CN101939024A

CN101939024A - Compositions for the treatment of inflammation of the gastrointestinal tract

Info

Publication number: CN101939024A
Application number: CN2008801247076A
Authority: CN
Inventors: E·菲利普斯; M·希尔
Original assignee: Meritage Pharma Inc
Current assignee: Meritage Pharma Inc
Priority date: 2007-11-13
Filing date: 2008-11-12
Publication date: 2011-01-05
Also published as: CN101969957A; CN101969956A; CN101969956B

Abstract

Provided herein are methods for preventing or alleviating the symptoms of and inflammation associated with inflammatory diseases and conditions of the gastrointestinal tract, for example, those involving the esophagus. Also provided herein are pharmaceutical compositions useful for the methods of the present invention.

Description

The compositions that is used for the treatment of gastroenteritis

Cross reference

The application requires the U.S. Provisional Application 60/987 of submission on November 13rd, 2007,720, the U.S. Provisional Application 61/012 of December in 2007 submission on the 6th, 012, the U.S. Provisional Application 61/015 of December in 2007 submission on the 21st, 998, the U.S. Provisional Application 61/019 that on January 8th, 2008 submitted to, 818, the U.S. Provisional Application 61/034 that on March 7th, 2008 submitted to, 941, the U.S. Provisional Application 61/035 that on March 10th, 2008 submitted to, 348, the U.S. Provisional Application 61/054 that on May 16th, 2008 submitted to, 103, the U.S. Provisional Application 61/054 that on May 16th, 2008 submitted to, 104, the U.S. Provisional Application 61/054 that on May 16th, 2008 submitted to, 105, the U.S. Provisional Application 61/054 that on May 16th, 2008 submitted to, 106, the U.S. Provisional Application 61/054 that on May 16th, 2008 submitted to, the U.S. Provisional Application 61/090 that on August 20th, 107 and 2008 submitted to, 658 priority, described application is incorporated herein by reference.

Background of invention

Adult and child's esophagitis disease is all increasing.An example is eosinophil esophagitis (EE or EoE), and it is a kind of disease of emerging, quick growth, it is characterized in that eosinophil level height and basal layer hypertrophy in the esophagus.Someone think EE (EoE) at least one class patient by food anaphylaxis or be exposed to the air sensitinogen and cause (1-5,44).EE (EoE) diagnosis is relevant with other hypersensitivity disease usually, comprises asthma, rhinitis and other food and aeroallergen inhalant allergy (39-40).Usually for example diagnosing among the child, this diagnosis depend in esophageal mucosa membrane injury tissue biopsy find to have in every high power field 15-20 or more nearly 24 or more eosinophils (eos/hpf) (6-12).

As if the same with other atopic diseases, the sickness rate of EE (EoE) is improving (15,35).This disease may present anti-stream sample symptom, pain and dysphagia, be similar to the clinical symptoms (42) of the performance of gastroesophageal reflux disease (" GERD ").The symptom of EE (EoE) comprises, for example stomachache, chest pain, feel oppressed, be difficult to swallow, growthing lag, feel sick, can not reduce by anti-stream, erythra or welt, vomiting and the weight that the anti-stream treatment of standard is eliminated.In one group, 15% EE (EoE) patient has concurrent hypoevolutism (45).

Although (7,8,13-16), many aspects of this disease are still unknown, comprise its cause of disease, natural history and best therapy to diagnose out EE (EoE) more and more continually in developing country.The symptom of EE (EoE) is similar to the symptom of GERD usually, comprise vomiting, dysphagia, pain and food impaction (8,14,17-20).Yet the treatment of EE (EoE) and GERD is different, distinguishes that they are extremely important, particularly may relevant with esophageal stricture (14,18,20,21) because do not treat EE (EoE) under the 10-30% situation.The coincidence of GERD and EE (EoE) symptom is very common, and can not respond high PPI GERD treatment may be the diagnosis guide (42) of EE (EoE).With the common mistaken diagnosis of EE (EoE) is that GERD generally causes EE patient's treatment to postpone (42).

Secular whole body steroid therapy can produce significant secondary side effect to growth and skeleton development.Although reported that the treatment of adopting anti-IL-5 monoclonal antibody to carry out is successful on EE, present this treatment is not approved for child (36).

Existing treatment comprises gets rid of diet (22,23) and key element prescription (elemental formula) (2,24).Confirm that real irritable food anaphylactogen may be difficult, and the common taste of key element prescription is not good, thereby makes diet intervention become complicated (1,22).Interim air blowing-hypopharynx technology may be difficult for patients, and particularly for child, and particularly late-blooming child is difficult to finish effectively.This topical steroids that may cause being less than effective dose is transported to esophagus.

Summary of the invention

Some embodiment provides a kind of combination of oral medication herein, and described pharmaceutical composition comprises corticosteroid and mucomembranous adhesion agent.In some specific embodiments, described combination of oral medication is stable combination of oral medication, chemistry and physically all stablize at least one month (for example, under environmental condition or under the inert conditions, under noble gas or vacuum).In some embodiments, described combination of oral medication also comprises liquid-carrier.In some embodiment, described corticosteroid is the corticosteroid of Topically active.In some embodiments, described corticosteroid is a budesonide.In the other embodiment, described corticosteroid is a fluticasone propionate.

In some embodiments, when described combination of oral medication is administered to esophagus herein, for example by oral administration, at least 50%, 20%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% described combination of oral medication adheres to or rests on the esophagus at least 15 seconds or 1 minute.In some embodiment, when described combination of oral medication is administered to esophagus herein, for example by oral administration, at least 50%, 20%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% described corticosteroid is adhered to or is rested on the esophagus at least 15 seconds at least 1 minute.In some embodiments, described in this article combination of oral medication is administered to esophagus after at least 15 seconds at least 1 minute, for example by behind the oral administration, at least 50%, 20%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% described corticosteroid is attached on the esophagus or is absorbed.In some embodiment, described combination of oral medication is administered to esophagus comprises oral administration and/or swallow to the part dosage of described combination of oral medication of small part or described combination of oral medication.

In some embodiment, administration (for example passing through oral administration) is to esophagus after 15 seconds or 1 minute, adhere to or the percentage by weight that rests on supraoesophageal described combination of oral medication herein greater than reference composition administration (for example passing through oral administration) to esophagus 15 seconds or 1 minute postadhesion or rest on the percentage by weight of supraoesophageal reference composition.In some embodiments, described herein combination of oral medication administration (for example passing through oral administration) to esophagus 15 seconds or 1 minute postadhesion or the amount that rests on supraoesophageal corticosteroid greater than reference composition administration (for example passing through oral administration) to esophagus 15 seconds or 1 minute postadhesion to or rest on the amount of supraoesophageal corticosteroid.In some embodiments, described herein combination of oral medication administration (for example passing through oral administration) to esophagus 15 seconds or 1 minute postadhesion to esophagus or the amount of the corticosteroid that is absorbed greater than reference composition administration (for example passing through oral administration) to esophagus 15 seconds or 1 minute postadhesion to esophagus or the amount of the corticosteroid that is absorbed.In some specific embodiments, described herein reference composition comprise with described combination of oral medication in commensurability identical corticosteroid, and (for example comprise the about 4mL aqueous compositions of every 0.5mg corticosteroid

Preparation) and 10 the bag

(being sold by McNeil Nutritionals, LLC FortWashington, PA 19034-2299).

In some embodiment, described herein mucomembranous adhesion agent is, as non-limiting example, and mucosal adhesive polysaccharide, card bohr.Block bohr and comprise, as non-limiting example, crosslinked acrylic acid polymer, Carbopol Ultrez and Carbopol 974P.In some embodiments, described herein mucomembranous adhesion agent is, as non-limiting example, and alginate.In some specific embodiments, described alginate are, as non-limiting example, and sodium alginate LF 120 and/or sodium alginate H 120L.In some embodiment, described mucomembranous adhesion agent comprises one or more maltodextrins.In some specific embodiments, described maltodextrin can not improve the viscosity (for example, compositions compare) identical with the others that lack described maltodextrin of described combination of oral medication significantly.In other or alternate embodiment, select maltodextrin according to mucoadhesive properties (for example, it gives the ability of described combination of oral medication mucoadhesive characteristics).In some embodiments, described combination of oral medication comprises second kind of maltodextrin improving described combination of oral medication viscosity (for example, compositions compare) identical with the others that lack described second kind of maltodextrin.In some specific embodiments, the mucoadhesive characteristics that described second kind of maltodextrin can the described pharmaceutical composition of appreciable impact (for example, identical compositions compare) with the others that lack described second kind of maltodextrin.

In some embodiments, be used for the mucomembranous adhesion agent of described combination of oral medication herein and given the viscosity that described combination of oral medication improves (for example, identical compositions compare) with the others that lack described mucomembranous adhesion agent.In other embodiment, described mucomembranous adhesion agent can not improve the viscosity (for example, compositions compare) identical with the others that lack described mucomembranous adhesion agent of described combination of oral medication significantly.

In some embodiment, described herein combination of oral medication also comprises second kind of mucomembranous adhesion agent.In other or alternate embodiment, described herein combination of oral medication also comprises viscosifier.

Treatment also is provided, prevents or has alleviated the method for patient's gastroenteritis or gastroenteritis symptom herein, described method comprises and is administered orally to the described any pharmaceutical composition of described patient herein.In some embodiment, described gastroenteritis is, as non-limiting example, and esophagitis.In some specific embodiments, described individuality is suffered from the eosinophil esophagitis by diagnosis, the inflammatory bowel that relates to esophagus, Crohn disease, proximal gastric intestinal pathology (for example hypothyroid patient of gallbladder), eosinophil property gastroenteritis, celiac disease, eosinophil property duodenitis, the duodenum hypereosinophilia, functional dyspepsia, mid-term esophagitis, epithelial proliferation, basal cell hyperplasia, the mastoid process of elongation, nipple vasodilation, fungous esophagitis (candida mycoderma for example, torulopsis, histoplasma capsulatum, aspergillosis etc.), viral esophagitis (HSV for example, CMV, V2V), bacillary esophagitis (pulmonary tuberculosis for example, actinomycosis, syphilis), erosive esophagitis, radiation esophagitis, the chemotherapy esophagitis, graft versus host disease, dermatosis (the bullous pemphigoid for example that relates to esophagus, pemphigus vulgaris, epidermolysis bullosa, Shi-Yue syndrome), Behcet disease, sarcoidosis, congenital esophagitis, eosinophil property gastroenteritis, giant hypertrophy gastritis, parasitic gastritis, the lymphocyte esophagitis, the inflammatory bowel esophagitis of being correlated with, parasitic gastritis, be secondary to the esophagitis that corrosivity/stimulus object is swallowed, any reason and comprise that corrosivity/stimulus object swallows the esophageal stricture of the persistence that causes/repeatedly, the pill esophagitis, systemic disease, congenital diseases, post-operation inflammatory or gastroenteritis.More specifically in the embodiment, described patient suffers from the eosinophil esophagitis.In other specific embodiments, the patient is suffered from gastroesophageal reflux disease (GERD), erosive reflux disease (NERD) or erosive esophagitis by diagnosis.In some embodiments, described gastroenteritis is, as non-limiting example, and gastritis and/or enteritis, for example gastroenteritis.

In some embodiment, described pharmaceutical composition comprises the about 20mg corticosteroid of about 0.1mg-, the about 10mg corticosteroid of about 0.1mg-, the about 5mg corticosteroid of about 0.3mg-, the about 4mg corticosteroid of about 0.3mg-, the about 2mg corticosteroid of about 1-, about 3mg corticosteroid of about 2-or the about 2.5mg corticosteroid of about 0.25-; Or method as herein described comprises and gives patient's aforementioned pharmaceutical compositions (for example every day or every dosage).

In some embodiments, described herein method comprises and is administered to the described compositions of child herein.In some specific embodiments, described child is less than 19 years old, less than 16 years old, less than 12 years old, less than 8 years old, less than 6 years old, less than 4 years old or less than 2 years old.In some embodiments, described herein method comprises and is administered to the described compositions of adult herein.

Combination by reference

All publications and the patent application mentioned in this description are all incorporated herein by reference, and its degree is pointed out clearly and individually that with each publication or patent application bonded by reference degree is identical.

The accompanying drawing summary

Appended claims has been illustrated new feature of the present invention particularly.By understanding the features and advantages of the present invention better with reference to following detailed description and accompanying drawing, in the described detailed description exemplary embodiment has been described, described embodiment has utilized principle of the present invention, in the described accompanying drawing:

The percentage composition that Fig. 1 has shown the compositions that exists in the esophagus to oral administration after the figure (by measuring the radiolabeled amount that exists in the esophagus) that does of time.

Detailed Description Of The Invention

In certain embodiments, the present invention relates to be used for the treatment of, prevent or alleviate method and the pharmaceutical composition that intestines and stomach comprise symptom and the relative inflammation of esophagus, stomach and/or gastral diseases associated with inflammation. Treatment is provided, has prevented or has alleviated for example method of patient's esophagitis herein. In some embodiment, these methods comprise and are administered orally to described patient's corticosteroid, and described corticosteroid and at least a excipient (mucomembranous adhesion agent) are in conjunction with to improve the mucoadhesive properties of described composition. The pharmaceutical composition that comprises corticosteroid and mucomembranous adhesion agent is provided in some embodiments. In some embodiment, described pharmaceutical composition also comprises liquid-carrier. In other or alternate embodiment, described pharmaceutical composition is suitable for oral administration. In some embodiments, the mucoadhesive properties of the raising of described composition so that after the administration described composition contact with esophagus the longer time.

In some embodiment, selected excipient has improved at least 1.02 times of the interactions of described composition and intestines and stomach surface (for example mucous membrane and/or the epithelium of the concrete position of intestines and stomach or intestines and stomach such as esophagus), at least 1.05 times, at least 1.1 times, at least 1.2 times, at least 1.25 times, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times or at least 5 times. In some embodiment, the described composition bolus that the interaction of the raising of described composition is swallowed is by at least 1.02 times of rear described composition and esophagus interaction, at least 1.05 times, at least 1.1 times, at least 1.2 times, at least 1.25 times, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, or at least 5 times. In some embodiment, these raisings have been carried out measuring and improved the composition analogous composition identical with the other side of the excipient of intestines and stomach surface interaction and compare with lacking. In some situation, selected or target part is such as the function mensuration of the amount of composition that exists in the esophagus (for example as intestines and stomach with the interaction of the raising of described composition, described bolus is measured after by esophagus, and it can be just swallowed behind the described composition of at least a portion 5 seconds, 6 seconds, 7 seconds, 8 seconds, 9 seconds, 10 seconds, 11 seconds, 12 seconds, 13 seconds, 14 seconds, 15 seconds etc.). Under some concrete condition, measure the amount of the composition that exists in the esophagus with any suitable method, for example, by with the described composition of labelled with radioisotope and adopt the amount of composition in the gamma-radiation development method mensuration esophagus. Can measure interaction between described composition and intestines and stomach surface (for example esophagus surface) in the time of staying on certain-length intestines and stomach surface (for example esophagus surface) by measuring material, wherein compare with there not being described excipient, in the presence of described excipient, the described time of staying is improved. In another embodiment, can physiological performance or symptom by disease to be controlled reduce, comprise that the minimizing of total eosinophil counting in the target sample measures the interaction of raising.

In one aspect of the invention, excipient can be used for reducing described excipient and does not have the lower amount of replying needed activating agent that causes. In some embodiments, described excipient can reduce the amount of used corticosteroid. Thereby the composition that provides herein may have the treatment of minimizing and suffer from the attendant advantages that intestines and stomach comprise the amount of the activating agent that esophagus, stomach and/or gastral diseases associated with inflammation patient are required.

In some embodiment, be used for the activating agent of described pharmaceutical composition herein and will have benefited from interaction (for example, Topically active corticosteroid) with the raising on intestines and stomach surface.

The patient of described combination treatment may herein for suitable usefulness, for example diagnosed and suffered from disease, it is including, but not limited to the eosinophil esophagitis, the inflammatory bowel disease that relates to esophagus, eosinophil cellularity gastroenteritis, Crohn disease, chylous diarrhea, proximal gastric Intestinal pathology (for example hypothyroid patient of gall-bladder), eosinophil property gastroenteritis, chylous diarrhea, eosinophil property duodenitis, the duodenum hypereosinophilia, functional dyspepsia FD, mid-term esophagitis, epithelial proliferation, basal cell hyperplasia, the mastoid process of elongation, nipple blood vessel dilatation, fungous esophagitis (Candida for example, torulopsis, histoplasma capsulatum's Aspergillus etc.), viral esophagitis (HSV for example, CMV, V2V), bacillary esophagitis (pulmonary tuberculosis for example, lumpy jawl clams, syphilis), corrosive oesophagitis, radiation esophagitis, the chemotherapy esophagitis, graft versus host disease(GVH disease), skin disease (the bullous pemphigoid for example that relates to esophagus, pemphigus vulgaris, epidermolysis bollosa, Shi-Yue syndrome), Behcet's disease, sarcoidosis, congenital esophagitis, eosinophil property gastroenteritis, Me﹠1﹠ne﹠1﹠trier disease, parasitic gastritis, the lymphocyte esophagitis, the esophagitis that inflammatory bowel disease is relevant, parasitic gastritis, be secondary to the esophagitis that corrosivity/stimulus is swallowed, any reason and comprise that corrosivity/stimulus swallows the esophageal stricture of the continuation that causes/repeatedly, the pill esophagitis, systemic disease, congenital disorders, post-operation inflammatory or gastroenteritis. Described composition also can be used for treating other gastrointestinal disease, comprises gastric duodenal ulcer, excessive acid discharge disease (hyperactive acidic discharge disorder) such as zes, and throat diseases.

The patient of described combination treatment may herein for suitable usefulness, for example diagnosed and suffered from disease, it is including, but not limited to the eosinophil esophagitis, the inflammatory bowel disease that relates to esophagus, Crohn disease, chylous diarrhea, proximal gastric Intestinal pathology (for example hypothyroid patient of gall-bladder), eosinophil property gastroenteritis, chylous diarrhea, eosinophil property duodenitis, the duodenum hypereosinophilia, functional dyspepsia FD, mid-term esophagitis, epithelial proliferation, basal cell hyperplasia, the mastoid process of elongation, nipple blood vessel dilatation, fungous esophagitis (Candida for example, torulopsis, histoplasma capsulatum's Aspergillus etc.), viral esophagitis is (such as HSV, CMV, V2V), bacillary esophagitis (pulmonary tuberculosis for example, lumpy jawl clams, syphilis), corrosive oesophagitis, radiation esophagitis, the chemotherapy esophagitis, eosinophil property stomach pyloric stenosis and related inflammation, graft versus host disease(GVH disease), skin disease (the bullous pemphigoid for example that relates to esophagus, pemphigus vulgaris, epidermolysis bollosa, Shi-Yue syndrome), Behcet's disease, sarcoidosis, congenital esophagitis, eosinophil property gastroenteritis, Me﹠1﹠ne﹠1﹠trier disease, parasitic gastritis, the lymphocyte esophagitis, the esophagitis that inflammatory bowel disease is relevant, parasitic gastritis, be secondary to the esophagitis that corrosivity/stimulus is swallowed, any reason and comprise that corrosivity/stimulus swallows the esophageal stricture of the continuation that causes/repeatedly, the pill esophagitis, systemic disease, congenital disorders, post-operation inflammatory or gastroenteritis. Described composition also can be used for treatment and is suffered from other gastrointestinal disease by diagnosis, comprises that stomach and duodenum fester, excessively acid discharge disease (hyperactive acidic discharge disorder) is such as the patient of zes and throat diseases. In some embodiments, described composition or method are used for the treatment of the method for being suffered from the patient of other gastrointestinal disease by diagnosis herein, described disease comprises, as non-limiting example, Barrett esophagus, GERD (GERD), Non-erosive reflux disease (NERD) or erosive esophagitis. In some embodiments, described treatment, prevent or reduce inflammation or the method for inflammatory symptom comprises the method for the treatment of any described gastrointestinal disease herein. In some embodiment, these methods comprise and are administered orally to the described patient composition of described corticosteroid-containing herein.

Treatment is provided herein, prevents and alleviates and anyly relate to intestines and stomach such as esophagus and respond the chronic inflammation of steroid therapy or the method for malignant state. The inventive method and composition can be used for, for example treatment, the prevention and alleviate the inflammation relevant with following disease and/or the method for symptom: the eosinophil esophagitis, the inflammatory bowel disease that relates to esophagus, Crohn disease, chylous diarrhea, proximal gastric Intestinal pathology (for example hypothyroid patient of gall-bladder), eosinophil property gastroenteritis, chylous diarrhea, eosinophil property duodenitis, the duodenum hypereosinophilia, functional dyspepsia FD, mid-term esophagitis, epithelial proliferation, basal cell hyperplasia, the mastoid process of elongation, nipple blood vessel dilatation, fungous esophagitis (Candida for example, torulopsis, histoplasma capsulatum's Aspergillus etc.), viral esophagitis (HSV for example, CMV, V2V), bacillary esophagitis (pulmonary tuberculosis for example, lumpy jawl clams, syphilis), corrosive oesophagitis, radiation esophagitis, the chemotherapy esophagitis, eosinophil cellularity stomach pyloric stenosis and related inflammation, graft versus host disease(GVH disease), skin disease (the bullous pemphigoid for example that relates to esophagus, pemphigus vulgaris, epidermolysis bollosa, Stevens Johnson syndrome), Behcet's disease, sarcoidosis, congenital esophagitis, eosinophil property gastroenteritis, Me﹠1﹠ne﹠1﹠trier disease, parasitic gastritis, the lymphocyte esophagitis, the esophagitis that inflammatory bowel disease is relevant, parasitic gastritis, be secondary to the esophagitis that corrosivity/stimulus is swallowed, any reason and comprise that corrosivity/stimulus swallows the esophageal stricture of the continuation that causes/repeatedly, the pill esophagitis, systemic disease, congenital disorders, epidermolysis bollosa, post-operation inflammatory and gastroenteritis. The inventive method also can be used for treating, prevent or alleviates and other intestines and stomach relevant symptom and/or inflammation of upper gastrointestinal disease or symptom for example, wherein to the specific target site of target rather than provide systemic treatment favourable. The pharmaceutical composition that can be used for the application's method also is provided herein. That the inflammation that imbalance used herein with disclosed herein or disease are relevant and/or symptom comprise is relevant with described imbalance or disease, caused and/or caused the inflammation and/or the symptom that produce by it by it.

Except as otherwise noted, term used herein " " comprises odd number and plural embodiment. Term used herein " individual patient " comprises any animal. In some embodiments, described animal is mammal. In some embodiment, described mammal is behaved. In some specific embodiments, described artificial adult. In other embodiment, described people is children (for example less than 12 years old children or less than 6 years old children). In some embodiment, described people is the baby. In some embodiments, term used herein " methods for the treatment of " can comprise prevention method, the method that reduces the incidence of disease, the method that preventative-therapeutic method is provided, treats and alleviates. Term used herein " effective dose " refers to enough cause the symptom relevant with gastrointestinal disease or the amount of inflammatory activity with " treatment effective dose ", and described gastrointestinal disease is including, but not limited to esophagitis, eosinophil esophagitis, GERD, NERD or erosive esophagitis. Term "or" used herein comprise " with " and "or".

Term used herein " treatment relates to the diseases associated with inflammation of esophagus " comprises the symptom inflammation relevant with described disease with treatment for the treatment of these diseases.

Used " significantly " improves or impact comprises and improves respectively or depart from some embodiment, as non-limiting example, and about amount of 10%, 5%, 3%, 2% or 1%.

Method and composition

In some embodiment, be used for corticosteroid of the present invention and comprise topical steroids, comprise for example budesonide or fluticasone propionate.In some embodiments, corticosteroid is selected from, as non-limiting example, alclometasone (aclometasone), Anxi Mead (amcinomide), beclometasone, betamethasone, budesonide, ciclesonide, clobetasol, clobetasone, clocortolone, cloprednol, can send out azoles, deflazacort, deoxycorticosterone, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, the fluclorolone, fludrocortisone, flurandrenolide, flumetasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin, fluocortolone, fluorometholone, fluperolone, fluticasone, fluprednidene, formocortal, halcinonide, halometasone, hydrocortisone aceponate, the hydrocortisone buteprate, the hydrocortisone butyrate, the Lip river is for sprinkling promise, medrysone, meprednisone, methylprednisolone, methylprednisolone aceponate, the saccharic acid mometasone, paramethasone, prednicarbate, prednisone, prednisolone, prednylidene, rimexolone, tixocortol, triamcinolone and ulobetasol, and their compositions, pharmaceutically acceptable salt and ester.In one specific embodiments, described corticosteroid is a budesonide.In another embodiment, described corticosteroid is the ester of fluticasone, for example fluticasone propionate.

Treatment is provided, has prevented or has alleviated gastrointestinal tract herein including, but not limited to the symptom of the diseases associated with inflammation of upper gastrointestinal (for example esophagus) and the method and the pharmaceutical composition of relative inflammation.Also provide herein and be used for the treatment of or alleviate method and the pharmaceutical composition that gastrointestinal tract improves including, but not limited to the relevant gastrointestinal reflux symptom of the diseases associated with inflammation of esophagus and stomach pH value.

In some embodiment, the corticosteroid of oral administration in the preparation of the mucoadhesive characteristics with raising (for example budesonide or fluticasone propionate) is transported to esophagus for example to reduce the inflammation of esophagus with effective dose.

An aspect provides the combination of oral medication that comprises corticosteroid and mucomembranous adhesion agent herein.In the each side, exemplary corticosteroid is a budesonide, 16,17-(butylidene dioxy base)-11, the 21-dihydroxy-, (11-β, 16-α)-pregnant steroid-1,4-diene-3,20-diketone or fluticasone propionate, 6 α, 9-two fluoro-11 β-17-dihydroxy-16 Alpha-Methyls-3-oxo androstane-1,4-diene-17 β-carbithionic acid S-fluorine methyl ester, 17 propanoic acid S-fluorine methyl ester or (6 α, 11 β, 16 α, 17 β)-6,9-two fluoro-11-hydroxyls-16-methyl-3-oxo-17-(1-oxopropoxy) androstane-1,4-diene-17-carbithionic acid S-fluorine methyl ester.

In some embodiment, disclosed herein and pharmaceutical composition that be used for herein comprises one or more excipient.The excipient that can be used for herein comprises, as non-limiting example, mucomembranous adhesion agent, viscosifier, binding agent, filler, lubricant, solvent, suspending agent, flavoring agent, coloring agent, sweeting agent, antiseptic, antioxidant, buffer agent, wetting agent, chelating agen, surfactant etc.

In some embodiment, corticosteroid used herein is used (for example be suspended in or be scattered in corticosteroid granule in the water-bearing media) with particulate form.In some specific embodiments, described granule is a microgranule.In some embodiments, the mean diameter of described microgranule is about 0.1 micron-Yue 50 microns.In some specific embodiments, the mean diameter of described microgranule is about 1 micron-Yue 20 microns.In some embodiment, the diameter of at least 95%, at least 98% or at least 99% microgranule is less than 10 microns.

In some embodiments, compositions described herein or preparation comprise and be less than 50%w/w, be less than 40%w/w, be less than 30%w/w, be less than 20%w/w, be less than 10%w/w, be less than 8%w/w, be less than 6%w/w, be less than 5%w/w, be less than 4%w/w, be less than 3%w/w, be less than 2%w/w or about 2%w/w, be less than 1%w/w, be less than 0.5%w/w, be less than 0.3%w/w, be less than the insoluble particles of 0.2%w/w or about 0.2%w/w.In some embodiment, described herein compositions or preparation be corticosteroid granule nothing but basically.

In some embodiments, described herein active corticosteroid is substituted by another activating agent.In some embodiment, described activating agent is the therapeutic agent of targeting esophagus, for example is used for the treatment of the therapeutic agent of esophagitis, mucositis (mucusitis), esophageal carcinoma, esophagus infection (for example antibacterial or fungal infection), esophagus wound and/or contusion etc.In some embodiments, described activating agent is by the therapeutic agent of esophagus systematicness absorption.In some specific embodiments, the described therapeutic agent that is absorbed by the esophagus systematicness is the reagent of degraded under one's belt or loss part effect, for example therapeutical peptide.

Used in this article mucomembranous adhesion agent comprises, as non-limiting example, soluble polyvinyl pyrrolidone polymers (PVP), card bohr, cross linked polyacrylate (for example Carbopol 974P), carbomer homopolymer, carbomer copolymer, water-soluble expanding but the ethene polymers of the polycarboxylic acids esterification of water-insoluble fibrous crosslinked carboxyl functional polymer, mucosa-adherent polysaccharide (for example hydrophilic polysaccharide glue), one or more maltodextrins, alginate, crosslinked alginate glue gel, aqueous dispersion.In some embodiments, described mucomembranous adhesion agent is the card bohr.In the specific embodiments, described mucomembranous adhesion agent is selected from, as non-limiting example, and Carbopol 974P, Carbopol Ultrez 10, sodium alginate LF120 and sodium alginate H120L.Mucomembranous adhesion agent used herein is for being attached to the reagent on gastrointestinal surface (for example one of gastrointestinal epithelial or mucosa or both).In some embodiments, described mucomembranous adhesion agent is a cellulose.In some specific embodiments, described mucomembranous adhesion agent is carboxymethyl cellulose (CMC), for example sodium carboxymethyl cellulose (NaCMC), microcrystalline Cellulose (MCC) or its combination.In the non-limiting example, described mucomembranous adhesion agent is the compositions (for example Avicel RC-591) of MCC and CMC.In some embodiments, CMC/MCC compositions described in the described compositions (for example

RC-591) amount is the about 150mg/mL of about 1mg/mL-, the about 75mg/mL of 1mg/mL-or the about 40mg/mL of about 5mg/mL-.In some embodiment, the mixed weight of CMC/MCC is than, about 20/80-about 5/95 about 99/1 for about 1/99-or about 15/85-about 10/90.In the specific embodiments, described CMC is NaCMC, and the mixed weight of described CMC/MCC is than about 11/89.

Some specific embodiments provide the compositions that comprises CMC (for example CMC/MCC mixture) and maltodextrin.In some embodiment, compare with the independent CMC with analog quantity (for example CMC/MCC mixture) or the compositions of maltodextrin, the compositions of CMC (for example CMC/MCC mixture) and maltodextrin makes to be increased in the time of staying of the ill or target surface of gastrointestinal tract (for example esophagus).

In some embodiment, described mucomembranous adhesion agent comprises one or more maltodextrins.In all fields, the physical features of maltodextrin changes according to for example Fructus Vitis viniferae candy equivalent of concrete maltodextrin.In some aspects, the Fructus Vitis viniferae candy equivalent of concrete maltodextrin may influence viscosity, hygroscopicity, sugariness, degree of wetting, plasticity, dissolubility and/or the mucosa-adherent of this maltodextrin.Therefore, in each embodiment, give the concrete feature selection maltodextrin of described pharmaceutical composition herein according to hope.In some embodiment, select to improve the mucoadhesive characteristics of described compositions herein and do not improve the maltodextrin of the viscosity (for example identical with the others that lack described maltodextrin compositions is compared .) of described compositions significantly.In some embodiments, described combination of oral medication comprises the second kind of maltodextrin (for example identical with the others that lack described second kind of maltodextrin compositions is compared) that improves described combination of oral medication viscosity.In some specific embodiments, described second kind of maltodextrin influences the mucoadhesive characteristics (for example identical with the others that lack described second kind of maltodextrin compositions is compared) of described pharmaceutical composition indistinctively.

In some embodiments, described mucomembranous adhesion agent can not improve the viscosity (for example identical with the others that lack described mucomembranous adhesion agent compositions is compared) of described combination of oral medication significantly.In other or alternate embodiment, select described mucomembranous adhesion agent according to mucoadhesive characteristics (for example it gives the ability of described combination of oral medication mucoadhesive characteristics).

In some embodiments, be used for the mucomembranous adhesion agent of described combination of oral medication herein and give the viscosity (for example identical with the others that lack described mucomembranous adhesion agent compositions is compared) that described combination of oral medication improves.In other embodiment, described mucomembranous adhesion agent can not improve the viscosity (for example identical with the others that lack described mucomembranous adhesion agent compositions is compared) of described combination of oral medication significantly.

In some embodiments, select at least a mucomembranous adhesion agent and be used for described pharmaceutical composition to make the described at least a mucomembranous adhesion agent of adding also improve the viscosity (for example identical with the others that lack described mucomembranous adhesion agent compositions is compared) of gained combination of oral medication indistinctively.

In some embodiments, select at least two kinds of mucomembranous adhesion agents and be used for described pharmaceutical composition to make the described at least two kinds of mucomembranous adhesion agents of adding also improve the viscosity (for example identical with the others that lack described mucomembranous adhesion agent compositions is compared) of gained combination of oral medication indistinctively.In some embodiments, at least a mucomembranous adhesion agent, if be used for the viscosity that described pharmaceutical composition will improve described pharmaceutical composition separately, but use the viscosity (for example identical with the others that lack described at least a mucomembranous adhesion agent compositions is compared) that then improves the gained combination of oral medication indistinctively together with all components in the described pharmaceutical composition.

In some embodiments, the viscosity of described compositions is at least about 2 centipoises (cP), at least about 5cP, at least about 10cP, at least about 20cP, at least about 25cP, at least about 35cP, at least about 40cP, at least about 50cP, at least about 200cP or at least about 225cP.In some embodiments, the viscosity of described compositions is at least about 100cP.In some embodiment, described compositions is about 250 for about 50cP-25 degrees centigrade of viscosity that record, 000cP, about 50cP-about 70,000cP, about 50cP-are about 25, and 000cP, about 50cP-are about 10,000cP, about 50cP-about 3,000cP or about 50cP-are about 2,000cP.In one aspect, described compositions is about 25 centipoises (cP)-Yue 800cP, about 50cP-about 800 or the about 800cP of about 300cP-(for example measuring by Brookfield viscometer) 25 degrees centigrade of viscosity that record.On the other hand, the viscosity of described compositions can be the about 200cP of about 100cP-, the about 300cP of about 200cP-, the about 600cP of about 250cP-or the about 600cP of about 400cP-.In some specific embodiments, the viscosity of described preparation is about 30cP, about 100cP, about 200cP, about 300cP, about 400cP, about 500cP or about 250,000cP (for example adopt and be equipped with the Brookfield viscometer of ultra-low viscosity adapter 25 degrees centigrade of mensuration).

In some embodiments, the viscosity of described compositions under the room temperature (about 25 degrees centigrade), shear rate is for measuring under the condition of about 13.2sec-1.In some embodiment, provide the following compositions of viscosity under this condition: at least about 2 centipoises (cP), at least about 5cP, at least about 10cP, at least about 20cP, at least about 25cP, at least about 30cP, at least about 35cP, at least about 40cP, at least about 50cP, at least about 200cP, at least about 225cP, at least about 250cP, at least about 300cP or at least about 400cP.In some embodiments, the viscosity of described compositions under this condition is about 250 for about 50cP-, 000cP, about 50cP-about 70,000cP, about 50cP-are about 25, and 000cP, about 50cP-are about 10,000cP, about 50cP-about 3,000cP, about 50cP-about 2,000cP, about 250cP-are about 250, and 000cP, about 250cP-are about 70,000cP, about 250cP-about 25,000cP, about 250cP-about 10,000cP, about 250cP-are about 3, and 000cP or about 250cP-are about 2,000cP.On the one hand, described compositions is about 25 centipoises (cP)-Yue 800cP, about 50cP-about 800 or the about 800cP of about 300cP-(for example measuring by Brookfield viscometer) 25 degrees centigrade of viscosity of measuring down.On the other hand, the viscosity of described compositions under this condition can be the about 200cP of about 100cP-, the about 300cP of about 200cP-, the about 600cP of about 250cP-or the about 600cP of about 400cP-.In some specific embodiments, the viscosity that described preparation is measured under this condition is about 30cP, about 40cP, about 100cP, about 200cP, about 300cP, about 400cP, about 500cP or about 250,000cP.

In some embodiments, the viscosity of described compositions under the room temperature (about 25 degrees centigrade), shear rate is mensuration (for example the gap between spindle and the sample locular wall is about 6mm or bigger) under the condition of about 15sec-1.In some embodiment, provide the following compositions of viscosity under this condition: at least about 150 centipoises (cP), at least about 160cP, at least about 170cP, at least about 180cP, at least about 190cP or at least about 200cP.In some embodiments, the viscosity of described compositions under this condition is about 250 for about 150cP-, and 000cP, 160cP-are about 250, and 000cP, 170cP-are about 250, and 000cP, 180cP-are about 250, and 000cP or 190cP-are about 250,000cP.

In some specific embodiments, the mucomembranous adhesion agent that is used for described any compositions herein for or comprise at least a maltodextrin.

In some embodiment, mucomembranous adhesion agent (for example maltodextrin) fully or at least is partially dissolved in the liquid-carrier.In some embodiments, described herein combination of oral medication is included in that every mL liquid-carrier is less than about 0.1g or is less than about 1g maltodextrin in the described combination of oral medication.Under the certain situation, described herein compositions or preparation comprise and are less than 2g maltodextrin/mL compositions, be less than 1.5g maltodextrin/mL compositions, be less than 1g maltodextrin/mL compositions, be less than 0.5g maltodextrin/mL compositions, be less than 0.25g/mL maltodextrin/mL compositions, about 0.05g maltodextrin/mL compositions-Yue 0.5g maltodextrin/mL compositions, about 0.05g maltodextrin/mL compositions-Yue 0.4g maltodextrin/mL compositions, about 0.05g maltodextrin/mL compositions-Yue 0.3g maltodextrin/mL compositions, about 0.1g maltodextrin/mL compositions-Yue 0.5g maltodextrin/mL compositions, about 0.1g maltodextrin/mL compositions-Yue 0.4g maltodextrin/mL compositions, about 0.1g maltodextrin/mL compositions-Yue 0.3g maltodextrin/mL compositions, about 0.2g maltodextrin/mL compositions-Yue 0.5g maltodextrin/mL compositions, about 0.2g maltodextrin/mL compositions-Yue 0.4g maltodextrin/mL compositions or about 0.2g maltodextrin/mL compositions-Yue 0.3g maltodextrin/mL compositions.In some embodiments, described maltodextrin fully is dissolved in described liquid-carrier.In some embodiment, the glucose equivalent of described maltodextrin (DE) be greater than 4, greater than 5, greater than 10, greater than 11, greater than 12, greater than 13, greater than 14, greater than 15, about 19, the about 13-about 18 of about 20, the about 12-of about 8, the about 11-of about 9, the about 4-of about 10, the about 4-of about 15, about 4-or about 14-about 16.In some specific embodiments, the DE of described first kind of maltodextrin is about 10 for about 4-, the DE of about 4-about 9 or about 4-about 8 described second kind of maltodextrin is about 20 for about 10-, about 12-about 19 or about 13-about 18.In some embodiments, be used for the enough high solubility property of molecular weight of at least a maltodextrin of described compositions herein, or improve the particulate suspension of corticosteroid with the raising corticosteroid.

In some embodiments, mucomembranous adhesion agent exists, and for example United States Patent (USP) 6,638, and 521,6,562,363,6,509,028,6,348,502,6,306,789, describe in 5,814,330 and 4,900,552, described United States Patent (USP) separately by reference its full content be incorporated into this.

Among the indefiniteness embodiment, mucomembranous adhesion agent can be, and as non-limiting example, is selected from least two kinds of concrete components of titanium dioxide, silicon dioxide and clay.In some embodiments, when need not any liquid before the administration further during the described compositions of dilution, the level of silicon dioxide be about 3%-about 15% of described composition weight.In some embodiment, silicon dioxide is selected from, as non-limiting example, and aerosil, precipitated silica, cohesion silicon dioxide, gel silicas and composition thereof.In some embodiments, clay is selected from, as non-limiting example, and kaolin ore, serpentine, Montmorillonitum, illite or its mixture.In some embodiment, clay is selected from, as non-limiting example, and hectorite, bentonite, Strese Hofmann's hectorite., saponite, Montmorillonitum or its mixture.

In some embodiment, the amount of described mucomembranous adhesion agent is enough to make described corticosteroid to be exposed to the enough time of gastrointestinal tract surface (for example esophagus surface), make contain described corticosteroid peroral dosage form with single dose or multiple dose administration after the symptom of diseases associated with inflammation of gastrointestinal tract (for example esophagus, stomach and/or digestive tract) and/or associated inflammation alleviated.

In some embodiments, the amount of selecting described mucomembranous adhesion agent and selecting is enough to make administration (as passing through oral administration) after gastrointestinal tract surface (for example esophagus surface), and the pharmaceutical composition of described corticosteroid-containing adheres to or rests on gastrointestinal tract surface (for example esophagus surface) last 5 second, 10 seconds, 15 seconds, 30 seconds, 45 seconds or 1 minute.In some embodiment, the amount of selecting mucomembranous adhesion agent and selecting be enough to make be administered to gastrointestinal tract surface (for example esophagus surface) after, the pharmaceutical composition of described corticosteroid-containing adheres to or rests on last 1.5,2,3,4,5,6,7,8,9,10,15,20,25,30,35,40,45,50,55 or 60 minutes of gastrointestinal tract surface (for example esophagus surface).In some embodiments, be administered to gastrointestinal tract surface (for example esophagus surface) postadhesion on the gastrointestinal tract surface (for example esophagus surface) last 5 second, 10 seconds or 0.25,0.5,0.75,1,1.5,2,3,4,5,6,7,8,9,10,15,20,25,30,35,40,45,50, the amount of 55 or 60 minutes corticosteroid-containing compositions is at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95% weight.In some specific embodiments, be administered to gastrointestinal tract surface (for example esophagus surface) after, at least 50% pharmaceutical composition adheres to or rests on gastrointestinal tract surface (for example esophagus surface) at least 1 minute or at least 15 minutes.

In some embodiment, the amount of selecting mucomembranous adhesion agent and selecting is enough to make administration (as passing through oral administration) to gastrointestinal tract surface (for example esophagus surface) 5 seconds, after 10 seconds or 0.25,0.5,0.75,1,1.5,2,3,4,5,6,7,8,9,10,15,20,25,30,35,40,45,50,55 or 60 minute, and described corticosteroid is attached to intestines and stomach surface (for example esophagus surface) and goes up and/or be absorbed.In some embodiments, postadhesion is to the gastrointestinal tract surface and/or be absorbed 5 seconds to be administered to gastrointestinal tract surface (for example esophagus surface), 10 seconds or 0.25,0.5,0.75,1,1.5,2,3,4,5,6,7,8,9,10,15,20,25,30,35,40,45,50, the amount of 55 or 60 minutes corticosteroid (promptly adhere to or rest on supraoesophageal amount and by the summation of the amount of the gastrointestinal absorption of inflammation) is at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95% weight.In some embodiments, be administered to gastrointestinal tract surface (for example esophagus surface) after, at least 50% corticosteroid is attached to gastrointestinal tract surface (for example esophagus surface) and goes up and/or be absorbed at least 1 minute or at least 15 minutes.

In some specific embodiments, will be herein described composition oral be administered to esophagus after (for example swallow at first or drink described compositions after), described compositions was administered to esophagus at least 5 seconds, 10 seconds, 15 seconds, 20 seconds, 25 seconds, 30 seconds, 40 seconds, 45 seconds, 50 seconds or 1,1.5,2,3,4,5,6,7,8,9,10,15,20,25,30,35,40,45,50, after 55 or 60 minutes, at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, the administration corticosteroid of 90% or 95% weight or compositions are present in esophagus (for example measuring by the gamma-radiation development method).Under some situation, even the result or the improvement that also can produce treatment meaning or clinical meaning in the little difference (for example increasing) of adhering to the time on (for example time of staying) between the preparation.

In some embodiments, 5,10,15,30 or 45 seconds or 1,1.5,2,3,4,5,6,7,8,9,10,15,20,25,30,35,40,45,50,55 or 60 minute postadhesion or the percentage by weight that rests on the corticosteroid-containing compositions on the gastrointestinal tract surface (for example esophagus surface) are greater than (for example surpassing 1.1x, 1.2x, 1.3x, 1.4x, 1.5x, 2x, 3x, 4x, the 5x) percentage by weight attached to the reference composition on gastrointestinal tract surface (for example esophagus surface).In some embodiment, for every 0.5mg, 1mg or 2mg corticosteroid, described compositions comprises corticosteroid, 4mL aqueous compositions and 10 bags of same amount

(being sold by McNeil Nutritionals, LLC FortWashington, PA 19034-2299) (2Respules of for example Every 2mL suspension comprises 0.25mg, 0.5mg or the micronized budesonide of 1mg).For example, some contain in the embodiment of pharmaceutical composition of budesonide, and described reference composition comprises 4mL With 10 bags

In some embodiments, described reference composition comprises corticosteroid, 8mL aqueous compositions and 20 bags of every 0.5mg, 1mg or 2mg corticosteroid same amount

(

Bag is sold by McNeil Nutritionals for about 1g, LLC Fort Washington, PA19034-2299) (4Respules of for example Each 2mL suspension comprises 0.25mg, 0.5mg or the micronized budesonide of 1mg).In some embodiment, the corticosteroid that comprises in the described reference composition is identical with the corticosteroid capacity that described stable oral pharmaceutical composition exists, amount is identical and kind is identical, and described reference composition is that viscosity under about 13.2sec-1 condition is about 1cP (Respules of for example at 25 ℃, shear rate

).The preparation of compositions description also is desired herein in contrast herein.Adhere to or rest on amount that the percentage by weight of the corticosteroid-containing compositions on the gastrointestinal tract surface (for example esophagus surface) can be by will being attached to the corticosteroid-containing compositions on the gastrointestinal tract surface (for example esophagus surface) divided by the total amount of the corticosteroid-containing compositions that is administered to gastrointestinal tract surface (for example esophagus surface) and the result be multiply by 100% determine.Equally, be attached to amount that the percentage by weight of the reference composition on the gastrointestinal tract surface (for example esophagus surface) can be by will being attached to the reference composition on the gastrointestinal tract surface (for example esophagus surface) divided by the total amount of the reference composition that is administered to gastrointestinal tract surface (for example esophagus surface) and the result be multiply by 100% determine.In some embodiments, 5, after 10,15,30 or 45 seconds or 1,1.5,2,3,4,5,6,7,8,9,10,15,20,25,30,35,40,45,50,55 or 60 minute, the amount that is attached to the corticosteroid that goes up or be absorbed in gastrointestinal tract surface (for example esophagus surface) is greater than (for example surpassing 1.1x, 1.2x, 1.3x, 1.4x, 1.5x, 2x, 3x, 4x, 5x) reference composition, described reference composition comprises the corticosteroid of every 0.5mg or 1mg corticosteroid same amount, for example 4mL aqueous compositions and 10 bags

One bag

The mixture that comprises about 1 gram glucose, maltodextrin and sucralose (sucralose).

In some embodiment, when comparing with the reference composition of the corticosteroid that comprises same amount, described herein pharmaceutical composition has the higher mucoadhesive characteristics and the viscosity of reduction.In some embodiments, when comparing with reference composition, described herein pharmaceutical composition has the close substantially mucoadhesive characteristics and the viscosity of reduction.In some embodiment, described herein pharmaceutical composition adheres to or the time on the gastrointestinal position (for example esophagus) of resting on surpasses or equals the time of reference composition and viscosity is less than or equal to the viscosity of described reference composition.In some specific embodiments, when the time that described pharmaceutical composition herein was attached to or rested on the intestines and stomach position (for example esophagus) equaled the time of reference composition, the viscosity of described pharmaceutical composition was less than the viscosity of described reference composition herein.In some embodiment, described reference composition used herein comprises 4mL

(for example every 2mL dosage 0.25mg or 0.5mg budesonide) and 10 bags

(for example for every 0.5mg or 1mg corticosteroid, 4mL aqueous compositions and 10 bags

).In some embodiments, described reference composition comprises corticosteroid, 8mL aqueous compositions and 20 bags of every 0.5mg, 1mg or 2mg corticosteroid same amount

(every bag Comprise about 1g, be sold by McNeil Nutritionals, LLC Fort Washington, PA 19034-2299) (4Respules of for example

Every 2mL suspension comprises 0.25mg, 0.5mg or the micronized budesonide of 1mg).

In some embodiment, described herein pharmaceutical composition or corticosteroid are attached to and/or are adsorbed onto on the gastrointestinal tract surface (for example esophagus surface) and can determine by scintigraphy or by detecting.In some embodiments, this determine can be in vivo or external carrying out.In some embodiment, in the body scintiscan can comprise with described pharmaceutical composition herein with can mix by detected radiosiotope, the compositions of gained labelling is administered to the curee and adopts and detect and/or measure radioactive equipment (for example camera) detection and/or mensuration pharmaceutical composition or corticosteroid and be attached on the gastrointestinal tract surface (for example esophagus surface).In some embodiments, in the body scintiscan can comprise with described corticosteroid herein with can be connected by detected radiosiotope, the corticosteroid of gained labelling is mixed with the compositions described in this paper, resulting composition is administered to the patient and detects and/or measure pharmaceutical composition or corticosteroid is attached on the gastrointestinal tract surface (for example esophagus surface) with detecting and/or measure radioactive equipment (for example camera).In some embodiment, be used for detecting described pharmaceutical composition or corticosteroid herein and be attached to vitro detection on the gastrointestinal tract surface (for example esophagus surface) and can comprise and described compositions herein is applied to one section of gastrointestinal surface texture (for example pig feed road tissue) terminal and described compositions stood and the rightabout artificial saliva of this section end is flowed.The residual compositions and/or the amount of corticosteroid are determined adhering to of described compositions and/or corticosteroid on compositions that can be by detecting elution in a certain preset time and/or the amount of corticosteroid or the gastrointestinal surface texture.

In some embodiments, the esophagus of described herein pharmaceutical composition (or corticosteroid of administration in the described in this article compositions) surpasses 5,10,15,30 or 45 seconds or 1,1.5,2,3,4,5,6,7,8,9,10,15,20,25,30,35,40,45,50,55 or 60 minute by the time, and wherein said esophagus is to be reduced to from described pharmaceutical composition administration herein (for example oral and/or to esophagus) to activity≤lag time of 10% peak activity (peak activity) by the time.In some embodiment, the esophagus of described herein pharmaceutical composition (or corticosteroid of administration in the described in this article compositions) is about 5,10,15,30 or 45 seconds or 1,1.5,2,3,4,5,6,7,8,9,10,15,20,25,30,35,40,45,50,55 or 60 minute by the time.In some embodiments, active back 10 seconds of peak, the esophagus emptying of described herein pharmaceutical composition (or corticosteroid of administration in the described in this article compositions) is less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99%.

Being used for herein, the optional tackify excipient of described pharmaceutical composition comprises, as non-limiting example, cross linked polyacrylate (for example Carbopol 974P), glycerol, the carbomer homopolymer, the carbomer copolymer, Radix Acaciae senegalis, agar, Magnesiumaluminumsilicate, sodium alginate, sodium stearate, bladder-wrack, bentonite, carbomer, carrageenin, Carbopol, cellulose, microcrystalline Cellulose (MCC), algaroba glue, carrageenin, glucose, Furcellaran, gelatin, ghatti gum, guar gum, lithium montmorillonite, lactose, sucrose, maltodextrin, mannitol, sorbitol, Mel, corn starch, wheaten starch, rice starch, potato starch, gelatin, karaya, goat glue, Polyethylene Glycol (for example PEG 200-4500), tragacanth, ethyl cellulose, ethylhydroxyethylcellulose, ethylmethylcellulose, methylcellulose, hydroxy ethyl fiber, hydroxyethylmethyl-cellulose, hydroxypropyl cellulose, poly hydroxy ethyl acrylate, oxypolygelatin, pectin, polygeline, polyvidone, Allyl carbonate, methyl vinyl ether/copolymer-maleic anhydride (PVM/MA), poly-methyl methacrylate oxygen base ethyl ester, poly-methyl methacrylate oxygen base oxethyl ethyl ester, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose (CMC) (comprising, for example sodium carboxymethyl cellulose (NaCMC)), silicon dioxide, polyvinylpyrrolidone (PVP: polyvidone);

(glucose, maltodextrin and sucralose) or its compositions.

In some embodiment, described herein pharmaceutical composition is non-Newtonian fluid or Newtonian fluid.In some embodiments, described herein pharmaceutical composition is a non-Newtonian fluid.In some specific embodiments, described non-Newtonian fluid is plasticity, pseudoplastic behavior or bloated plasticity non-Newtonian fluid.In some specific embodiments, described non-Newtonian fluid is the thixotropic non-Newtonian fluid.In some embodiment, the shear shinning of described non-Newtonian fluid compositions does not have the retrogradation of when shearing.Therefore, some embodiments provide and have been suitable for simple and easy fluid medicine compositions of toppling over after the slight or medium stirring.In addition, some embodiments provide the fluid medicine compositions, although described compositions is suitable for simple and easyly after slight or medium stirring toppling over, but behind oral administration, become enough sticking, thereby allow this pharmaceutical composition to small part to be coated in esophagus and the corticosteroid part that will treat effective dose is transported to esophagus.

In some embodiment, the pharmaceutical composition that provides herein is used for the treatment of, prevents or alleviate to relate to gastrointestinal tract and comprise esophagus, stomach and/or gastral diseases associated with inflammation.In some embodiments, described pharmaceutical composition is a liquid dosage form.Liquid dosage form comprises, as non-limiting example, and emulsion agent, solution, suspending agent, syrup, slurry agent, dispersion liquid, colloidal powder etc.The pharmaceutical composition of the solution tablet, the agent of dissolving disk, capsule or the gel capsule form that comprise corticosteroid (for example local corticosteroid, as budesonide etc.) and mucomembranous adhesion agent also is provided.In some embodiments, described herein pharmaceutical composition is liquid, semisolid or solid dosage forms.In some specific embodiments, described herein pharmaceutical composition is a semisolid dosage form, example gel, gel-type vehicle, cream, paste etc.In some embodiments, semisolid dosage form comprises liquid-carrier.

The inventive method and compositions are used by the patient at various ages." patient " is meant any animal, and mammal for example, or people for example comprise for example needing the patient that treats.

" patient " is meant any animal, and mammal for example, or people for example comprise for example needing the patient that treats.In some embodiments, described people is the child.The child needs treatment usually, because they may blow-pharynx technology (puff and swallow technique) in the most difficult use.In some embodiment, the inventive method is used for the patient at various ages, comprises the adult.

In some embodiment, the compositions that provides herein adopts the preparation of any suitable activity agent source.In some embodiments, being used for herein, the corticosteroid of described compositions (for example budesonide) is pure corticosteroid (a for example budesonide).In some embodiments, described pure corticosteroid (for example budesonide) is pure corticosteroid in bulk.In some embodiment, described pure corticosteroid (for example budesonide) is koniocortex steroid class (a for example budesonide).In some specific embodiments, described pure corticosteroid (for example budesonide) is micronized corticosteroid (a for example budesonide).

In some embodiments, the preparation administration of described corticosteroid can buy on the market.In other embodiment, described corticosteroid is to comprise the compositions administration of the corticosteroid preparation that can buy on the market.For example, in some embodiments, the corticosteroid-containing compositions comprises the preparation that can buy on the market and excipient (as the excipient of compositions mucoadhesive characteristics as described in giving) and/or diluent.In some embodiments, wherein said corticosteroid is a budesonide, and the preparation that can buy on the described market is Pulmicort

In other embodiment, wherein said corticosteroid is a budesonide, and the preparation that can buy on the described market is Rhinocort

In some embodiments, wherein said corticosteroid is a fluticasone, and the preparation that can buy on the described market is

In some embodiments, the preparation that can buy on the market is 1 with the ratio of optional diluent: about 1: 100 of 0.5-.Diluent comprises that any pharmaceutically acceptable oral diluent comprises, for example powdery diluent (as Talcum) and liquid diluent (as water, ethanol and combination thereof).In some embodiment, the preparation that can buy on the described market is In some embodiment, will

Preparation dissolves and/or is scattered in the water carrier.In some specific embodiments, with described

Preparation is scattered in the liquid-carrier, and the pH of described liquid-carrier is enough to remove the particulate enteric coating of budesonide.In other embodiment, described with solvent pre-treatment

Preparation, the pH of described solvent are enough to remove the particulate enteric coating of budesonide, and described granule is mixed with the compositions described in this paper subsequently.

In some embodiment, described corticosteroid-containing compositions comprises micronized budesonide, disodium edetate, sodium chloride, sodium citrate, citric acid, polysorbate (for example polysorbate80), water and chooses any one kind of them or multiple excipient, and wherein said excipient is selected from any those that mention herein.In some embodiment, described compositions comprises the about 1.0mg budesonide/2mL of about 0.1mg-(or the about 0.5mg/ gram of about 0.05mg-) compositions.In some embodiments, described compositions comprises the about 0.6mg budesonide/2mL of about 0.2mg-(or the about 0.3mg/ gram of about 0.1mg-) compositions.In some specific embodiments, described compositions comprises about 0.25mg/2mL compositions.In other specific embodiments, described compositions comprises about 0.5mg/2mL compositions.

In other embodiment; described corticosteroid-containing compositions comprises micronized budesonide, microcrystalline Cellulose (MCC), carboxymethyl cellulose and (comprises; sodium carboxymethyl cellulose for example), glucose, polysorbate (for example polysorbate80), disodium edetate, Pyrusussuriensis potassium alcoholate, water, optional hydrochloric acid and choose any one kind of them or multiple excipient, wherein said excipient is selected from any those that mention herein.In some specific embodiments, the pH of described compositions is about 4.5.In some embodiments, described compositions comprises the about 1.0mg budesonide of about 0.1mg-/g compositions.In some embodiment, described compositions comprises the about 0.6mg budesonide of about 0.3mg-/g compositions.In some specific embodiments, described compositions comprises about 0.4mg or 0.44mg budesonide/g compositions.In some specific embodiments, described compositions comprises about 3.8mg/8.6g compositions.In some embodiments, described compositions comprises the about 1.0mg budesonide of about 0.1mg-/mL compositions (the about 0.1%w/w of about 0.01-).In some embodiment, described compositions comprises the about 0.8mg budesonide of about 0.3mg-/mL compositions (the about 0.08%w/w of about 0.03-).In some specific embodiments, described compositions comprises the about 0.7mg budesonide of about 0.6-/mL compositions (the about 0.07%w/w of about 0.06-).In embodiment more specifically, described compositions comprises about 0.63mg budesonide/mL compositions (about 0.063%w/w).

In some embodiments, described corticosteroid-containing compositions comprises fine fluticasone propionate, microcrystalline Cellulose, carboxymethyl cellulose and (comprises, sodium carboxymethyl cellulose for example), glucose, benzalkonium chloride, polysorbate (for example polysorbate80), phenethanol and choose any one kind of them or multiple excipient, wherein said excipient is selected from those that mention herein.In some embodiments, the pH of described compositions is about 5-about 7.In some embodiment, described compositions comprises the about 80 μ g fluticasone propionate/mg compositionss of about 20-.In some embodiments, described compositions comprises the about 60 μ g fluticasone propionate/mg compositionss of about 40-.In some specific embodiments, described compositions comprises about 50 μ g fluticasone propionate/mg compositionss.In some embodiments, described compositions comprises about 0.02%w/w benzene and pricks sodium ammonium and about 0.25%w/w phenethanol.

Preparation

Although the present composition can be generally used for treating human patients, yet in some embodiment, they are used for veterinary drug treat similar or identical disease.In some embodiments, described compositions is used for, and for example treats mammal, including, but not limited to the mammal of primates and instructionization.In some embodiments, described compositions is used for, and for example treats plant-eating animal.The present composition comprises how much and optical isomer.

Being applicable to that pharmaceutical composition of the present invention comprises wherein comprises effective amount of actives to reach the compositions of its intended purposes.

Exact dose will depend on the form of administration path, described compositions administration, patient to be controlled, patient's age to be controlled, body weight/height and attending doctor's preference and experience.In some embodiment, the optium concentration of corticosteroid depends on the character of used concrete corticosteroid, patient characteristic, inflammation to be treated in the described compositions.In the various embodiments, the technical staff in the field of medicaments can determine these factors according to the present invention.

Usually, need the treatment effective dose.The treatment effective dose is meant that the state of symptom before the relative treatment and/or inflammation produces symptom and/or the corticosteroid amount improved of inflammation to a certain degree.The dosage form and the using method thereof that comprise effective dose belong to the scope of the invention.In the various embodiments, the amount that is used for the corticosteroid (for example budesonide or fluticasone propionate) of described method or compositions herein is about 2.5-400 μ g/kg body weight every day, or for example 5-300 μ g/kg/ days, or for example 5-200 μ g/kg/ days, or for example 5-100 μ g/kg/ days, or for example 10-100 μ g/kg/ days, or for example 10-50 μ g/kg/ days, or for example 10-100 μ g/kg/ days, or for example 5-50 μ g/kg/ days, or in exemplary, be 10-60 μ g/kg/ days.In some embodiments, be used for described method herein, the amount of the corticosteroid in compositions or the composition dosage (for example budesonide or fluticasone propionate) comprises, as non-limiting example, the about 500mg of about 50 μ g-, the about 200mg of about 50 μ g-, the about 100mg of about 50 μ g-, the about 50mg of about 50 μ g-, the about 20mg of about 100 μ g-, the about 20mg of about 250 μ g-, the about 15mg of about 250 μ g-, the about 10mg of about 250 μ g-, the about 5mg of about 250 μ g-, the about 4mg of about 300 μ g-, the about 2mg of about 350 μ g-, about about 3mg of 250 μ g-or the about 3mg of about 500 μ g-, about about 1.5mg of 375 μ g-or about about 2mg of 500 μ g-or the about 3mg of about 1mg-.In exemplary, the capacity of the dosage that provides is enough to allow the described compositions of effective dose to arrive esophagus.In some embodiments, described herein compositions comprises 1 dose or multi-agent.In some embodiment, described herein compositions is contained in the multiple dose unit packaging.Therefore, the invention provides the test kit that comprises described compositions and packing (for example multiple dose unit or single dosage unit packing) herein.In some embodiment, the invention provides compositions or comprise the test kit of compositions, described compositions comprises that about 2-is about 180, about 10-about 60, about 14 or about 30 dosage.

In the exemplary, in the compositions of enough capacity, provide the corticosteroid of doses or amount (comprising dosage separately) to arrive gastrointestinal target and/or inflammation part herein, comprise for example esophagus with the described any compositions that allows effective dose.In some embodiments, the effective dose that is transported to the compositions of esophagus is meant and is enough to apply or applies esophagus and with the amount of described delivery of composition to involved area, described involved area comprises (only as example) esophagus, esophagus-stomach joint portion, stomach and/or duodenum down to small part.In some embodiment, the capacity of described compositions is herein, for example about 1-50mL or for example about 1-40mL or for example about 1-30mL or for example about 1-25mL or for example about 1-20mL or for example about 5-25mL or for example about 10-20mL or for example about 10mL or for example about 15mL or for example about 20mL or for example about 1-15mL or for example about 1-10mL or for example about 2-8mL or for example about 3-7mL or for example about 4-6mL or for example about 5mL or for example about 6-14mL or for example about 8-12mL or for example about 9-11mL or for example about 10mL.In embodiment more specifically, will the about 6mg of about 0.25mg-, about 0.375mg, about 0.5mg, about 0.75mg, about 1mg, about 1.25mg, about 1.5mg or about 2mg corticosteroid (for example budesonide) are mixed with the described pharmaceutical composition of single agent or unit dose herein, and the total capacity of described single agent or unit dose is about 10-20mL, or for example about 10mL, or for example about 15mL, or for example about 20mL, or for example about 1-15mL, or for example about 1-10mL, or for example about 2-8mL, or for example about 3-7mL, or for example about 4-6mL, or for example about 5mL, or for example about 6-14mL, or for example about 8-12mL, or for example about 9-11mL, or for example about 10mL." liquid " used herein comprises serosity, solution, suspension, dispersion liquid or its any combination, and this depends on dissolubility and the amount and the used carrier and the solvent of each single component.In some embodiments, the capacity of suitable good to eat dosage is enough to apply or applies described esophagus to small part, in the exemplary, described capacity is enough to apply or is transported to affected zone to small part coating esophagus and with described corticosteroid, comprises (only as example) esophagus, esophagus-stomach joint portion, stomach and/or duodenum down.Described compositions can be carried as lower frequency: for example every day four times, every day three times, twice of every day, once a day, per two days once, on every Wendesdays time, twice or weekly weekly.Described dosage can, for example be divided into many parts of medicaments every day, or provide with for example four doses, three doses, two doses of every days, potion.Under some situation, administration more continually (for example being every day twice, relatively once a day) provides shorter comprehensive treatment or has begun remission sooner.In the exemplary embodiment, described medicament is to provide once a day.

In some embodiment, described herein medicament or compositions are with the food administration.In some embodiments, described herein medicament or compositions be not with the food administration.In some embodiment, described herein compositions is with state of being satiated with food or fasting state administration.In some embodiments, described herein medicament or compositions in the morning, noon, at dusk, evening or its combination medicine-feeding.In some embodiments, the administration at night of described medicament.On the other hand, described medicament is not taken food or water after the described herein compositions administration in the precontract administration in 30 minutes of going to bed.In another embodiment of the present invention, the administration before going to bed of described medicament, after the wherein said compositions administration, this patient or the basic back floating position of individual maintenance at least 30 minutes, at least 1 hour, at least 2 hours, at least 4 hours or at least 8 hours.

In some embodiments, treatment is provided, prevents or has alleviated the gastrointestinal tract for example inflammation of esophagus or the method for the symptom relevant with inflammation, described method comprises and is administered to the patient that needs it the described pharmaceutical composition from the single dose of multiple-unit container herein.In some specific embodiments, administration comprises that from the single dose of multiple-unit container (1) rock multiple-unit container, and described multiple-unit container comprises the described pharmaceutical composition of at least one unit dose herein; (2) single dose in the multiple-unit container is poured in (or being assigned to) administration device (for example being suitable for being administered to the equipment of human patients) as spoon, cup or syringe; (3) described single-dose agent is administered to the patient who needs it.In embodiment more specifically, rock described multiple-unit container and be suitable for toppling over (for example toppling over easily) up to fluidic viscosity wherein.In some specific embodiments, this method also is included in to topple over after the described single dose medicament and described single dose medicament is administered to the patient who needs it waits for certain hour before.In some specific embodiments, the waiting time is to be enough to allow the viscosity of compositions to reach the time of desired level (for example improving the viscosity that described compositions applies ability).In some embodiments, the waiting time is for example about 3 seconds or more; About 5 seconds or more; About 10 seconds or more; About 15 seconds or more; About 20 seconds or more; About 25 seconds or more; About 30 seconds or more; About 40 seconds or more; About 45 seconds or more; About 50 seconds or more; Or about 60 seconds or more.In other specific embodiments, described compositions is administration immediately after pouring doser into.In some embodiments, described method comprises fully rocks described multiple-unit container.

In some embodiments, for acute disease, the first processing continuously, for example about 3 days-2 weeks, or for chronic disease, first handle continuously about 4 the week-Yue 16 weeks, or about 8 the week-Yue 12 weeks.In the different embodiments, need longer treatment, for example be similar to the treatment of the chronic treatment that continues asthma.Some aspects of the present invention, the patient for example will be reached 6 months by treatment, or reach 1 year.Treatment was kept lasting 1 year or the longer time in some aspect.In some embodiments,, in difficult situation (problematic episode) process, treat the patient to keep essential drug or required essential drug according to the order of severity of disease.In some embodiment,, wherein provide the treatment of a period of time, allow patient's drug withdrawal a period of time then, resume treatment again with alternating treatment medication (rotating treatment basis) treatment patient.During drug withdrawal, may not give patient treatment, reduce with another Drug therapy or therapeutic dose.In some embodiment, the combination treatment patient with higher dosage alleviates state up to the disease that reaches hope, then to continue than the low dose group compound.

In some embodiments, the corticosteroid in the described herein pharmaceutical composition is any effective dose.In some embodiments, effective dose is meant, compare with the inflammation relevant or the level of inflammatory symptom before the described effective dose of administration, be enough to reduce the inflammation relevant or the amount of inflammatory symptom with the diseases associated with inflammation of gastrointestinal tract (for example esophagus) or disease with diseases associated with inflammation.In some embodiment, effective dose is to be enough to keep by any way the amount that the inflammation that realizes or inflammatory symptom reduce, and described mode includes but not limited to be enough to realize by administration the effective dose of this minimizing.In some embodiments, described effective dose is the about 10mg of about 0.05mg-, the about 7.5mg of about 0.05mg-, the about 5mg of about 0.05mg-, the about 3mg of about 0.25mg-, the about 2.5mg of about 0.25mg-, the about 3mg of about 0.5mg-, the about 2mg of about 0.5mg-, the about 0.1mg of about 0.5mg-, the about 5mg of about 0.5mg-, the about 4mg of about 0.5mg-, the about 4mg of about 1mg-, the about 3mg of about 1mg-, the about 3mg of about 2mg-or the about 4mg of about 2mg-.In some specific embodiments, the effective dose of corticosteroid is about 0.05mg, about 0.1mg, about 0.15mg, about 0.25mg, about 0.3mg, about 0.35mg, about 0.4mg, about 0.37mg, about 0.375mg, about 0.7mg, about 0.8mg, about 0.75mg, about 1mg, about 1.2mg, about 1.25mg, about 1.3mg, about 1.5mg, about 2mg, about 2.5mg, about 3mg, about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg or about 7.5mg or more.In some embodiment, the concentration of corticosteroid is the about 2mg/mL compositions of about 0.01mg/mL-in the pharmaceutical composition.In some specific embodiments, the concentration of corticosteroid is the about 1.5mg/mL of about 0.01mg/mL-, the about 1.5mg/mL of about 0.03mg/mL-, the about 1.5mg/mL of about 0.05mg/mL-or the about 1.5mg/mL of about 0.07mg/mL-in the pharmaceutical composition.In embodiment more specifically, the concentration of corticosteroid is the about 1mg/mL of about 0.07mg/mL-in the pharmaceutical composition.

In some specific embodiments, described herein compositions is the compositions that comprises following material: corticosteroid, glucose, maltodextrin, edetate, citrate, polysorbate80, optional antiseptic, optional flavoring agent, optional sweeting agent, at least a other excipient and liquid-carrier.In some specific embodiments, described compositions comprises antiseptic.In other or alternate embodiment, described compositions comprises flavoring agent.In other or alternate embodiment, described liquid-carrier is water-bearing media (a for example water).In some specific embodiments, corticosteroid granule (for example microgranule) is suspended in the described water-bearing media.

In some embodiments, described corticosteroid is selected from, as non-limiting example, and budesonide, fluticasone propionate and combination thereof.In some specific embodiments, the amount of the corticosteroid that exists in described herein compositions or the preparation (for example budesonide or fluticasone propionate) is the about 1.5mg/mL of about 0.005mg/mL-or the about 1mg/mL of about 0.01mg/mL-, the about 5mg/mL of about 0.01mg/mL-, the about 3mg/mL of about 0.01mg/mL-, the about 2mg/mL of about 0.01mg/mL-, the about 1.5mg/mL of about 0.01mg/mL-, the about 0.5mg/mL of about 0.05mg/mL-, the about 0.4mg/mL of about 0.05mg/mL-, the about 1.5mg/mL of about 0.07mg/mL-or the about 1mg/mL of about 0.07mg/mL-.In embodiment more specifically, the amount of budesonide is the about 3mg/mL of about 0.01mg/mL-, the about 1.5mg/mL of about 0.01mg/mL-, the about 0.5mg/mL of about 0.05mg/mL-, the about 0.4mg/mL of about 0.05mg/mL-or the about 1mg/mL of about 0.07mg/mL-.In other specific embodiments, the amount of fluticasone propionate is about 1.5mg/mL of about 0.005mg/mL-or the about 1mg/mL of about 0.01mg/mL-.

In some embodiments, the capacity of described herein compositions or composition dosage is the amount of the esophagus length that is enough to fully apply the patient who is given described compositions (for example at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98% or at least 99%).In some embodiment, the capacity of described herein compositions or composition dosage is about 0.05mL/cm esophagus length-Yue 1mL/cm esophagus length, about 0.1mL/cm esophagus length-Yue 0.8mL/cm esophagus length, about 0.2mL/cm esophagus length-Yue 0.6mL/cm esophagus length or about 0.3mL/cm esophagus length-Yue 0.5mL/cm esophagus length, and wherein said esophagus length is the esophagus length that is given the patient of described compositions.In some embodiments, the capacity of described herein compositions or composition dosage depends on patient's's (for example male, women or both) esophagus length, and described patient's esophagus length is the 50th percentage point of height under its age.Therefore, in some embodiments, the capacity of described herein compositions or composition dosage is about 0.05mL/cm esophagus length-Yue 1mL/cm esophagus length, about 0.1mL/cm esophagus length-Yue 0.8mL/cm esophagus length, about 0.2mL/cm esophagus length-Yue 0.6mL/cm esophagus length, about 0.3mL/cm esophagus length-Yue 0.5mL/cm esophagus length, about 0.32mL/cm esophagus length-Yue 0.41mL/cm esophagus length or about 0.3mL/cm esophagus length-Yue 0.46mL/cm esophagus length, the esophagus length that wherein said esophagus length is the patient, described patient's height are to be given the 50th percentage point of height under the patient age of described compositions.Under some situation, esophagus length is patient's actual esophagus length or calculates according to following equation: esophagus length=1.048 (cm)+(0.167* height (cm)).Under some situation, for example, the 50th percentage point of height (CDC2000) of male children is: 2 years old is 87cm; 3 years old is 95cm; 4 years old is 102cm; 5 years old is 109cm; 6 years old is 115cm; 7 years old is 122cm; 8 years old is 128cm; 9 years old is 134cm; 10 years old is 139cm; 11 years old is 144cm; 12 years old is 149cm; 13 years old is 156cm; 14 years old is 164cm; 15 years old is 170cm; 16 years old is 174cm; 17 years old be 175cm and be 176cm in 18 years old.

In addition, in some embodiment, the amount of therapeutic agent in described herein compositions or the composition dosage (for example corticosteroid such as budesonide) is about 0.005mg/cm esophagus length-Yue 0.3mg/cm esophagus length, about 0.008mg/cm esophagus length-Yue 0.2mg/cm esophagus length, about 0.01mg/cm esophagus length-Yue 0.15mg/cm esophagus length or about 0.015mg/cm esophagus length-Yue 0.1mg/cm esophagus length, and wherein said esophagus length is the esophagus length that is given the patient of described compositions.In some embodiments, the capacity of described herein compositions or composition dosage depends on patient's's (for example male, women or both) esophagus length, and described esophagus length is the 50th percentage point of height under the patient age.Therefore, in some embodiments, the amount of therapeutic agent in described herein compositions or the composition dosage (for example corticosteroid such as budesonide) is about 0.005mg/cm esophagus length-Yue 0.3mg/cm esophagus length, about 0.008mg/cm esophagus length-Yue 0.2mg/cm esophagus length, about 0.01mg/cm esophagus length-Yue 0.15mg/cm esophagus length or about 0.015mg/cm esophagus length-Yue 0.1mg/cm esophagus length, the esophagus length that wherein said esophagus length is the patient, described patient's height are to be given the 50th percentage point of height under the patient age of described compositions.

In some embodiments, described herein any pharmaceutical composition or pharmaceutical composition dosage are to be enough to provide the capacity administration of bolus when being administered orally to the patient.In some embodiment, the capacity of described compositions can not systematically be carried excessive activating agent.In some embodiments, the pharmaceutical composition that provides or the capacity of dosage are enough to provide bolus when being administered to the patient, wherein the pill size at distal esophagus place (for example enters or by before the lower oesophageal sphincter, for example just in before pill size) for the pill size that enters esophagus (for example by after the last sphincter of gullet, for example be right after after the pill size) be less than 90%, be less than 85%, be less than 80%, be less than 75%, be less than 70%, be less than 65%, be less than 60%, be less than 55%, be less than 50%, be less than 45%, be less than 40%, be less than 35%, be less than 30%, be less than 25%, be less than 20%, be less than 15%, be less than 10% or be less than 5%.In some embodiments, the pill size is with the mensuration of measuring of diameter or capacity.In some embodiment, sphincteral diameter can adopt gamma-radiation development method technology to determine.In some specific embodiments, according to the patient's who is given described compositions or dosage the esophagus length and/or the capacity of described compositions of diameter adjustment or dosage.

In other exemplary of the present invention, described herein compositions provides with the form of buccal tablet, it can be orally-dissolvable, thereby arrive and apply esophagus to small part, described delivery of composition to involved area, is comprised (only as example) esophagus, esophagus-stomach joint portion, stomach and/or duodenum down.Buccal tablet or other similar dosage form (for example tablet, capsule or other solid) can be dissolved in mouth or the esophagus, to produce the solution that can apply esophagus subsequently to small part, afterwards described delivery of composition is arrived involved area, comprise (only as example) esophagus, esophagus-stomach joint portion, stomach and/or duodenum down.Perhaps, for child, baby or adopt the dissolving buccal tablet to have other patient of difficulty, described buccal tablet can be ground or be dissolved in low amounts of water or other the pharmaceutically suitable liquid, for example, reach the total capacity that is provided in the embodiment herein.In other exemplary of the present invention, described herein compositions is with tablet, capsule, or for example designs to discharge at a slow speed and to be transported to gastrointestinal tract and comprise that the gel capsule form of esophagus provides.

In some embodiments, for acute disease, the first processing continuously, for example about 3 days-2 weeks, for chronic disease, first handle continuously about 4 the week-Yue 16 weeks, or about 8 the week-Yue 12 weeks.In the different embodiments, need longer treatment, for example be similar to the treatment of the chronic treatment that continues asthma.Some aspects of the present invention, the patient for example will be reached 6 months by treatment, or reach 1 year.In some aspect, kept treatment lasting 1 year or the longer time.In some embodiments,, in difficult situation (problematic episode) process, treat the patient to keep essential drug or required essential drug according to the order of severity of disease.In some embodiment,, wherein provide the treatment of a period of time, allow patient's drug withdrawal a period of time then, resume treatment again with alternating treatment medication (rotating treatment basis) treatment patient.During drug withdrawal, may not give patient treatment, reduce with another Drug therapy or therapeutic dose.In some embodiment, the combination treatment patient with higher dosage alleviates state up to the disease that reaches hope, then to continue than the low dose group compound.In some embodiment, the patient will with described combination treatment herein with combine with another Drug therapy and/or dietetic therapy.In some embodiment, the combination treatment patient with higher dosage alleviates state up to the disease that reaches hope, then to continue than the low dose group compound.

In some embodiments, described herein Therapeutic Method comprises intermittent therapy or treatment continuously.In some embodiment, the method for described herein treatment gastroenteritis comprises the prophylactic treatment of gastroenteritis (treatment that for example prevents symptom and/or inflammation to take place).In some embodiments, the method for described herein treatment gastroenteritis comprises by give or give continuously the method that described pharmaceutical composition prolongs and/or keep the alleviation of gastroenteritis herein after inflammation and/or inflammatory symptom alleviation.In some specific embodiments, preventative and/or remissive treatment gives described compositions herein optional comprising, corticosteroid amount used when not slowing down with inflammation and/or inflammatory symptom is compared, and described compositions comprises the corticosteroid of reduction.

In some embodiments, provide method: give described pharmaceutical composition herein by following diagnosis gastroenteritis (for example EoE) patient; With the effect of determining this treatment.Under some situation, the patient is for suffering from the gastroenteritis of at least a acid inhibitor (for example PPI and/or H2A) stubbornness and/or the patient of its symptom.In some embodiments, the gastroenteritis that carries out with described compositions herein effectively treatment is the positive indication of EoE.In some embodiment, adopt this diagnostic method to replace esophagus tissue biopsy.

In each embodiment, the present composition comprises pharmaceutically acceptable salt.Pharmaceutically acceptable salt is generally those skilled in the art and knows, comprise, as non-limiting example, acetate, benzene sulfonate (benzenesulfonate), benzene sulfonate (besylate), benzoate, bicarbonate, biatrate, bromide, Ca-EDTA, d-camphorsulfonic acid salt (carnsylate), carbonate, citrate, edetate, ethanedisulphonate, Estolate, mesylate, fumarate, gluceptate, gluconate, glutamate, Glu, sweet arsenobenzene salt, hexyl resorcin salt, breathe out amine, hydrobromate, hydrochlorate, hydroxynaphthoate, iodide, isethionate, lactate, Lactobionate, malate, maleate, mandelate, mesylate, mucate, naphthalene sulfonate, nitrate, pamoate (embonate), pantothenate, phosphate/diphosphate, Polygalacturonate, Salicylate, stearate, basic acetate, succinate, sulfate, tannate, tartrate or chloro theophylline salt.Other pharmaceutically acceptable salt can, Remington:The Science and Practice of Pharmacy (pharmaceutics science with put into practice) (20.sup.th ed.) Lippincott for example, Williams﹠amp; Wilkins finds in (2000).In some specific embodiments, pharmaceutically acceptable salt comprises, for example acetate, benzoate, bromide, carbonate, citrate, gluconate, hydrobromate, hydrochlorate, maleate, mesylate, naphthalene sulfonate, pamoate (embonate), phosphate, Salicylate, succinate, sulfate or tartrate.In some embodiment, this salt is used for described any corticosteroid herein.

Disease specific according to being treated can be mixed with described compositions liquid or solid dosage form and whole body or topical.In some embodiments, described medicament with, for example known time-delay release of those skilled in the art or slow release form are carried.The preparation and the technology of administration can be at Remington:The Science and Practice of Pharmacy (pharmaceutics science and put into practice) (20th ed.) Lippincott, Williams ﹠amp; Wilkins finds in (2000).

Except described activating agent, each embodiment of the present invention provides and has comprised the suitable pharmaceutically acceptable excipient and the pharmaceutical composition of auxiliary agent.For example, in some embodiments, for the present invention's practice, described corticosteroid is mixed with the dosage form that is suitable for the whole body administration to adopt pharmaceutically acceptable excipient and/or auxiliary agent to incite somebody to action herein, and this belongs to the scope of the invention.In some embodiments, adopt pharmaceutically acceptable excipient and/or the auxiliary agent known in this area easily corticosteroid to be mixed with the dosage form that is suitable for oral administration.This excipient and/or auxiliary agent can be mixed with the present composition tablet, pill, dragee, capsule, liquid agent, soft chewable tablet, cream, paste, chewable tablet, gel or gel-type vehicle, syrup, serosity agent, suspending agent, chewing gum agent, contain tablet etc., for waiting to control patient's orally ingestible.Under some situation, preparation oral formulations (for example suspending agent, cream or gel-type vehicle) makes and forms the interface between oral formulations (for example suspending agent, cream or gel-type vehicle) and gastrointestinal tract surface (for example esophagus surface) behind the oral administration.Under the certain situation, the oral formulations (for example suspending agent, cream or gel-type vehicle) that contacts with gastrointestinal tract surface (for example esophagus surface) is transported to corticosteroid by boundary layer and/or by gastrointestinal tract surface (for example esophagus surface), and when the oral formulations (for example suspending agent, cream or gel-type vehicle) near boundary layer lacks corticosteroid, form Concentraton gradient.Under some situation, oral formulations (for example suspending agent, cream or the gel-type vehicle) part that has a high concentration corticosteroid near the oral formulations (for example suspending agent, cream or gel-type vehicle) of described boundary layer part is replenished near the corticosteroid in oral formulations (for example suspending agent, cream or the gel-type vehicle) part of described boundary layer relatively.Under some situation, after described oral formulations is administered orally to the patient, between the mixture of gastrointestinal tract surface (for example esophagus surface) and oral formulations (for example chewable tablet) and patient's saliva, form boundary layer herein.

In some embodiment, medicine preparation for oral use can be by mixing corticosteroid with solid excipients, the optional gained mixture that grinds, and process (if desired, after the adding suitable auxiliary agents) gained granulate mixture to obtain tablet or the dragee core obtains.Suitable excipient comprises that as non-limiting example, filler such as sugar or starch comprise glucose, lactose, maltodextrin, sucrose, sucralose, mannitol or Sorbitol; Cellulose preparation, for example corn starch, wheaten starch, rice starch, potato starch or its combination.The optional disintegrating agent that adds is as crospolyvinylpyrrolidone, agar or alginic acid or its salt such as sodium alginate.In some embodiments, pharmaceutical compositions for use comprises excipient such as sweeting agent or the flavoring agent that is suitable for providing described solution tablet delicious food.

In some embodiments, described herein pharmaceutical composition is a liquid.The appropriate excipients that is used for the liquid form medicine compositions comprises, for example improves those of described fluid composition mucoadhesive characteristics.Optional excipient also comprises, as non-limiting example, provides described fluid composition delicious or improve those of described fluid composition viscosity.Improve the optional excipient of palatability, as non-limiting example, comprise sugar and Mel or its combination etc., described steamed bun stuffed with sugar is drawn together glucose, lactose, sucrose, sucralose, maltodextrin, mannitol or Sorbitol.

Optional one or more viscosifier that comprise of any described herein compositions or preparation, optional one or more binding agents that comprises, optional one or more filleies that comprises, optional one or more lubricants that comprises, optional one or more solvents that comprises, optional one or more suspending agents that comprises, optional one or more flavoring agents that comprises, optional one or more coloring agent that comprises, optional one or more sweeting agents that comprises, optional one or more antiseptic that comprises, optional one or more antioxidant that comprises, optional one or more buffer agents that comprises, optional one or more wetting agents that comprises, optional one or more chelating agen that comprises, optional one or more surfactants or their compositions of comprising.

Antiseptic comprises, as non-limiting example, benzalkonium chloride, cetrimonium bromide (cetyl trimethyl ammonium bromide), benzoic acid, benzyl alcohol, methyl parahydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate and butyl p-hydroxybenzoate, chlorhexidine, methaform, phenylmercuric acetate, borate and nitrate, Pyrusussuriensis potassium alcoholate, sodium benzoate, sorbic acid, thimerosal (thiosalicylic acid hydrargyrum), their combination etc.Optional one or more antiseptic that comprise the about 5%w/w of about 0.1%w/w-, the about 3%w/w of about 0.1%w/w-, the about 1%w/w of about 0.1%w/w-, the about 0.5%w/w of about 0.1%w/w-, about 0.2%w/w of described herein compositions and preparation.

Antioxidant comprises, as non-limiting example, ascorbyl palmitate, BHA, fourth hydroxy-methylbenzene, thioglycerol, sodium ascorbate, rongalite, sodium pyrosulfite, BHT, BHA, sodium sulfite, vitamin e or derivatives thereof, propyl gallate, edetate (EDTA) (for example disodium edetate), diethylene triamine pentacetic acid (DTPA) (DTPA), complexon I salt (NT), their combination etc.Optional one or more antioxidant that comprise the about 1%w/w of about 0.01%w/w-, the about 0.5%w/w of about 0.01%w/w-, the about 0.3%w/w of about 0.01%w/w-or the about 0.1%w/w of about 0.01%w/w-of described herein compositions and preparation.

Buffer agent comprises, as non-limiting example, and citric acid buffer agent (being citric acid and citrate), phosphoric acid buffer agent, acetate buffer agent, their combination etc.

" citrate " used herein comprises the chemical compound of all formula I, and wherein each R independently is selected from H and negative charge (for example salt or isolating salt or acid).In some embodiment, citrate is selected from, as non-limiting example, and sodium citrate, citric acid etc.

Formula I

Wetting agent comprises, as non-limiting example, and glycerol, propylene glycol, ethylene glycol, triacetyl glycerine, polyhydric alcohol (for example Sorbitol, xylitol, maltose alcohol, polydextrose) etc.The optional wetting agent that comprises the about 10%w/w of about 0.1%w/w-, the about 10%w/w of about 1%w/w-, the about 8%w/w of about 1%-or about 5%w/w of described herein compositions and preparation.In some embodiment, wetting agent suppresses one or more components (for example sweeting agent, mucomembranous adhesion agent or viscosifier) sedimentation and/or the crystallization of described compositions or preparation herein.

Chelating agen comprises, as non-limiting example, and edetate (EDTA) (for example disodium edetate), diethylene triamine pentacetic acid (DTPA) (DTPA), complexon I salt (NT) etc.Optional one or more chelating agen that comprise the about 0.5%w/w of about 0.01%w/w-, the about 0.3%w/w of about 0.01%w/w-or the about 0.1%w/w of about 0.01%w/w-or about 0.05%w/w of described herein compositions and preparation.

" edetate " used herein comprises the chemical compound of all formula II, wherein independently is selected from H and negative charge (for example salt or isolating salt or acid).In some embodiment, edetate is selected from, as non-limiting example, and disodium edetate, Ca-EDTA, ethylenediaminetetraacetic acid etc.

Formula II

In some embodiment, sweeting agent comprises that as non-limiting example, glycerol, fourth sulfanilamide potassium (AceK), monoammonium glycyrrhizinate are (for example

), sucrose, lactose, glucose, fructose, Arabinose, xylose, ribose, mannose, galactose, glucose, sorbose, Sorbitol, mannitol, maltose, cellobiose, xylitol etc.In some embodiments, flavoring agent comprises, as non-limiting example, and peppermint candy, orange, bubble gum, Ilicis Purpureae, Fructus Vitis viniferae and Fructus Pruni pseudocerasi.

Surfactant comprises; anionic for example; cationic; nonionic or amphoteric ionic surfactant; as; as non-limiting example, polysorbate (polysorbate20 for example; polysorbate60; polysorbate40; polysorbate80; polysorbate 81; polysorbate85; polysorbate 120); bile acid or their salt (sodium taurocholate for example; sodium taurodeoxycholate; chenodeoxy cholic acid and ursodeoxycholic acid); nonoxynolum or polyoxyethylene glycol fatty acid ester; pluronic (addition polymers of polypropylene glycol and oxirane) or poloxamer such as Pluronic F68; Pluronic L44; Pluronic L101; their combination etc.Optional one or more surfactants that comprise the about 0.5%w/w of about 0.001%w/w-, the about 0.3%w/w of about 0.001%w/w-or the about 0.1%w/w of about 0.001%w/w-of described herein compositions and preparation.

The invention provides the dragee core of suitable coating.In some embodiments, concentrated sugar solution is used for this purpose, its optional Radix Acaciae senegalis, Talcum, polyvinylpyrrolidone, card bohr gel, Polyethylene Glycol (PEG) and/or titanium dioxide, lacquer solution and appropriate organic solvent or solvent mixture of comprising.Optional will dyestuff or pigment add the various combination of determining or characterize active corticosteroid medicament in tablet or the dragee coating.

In each embodiment, the pharmaceutical preparation that orally uses comprises sucking fit (push-fit) capsule of being made up of gelatin and the sealing soft capsule of being made up of gelatin, plasticizer such as glycerol or Sorbitol.In some embodiments, described sucking fit capsule comprises active component, with filler, binding agent, lubricant, stabilizing agent or its combined hybrid together.Filler comprises, as non-limiting example, and lactose.Binding agent comprises, as non-limiting example, and starch.Lubricant comprises, as non-limiting example, and Talcum and magnesium stearate.In the soft capsule, described corticosteroid solubilized or be suspended in the suitable liquid is as fatty oil, liquid paraffin or liquid macrogol (PEG).In addition, the optional stabilizing agent that adds.

In the embodiment, the invention provides the low corticosteroid of bioavailability.Because bioavailability is low, described corticosteroid is used in the certain embodiments of the invention, and described corticosteroid is retained in gastrointestinal tract for example in the esophagus.In some embodiments, low systemic side effects and the complication of causing of bioavailability reduces, and allows the patient who suffers from chronic disease to accept treatment for more time.

In some embodiments, described herein pharmaceutical composition or dosage form are for comprising the suspension or the solution of corticosteroid (for example budesonide).In some embodiments, compositions (for example suspension or solution) comprises certain density corticosteroid (for example budesonide), and described corticosteroid is dissolved in the liquid medium (for example used solvent or liquid-carrier are as water, alcohol, aqueous alcohol etc.).In some embodiment, the amount of corticosteroid (for example budesonide) that is dissolved in (for example in the balance sample) in the described liquid medium is greater than 4 μ g/mL, greater than 5 μ g/mL, greater than 10 μ g/mL, greater than 15 μ g/mL, greater than 20 μ g/mL, greater than 21 μ g/mL, greater than 22 μ g/mL, greater than 23 μ g/mL, greater than 24 μ g/mL, greater than 25 μ g/mL, about 25 μ g/mL, greater than 30 μ g/mL, the about 80 μ g/mL of about 25 μ g/mL-, the about 80 μ g/mL of about 30 μ g/mL-, about 30 μ g/mL, about 35 μ g/mL, about 40 μ g/mL, about 45 μ g/mL, about 50 μ g/mL, about 55 μ g/mL, about 60 μ g/mL, about 65 μ g/mL or about 70 μ g/mL.

In some embodiments, described herein compositions comprises certain density budesonide, and described budesonide is dissolved in the liquid medium (for example used solvent or liquid-carrier are as water, alcohol, aqueous alcohol etc.).In some specific embodiments, the amount of dissolved budesonide R epimer (comparing) with the gross weight of budesonide for greater than 28%w/w, greater than 30%w/w, greater than 39%w/w, greater than 40%, about 39-50%, about 40-50%, be less than 38%w/w, about 29%-37%w/w, be less than 27%w/w etc.Under some situation, in the compositions that total %R epimer (comparing with total budesonide) is about 50-55%w/w or about 53-54%w/w, obtain the % epimer.Under some situation, in case it is basicly stable to be dissolved in the concentration of the corticosteroid (for example budesonide) in the liquid, behind for example 2 days, 3 days, 4 days, 5 days, a week, one month etc., sample has just reached balance.In some specific embodiments, sample reached balance after 2 days.

In some embodiments, the preparation administration of described corticosteroid can buy on the market.In other embodiment, described corticosteroid is to comprise the corticosteroid preparation and the composition prepared administration as described herein that can buy on the market.For example, in some embodiments, the corticosteroid-containing compositions that provides herein comprises the preparation and the excipient that can buy on the market, as diluent, flavoring agent, mucomembranous adhesion agent, viscosifier, binding agent, filler, lubricant, solvent, suspending agent, coloring agent, sweeting agent, antiseptic, antioxidant, buffer agent, wetting agent, chelating agen, surfactant, their combination etc.In some embodiments, wherein said corticosteroid is a budesonide, and the preparation that can buy on the described market is Pulmicort

(be sold by AstraZeneca, for example shown in the NDA 20-929, its full content is incorporated herein by reference).In other embodiment, wherein said corticosteroid is a budesonide, and the preparation that can buy on the described market is Rhinocort

(be sold by AstraZeneca LP, Wilmington, DE 19850, for example shown in the NDA 20-746, its full content (comprising all supplementary issues) is incorporated herein by reference).In other embodiment, wherein said corticosteroid is a budesonide, and the preparation that can buy on the described market is

(originate from AstraZeneca Dunkerque Production, Dunkerque, France, for example shown in the NDA 21-929, its full content (comprising all supplementary issues) is incorporated herein by reference).In some embodiments, wherein said corticosteroid is a fluticasone, and the preparation that can buy on the described market is In some embodiments, the preparation that can buy on the market is about 1 with the ratio of the diluent of choosing wantonly: about 1: 100 of 0.5-.Diluent comprises any pharmaceutically acceptable oral diluent, comprises for example powdery diluent (as Talcum) and liquid diluent (as water, ethanol and combination thereof).In some embodiment, the preparation that can buy on the described market is

(originate from AstraZeneca AB, S-15185Sodertalje, Sweden, be sold by Prometheus Laboratories Inc, San Diego, CA 92121, as shown in NDA21-324, its full content (comprising all supplementary issues) is incorporated herein by reference).In some embodiment,

Preparation dissolves and/or is scattered in the aqueous carrier.In some specific embodiments, described

Preparation is scattered in the liquid-carrier, and the pH of described liquid-carrier is enough to remove the particulate enteric coating of budesonide.In other embodiment, described

The preparation solvent pre-treatment, the pH of described solvent is enough to remove the particulate enteric coating of budesonide, then described particle formulation is become the compositions described in this paper.

In some embodiment, described herein corticosteroid compositions comprises the preparation that can buy on corticosteroid, the market and chooses any one kind of them or multiple other excipient.In some embodiments, described herein corticosteroid compositions comprise the corticosteroid (one or more active component that for example lack described preparation) prepared in the mode that is similar to commercial formulation and, choose any one kind of them or multiple other excipient.Described one or more other excipient can be used for obtaining described preparation herein.In some specific embodiments, the preparation that can buy on the described market be Ultra XCID (originate from Matrixx Initiatives, Inc., Phoenix, AZ).

In some embodiment, the compositions that provides herein comprises or mixes and prepare by showing among the 1-12 any listed component.In each embodiment, among maltodextrin, glucose, HEC, CMC, MCC, carbomer and the HPMC one or more have been used.

Table 1: budesonide compositions #1

Composition	Amount
		Budesonide	1mg-150mg
CMC, MCC, carbomer, HPMC and/or HEC	0.5g-10g
		Glucose	0g-100g
Maltodextrin	0g-100g

EDTA (as disodium edetate)	5mg-200mg
		Citric acid	10mg-1g
Citrate (as sodium citrate)	10mg-2g
		Polysorbate salt 80 (as Tween 80)	5mg-100mg
Flavoring agent	Optional
		Sweeting agent	Optional
Antiseptic	Optional
		Water	Standardize solution is to 100mL

Table 2: budesonide compositions #2

Composition	Amount
		Budesonide	1mg-150mg
CMC, MCC, carbomer, HPMC and/or HEC	0g-10g
		Glucose	1g-100g
Maltodextrin	0g-100g
		EDTA (as disodium edetate)	5mg-200mg
Citric acid	10mg-1g
		Citrate (as sodium citrate)	10mg-2g
Polysorbate salt 80 (as Tween 80)	5mg-100mg
		Flavoring agent	Optional
Sweeting agent	Optional
		Antiseptic	Optional
Water	Standardize solution is to 100mL

Table 3: budesonide compositions #3

Composition	Amount
		Budesonide	1mg-150mg
CMC, MCC, carbomer, HPMC and/or HEC	0g-10g
		Glucose	0g-100g
Maltodextrin	1g-100g
		EDTA (as disodium edetate)	5mg-200mg
Citric acid	10mg-1g
		Citrate (as sodium citrate)	10mg-2g
Polysorbate salt 80 (as Tween 80)	5mg-100mg
		Flavoring agent	Optional
Sweeting agent	Optional
		Antiseptic	Optional
Water	Standardize solution is to 100mL

Table 4: budesonide compositions #4

Composition	Amount
		Budesonide	0.5mg-2mg
CMC and MCC (as Avicel RC-591)	0.01g-0.3g
		Glucose	0.1g-1g
Maltodextrin	0.5g-2g
		EDTA (as disodium edetate)	1mg-10mg
Citric acid	0.1mg-100mg
		Citrate (as sodium citrate)	0.1mg-200mg

Polysorbate salt 80 (as Tween 80)	0.1mg-10mg
		Cherry essence	1mg-100mg
Sweeting agent	100mg-1g
		Sodium benzoate	1mg-50mg
Pyrusussuriensis alkyd potassium	1mg-50mg
		Water	Standardize solution is to 5mL

Table 5: budesonide compositions #5

Composition	Amount
		Budesonide	0.5mg-2mg
CMC and MCC (as Avicel RC-591)	0.02g-0.6g
		Glucose	0.2g-2g
Maltodextrin	1g-4g
		EDTA (as disodium edetate)	2mg-20mg
Citric acid	0.2mg-200mg
		Citrate (as sodium citrate)	0.2mg-400mg
Polysorbate salt 80 (as Tween 80)	0.2mg-20mg
		Cherry essence	2mg-200mg
Sweeting agent	200mg-2g
		Sodium benzoate	2mg-100mg
Pyrusussuriensis alkyd potassium	2mg-100mg
		Water	Standardize solution is to 10mL

Table 6: budesonide compositions #6

Composition	Amount (mg/mL)
		Budesonide	0.01-5
CMC and MCC (as Avicel RC-591)	2-100
		Glucose	10-500
Maltodextrin (M150)	10-500
		EDTA (as disodium edetate)	0.01-10
Citric acid	0.1-10
		Citrate (as sodium citrate)	0.1-10
Polysorbate salt 80 (as Tween 80)	0.01-1
		Flavoring agent (as cherry essence)	0.1-100
Glycerol	10-100
		Fourth sulfanilamide potassium	0.1-40
Glycyrrhizin 110	0.1-40
		Sodium benzoate	0.1-10
Pyrusussuriensis alkyd potassium	0.1-10
		Water	Standardize solution is to 1-15mL

Table 7: budesonide compositions #7

Composition	Amount (mg/mL)
		Budesonide	About 0.05-about 0.2
CMC and MCC (as Avicel RC-591)	5-50

Glucose	50-250
		Maltodextrin (M150)	200-500
EDTA (as disodium edetate)	0.1-1
		Citric acid	0.5-5
Citrate (as sodium citrate)	0.2-2
		Polysorbate salt 80 (as Tween 80)	0.01-0.4
Flavoring agent (as cherry essence)	1-10
		Glycerol	30-80
Fourth sulfanilamide potassium	1-10
		Glycyrrhizin 110	1-10
Sodium benzoate	0.5-4
		Pyrusussuriensis alkyd potassium	0.5-4
Water	Standardize solution is to 1-15mL

Table 8: budesonide compositions #8

Composition	Amount (mg/mL)	Amount %w/w
			Budesonide	0.05	0.004
Avicel?RC-591	23.6	2
			Glucose	118	10
Maltodextrin (M150)	306.8	26
			Disodium edetate	0.59	0.05

Citric acid	1.77	0.15
			Sodium citrate	0.59	0.05
Polysorbate salt 80	0.12	0.01
			Cherry essence	5.9	0.5
Glycerol	59	5
			Fourth sulfanilamide potassium	5.9	0.5
Glycyrrhizin 110	5.9	0.5
			Sodium benzoate	2.36	0.2
Pyrusussuriensis alkyd potassium	2.36	0.2
			Water	Standardize solution to 1,2,3,4,5,6,7,8,9,10,11,12,13,14 or 15mL	Standardize solution to 1,2,3,4,5,6,7,8,9,10,11,12,13,14 or 15mL

Table 9: budesonide compositions #9

Composition	Amount (mg/mL)	Amount %w/w
			Budesonide	0.2	0.17
Avicel?RC-591	23.6	2
			Glucose	118	10
Maltodextrin (M150)	306.8	26
			Disodium edetate	0.59	0.05
Citric acid	1.77	0.15
			Sodium citrate	0.59	0.05

Polysorbate salt 80	0.12	0.01
			Cherry essence	5.9	0.5
Glycerol	59	5
			Fourth sulfanilamide potassium	5.9	0.5
Glycyrrhizin 110	5.9	0.5
			Sodium benzoate	2.36	0.2
Pyrusussuriensis alkyd potassium	2.36	0.2
			Water	Standardize solution to 1,2,3,4,5,6,7,8,9,10,11,12,13,14 or 15mL	Standardize solution to 1,2,3,4,5,6,7,8,9,10,11,12,13,14 or 15mL

Table 10: fluticasone propionate compositions #1

Composition	Amount
		Fluticasone propionate	0.5mg-150mg
CMC, MCC, carbomer, HPMC and/or HEC	0.5g-10g
		Glucose	0g-100g
Maltodextrin	0g-100g
		EDTA (as disodium edetate)	5mg-200mg
Citric acid	10mg-1g
		Citrate (as sodium citrate)	10mg-2g
Polysorbate salt 80 (as Tween 80)	5mg-100mg
		Flavoring agent	Optional

Sweeting agent	Optional
		Antiseptic	Optional
Water	Standardize solution is to 100mL

Table 11: fluticasone propionate compositions #2

Composition	Amount
		Fluticasone propionate	0.5mg-150mg
CMC, MCC, carbomer, HPMC and/or HEC	0g-10g
		Glucose	1g-100g
Maltodextrin	0g-100g
		EDTA (as disodium edetate)	5mg-200mg
Citric acid	10mg-1g
		Citrate (as sodium citrate)	10mg-2g
Polysorbate salt 80 (as Tween 80)	5mg-100mg
		Flavoring agent	Optional
Sweeting agent	Optional
		Antiseptic	Optional
Water	Standardize solution is to 100mL

Table 12: fluticasone propionate compositions #3

Composition	Amount
		Fluticasone propionate	0.5mg-150mg
CMC, MCC, carbomer, HPMC and/or HEC	0g-10g

Glucose	0g-100g
		Maltodextrin	1g-100g
EDTA (as disodium edetate)	5mg-200mg
		Citric acid	10mg-1g
Citrate (as sodium citrate)	10mg-2g
		Polysorbate salt 80 (as Tween 80)	5mg-100mg
Flavoring agent	Optional
		Sweeting agent	Optional
Antiseptic	Optional
		Water	Standardize solution is to 100mL

Disease

In some embodiments, the invention provides treatment, prevent or alleviate gastrointestinal tract for example esophagus inflammation or with the method for the symptom of inflammation-related.In some specific embodiments, the method that provides herein is to reduce or alleviate the method for the symptom of gastrointestinal tract inflammation.In embodiment more specifically, described gastrointestinal tract inflammation is eosinophil esophagitis (EoE).In some embodiments, the method that provides herein is the method for the treatment inflammation relevant with eosinophil esophagitis (EoE).In some embodiment, the method that provides herein is the method for the treatment dysphagia relevant with eosinophil esophagitis (EoE).In some embodiments, the method that provides herein is the treatment inflammation relevant with eosinophil esophagitis (EoE) and the method for dysphagia.In some embodiment, provide by giving described combination treatment gastroenteropathy or the disease method of (for example upper gastrointestinal disease or disease comprise the disease or the disease of esophagus) herein.

In some embodiments, give described combination treatment herein, prevent or alleviate inflammation or the symptom relevant with diseases associated with inflammation or disease.Gastrointestinal disease or disease comprise, as non-limiting example, relates to gastrointestinal tract (for example upper gastrointestinal, esophagus, stomach and/or digestive tract) and respond any chronic inflammatory states or the malignant state of steroid therapy.Under some situation, the disease of described combination treatment or disease comprise upper gastrointestinal (comprising preceding disease of colon or disease), esophagus, stomach and/or digestive tract disease or disease herein.The inventive method can be used for, and for example treats, prevents and alleviate inflammation or the symptom relevant with following disease: the esophageal stricture of eosinophil esophagitis, the inflammatory bowel that relates to esophagus, Crohn disease, be secondary to acute oesophagitis that corrosivity/stimulus object swallows, be secondary to the persistence that corrosivity/stimulus object swallows/repeatedly, swallow the disease, systemic disease, congenital diseases, post-operation inflammatory and the gastroenteritis that cause.The present invention's invention also can be used for, and for example treats, prevents and alleviate inflammation or the symptom relevant with following disease: gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD), Barrett esophagus and/or erosive esophagitis.

Be understandable that the treatment of mentioning may extend into the prevention and the treatment of inflammation or other symptom herein.

In some embodiment, treatment is provided, prevents or has alleviated the method for the inflammation of patient's gastrointestinal tract, described gastrointestinal tract comprises, as the indefiniteness example, esophagus, stomach and/or digestive tract, described method comprise the described any compositions of the described patient of oral administration herein.In some embodiment, described peroral dosage form comprises liquid-carrier and is formulated into for example serosity agent, suspension liquor, syrup, dispersion liquor, solution etc.

On the one hand, give patient's corticosteroid such as budesonide or fluticasone propionate.

In some embodiments, inflammation and the eosinophil property inflammation and/or the neutrophil cell inflammation-related of described herein method and composition treatment.In some embodiments, comprise with the patient of described combination treatment herein and to diagnose those that suffer from following disease: the eosinophil esophagitis, the inflammatory bowel that relates to esophagus, Crohn disease, celiac disease, proximal gastric intestinal pathology (for example hypothyroid patient of gallbladder), eosinophil property gastroenteritis, celiac disease, eosinophil property duodenitis, the duodenum hypereosinophilia, functional dyspepsia, mid-term esophagitis, epithelial proliferation, basal cell hyperplasia, the mastoid process of elongation, nipple vasodilation, fungus (candida mycoderma for example, torulopsis, histoplasma capsulatum's aspergillosis etc.) esophagitis, viral esophagitis (HSV for example, CMV, V2V), bacillary esophagitis (pulmonary tuberculosis for example, actinomycosis, syphilis), erosive esophagitis, radiation esophagitis, the chemotherapy esophagitis, graft versus host disease, dermatosis (the bullous pemphigoid for example that relates to esophagus, pemphigus vulgaris, epidermolysis bullosa, Stevens Johnson syndrome), Behcet disease, sarcoidosis, congenital esophagitis, eosinophil property gastroenteritis, giant hypertrophy gastritis, parasitic gastritis, the lymphocyte esophagitis, the esophagitis that inflammatory bowel is relevant, parasitic gastritis, be secondary to the esophagitis that corrosivity/stimulus object is swallowed, any reason and comprise that corrosivity/stimulus object swallows the esophageal stricture of the persistence that causes/repeatedly, the inductive esophagitis of pill, systemic disease, congenital diseases, post-operation inflammatory or gastroenteritis.Among the indefiniteness embodiment, described patient suffers from the eosinophil esophagitis.In some embodiments, comprise and diagnose those that suffer from following disease with the patient of described combination treatment herein (as, patient): Barrett esophagus, gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD) and/or erosive esophagitis.In some embodiments, described patient is the adult.In other embodiment, described patient is child or baby.In the each side, the patient be less than 16 years old, less than 12 years old, less than 8 years old, less than 6 years old, less than 4 years old, less than 2 years old child or baby.

In some embodiments, compositions is the unit dose formulations that is used for patient's oral administration.In some embodiments, the unit dose formulations of corticosteroid is from the administration of dosed administration equipment.In some embodiments, the described dosed administration equipment quantitative unit dose of described compositions herein is transported to the patient's who needs it oral cavity or throat.In some embodiment, described dosed administration equipment is metered-dose inhaler, and it is used for quantitative unit dose is administered to patient's oral cavity or throat's (this patient swallows rather than suck this quantitative unit dose).In some embodiment, the dosed administration equipment quantitative unit dose of described compositions herein is assigned in the container (for example cup), and it is used for quantitative unit dose is administered orally to oral cavity or throat.Some aspect is administered to the patient with every day or every dose of about 20mg of about 0.01mg-, the about 15mg of about 0.01mg-or the about 10mg of about 0.01mg-(for example about 0.1-10mg, about 0.25-5mg, about 0.25-2.5mg, about 1-2mg or about 2-3mg) corticosteroid.In some embodiments, the amount of corticosteroid is the about 10mg of about 0.01mg-(for example about 0.1-10mg, about 0.25-5mg, about 0.3-4mg, about 0.25-2.5mg, about 1-2mg or about 2-3mg) in described herein compositions or the units dosage composition.In some embodiments, the amount of corticosteroid is the about 3mg of about 0.5mg-in administration every day or the unit dose.In other embodiment, the amount of the corticosteroid of unit dose or administration every day is the about 3mg of about 1-or about 2mg of about 1-or the about 3mg of about 2-.

The full content of each patent, patent application, publication and the document of quoting herein is incorporated herein by reference.Quoting of above patent, patent application, publication and document is not to admit that any foregoing all is relevant prior art, and any of interior perhaps date who does not also constitute these publications or document admits.

Unless expressly stated otherwise,, all technology used herein and scientific terminology have the same meaning of understanding with those skilled in the art.Although similar or be equal to described any method herein and system can be used for practice of the present invention or experiment, now these equipment, equipment and material are described.All publications of mentioning herein incorporated herein by reference with describe with described publication is disclosed in method, system and methodology that report, may be relevant with the present invention.Should understand and not admit that herein the present invention does not lead over these disclosures owing to have the existence of invention now.

Can improve foregoing and do not deviate from basic principle of the present invention.Although the present invention is described in detail very much with reference to one or more specific embodiments, those skilled in the art will recognize that and to change concrete disclosed embodiment among the application, and these modification and improvement belong to the scope of the invention and spirit.Described herein invention is adapted at carrying out under not concrete herein disclosed any key element existence.Therefore, under for example various in this article situations, term " comprises ", " substantially by ... form " and " by ... form " in any all can be alternative by two other.Therefore, used term and expression only are used for describing, and non-limiting, do not get rid of equivalents or its partial content of the feature of shown and description, should be realized that various modification may belong to the scope of the invention.

In some embodiments, provide the multiple dose unit packaging, described multiple dose unit packaging comprises that about 2-is about 180, described herein any pharmaceutical composition of about 10-about 60, about 14 or about 30 unit dose.In embodiment more specifically, each agent comprises the about 25mL of about 1mL-, the about 20mL of about 1mL-, the about 25mL of about 7mL-, the about 20mL of about 10-, about 15mL, about 20mL, the about 7mL of about 3-, about 5mL, the about 12mL of about 8mL-or about 10mL.More specifically in the embodiment, each agent comprises the about 20mg of about 0.1-, the about 10mg of about 0.1-, the about 7.5mg of about 0.1-, the about 5mg of about 0.1-, the about 4mg of about 0.3-, the about 2.5mg of about 0.25-, the about 2mg of about 0.3mg-, the about 1mg of about 0.5mg-, the about 1.5mg of about 0.7mg-, about 0.375mg, about 0.75mg, about 1mg, about 1.25mg, about 1.5mg or about 2mg corticosteroid.In some embodiment, provide the multiple dose unit packaging, described multiple dose unit packaging comprises the about 1500mL of about 10mL-, the about 600mL of about 50mL-, about 150mL, about 300mL, about 600mL or about 1, the described any pharmaceutical composition of 200mL herein.In some specific embodiments, described multiple-unit container comprises about 330mL or the described compositions of about 55mL herein.In some embodiments, the test kit that provides herein comprises described any multiple-unit container, described pharmaceutical composition (in for example described capacity) and conveying equipment (for example syringe, cup, spoon etc.) herein herein.In some specific embodiments, described conveying equipment is attached to (for example aerosol apparatus, nebulizer, pump etc.) in the described packing.In some embodiment, the pharmaceutical composition that comprises in described herein any multiple dose unit packaging is a physics and chemically stable.

In some aspects, give the about 20mg of the about 0.1mg-of patient, the about 20mg of about 0.25mg-, the about 15mg of about 0.25mg-, the about 10mg of about 0.25mg-or the about 5mg of about 0.25mg-(the about 5mg of for example about 0.1-, the about 4mg of about 0.3mg-, the about 2.5mg of about 0.25-, the about 2mg of about 0.3mg-, the about 1mg of about 0.5mg-, the about 1.5mg of about 0.7mg-, about 0.375mg, about 0.75mg, about 1mg, about 1.25mg, about 1.5mg or about 2mg) corticosteroid every day.In some embodiments, the amount of corticosteroid is the about 5mg of about 0.25mg-in the unit dose medicament.In some embodiments, the amount of the corticosteroid in administration every day or the unit dose medicament is the about 4mg of about 0.3mg-.In some embodiment, the amount of the corticosteroid in administration every day or the unit dose medicament is the about 3mg of about 0.5mg-.In other embodiment, in the unit dose medicament or the amount of the corticosteroid of administration every day be the about 3mg of about 1-or about 2mg of about 1-or the about 3mg of about 2-.

In some embodiments, described herein any compositions or preparation all are stable.In some specific embodiments, described compositions is a chemistry and physically stable.In some embodiment, chemical stability obtains proof during comprising the corticosteroid of at least 80%, 90%, 95%, 98% or 99% primary quantity or labelled amount and/or choose other activating agent (as the indefiniteness example) 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, 2 years or shelf life wantonly by compositions.In some embodiments, physical stability can obtain uniformity, keeps substantially evenly (for example at least 1 day, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, 2 years etc.) by pharmaceutical composition or recover uniformity (after for example leaving standstill 1 day, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, 2 years etc., by slight or medium stirring) substantially to obtain proof substantially.In some embodiment, physical stability obtains proof during comprising the corticosteroid of at least 80%, 90%, 95%, 98% or 99% primary quantity or labelled amount and/or choose other activating agent (as the indefiniteness example) 2 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, 2 years or shelf life wantonly by compositions.In some embodiment, described herein uniformity shows as one or more components concentration uniformity in described pharmaceutical composition etc. in uniformity in pharmaceutical composition of the uniformity of corticosteroid Dispersion of Particles in pharmaceutical composition, corticosteroid dispersion, the described compositions.In some embodiment, slight or medium stirring comprises, as non-limiting example, rocks, fully rocks, mixes, mixes gently etc.In some embodiments, slight or medium stirring comprises without special installation stirs.In some embodiments, the uniformity of pharmaceutical composition is meant medicament uniformity (corticosteroid that for example comprises basic analog quantity from delivery of composition or each medicament of obtaining), or the corticosteroid concentration at least some or all medicament in the multiple dose preparation is similar substantially.In some embodiment, similar substantially for example comprising in 20%, 15%, 10%, 7%, 5%, 3%, 2% or 1%.

In some embodiments, regulate the dosage or the capacity of the compositions of administration herein according to therapeutic efficiency.In some embodiment, by the described herein compositions of administration and measure therapeutic efficiency and diagnose the eosinophil esophagitis.In some embodiment, adopted the described and definite respectively compositions that can effectively treat the eosinophil esophagitis herein.Therapeutic efficiency can be determined by any suitable method, comprised for example symptom mark assessment, gastrointestinal tract splanchnoscopy (for example EGD), gastrointestinal tract (for example esophagus) tissue biopsy, Histological assessment or its combination.The method of diagnosis eosinophil esophagitis and/or definite therapeutic efficiency comprises any appropriate method, comprises, and as non-limiting example, people such as Aceves, J Allergy Clin Immunol, Feb.2008; People such as abstract 270 or Aceves, Am J Gastroenterol., Oct.2007,102 (10): listed method among the 2271-9, described boths its full content by reference are incorporated herein.

In some embodiments, the method of described herein definite treatment (for example eosinophil esophagitis) effect is clinical symptoms mark assessment, comprise (i) herein described compositions be administered to and suffered from by diagnosis or suspect the patient who suffers from the eosinophil esophagitis; (ii) estimate one or more symptoms of described patient.The symptom of optional scoring comprises, as non-limiting example, feels sick, vomiting, pain and pyrosis.Optional adopt total points or mark to change to come diagnose medical conditions and/or definite therapeutic efficiency.

In some embodiment, herein the method for described definite therapeutic efficiency comprise (i) will be herein described compositions be administered to the patient who is diagnosed or suspect suffer from gastrointestinal tract inflammation (for example eosinophil esophagitis) and/or relative symptom; (ii) endoscopic observation patient's gastrointestinal tract surface; The (iii) described gastrointestinal tract surface texture of tissue biopsy; (iv) estimate biopsy and optional endoscope's mark of determining biopsy.In some specific embodiments, described method comprises that also just described compositions is administered to biopsy and/or the biopsy after endoscope's mark and the described compositions of administration and/or endoscope's mark comparison of the evaluation that obtains before the biopsy.

In some embodiments, provide method: (i) detecting and/or measuring described patient's symptom herein with before described compositions is administered to the patient by following diagnosis gastroenteritis patient; (ii) described any compositions is administered to the patient herein; (iii) detect and/or measure patient's symptom after the described compositions of administration; The symptom of forward and backward mensuration of (iv) described compositions administration or detection.If the symptom that the patient represents reduces (for example by statistical significance or clinical correlative), then obtain sure diagnosis.In some specific embodiments, diagnosis gastroenteritis patient's method is diagnosis eosinophil esophagitis patient.

Compositions

As discussed herein, described compositions and preparation comprise at least a corticosteroid (for example budesonide or fluticasone propionate).In some embodiments, described herein compositions or preparation also comprise at least a other activating agent.In some specific embodiments, described herein compositions or preparation comprise corticosteroid for the treatment of effective dose and at least a other activating agent for the treatment of effective dose.In some embodiments, described at least a other activating agent is to treat, prevent or alleviate intestines and stomach (for example esophagus) symptom of diseases associated with inflammation and/or the medicament of relative inflammation.It should be understood that under some situation, when corticosteroid combines with another activating agent, the amount when the treatment effective dose of described corticosteroid is lower than described other activating agent and does not exist.

In addition, the invention provides the method for preventing or alleviating patient's gastrointestinal tract (for example esophagus) inflammation, described method comprises the corticosteroid that is administered orally to described patient and at least a other activating agent associating.In some embodiment, described corticosteroid and described at least a other activating agent are present in the single dosage form.In other embodiment, described corticosteroid and described at least a other activating agent are present in separately the dosage form and administration by any way, comprise, as non-limiting example, simultaneously, in succession or at different time.For example, in some embodiment, give several doses of corticosteroid compositionss in a period of time, the administration that stops described corticosteroid compositions gives at least a other activating agent at least once afterwards.

In some embodiments, at least a other activating agent that uses in described herein compositions, preparation or the method is to treat, prevent or alleviate gastrointestinal tract (for example esophagus) symptom of diseases associated with inflammation and/or the medicament of relative inflammation.In embodiment more specifically, described at least a other activating agent is not second kind of corticosteroid.In some embodiment, described at least a other activating agent is acid inhibitor (for example H2 antagonist and/or PPI).In some embodiment; described at least a other activating agent is; as non-limiting example, proton pump inhibitor (PPI), H2 antagonist, the property crossed relaxation of lower esophageal sphincter (TLESR) Reducing agent, 5-hydroxy tryptamine energy agent/motor activation regulator, the competitive sour blocker (P-CAB) of potassium ion, mucosa protective agent, histamine H 3 agonist, anti-gastrin agent or its combination.

In some embodiment, the patient will be with described combination treatment herein with another Drug therapy and/or Diet Therapy associating.

Embodiment

Embodiment 1:

This embodiment has illustrated: with by with Pulmicort

(4mL) with ^99mTc Pertechnetate associating is also compared the interaction increase between described compositions and the esophagus herein with the radiolabeled Orally administered composition (M0) that saline is diluted to about 7-8mL preparation.Described M0 compositions is at 13.2sec ^-1Under viscosity be about 1cP.What give the healthy people of a group is radiolabeled oral budesonide compositions (Ml).Described radiolabeled budesonide compositions (Ml) is passed through Pulmicort About 10 bags

(being sold by McNeil Nutritionals, LLC FortWashington, PA 19034-2299) and ^99mThe Tc Pertechnetate is combined preparation in the capacity of about 7-8mL, and it comprises about 7%w/w maltodextrin, at 13.2sec ^-1Under viscosity be about 200cP.Radiolabeled budesonide compositions (M2) is passed through Pulmicort

The 70%w/w maltodextrin and ^99mThe Tc Pertechnetate is combined preparation in about 7-8mL capacity, and it is at 13.2sec ^-1Under viscosity be about 1450cP.Also give the radiolabeled budesonide compositions of healthy population (Rhinocort

M3), it is at 13.2sec ^-1Under viscosity be about 39.The interaction of the increase of budesonide compositions is determined by measuring the radiolabeled amount that exists in the esophagus after the described oral tack cloth desonide compositions of oral administration.Fig. 1 has shown the figure that the percentage amounts (by measuring the radiolabeled amount that exists in the esophagus) of the compositions that exists in the esophagus is done time function behind the oral administration.

The area under curve (AUCr) of the figure that dosage percentage ratio is done time function (% medicament-time (min)) by from 50% swallow (promptly 50% administration medicament has passed through the oral cavity) the time be carved into the esophagus activity and reach peak value and drop to 10% of peak value then and determine.Also determine the area under curve (AUC from t=0min to t=1min _0-1) and the area under curve (AUC from t=0min to t=2min _0-2).Below these results (ratio that comprises non-sticky sample and viscosity sample) are listed in:

Embodiment 2:

This embodiment describes in detail in 5mL and the described herein preparation of 7mL dosage once a day and uses for twice every day budesonide inducing and keeping effect and safety in the disease activity of alleviating the EE child patient.Some children (for example per unit budesonide medicament frequency, amount and 20 patients of capacity) are assessed to determine the on average the highest eosinophil counting of the highest eosinophil counting (eos/hpf) and this group.Also determine the on average the highest eosinophil counting of the highest eosinophil counting (eos/hpf) and this group after the treatment.Before and after treatment, also determine symptom score and average symptom score.

Under the certain situation, comprise in the inspection obtained proton pump inhibitor, according to the irritated eliminating diet that detects of skin or blood or get rid of diet or refusal is got rid of the treatment of diet but have continuously on the esophagus slicer 〉=patient of 24eos/hpf.If RAST and/or skin prick test are positive, then the patient is defined as and has food anaphylaxis or source of the gas sensitization source allergy.The long-term treatment that is used for the treatment of chronic disease such as asthma or eczema is not changed and do not have the child to accept synergetic immunity adjustment of treatment (concurrent immune-modulatory treatment).

Adopt Olympus P160 endoscope (originating from RD) to carry out splanchnoscopy and and carry out complete-esophagus, harmonization of the stomach duodenum tissue biopsy.When at the esophagus position of at least one tissue biopsy discovery 〉=24eos/hpf, be diagnosed as the eosinophil esophagitis.From esophagus near-end (3cm under the cricopharyngeus), esophagus end (gastroesophageal junction (GEJ) is gone up 3cm) and esophagus (mid point between cricopharyngeus and the GEJ) carry out mucosa tissue biopsy again twice.Regularly carry out tissue biopsy and assessment by pediatric pathology man (RN).To the highest eosinophil counting number in every X400 high power field.When basal layer cell when epithelial luminal surface extends (＞25% epithelial thickness), be reported as basal layer hypertrophy (BZH).

Treatment was carried out endoscope's slicer follow-up investigations after 3-4 month.In tissue biopsy to the highest counting number of eos/hpf determine the response treatment and with the patient be categorized into respondent (0-7eos/hpf), partial response person (8-23eos/hpf) and not the respondent (〉=24eos/hpf).

The scoring of design EE (EoE) splanchnoscopy is with the relatively discovery of treatment front and back.This calculates by step report and photo.Four classes: (1) pale and tremulous pulse impression minimizing; (2) wrinkle that have " thickening " mucosa; (3) white mucous patch; (4) concentric ring or narrow.With regard to all kinds of, if relate to 1 or 2 esophagus position, then give 1 fen, relate to the total eclipse road and then give 2 fens.Best result is 8.

The patient obtains the described preparation of 0.25-2mg every day herein and is instructed to not swallow any solid or liquid in 30 minutes after the administration.Do not change the diet that carries out the patient of diet control.

Usually adopt improvement symptom score during EE (EoE) is clinical based on the child who suffers from acid-peptide disease.The symptom classification comprises (1) pyrosis or backflows; (2) child's stomachache or unaccountable irritability; (3) n or V; (4) anorexia or early full; (5) dysphagia or swallow pain; (6) wake up with a start symptom; (7) gastrointestinal hemorrhage (preceding 4 months).Every class meter 0-2 branch is the highest 14 minutes.If there is not the symptom must 0 minute; If symptom is slight, do not disturb daily routines, then counted 1 fen; If serious symptom is to being enough to interrupt daily routines then counted 2 fens.If there is not the relevant compensatory or anemia of hematodinamics, then think existing GI hemorrhage be slight (1 minute), and if repeatedly hemorrhage, cause anemia maybe to need blood transfusion, then think serious (2 minutes).

All statistical analysiss adopt NCSS statistical software tool kit to carry out.Adopt paired t-test to calculate two tail p values, with eos/hpf meansigma methods, the scoring of EE (EoE) splanchnoscopy and the symptom score of patient before and after relatively budesonide is treated.Adopt two tail non-paired t tests with relatively respondent's group and the not variable of respondent's group.Adopt GraphPad Prism software to generate Spearman's correlation coefficient.The result of p value＜0.05 is considered to have statistical significance.Average and the meta statistical value of regeneration, both are equal and represent the average statistics value.

The experimenter.A certain amount of child is carried out graphic analyses.All have＞24eos/hpf on the repetition esophagus slicer of all children before begin treatment.

Treatment.The time structure (for example 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 6 months etc.) of the specified amount that patient's acceptance has been stated before repeating tissue biopsy.The amount that each patient accepts budesonide is 0.25-2mg/ days.

The histology.Before treatment, measure all patients' on average the highest eosinophil counting, comprise far-end, middle part and near-end esophagus position.At the appointed time all sites is carried out same assessment, then repeat once if desired.

The upper digestive tract splanchnoscopy.Before treatment, measure all patients' average EE (EoE) splanchnoscopy scoring.After the treatment, repeat the scoring of average EE (EoE) splanchnoscopy.Patient's splanchnoscopy scoring decline (for example decline＞95%,＞90%,＞85%,＞75%,＞50%,＞25% etc.) represent successfully to treat.

Symptom score.Before treatment, determine all patients' average symptom score.Determine once more after the treatment.Patient's symptom score decline (for example decline＞95%,＞90%,＞85%,＞75%,＞50%,＞25% etc.) represent successfully to treat (uniting separately or with above-mentioned splanchnoscopy scoring).

Adult: the adult is repeated these parameters to determine its effect and safety.

Embodiment 3:

This embodiment describes in detail in the described in this article preparation once a day and uses for twice every day budesonide reducing and keeping effect and safety in the disease activity of alleviating GERD patient (child and/or adult).With once a day, twice of every day or every day three times be according to every day dosage 0-1mg, 1-2mg, 2-3mg, 3-4mg, 4-5mg and 5-6mg dosed administration, capacity is 3,5,7,10,12,15 or 17.5mL.A certain amount of patient (for example every kind of budesonide dose frequency, amount and 20 patients of capacity) is assessed with the symptom before determining treatment, after the treatment neutralization treatment.Administration 7 days, 14 days and 28 days.Main index (Primary Outcome Measure) as a result comprises pyrosis and the elimination fully of backflowing (for example put in preceding 7 days slight pyrosis or backflow for the evaluation time and be no more than a day).Less important result's treatment comprises: the natural law of pyrosis (daytime and night); The natural law that backflows (daytime and night); Scorching hot and the natural law (24 hours) that backflows in the no pit of the stomach; The compound scoring of pyrosis and backflow frequency and seriousness; The time that the pyrosis/symptom of backflowing is eliminated; The seriousness of other GERD symptom; Quality of life (adopting PAGI-QOL to estimate) to PGIC (general impression of patient) to changing; Pyrosis is eliminated fully; Backflow and eliminate fully; The average seriousness of pyrosis (daytime and night); The average seriousness of backflowing (daytime and night).These symptoms are marked (for example serious symptoms was given 3 fens and asymptomatic be 0 minute) and are used for determining therapeutic efficiency.

Although some embodiment is showed and describe, those skilled in the art be it is evident that these embodiments only provide as example herein.Those skilled in the art can associate many modification, remodeling and substitute and they belong to scope disclosed herein.Should be appreciated that the various replacement schemes of described embodiment of the present invention can be used for implementing the present invention herein.Method and structure and equivalent technologies thereof that following claim limits in the scope of the invention and these claim scopes also belong to the scope of the invention.

List of references

1.Liacouras C A, Ruchelli E.Eosinophilic esophagitis (eosinophil esophagitis) .Cuff.Opin.Pediatr.2004; 16:560-6.

2.Kelly K J, Lazenby A J, people such as Rowe P C, Eosinophilic esophagitis attributed to gastroesophageal reflux:improvement with an amino acid-based formula (owing to the eosinophil esophagitis of gastroesophageal reflux: improve) .Gastroenterology 1995 with the aminoacid prescription; 109:1503-12.

3.Fogg M I, Ruchelli E, Spergel J M.Pollen and eosinophilic esophagitis (pollen and eosinophil esophagitis) .J.Allergy Clin.Immunol.2003; 112:796-7.

4.Mishra A, Hogan S P, Brandt E B, Rothenberg M E.An etiological role for aeroallergens and eosinophils in experimental esophagitis (reasonable function of aeroallergen and eosinophil in the experimental esophagitis) .J.Clin.Invest.2001; 107:83-90.

5.Spergel J M, Beausoleil J L, Mascarenhas M, Liacouras C A.The use of skin prick tests and patch tests to identify causative foods in Eosinophilic esophagitis (skin points acupuncture manipulation and patch test be the application in the reason food in determining the eosinophil esophagitis) .J.Allergy Clin.Immunol.2002; 109:363-8.

6.Ruchelli E, Wenner W, Voytek T waits people .Severity of esophageal eosinophilia predicts response to conventional gastroesophageal reflux therapy (the seriousness prediction of esophagus eosinophilia is to the response of conventional gerd treatment) .Pediatr.Dev.Pathol.1999; 2:15-8.

7.Steiner S J, Gupta S K, Croffie J M, Fitzgerald J F.Correlation between number of eosinophils and reflux index on same day esophageal biopsy and 24hour esophageal pH monitoring (the esophagus tissue biopsy and the eosinophil number of esophageal pH monitoring in 24 hours and the dependency between the anti-stream index on the same day) .Am.J.Gastroenterol.2004; 99:801-5.

8.Orenstein S R, Shalaby T M, Di Lorenzo C, (characteristic range of children's eosinophil esophagitis surpasses the baby: 30 children's clinical series) .Am.J.Gastroenterol.2000 to wait people .The spectrum of pediatric eosinophilic esophagitis beyond infancy:a clinical series of 30children; 95:1422-30.

9.Rothenberg M E, Mishra A, Collins M H, Putnam P E.Pathogenesis and clinical features of eosinophilic esophagitis (pathogeny of eosinophil esophagitis and Clinical symptoms) .J.Allergy Clin.Immunol.2001; 108:891-4,

10.Ravelli A M, Villanacci V, Ruzzenenti N waits the people .Dilated Intercellular Spaces:A Major Morphological Feature of esophagitis (intercellular substance of broadening: the main morphological characteristic of esophagitis) .J.Pediatr.Gastroenterol.Nutr.2006; 42:510-515.

11.Steiner S J, Kernek K M, Fitzgerald J F.Severity of Basal Cell Hyperplasia Differs in Reflux versus Eosinophilic Esophagitis (anti-stream is different with basal cell hyperplasia severity in the eosinophil esophagitis), J.Pediatri.Gastroenterol, Nutr.2006; 42:506-509

12.Mueller S, Aigner T, Neureiter D, Stolte M.Eosinophil infiltration and degranulation in oesophageal mucosa from adult patients with eosinophilic oesophagitis:a retrospective comparative study on pathologic biopsy (soak into and threshing in the eosinophil esophagitis adult patient esophageal mucosa membrane injury: the retrospective comparative study of pathology tissue biopsy) .J.CHn.Pathol.2006 by eosinophil; 59:U 75-80.

13.Croese J, Fairley S K, people such as Masson J W, Clinical and endoscopic features of eosinophilic esophagitis in adults (the clinical and splanchnoscopy feature of eosinophil esophagitis among the adult) .Gastrointest.Endosc.2003; 58:516-22.

14.Aceves S, Newbury, RO, Dohil R, Schwimmer J, Bastian J.Distinguishing eosinophilic esophagitis in pediatric patients:clinical, endoscopic, and histologic features of an emerging disorder (differentiation of pediatric patient eosinophil esophagitis: clinical, the splanchnoscopy of New Development disease and histologic characteristics) .Journal of Clinical Gastroenterology 2006; 41 (3): 252-6.

15.Straumann A, Simon H U.Eosinophilic esophagitis:escalating epidemiology (eosinophil esophagitis: progressively the epidemiology of Shang Shenging)? J.Allergy Clin.Immunol.2005; 115:418-9.

16.Cherian S, Smith N M, Forbes D A.Rapidly increasing prevalence of eosinophilic oesophagitis in Western Australia (the eosinophil esophagitis is popular rapidly western Australia) .Arch.Dis.Child 2006; 91:1000-4.

17.Sant ' Anna A M, Rolland S, people such as Fournet J C, Eosinophilic Esophagitis in Children:Symptoms, Histology and pH Probe Results (child eosinophil esophagitis: symptom, histology and pH probe result) .J.Pediatr.Gastroenterol.Nutr.2004; 39:373-377.

18.Potter J W, Saeian K, people such as Staff D, Eosinophilic esophagitis in adults:an emerging problem with unique esophageal features (adult eosinophil esophagitis: the new problem with unique esophagus feature) .Gastrointest.Endosc.2004; 59:355-61.

19.Parfitt J R, Gregor J C, people such as Suskin N G, Eosinophilic esophagitis in adults:distinguishing features from gastroesophageal reflux disease:a study of 41patients (adult's eosinophil esophagitis: with the distinguishing characteristics of gastro oesophageal reflux disease (GORD): to 41 patients' research) .Mod.Pathol. 2006; 19:90-6.

20.Desai T K, Stecevic V, people such as Chang C H, Association of eosinophilic esophagitis with esophageal food impaction in adults (relation of adult's eosinophil esophagitis and esophagus food impaction) .Gastrointest.Endosc.2005; 61:795-80l.

21.Straumann A, Spichtin H P, people such as Grize L, Natural history of primary eosinophilic esophagitis:a follow-up of 30adult patients for up to 11.5years (natural history of elementary eosinophil esophagitis: 30 adult patients are reached follow-up study in 11.5) .Gastroenterology 2003; 125:1660-9.

22.Spergel J M, Andrews T, people such as Brown-Whitehorn T F, Treatment of Eosinophilic esophagitis with specific food elimination diet directed by a combination of skin prick and patch tests (the eosinophil esophagitis treatment of the special eliminating diet that instructs by skin prick and patch test) .Ann.Allergy Asthma Immunol.2005; 95:336-43.

23.Kagalwalla A F, Sentongo T A, people such as Ritz S, Effect of six-food elimination diet on clinical and histologic outcomes in Eosinophilic esophagitis (six kinds of food is got rid of diet clinical to the eosinophil esophagitis in histology result's influence) .Clin.Gastroenterol.Hepatol. 2006; 4:1097-102.

24.Markowitz J E, Spergel J M, Ruchelli E, Liacouras C A.Elemental diet is an effective treatment for Eosinophilic esophagitis in children and adolescents (elemental diet is effective Therapeutic Method of child and teenager eosinophil esophagitis) .Am.J.Gastroenterol.2003; 98:777-82.

25.Liacouras C A, Wenner W J, Brown K, Ruchelli E.Primary Eosinophilic esophagitis in children:successful treatment with oral corticosteroids (the elementary eosinophil esophagitis of child :) .J.Pediatr.Gastroenterol.Nutr.1998 with the successful treatment of oral corticosteroid; 26:380-5.

26.Teitelbaum J E, Fox V L, people such as Twarog F J, Eosinophilic esophagitis in children:immunopathological analysis and response to

Propionate (child eosinophil esophagitis: immunopathogenesis analysis and to the response of fluticasone propionate) .Gastroenterology 2002; 122:1216-25.

27.Faubion W A, Jr., Perrault J, people such as Burgart L J, Treatment of Eosinophilic esophagitis with inhaled corticosteroids (with the corticosteroid treatment eosinophil esophagitis that sucks) .J.Pediatr.Gastroenterol.Nutr.1998; 27:90-3.

28.Aceves S S, Dohil R, Newbury R O, Bastian J F.Topical viscous budesonide suspension for treatment of Eosinophilic esophagitis (the local tack cloth desonide suspension that is used for the treatment of the eosinophil esophagitis) .J.Allergy Clin.Immunol. 2005; 116:705-6.

29.Noel R J, Putnam P E, people such as Collins M H, Clinical and immunopathologic effects of swallowed fluticasone for Eosinophilic esophagitis (fluticasone of swallowing is to the clinical and immunopathogenesis influence of eosinophil esophagitis) .Clin.Gastroenterol.Hepatol.2004; 2:568-75.

30.Remedios M, Campbell C, Jones D M, Kerlin P.Eosinophilic esophagitis in adults:clinical, endoscopic, histologic findings, and response to treatment with fluticasone propionate (adult's eosinophil esophagitis: clinical, splanchnoscopy, the histology finds and to response with fluticasone propionate in treatment) .Gastrointest.Endosc.2006; 63:3-12.31.Dohil R, Newbury R O, people such as Sellers Z M, The evaluation and treatment of gastrointestinal disease in children with cystinosis receiving cysteamine (accepting the gastroenteropathy assessment and treatment of the cystinosis child patient of cysteamine) .J.Pediatr.2003; 14:224-30.

32.Cheung K M, Oliver M R, people such as Cameron D J, Esophageal eosinophilia in children with dysphagia (dysphagia child's eosinophil esophagitis) .J.Pediatr.Gastroenterol.Nutr.2003; 37:498-503.

33.Fox V L, Nurko S, Furuta G T.Eosinophilic esophagitis:it ' s not just kid ' s stuff.Gastrointest (eosinophil esophagitis: be not only children problem) .Gastrointest.Endosc.2002; 56:260-70

34.Budin C, Villard-Truc F, people such as Rivet C, [Eosinophilic esophagitis:3case reports (eosinophil esophagitis: 3 example reports)] .Gastroenterol.Clin.Biol.2005; 29:73-5.

35.Noel R J, Putnam P E, Rothenberg M E.Eosinophilic esophagitis (eosinophil esophagitis) .N.Engl.J.Med.2004; 351:940-1.

36.Guaj ardo J R, Plotnick L M, people such as Fende J M, the Eosinophil-associated gastrointestinal disorders:a world-wide-web based registry (gastrointestinal disease that eosinophil is relevant: online registration) .J.Pediatr.2002; 141:576-81.

37.Liacouras C A, Spergel J M, people such as Ruchelli E, Eosinophilic esophagitis:a10-year experience in 381 children (eosinophil esophagitis :) .Clin.Gastroenterol.Hepatol.2005 to 10 years experiences of 381 children; 3:1198-206.

38.Liacouras C A.Eosinophilic esophagitis:treatment in 2005 (eosinophil esophagitis: the treatment in 2005) .Curr.Opin.Gastroenterol.2006; 22:147-152.

39.Spergel JM.Eosinophilic esophagitis in adults and children:evidence for afood allergy component in many patients (adult and child eosinophil esophagitis: .Curr.Opin.Allergy Clin.Immunol.2007 many patients' food anaphylaxis component evidence); 7:274-8.

40.Plaza-Martin, AM, Jimenez-Feijoo R, Andaluz C, Giner-Munoz MT, Martin-Mateos MA, Piquer-Gibert M, the Sierra-Martinez JI.Polysensitization to aeroallergens and food in Eosinophilic esophagitis in a pediatric population multiple sensitivity of aeroallergen and food (in the juvenile eosinophil esophagitis to) .Alergol.Immunopathol.2007; 35:35-7.

41.Nicolazzo, JA, Reed, BL, Finnin, BC.Buccal penetration enhancers-how do they really work (oral cavity penetration enhancer-they how really to work)? J.Controlled Release 2005; 105:1-15.

42.Furuta, GT, Liacouras, CA, Collins, MH, Sandeep, KG, Justinich, C, Putnam, PE, Bonis, P, Hassall, E, Straumann, A, Rothenberg, ME.Eosiniophilic esophagitis in children and adults:A systematic review and consensus recommendations for diagnosis and treatment (child and adult eosinophil esophagitis: the system review and consistent recommendation of diagnosis and treatment) .Gastroenterology 2007; 133:1342-1363.

43.Aceves, SS, Bastian JF, Newbury, RO, Dohil, R.Oral viscous budesonide:Apotential new therapy for Eosinophilic esophagitis (oral tack cloth desonide: .Amer.Journal of Gastroenterology 2007 effective new treatment of eosinophil esophagitis); 102:1-9.

44.Rothenberg M E.Eosinophilic gastrointestinal disorders (eosinophil property gastroenteropathy) .J.Allergy Clin.Immunol.2004; 113:11-28.

45.Garrett J K, Jameson S C, Thomson B, Collins M H, Wagoner L E, Freese, D K, Deng the people, Anti-interleukin-5 (mepolizumab) therapy for hypereosinophilic syndromes (eosinophil cytosis syndromic anti-IL-8-5 (mepolizumab) treatment) .J.Allergy Clin.Immunol.2004; 113:115-9.

Claims

1. stable combination of oral medication, described stable combination of oral medication comprises corticosteroid, liquid-carrier and mucomembranous adhesion agent, wherein said stable combination of oral medication chemistry and physically stablizing at least one month.

2. the stable combination of oral medication of claim 1, wherein said corticosteroid is the corticosteroid of Topically active.

3. the stable combination of oral medication of claim 1, wherein said corticosteroid is a budesonide.

4. the stable combination of oral medication of claim 1, wherein said corticosteroid is a fluticasone propionate.

5. the stable combination of oral medication of claim 1, wherein behind the described stable combination of oral medication of oral administration, at least 10% of described stable combination of oral medication is attached on the esophagus at least 15 seconds.

6. the stable combination of oral medication of claim 1, wherein behind the described stable combination of oral medication of oral administration, at least 10% of described corticosteroid is attached on the esophagus at least 15 seconds.

7. the stable combination of oral medication of claim 1, wherein at the described stable combination of oral medication of oral administration after at least 15 seconds, at least 10% of described corticosteroid is attached on the esophagus or is absorbed.

8. the stable combination of oral medication of claim 1, wherein 15 seconds postadhesion of the described stable combination of oral medication of oral administration to the percentage by weight of supraoesophageal combination of oral medication greater than the percentage by weight of 15 seconds postadhesion of oral administration reference composition to supraoesophageal reference composition

Wherein said reference composition comprise with described stable combination of oral medication in commensurability homogenic cortex steroid class,

And wherein said reference composition also comprises about 4mL aqueous compositions of every 0.5mg corticosteroid and 10 bags

9. the stable combination of oral medication of claim 1, wherein 15 seconds postadhesion of the described stable combination of oral medication of oral administration to the amount of supraoesophageal corticosteroid greater than 15 seconds postadhesion of oral administration control drug compositions to esophagus or the amount of the corticosteroid that is absorbed

10. the stable combination of oral medication of claim 1, wherein 15 seconds postadhesion of the described stable combination of oral medication of oral administration to esophagus or the amount of the corticosteroid that is absorbed greater than 15 seconds postadhesion of oral administration reference composition to esophagus or the amount of the corticosteroid that is absorbed

Wherein said reference composition comprise with described stable combination of oral medication in the commensurability capacity corticosteroid identical with kind,

And wherein said reference composition is about 13.2sec at 25 ℃, shear rate ^-1Under viscosity be about 1cP.

11. the stable combination of oral medication of claim 1, wherein said mucomembranous adhesion agent are the mucosal adhesive polysaccharide.

12. the stable combination of oral medication of claim 1, wherein said mucomembranous adhesion agent is the card bohr.

13. the stable combination of oral medication of claim 12, wherein said card bohr is chosen to be crosslinked acrylic acid polymer.

14. the stable combination of oral medication of claim 1, wherein said mucomembranous adhesion agent are alginate.

15. the stable combination of oral medication of claim 14, wherein said alginate are sodium alginate.

16. the stable combination of oral medication of claim 1, wherein said mucomembranous adhesion agent comprises maltodextrin.

17. the stable combination of oral medication of claim 16, wherein said maltodextrin can not improve the viscosity of described stable combination of oral medication significantly.

18. the stable combination of oral medication of claim 17, wherein said stable combination of oral medication comprise the second kind of maltodextrin that improves described stable combination of oral medication viscosity.

19. the mucoadhesive characteristics that the stable combination of oral medication of claim 18, wherein said second kind of maltodextrin can the described pharmaceutical compositions of appreciable impact.

20. the stable combination of oral medication of claim 1, wherein said mucomembranous adhesion agent are given the viscosity that described stable combination of oral medication improves.

21. the stable combination of oral medication of claim 1, wherein said mucomembranous adhesion agent can not improve the viscosity of described stable combination of oral medication significantly.

22. the stable combination of oral medication of claim 1, described stable combination of oral medication also comprises second kind of mucomembranous adhesion agent.

23. the stable combination of oral medication of claim 1, described stable combination of oral medication also comprises viscosifier.

24. a treatment, prevent or alleviate the method for gastroenteritis in patient's body or gastroenteritis symptom, described method comprises a kind of stable combination of oral medication of the described patient of orally give, described stable combination of oral medication comprises corticosteroid, liquid-carrier and mucomembranous adhesion agent, wherein said stable combination of oral medication chemistry and physically stablizing at least one month.

25. the method for claim 24, wherein said corticosteroid are the corticosteroid of Topically active.

26. the method for claim 24, wherein said corticosteroid are budesonide.

27. the method for claim 24, the described fluticasone propionate of wherein said corticosteroid.

28. the method for claim 24, wherein behind the described stable combination of oral medication of oral administration, at least 10% of described stable combination of oral medication adhered to 15 seconds at least.

29. the method for claim 24, wherein behind the described stable combination of oral medication of oral administration, at least 10% of described corticosteroid is attached on the esophagus at least 15 seconds.

30. the method for claim 24, wherein at the described stable combination of oral medication of oral administration after at least 15 seconds, at least 10% of described corticosteroid is attached on the esophagus or is absorbed.

31. the method for claim 24, wherein said gastroenteritis are esophagitis.

32. the method for claim 24, wherein said gastroenteritis are the eosinophil esophagitis, the inflammatory bowel that relates to esophagus, Crohn disease, celiac disease, proximal gastric intestinal pathology, eosinophil property gastroenteritis, epithelial proliferation, basal cell hyperplasia, the mastoid process of elongation, nipple vasodilation, fungous esophagitis, viral esophagitis, bacillary esophagitis, erosive esophagitis, radiation esophagitis, the chemotherapy esophagitis, graft versus host disease, the dermatosis that relates to esophagus, bullous pemphigoid, pemphigus vulgaris, epidermolysis bullosa, Stevens Johnson syndrome, Behcet disease, sarcoidosis, congenital esophagitis, eosinophil property gastritis, huge gastric mucosal hypertrophy disease (giant hypertrophy gastritis), parasitic gastritis, the lymphocyte esophagitis, the esophagitis that inflammatory bowel is relevant, parasitic gastritis, the lymphocyte esophagitis, the esophagitis that inflammatory bowel is relevant, celiac disease, eosinophil property duodenitis, the duodenum hypereosinophilia, functional dyspepsia, mid-term esophagitis, be secondary to the esophagitis that corrosivity/stimulus object is swallowed, any reason and comprise that corrosivity/stimulus object swallows continuing/the repeatability esophageal stricture of causing, the pill esophagitis, systemic disease, congenital diseases, post-operation inflammatory or gastroenteritis.

33. the method for claim 32, wherein said patient suffers from the eosinophil esophagitis.

34. the method for claim 31, wherein said patient diagnosed suffer from the Barrett esophagus, gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD) or erosive esophagitis.

35. the method for claim 24 wherein is administered to the about 20mg corticosteroid of described patient's every day of about 0.1mg-.

36. the method for claim 24 wherein is administered to the about 4mg corticosteroid of described patient 0.3mg-every day.