to the measured value of same variable.
Untoward reaction (AE) is defined as any undesirable medical events that the patient occurs.This incident needn't have cause effect relation with treatment.
The report phase of untoward reaction stops certainly treating after 7 days and finishes from using heparin chitosan treatment beginning in this research.(after last research is followed up a case by regular visits to, only gather the spontaneous report of patient.)
The safety and the technical feasibility that focus on heparin chitosan complex rectally is used for acute UC of this exploratory study have been used descriptive statistic for this purpose.The patient has compared the treatment value with respect to baseline with from as contrast.Use Wilcoxon the test relatively average endoscopy and the histology score of treatment front and back, and estimated the difference of usefulness laboratory parameters.P value＜0.05 has been considered to significance.
Safety analysis is as the criterion with the report of untoward reaction.
Claims (10)
1. comprise the purposes of waterborne compositions in the rectal treatment of inflammatory bowel of the chitosan that combines with bioactive polysaccharide, wherein bioactive polysaccharide is selected from heparin, Heparan sulfate, chondroitin sulfate, hyaluronic acid, dermatan sulfate, keratan sulfate and dextran sulfate.
2. according to the purposes of the waterborne compositions of claim 1, wherein chitosan has and is higher than 50% deacetylation.
3. according to the purposes of the waterborne compositions of claim 1 or 2, wherein chitosan has and is lower than 100% deacetylation.
4. according to the purposes of the waterborne compositions of aforementioned arbitrary claim, wherein the pH of compositions is 4.0 to 6.8.
5. according to the purposes of the waterborne compositions of aforementioned arbitrary claim, wherein compositions has the 50mPas of being lower than, more preferably less than the viscosity of 10mPas.
6. according to the purposes of the waterborne compositions of aforementioned arbitrary claim, wherein the weight ratio of chitosan and bioactive polysaccharide is from 100: 1 to 1: 1.
7. according to the purposes of the waterborne compositions of aforementioned arbitrary claim, wherein chitosan combines the complex of formation with clean positive charge with bioactive polysaccharide.
8. according to the purposes of the waterborne compositions of aforementioned arbitrary claim, wherein bioactive polymer is a heparin.
9. according to the purposes of the waterborne compositions of aforementioned arbitrary claim, wherein bioactive polymer is a low molecular weight heparin.
10. test kit, comprise chitosan soln and bioactive polysaccharide solution, test kit, comprise the compositions that is used to mix with generation topical treatment of inflammation enteropathy, wherein bioactive polysaccharide is selected from heparin, Heparan sulfate, chondroitin sulfate, hyaluronic acid, dermatan sulfate, keratan sulfate and dextran sulfate.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IB2002/002275 WO2003090763A1 (en) | 2002-04-24 | 2002-04-24 | Composition and kit for the treatment of inflammatory bowel diseases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1627948A true CN1627948A (en) | 2005-06-15 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN02828982.XA Pending CN1627948A (en) | 2002-04-24 | 2002-04-24 | compositions and kits for treating inflammatory bowel disease |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1539192A1 (en) |
| CN (1) | CN1627948A (en) |
| AU (1) | AU2002309180A1 (en) |
| WO (1) | WO2003090763A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102458419A (en) * | 2009-06-10 | 2012-05-16 | 埃克塞拉医学有限责任公司 | Use of a composition for the treatment of mucositis |
| CN110312937A (en) * | 2017-01-19 | 2019-10-08 | 和田孝一郎 | Diagnostic drug, diagnostic method and diagnostic device for diagnosing intestinal mucosal permeability |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4856948B2 (en) | 2005-12-27 | 2012-01-18 | コニカミノルタビジネステクノロジーズ株式会社 | Toner for electrostatic image development |
| US9241953B2 (en) | 2008-05-13 | 2016-01-26 | Apharm S.R.L. | Glycosaminoglycan oral use and compositions |
| US8735373B2 (en) | 2008-05-13 | 2014-05-27 | Apharm S.R.L. | Glycosaminoglycan oral use and compositions |
| ITMI20131467A1 (en) | 2013-09-06 | 2015-03-07 | Sofar Spa | USE OF A COMPOSITION INCLUDING MICRO-ORGANISMS TO INCREASE THE INTESTINAL PRODUCTION OF BUTIRRIC ACID, FOLIC ACID OR NIACINE ACID AND / OR TO REDUCE THE INTESTINAL PRODUCTION OF SUCCINIC ACID |
| MA39710A (en) | 2014-04-23 | 2015-10-29 | Sofar Spa | Topical composition for use in the treatment of inflammatory bowel disease |
| MA45327A (en) | 2016-05-13 | 2019-03-20 | Sofar Spa | USE OF PROBIOTICS TO IMPROVE PROTEIN ABSORPTION |
| MA45288A (en) | 2016-06-08 | 2019-04-17 | Sofar Spa | New medical use of probiotics |
| IT201600122724A1 (en) | 2016-12-02 | 2018-06-02 | Sofar Spa | EXOPOLYSACCHARIDES AND USES THEREOF |
| IT201600127498A1 (en) | 2016-12-16 | 2018-06-16 | Sofar Spa | PROBIOTICS FOR USE IN DIVERTICULOSIS AND DIVERTICULAR DISEASE |
| US11751597B2 (en) | 2019-11-05 | 2023-09-12 | Alfasigma S.P.A. | Compositions comprising bacterial strains for use in increasing the bioavailability of amino acids derived from proteins, and related food product methods and systems |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5158940A (en) * | 1990-02-14 | 1992-10-27 | The United States Government As Represented By The Secretary, Dhhs | Use of suramin to treat rheumatologic diseases |
| US5980865A (en) * | 1995-08-18 | 1999-11-09 | Baker Norton Pharmaceuticals, Inc. | Method for treating late phase allergic reactions and inflammatory diseases |
| SE9602644D0 (en) * | 1996-07-04 | 1996-07-04 | Astra Ab | New use |
| US6653294B2 (en) * | 2000-02-29 | 2003-11-25 | Food Industry Research & Development Institute | Use of chitinous materials for inhibiting cellular nitric oxide production |
-
2002
- 2002-04-24 EP EP02735862A patent/EP1539192A1/en not_active Withdrawn
- 2002-04-24 AU AU2002309180A patent/AU2002309180A1/en not_active Abandoned
- 2002-04-24 CN CN02828982.XA patent/CN1627948A/en active Pending
- 2002-04-24 WO PCT/IB2002/002275 patent/WO2003090763A1/en not_active Application Discontinuation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102458419A (en) * | 2009-06-10 | 2012-05-16 | 埃克塞拉医学有限责任公司 | Use of a composition for the treatment of mucositis |
| CN110312937A (en) * | 2017-01-19 | 2019-10-08 | 和田孝一郎 | Diagnostic drug, diagnostic method and diagnostic device for diagnosing intestinal mucosal permeability |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1539192A1 (en) | 2005-06-15 |
| AU2002309180A1 (en) | 2003-11-10 |
| WO2003090763A1 (en) | 2003-11-06 |
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