CN101056624A

CN101056624A - Controlled release pharmaceutical compositions comprising a fumaric acid ester

Info

Publication number: CN101056624A
Application number: CNA2005800385728A
Authority: CN
Inventors: H·尼尔森; F·肖恩哈汀; B·W·米勒; J·R·罗宾逊
Original assignee: ADITECH PHARMA AB
Current assignee: ADITECH PHARMA AB
Priority date: 2004-10-08
Filing date: 2005-10-07
Publication date: 2007-10-17

Abstract

The present invention relates to controlled release pharmaceutical compositions comprising fumaric acid ester(s) as active substance(s). The compositions are suitable for use in the treatment of e.g. psoriasis or other hyperproliferative, inflammatory or autoimmune disorders and are designated to release the fumaric acid ester in a controlled manner so that local high concentrations of the active substance within the gastrointestinal tract upon oral administration can be avoided and, thereby, enabling a reduction in gastro-intestinal related side-effects.

Description

The controlled release pharmaceutical compositions that comprises fumarate

Invention field

The present invention relates to comprise the controlled release pharmaceutical compositions of fumarate as active substance.These compositionss are suitable for treating for example psoriasis or other excess proliferatives, inflammatory or autoimmunity illness, be designed to discharge in a controlled manner fumaric acid, so that can avoid the high local concentrations in gastrointestinal tract behind the active substance oral administration, can reduce gastrointestinal side-effect thus.

Background of invention

Fumarate, be that the combination of dimethyl fumarate and fumaric acid hydrogen ethyl ester has been used for the treatment of psoriasis and reaches a lot of years.The commercially available product of this combination is called Fumaderm ^It is mouthful dosage form with tablet, has two kinds of different dose intensities can use (Fumaderm ^Initial and Fumaderm ^):

Fumaderm ^ Initial Fumaderm ^

Dimethyl fumarate 30mg 120mg

Fumaric acid hydrogen ethyl ester calcium salt 67mg 87mg

Fumaric acid hydrogen ethyl ester magnesium salt 5mg 5mg

Fumaric acid hydrogen ethyl ester zinc salt 3mg 3mg

These two kinds of intensity are intended to be applied in the basic separately dosage regimen, start from Fumaderm ^Initial, dosage progressively enlarges, and is converted to Fumaderm then after for example treating for three weeks ^Fumaderm ^Initial and Fumaderm ^It all is enteric coated tablet.

Another kind of commercial composite is Fumaraat120 ^, contain 120mg dimethyl fumarate and 95mg monomethyl ester calcium (TioFarma, Oud-Beijerland, Netherlands).(Litjens et al.Br.J.Clin.Pharmacol.2004, vol.58:4 pp.429-432), has described Fumaraat120 in nearest a publication ^Pharmacokinetic curve in the health volunteer.The result shows, at the Fumaraat120 of single oral dose ^Afterwards, serum monomethyl fumarate concentration rises, and observes negligible dimethyl fumarate and fumaric acid concentration.These results show that dimethyl fumarate is hydrolyzed to monomethyl fumarate rapidly in alkaline environment, and are still according to author's view, quite different in sour environment.Because said composition is the enteric coating type, it is contemplated that the picked-up of fumarate mainly occurs in the small intestinal, because alkaline environment is hydrolyzed to monoesters, perhaps it can be transformed rapidly owing to esterase in circulation dimethyl fumarate before picked-up there.In addition, this studies show that t _MaxAnd C _MaxBe subjected to the influence of food, that is to say to be accompanied by food intake, t _MaxBe extended (meansigma methods of fasted conditions is 182min, and the meansigma methods of feed condition is 361min) (be 90min the lag time of fasting, and be 300min the lag time of feed), C _MaxBe lowered (fasting: 0.84mg/l, feed: 0.48mg/l).Another utilizes two Fumaderm ^The research that P forte carries out in the health volunteer (Reddingius W.G.Bioanalysis andPharmacokinetics of Fumarates in Humans.Dissertation ETHZurich No.12199 (1997)) has disclosed C _MaxBe worth (measuring) in 1.0 to 2.4 μ g/ml scopes, t according to monomethyl ester or mono-methyl _MaxIn 4.8 to 6.0 hours scopes.

US 6,277,882 and US 6,355,676 purposes of fumaric acid hydrogen Arrcostab and some fumaric acid mono alkyl ester salt is disclosed respectively, be used to prepare the micro chip of treatment psoriasis, arthritic psoriasis, neural dermatitis and Crow engler's regional enteritis.US 6,509, and 376 disclose the purposes of some dialkyl fumarate, are used for preparing the pharmaceutical preparations that is used in transplantation medicine or autoimmune disease therapy, are micro chip or particulate form.US 4,959, and 389 disclose compositions, contain the fumaric acid mono alkyl ester separately or with the different salt of the combination of dialkyl fumarate.GB 1,153, and 927 relate to medical composition, comprises dimethyl maleic anhydride and/or dimethyl maleic acid and/or dimethyl fumarate chemical compound.From BMC Dermatology, vol.2, no.5,2002 case report " Treatment of disseminated granuloma annularewith fumaric acid esters " relates to fumarate and treating.

But, the fumarate therapy, for example resemble Fumaderm ^Often cause gastrointestinal side-effect, for example swell, diarrhoea, epigastrium angor, flatulence and feel sick.Therefore, need exploitation to comprise the compositions that one or more have the fumarate of treatment or prophylactic activity, they provide improved treatment, the gastrointestinal side-effect behind the minimizing oral administration.

In addition, present commercially available product contains the combination of two kinds of different esters, and there be (just calcium salt, magnesium salt and zinc salt) in wherein a kind of ester (just fumaric acid hydrogen ethyl ester, it is single ethyl ester of fumaric acid) with three kinds of different salt forms.Although every kind of single form can have the treatment characteristic of himself, will be favourable but simpler product if possible is provided, purpose is to obtain suitable therapeutic effect.

Inventor's imagination, administration by a kind of pharmaceutical composition can obtain improved treatment system, this pharmaceutical composition is designed to delivery of active substances in a controlled manner, just the mode of comparing prolongation, delay and/or postponing with commercially available product.In addition, imagination is utilized independent single fumarate, and for example dimethyl fumarate can reach suitable treatment and reply, and replaces using the combination of different fumarates.

Brief description of drawings

Fig. 1 shows the capsular dissolution in vitro curve example as preparation as described in the embodiment 5.

Fig. 2 shows the dissolution in vitro curve example as the tablet samples (before enteric coated) of preparation as described in the embodiment 16.

Fig. 3 shows the dissolution in vitro curve example as the tablet samples (before enteric coated) of preparation as described in the embodiment 17.

Summary of the invention

Therefore, the present invention relates to pharmaceutical composition, comprise one or more fumarates, be selected from two of fumaric acid-(C as active substance ₁-C ₅) the list-(C of Arrcostab and fumaric acid ₁-C ₅) Arrcostab or its pharmaceutically acceptable salt, it is behind oral administration, with Isodose Fumaderm ^Compare behind the sheet oral administration, reduce GI (gastrointestinal) side effect.

As mentioned above, to be suitable for reducing the mode of gastrointestinal side-effect be the form administration of active substance with controlled release composition for inventor imagination.

Therefore, the present invention relates to mouth on the other hand and uses controlled release pharmaceutical compositions, comprises one or more fumarates as active substance, is selected from two of fumaric acid-(C ₁-C ₅) the list-(C of Arrcostab and fumaric acid ₁-C ₅) Arrcostab or its pharmaceutically acceptable salt, wherein the release of fumarate when carrying out extracorporeal dissoluting test is as follows, this test pro-adopts 0.1N hydrochloric acid as dissolve medium during 2 hours, then with 0.05M phosphate buffer pH6.5 as dissolve medium:

In preceding 3 hours, the fumarate total amount that said composition contained has about 70%w/w to be released at the most after on-test, and/or

In preceding 4 hours, the total amount of fumarate has about 92%w/w to be released at the most after on-test, and/or

In preceding 5 hours, the total amount of fumarate has about 94%w/w to be released at the most after on-test, and/or

In preceding 6 hours, the fumarate total amount that said composition contained has about 95%w/w to be released at the most after on-test, and/or

In preceding 7 hours, the fumarate total amount that said composition contained has about 98%w/w to be released at the most after on-test, and/or

In preceding 9 hours, the fumarate total amount that said composition contained has about 99%w/w to be released at the most after on-test, and/or

In preceding 12 hours, the fumarate total amount that said composition contained has about 99%w/w to be released at the most after on-test.

In this article, controlled release composition is a kind of like this compositions, it is designed to, and (for example with regard to research in the body: dosage is suitable when testing under comparable conditions, with or do not have standardization meals etc., perhaps with regard in vitro study: dosage is suitable, and solubility test device and working condition for example comprise composition, volume and the temperature of the dissolve medium that is adopted, rotary speed etc.), with commercially available product F umaderm ^Compare, discharge fumarate in the mode that prolongs, delays and/or postpone.

Release can followingly be tested in the body, measure plasma concentration at the fixed time, if the plasma concentration-time graph that obtains relevant fumarate or relevant its metabolite thus is (for example under the situation of dimethyl fumarate, active substance is envisioned as fumaric acid hydrogen methyl ester, just the monomethyl ester of fumaric acid).In addition, the imagination metabolism has occurred in the gastrointestinal tract or during passing gastrointestinal mucosa or after first by the liver circulation.Therefore, when giving dimethyl fumarate, the related component that will in blood plasma, seek may be the monomethyl ester of fumaric acid, rather than dimethyl esters.

Also can utilize other test determination activity in vivo materials to discharge or provide it measures.Thereby, can use animal (for example mice, rat, Canis familiaris L. etc.) as model.The compositions that animals received is studied is put to death animal after the specified time, measure or extract from intestinal contents the content of active component (or its metabolite, if relevant) in blood plasma or certain organs.

Another test involves the use of specific one section animal intestinal.This section placed suitable dissolver, and this device contains two cabins (donor and receptor), by this section intestinal separately, the compositions of being studied is placed the suitable medium in a cabin (donor cabin).Compositions is crossed over this intestinal segment transhipment subsequently with release of active agent.Therefore, with the active substance in the time interval measurement receptor cabin that is fit to (if perhaps being correlated with metabolite) concentration.

Those skilled in the art can adjust said method according to particular composition.

About external model, there is sophisticated method to use, especially the described method of official's monograph, for example American Pharmacopeia (USP) or European Pharmacopoeia.Those skilled in the art will know which kind of method of selection and how select specified conditions to carry out in vitro tests.For example, the in vitro tests of USP regulation is carried out under 37+/-1.0 degree centigrade, for example 37+/-0.5 degree.The solubility test that is fit to for example as embodiment 29 about as described in the capsule, wherein as described in American Pharmacopeia, measure solubility curve down at 37 ℃, use the rotation basket of 100rpm, during preceding 2 hours of test, adopt 0.1N hydrochloric acid as dissolve medium, then in all the other experimental stages with 0.05M phosphate buffer pH6.5 as dissolve medium, and for example as embodiment 30 about as described in the tablet, wherein as described in American Pharmacopeia, measure solubility curve down at 37 ℃, use the oar formula dissolver of 100rpm, during preceding 2 hours of test, adopt 0.1N hydrochloric acid as dissolve medium, then in all the other experimental stages with 0.05M phosphate buffer pH6.5 as dissolve medium.

As mentioned above, the commercially available Fumaderm of release ratio in the body of active substance ^Compositions prolongs, delays and/or has postponed.Herein, term " prolongation " is intended to show than Fumaderm ^Longer time durations release of active agent, for example time ratio Fumaderm ^Grow to few 1.2 times, for example at least 1.5 times, at least 2 times, at least 3 times, at least 4 times or at least 5 times.Thereby, if Fumaderm for example ^Sheet is 3 hours release 100% dimethyl fumarates after the on-test that is fit to, and compositions so according to the present invention is at least 3.6 hours release 100% dimethyl fumarates after the on-test that is fit to.

Herein, term " delay " is intended to show that discharging of active substance starts from compares Fumaderm ^More late time point (30min or more late for example, for example 45min or more late, 1 hour or more late or 1.5 hours or more late), select as an alternative, the initial release during preceding 2 hours is less than Fumaderm greatly ^(just be less than Fumaderm ^80%w/w, for example be less than 70%w/w, be less than 60%w/w or be less than 50%).

Used gastrointestinal (GI) side effect of the present invention can include but not limited to suffer from diarrhoea, the pain of having a stomachache, have a stomach-ache, abdominal pain, abdominal colic, feel sick, flatulence, tenesmus, tympanites, stool increase, swell sense and epigastrium angor.

This paper is heavy, and GI side effect minimizing is intended to expression and Fumaderm ^Viewed GI side effect is compared after the administration, and compositions administration according to the present invention reduces seriousness and/or incidence rate in the patient group who receives treatment.According to this definition, the minimizing of GI side effect thereby can be interpreted as that having of any above-mentioned GI side effect is substantive reduces has for example reduced at least 10%, has perhaps more preferably reduced at least 20%, perhaps and then has more preferably reduced more than 30%.The seriousness that the minimizing of GI side effect also can be represented as any above-mentioned GI side effect has substance to alleviate, the pain of for example suffering from diarrhoea, have a stomachache, have a stomach-ache, abdominal pain, abdominal colic, feel sick, flatulence, tenesmus, tympanites, stool increase, swell sense or the seriousness of epigastrium angor and/or the attenuating of frequency.Can in the clinic trial environment, monitor the minimizing of above-mentioned GI side effect, relatively according to compositions administration of the present invention and Fumaderm ^Or placebo.Under the trial state of placebo, accept to compare GI side effect incidence rate, Fumaderm according to the patient and the placebo group of compositions of the present invention ^Relatively more historical on probation with placebo, compare the two again (for example referring to Altmeyer et al, J.Am.Acad.Dermatol.1994; Complete reference: Altmeyer PJ et al, Antipsoriatic effect of fumaric acidderivatives.Results of amulticenter double-blind study in 100patients.J.Am.Acad.Dermatol.1994; 30:977-81).Usually, in a kind of like this research, comprise the psoriatic, surpass 10% body surface area usually and will be infected (serious psoriasis) by psoriasis.But, also can comprise infected 2 to 10% the patient of body surface area (moderate psoriasis).Also can select the patient based on the serious index of psoriasis area (PASI).Usually, comprise PASI patient within the specific limits, for example between 10 and 40, perhaps for example between 12 and 30, perhaps for example between 15 and 25.Can comprise any type psoriatic (chronic speckle type, rash are dripped shape type, pustule type, psoriasis erythroderma or palm toe type), but only comprise chronic speckle type patient in some cases.Each treatment group is (according to compositions of the present invention and Fumaderm ^Or placebo) about 15 to 20 patients are enough as a rule, but more preferably comprise about 30 to 50 patients in each research branch.The ultimate survey cycle can be lacked and reached one day to a week, but more preferably research will be carried out for 8 thoughtful 12 weeks or reach for 16 weeks.Certain side effect total degree that side effect can for example be assessed as in every group to be reported (irrelevant) with this side effect of how many patient experiences, perhaps side effect can be assessed as the patient's number that certain side effect reaches certain number of times of experiencing, for example during studying at least once or at least twice or at least three times.In addition, can monitor the seriousness of side effect under study for action, perhaps for the qualitative side effect that may need certain seriousness for side effect.The mode that is suitable for assessing side effect seriousness is naked eyes similar (VAS) evaluation.

Active substance

Active substance in the present composition is any fumarate.In a kind of invention embodiment, fumarate preferably is selected from the group of being made up of dimethyl fumarate, DEF, fumaric acid dipropyl, dibutyl fumarate, fumaric acid diamyl ester, fumaric acid Methylethyl ester, fumaric acid methyl-propyl ester, fumaric acid methyl butyl ester, fumaric acid methyl amyl ester, fumaric acid monomethyl ester, fumaric acid list ethyl ester, fumaric acid list propyl diester, fumaric acid monobutyl ester and fumaric acid list amyl group ester, comprises its pharmaceutically acceptable salt.

In specific invention embodiment, fumarate is the list-(C of fumaric acid ₁-C ₅) Arrcostab, exist with the pharmaceutically acceptable salt form.The salt that is fit to for example is slaine, for example is selected from the salt of alkali metal salt and alkali salt, comprises sodium, potassium, calcium, magnesium or zinc salt.

Term (C ₁-C ₅) alkyl represents branch or not ramose alkyl, has one to five (containing) carbon atom, for example methyl, ethyl, 1-propyl group, 2-propyl group, 1-butyl, 2-butyl, 2-methyl-2-propyl group, 2-methyl isophthalic acid-propyl group and amyl group.

In another embodiment, compositions according to the present invention comprises dimethyl fumarate as active substance.

In another embodiment, compositions according to the present invention comprises fumaric acid monomethyl ester as active substance, is pharmaceutically acceptable salt form, for example its sodium, potassium, calcium, magnesium and/or zinc salt alternatively.

In another embodiment, form by dimethyl fumarate in essence according to compositions of the present invention as active substance.

In another embodiment, compositions according to the present invention is made up of the dimethyl fumarate as active substance.

In another embodiment, being made up of the monomethyl fumarate as active substance in essence according to compositions of the present invention, is pharmaceutically acceptable salt alternatively, for example its sodium, potassium, calcium, magnesium and/or zinc salt.

In another embodiment, compositions according to the present invention is made up of the monomethyl fumarate as active substance, is pharmaceutically acceptable salt alternatively, for example its sodium, potassium, calcium, magnesium and/or zinc salt.

In another embodiment, compositions according to the present invention comprises dimethyl fumarate and monomethyl fumarate (is pharmaceutically acceptable salt alternatively, for example its sodium, potassium, calcium, magnesium and/or zinc salt) as active substance, its weight ratio is between about 1: 10 and about 10: 1.

In another embodiment, according to compositions of the present invention (is pharmaceutically acceptable salt by dimethyl fumarate and monomethyl fumarate as active substance in essence alternatively, for example its sodium, potassium, calcium, magnesium and/or zinc salt) to form, its weight ratio is between about 1: 10 and about 10: 1.

In another embodiment, compositions according to the present invention (is a pharmaceutically acceptable salt by dimethyl fumarate and the monomethyl fumarate as active substance alternatively, for example its sodium, potassium, calcium, magnesium and/or zinc salt) to form, its weight ratio is between about 1: 10 and about 10: 1.

Beauty treatment and/or pharmaceutical composition

Problem solved by the invention relates to behind the fumarate oral administration and gastrointestinal side-effect occurs.Discharge from compositions by prolonging and/or postponing active substance, can imagine that active substance has reduced (with Fumaderm at the local concentration of gastrointestinal tract specific part ^Compare), and then cause the minimizing of gastrointestinal side-effect.Therefore, can prolong and/or delay the compositions that fumarate discharges as defined above and fall into scope of the present invention.

This based composition is that the technical staff knows, and for example comprises DIFFUSION CONTROLLED drug delivery system, the controlled drug delivery system of osmotic pressure, erosibility drug delivery system etc.And, there is Pharma Inc. can provide specific compositions based on particular technology (for example above-mentioned), have specific active substance release characteristic.Therefore, in a single day those skilled in the art recognize the particular demands about definite drug substance, will know the product how to obtain being fit to.For example, Eurand is that this class provides one of company of technical scheme, and purpose is to obtain controlled release pharmaceutical compositions, contains specific active substance, have the particular requirement that from compositions, discharges about active substance (for example referring to Http:// www.eurand.com).Another company is MacroMed, Inc., and it has been developed one and has involved so-called SQZgel ^TMTechnology ( Http:// macromed.com, SQZgel ^TMThe mechanism of action be the pH-sensitive polymer mixture that is associated with outside coating.In the sour environment of stomach, this polymer absorbs water and swelling, embedding medicinal.In case enter the higher intestinal of pH, the slow atrophy of this polymer perhaps with " dialed-in " speed compression, discharges active compound with continuous fashion), perhaps Egaleta/s, it have a specific class technology of extruding ( Http:// www.egalet.com, Egalet ^The key element of technology is biodegradable coating and substrate, comprises active medicine, and it is a corrodible surface, hydrophobic, is made up of the PEG-stearate.Egalet ^One of technology is 2K Egalet ^Constant delivery system, it is by coating and substrate composed 2-component production models.Medicine is uniformly distributed in Egalet ^Substrate, constant in time release.This paper also pays close attention to following technology, and for example (active medicine is laminated on the neutral core, and for example sugared ball, crystal or granule succeeded by speed-controlled functional membrane, are created the drug release curve to the technology Diffucaps of Eurand.The size of Diffucaps/Surecaps beadlet is less, the about 1mm of diameter or following.By to the beadlet of hard gelatin capsule in conjunction with the different pharmaceutical release profiles, can reach the combination release profiles), (the Diffutab technology combines the admixture of hydrophilic polymer to Diffutabs, it by substrate tablet diffusion and corrode control drug release), (EurandMinitabs is that small (tablet of 2mm * 2mm) contains the gel-generative nature excipient of control drug release speed to Minitabs.Can add additional film, with further sustained release speed), (this technology utilization limits the class pelletize and extrudes beadlet with spheroid metallization processes production controlled amount and density Orbexa.The gained beadlet can wrap with the rate of release controlling diaphragm, with further sustained release speed, and can be filled in the capsule or with the medicine bag form provides) and SDS (the SDS technology function of use polymer of Eurand or the combination of functional polymer and special additive, composite polymeric material for example, with along the intestinal delivering drugs to the optimal absorption position.For this reason, Eurand at first produces the multiparticulates dosage form, for example Diffucaps or Eurand Minitabs, and they are combined with active medicine.Then with these dosage form bags with pH dependency/independence polymeric membrane, with delivering drugs to desired area.Then they are filled in the hard gelatin capsule).

The technology that another kind is used to prepare according to compositions of the present invention is so-called MeltDose ^Technology, as described in the WO03/004001 (referring to Http:// www.lifecyclepharma.comMeltDose ^Involve and to be mixed with tablet through the individual molecule of solubilising.By preparing one molecule, eliminated the major limitation of drugs of low aqueous solubility oral absorption, can realize excellent bioavailability).By adopting this technology, might obtain being suitable for being processed into the microparticle material of various pharmaceutical dosage forms, for example the form of granule or tablet.In addition, this technology is fit to use, since the active substance release profiles that might obtain being fit to, those release profiles for example described herein.In one embodiment, the suitable granule that uses can have the mean diameter greater than 2000 μ m.In another embodiment, the suitable granule that uses can have the mean diameter of about 0.01 μ m to about 250 μ m.

It is to prepare in lipophillic environment that another kind is particularly suitable for using preparation principle in this article, for example Perle.A kind of suitable example of this preparation principle is that the Vegicaps Soft from Scherer (based on the soft capsule technology of carrageenin and starch, although be 100% plant origin, still provides all determinant attributes of traditional soft gelatine capsule.They comprise soft and flexible dosage form, swallow easily) (further information referring to Http:// www.rpscherer.de/page.php? pageID=94).

The particular instance of the preparation that another is fit to comprises active substance with the preparation of vitamin E concentrate in soft or hard gelatin capsule.The improved form of this preparation is commodity cyclosporin Neoral ^The basis, except cyclosporin, also especially contain Semen Maydis oil-list-two-triglyceride, polyoxy 40 castor oil hydrogenated NF, DL-alpha-tocopherol USP (part of vitamin E family), gelatin NF, glycerol, iron oxide black, propylene glycol USP, titanium dioxide USP, carmine and ethanol.

The particular instance of the preparation that another is fit to comprises active substance and ethanol, tocopherol ethylene glycol 1000 succinates (TPGS), Semen Maydis oil and the preparation of wax in soft or hard gelatin capsule.This product can be semisolid or solid dosage forms.The rate of release of this preparation depends on the Degradation of lipase in the intestinal.

Another formulation examples that is fit to comprises active substance and ethanol, tocopherol ethylene glycol 1000 succinates (TPGS), Semen Maydis oil and the preparation of polyglycolyzed glyceride (for example Gelucire) in soft or hard gelatin capsule.This product can be semisolid or solid dosage forms.The rate of release of this preparation depends on the Degradation of lipase in the intestinal.

Another formulation examples that is fit to is Orally taken pulsed dose drug delivery system.This dosage form can be regarded as the improved form of Schering Repetab tablet.The part present composition is placed in the label.

Label for example can be made by conventional wet granulation or continuous pelletize, for example extrudes succeeded by the granule compacting in flakes.Utilize suitable technology coatings then, enteric coated polymers, for example Eudragits are used in preferred air suspension.

First discharges dosage is crushed on the label, perhaps by the air suspension bag with enteric coating or wrap on the enteric coating.In a kind of invention embodiment, first discharge dosage by the air suspension bag with enteric coating.In another invention embodiment, first discharges dosage is crushed on the label, and purpose is to avoid compositions according to the present invention to discharge before the enteric coating degraded, and this class degraded usually occurs in than under the higher pH value in stomach chamber; That is to say that the degraded of enteric coating usually occurs in by after the stomach chamber.

Another formulation examples that is fit to is oral lasting drug delivery system.The part present composition is placed in the label.

Label for example can be made by conventional wet granulation or continuous pelletize, for example extrudes succeeded by the granule compacting in flakes.Utilize suitable technology coatings then, ethyl cellulose and hydrophilic excipient, for example hydroxypropyl cellulose (HPC) are used in preferred air suspension.

First discharges dosage is crushed on the label, perhaps by the air suspension bag with enteric coating or wrap on the enteric coating.In preferred invention embodiment, first discharge dosage by the air suspension bag with enteric coating.In another invention embodiment, first discharges dosage is crushed on the label, and purpose is to avoid compositions according to the present invention to discharge before the enteric coating degraded, and this class degraded usually occurs in than under the higher pH value in stomach chamber; That is to say that the degraded of enteric coating usually occurs in by after the stomach chamber.

Another formulation examples that is fit to obtains via crystal engineering, and for example WO03/080034 is described, quotes at this as a reference.

Therefore, in another embodiment, the present composition comprises the microcrystalline form active substance on possess hydrophilic property surface.In addition, in another kind of invention embodiment, crystallite is direct film coating, and purpose is to realize extended release preparation.

The particular instance of the preparation that another is fit to comprises the coordination compound according to compositions of the present invention and true cyclodextrin and cyclodextrin derivative (for example alkyl-and hydroxy alkyl-derivant or sulfo group butyl-derivant).Coordination compound is to realize according to the method for knowing.Imagine a kind of like this coordination compound and cause to compare before compositions according to the present invention and the ligand compound to have higher dissolubility and the rate of dissolution of Geng Gao.In addition, a kind of like this coordination compound of imagination causes to compare before compositions according to the present invention and the ligand compound to have higher bioavailability.

In specific embodiment, the present invention relates to controlled release pharmaceutical compositions, it can be administered once by every day, twice or repeatedly, for example once a day or twice or three times.In addition, compositions can be designed to be relatively independent of pH ground and discharge fumarate, that is to say to discharge the pH that does not rely in the gastrointestinal tract.The example of this based composition for example is the compositions (for example tablet, capsule, granule, beadlet etc.) of solid dosage form, and they are surrounded by controlled release coat.The material that is suitable for controlled release coat for example is cellulose and cellulose derivative, comprises methylcellulose, ethyl cellulose and cellulose acetate, perhaps poly-(ethylene-co-vinyl acetate), poly-(vinyl chloride).

Fumarate discharges from the compositions that is surrounded by the DIFFUSION CONTROLLED film and divides three steps to take place usually:

I) at first, (from the GI road) water diffuses into dosage form from surrounding,

Ii) secondly, at least some fumarates that are present in the dosage form are dissolved by the effect of water,

Iii) dissolved fumarate diffuses out from dosage form, enters surrounding (GI road just).

Other examples for example comprise substrate tablet or contain the unitary dosage form of the matrix system form of respectively doing for oneself in a large number.Active substance is embedded in the substrate, substrate for example contains cellulose and cellulose derivative, comprise microcrystalline Cellulose, hydroxypropyl emthylcellulose, hydroxypropyl cellulose and methylcellulose, polyvidone, poly-(oxygen ethylene) (PEO), Polyethylene Glycol (PEG), poly-(vinyl alcohol) (PVA), xanthan gum, carrageenin and other synthetic materials.Can add the material that under normal circumstances is used as pharmaceutically acceptable excipient or additive to base composition.

Other compositions examples that are fit to for example are hydrogels, just whole (monolithic) system, and wherein active substance is embedded in the water-swellable network polymer.The material that be fit to use for example comprises hydrophilic ethylene base and acrylate copolymer, polysaccharide, resembles alginate and poly-(oxygen ethylene).

In specific embodiment, the controlled release of pH (being also referred to as the pH dependent release) that compositions according to the present invention has fumarate.Under normal circumstances, release is designed to have only a small amount of (if any) fumarate to be released in stomach (pH about at the most 3), and fumarate is released in intestinal (pH becomes about 6-7).By enteric coating (whole compositionss are provided for the present composition, if perhaps compositions is the individual unit of multiparticulates compositions), perhaps, can obtain the controlled release of a kind of like this pH by providing by pH-dependency penetration mechanism or adopting the enzyme that is fit to discharge the compositions of fumaric acid.

The material example that is suitable as enteric coating material comprises polyacrylamide; Phthalic acid ester derivant, for example the acid phthalic acid ester of carbohydrate, acetic acid amylose phthalic acid ester, cellulose acetate phthalic acid ester, other cellulose esters phthalic acid esters, cellulose ether phthalic acid ester, hydroxypropyl cellulose phthalic acid ester, Cellulose ethyl hydroxypropyl ether phthalic acid ester, hydroxypropyl emthylcellulose phthalic acid ester, methylcellulose phthalic acid ester, polyvinyl acetate phthalic acid ester; The polyacrylic acid methacrylic acid copolymer; Lac; Vinyl acetate and .beta.-methylacrylic acid copolymer etc.

The compositions that the above-mentioned pH of having independence discharges also can be formulated into for example by provide outer enteric coating to discharge fumarate for compositions.

In addition, compositions formulated in such a way is to obtain the initial delay that fumarate discharges.For example by select with time-the degrade outermost layer coating of (for example corroding) of controlled mode, can obtain a kind of like this delay, and and if only if this outermost layer coating when being etched, the release of fumarate begins.

Provide various explanations according to compositions of the present invention below, the fumarate that they are designed to obtain to be fit to discharges.Based on the handbook in above-mentioned explanation and the medicine controlled releasing field, those skilled in the art will know how to select different preparation principles, and purpose is the release characteristics that reaches required.

Be designed to that be administered twice every day or compositions repeatedly

PH independence discharges

Provide the explanation of specific implementations below, wherein fumarate is released with being independent of pH, and wherein release mode is suitable for that be administered twice every day or compositions repeatedly.The preparation principle example that is fit to for example be the compositions, matrix particles or the substrate tablet that have diffusion coating, for example controlled release diffusion coating, hydrogel, pulsed dosage drug delivery system, with the common preparation of vitamin E concentrate or ethanol, TPGS, Semen Maydis oil and wax etc., comprise any above-mentioned preparation principle.

Therefore, the present invention relates to mouth on the one hand and uses controlled release pharmaceutical compositions, comprises one or more fumarates as active substance, is selected from two of fumaric acid-(C ₁-C ₅) the list-(C of Arrcostab and fumaric acid ₁-C ₅) Arrcostab or its pharmaceutically acceptable salt, wherein the release of fumarate when adopting water as the extracorporeal dissoluting test of dissolve medium is as follows:

In preceding 6 hours, the fumarate total amount that said composition contained has about 60%w/w to be released at the most after on-test, and for example about 30% to about 60%w/w, about 40% to about 55%w/w or about 50%w/w, and/or

In preceding 9 hours, the fumarate total amount that said composition contained has about 85%w/w to be released at the most after on-test, and for example about 50% to about 85%w/w, about 60% to about 80%w/w or about 75%w/w, and/or

After on-test in preceding 12 hours, the fumarate total amount that said composition contained has at least about 80%w/w to be released, for example approximately 80%w/w or above, about 85%w/w or above, about 90%w/w or above or about 95%w/w or more than, and/or

The fumarate total amount that compositions contained was released in preceding 12 hours after on-test.

The controlled release of pH

Provide the explanation of specific implementations below, wherein fumarate is released with depending on pH, and wherein release mode is suitable for that be administered twice every day or compositions repeatedly.The preparation principle example that is fit to for example is the compositions that has the described type hydrogels of (US 6,537,584) and Bae (US 5,484,610) such as enteric coating or Zentner, quotes at this as a reference.Other preparation principle example that are fit to for example be the compositions, matrix particles or the substrate tablet that have diffusion coating, for example controlled release diffusion coating, hydrogel, pulsed dosage drug delivery system, with the common preparation of vitamin E concentrate or ethanol, TPGS, Semen Maydis oil and wax etc.; comprise any above-mentioned preparation principle, have enteric coating alternatively.

Therefore, the present invention relates to mouth on the one hand and uses controlled release pharmaceutical compositions, comprises one or more fumarates as active substance, is selected from two of fumaric acid-(C ₁-C ₅) the list-(C of Arrcostab and fumaric acid ₁-C ₅) Arrcostab or its pharmaceutically acceptable salt, wherein the release of fumarate when carrying out extracorporeal dissoluting test is as follows, this test pro-adopts 0.1N hydrochloric acid as dissolve medium during 2 hours, then with 0.05M phosphate buffer pH6.5 or 6.8 as dissolve medium:

In preceding 2 hours, the total amount of fumarate has at least about 1%w/w to be released after on-test, for example about at least 2%w/w, about at least 3%w/w or about 5%w/w, and/or

In preceding 3 hours, the total amount of fumarate has about 35%w/w to be released at the most after on-test, and for example about 15% to about 35%w/w, about 20% to about 30%w/w or about 25%w/w, and/or

After on-test in preceding 3 hours, the total amount of fumarate have about 10% to about 70%w/w, about 10% to about 65%w/w, about 10% to about 60%w/w, about 15% to about 50%w/w, about 15% to about 35%w/w, about 20% to about 30%w/w or approximately 20%w/w or approximately 25%w/w be released, and/or

After on-test in preceding 4 hours, the total amount of fumarate has about 92%w/w to be released at the most, for example about 10% to about 92%w/w, about 20% to about 85%w/w, about 20% to about 80%w/w, about 20% to about 70%w/w, about 25% to about 60%w/w, about 25% to about 55%w/w, about 30% to about 50%w/w or approximately 35%w/w or approximately 40%w/w or approximately 45%w/w, and/or

After on-test in preceding 5 hours, the total amount of fumarate has about 94%w/w to be released at the most, for example about 15% to about 94%w/w, about 25% to about 90%w/w, about 30% to about 85%w/w, about 35% to about 80%w/w, about 35% to about 75%w/w, about 40% to about 70%w/w, about 45% to about 70%w/w, about 55% to about 70%w/w, about 60% to about 70%w/w or approximately 45%w/w or approximately 50%w/w or approximately 55%w/w or approximately 60%w/w or approximately 65%w/w, and/or

After on-test in preceding 6 hours, the fumarate total amount that said composition contained has about 95%w/w to be released at the most, for example about 35% to about 95%w/w, about 40% to about 90%w/w, about 45% to about 85%w/w, about 50% to about 85%w/w, about 55% to about 85%w/w, about 60% to about 85%w/w, about 65% to about 85%w/w, about 70% to about 85%w/w, about 75% to about 85%w/w or approximately 65%w/w or approximately 70%w/w or approximately 75%w/w or approximately 80%w/w, and/or

After on-test in preceding 7 hours, the fumarate total amount that said composition contained has about 98%w/w to be released at the most, for example about 45% to about 98%w/w, about 50% to about 98%w/w, about 55% to about 98%w/w, about 60% to about 98%w/w, about 65% to about 98%w/w, about 70% to about 98%w/w, about 75% to about 95%w/w, about 80% to about 95%w/w, about 85% to about 95%w/w or approximately 75%w/w or approximately 80%w/w or approximately 85%w/w or approximately 90%w/w, and/or

After on-test in preceding 9 hours, the fumarate total amount that said composition contained has about 99%w/w to be released at the most, and for example about 60% to about 99%w/w, about 70% to about 99%w/w, about 80% to about 99%w/w, about 90% to about 99%w/w or about 95%w/w.

The present invention provides mouth to use controlled release pharmaceutical compositions on the other hand, comprises one or more fumarates as active substance, is selected from two of fumaric acid-(C ₁-C ₅) the list-(C of Arrcostab and fumaric acid ₁-C ₅) Arrcostab or its pharmaceutically acceptable salt, it is characterized in that it is made up of controlled release form, when in 0.1N hydrochloric acid, measuring during 2 hours according to the USP pro-, in 0.05M phosphate buffer pH6.5 or 6.8 outside the measuring body during solubility curve, this dosage form is gone through the two-(C that the scheduled time discharges fumaric acid then ₁-C ₅) Arrcostab and/or list-(C ₁-C ₅) Arrcostab or its pharmaceutically acceptable salt,

The fumarate total amount that wherein compositions contained has 5%w/w to be released in preceding 2 hours after on-test at the most, and/or

The fumarate total amount that wherein compositions contained has about 20% to about 75%w/w to be released in preceding 3 hours after on-test, and/or

The fumarate total amount that wherein compositions contained has about 50% to about 90%w/w to be released in preceding 4 hours after on-test, and/or

The fumarate total amount that wherein compositions contained has about 60% to about 90%w/w to be released in preceding 5 hours after on-test, and/or

The fumarate total amount that wherein compositions contained has about 70% to about 95%w/w to be released in preceding 6 hours after on-test, and/or

The fumarate total amount that wherein compositions contained has about 75% to about 97%w/w to be released in preceding 7 hours after on-test.

The present invention provides mouth to use controlled release pharmaceutical compositions on the other hand, comprises one or more fumarates as active substance, is selected from two of fumaric acid-(C ₁-C ₅) the list-(C of Arrcostab and fumaric acid ₁-C ₅) Arrcostab or its pharmaceutically acceptable salt, it is characterized in that it is made up of controlled release form, when in 0.1N hydrochloric acid, measuring during 2 hours according to the USP pro-, in 0.05M phosphate buffer pH6.5 or 6.8 outside the measuring body during solubility curve, this dosage form is gone through the two-(C that the scheduled time discharges fumaric acid then ₁-C ₅) Arrcostab and/or list-(C ₁-C ₅) Arrcostab or its pharmaceutically acceptable salt, the fumarate total amount that wherein compositions contained has 5%w/w to be released in preceding 2 hours after on-test at the most, the fumarate total amount that wherein compositions contained has about 20% to about 75%w/w to be released in preceding 3 hours after on-test, the fumarate total amount that wherein compositions contained has about 50% to about 90%w/w to be released in preceding 4 hours after on-test, the fumarate total amount that wherein compositions contained has about 60% to about 90%w/w to be released in preceding 5 hours after on-test, the fumarate total amount that wherein compositions contained has about 70% to about 95%w/w to be released in preceding 6 hours after on-test, the fumarate total amount that wherein compositions contained has about 75% to about 97%w/w to be released in preceding 7 hours after on-test, and the fumarate total amount that wherein compositions contained has at least 85%w/w to be released in preceding 8 hours after on-test.

The present invention provides controlled release pharmaceutical compositions on the other hand, comprises one or more fumarates as active substance, is selected from two of fumaric acid-(C ₁-C ₅) the list-(C of Arrcostab and fumaric acid ₁-C ₅) Arrcostab or its pharmaceutically acceptable salt, it is characterized in that it is made up of controlled release form, when in 0.1N hydrochloric acid, measuring during 2 hours according to the USP pro-, in 0.05M phosphate buffer pH6.5 or 6.8 outside the measuring body during solubility curve, this dosage form is gone through the two-(C that the scheduled time discharges fumaric acid then ₁-C ₅) Arrcostab and/or list-(C ₁-C ₅) Arrcostab or its pharmaceutically acceptable salt,

The fumarate total amount that wherein compositions contained has about 20% to about 50%w/w to be released in preceding 3 hours after on-test, and/or

The fumarate total amount that wherein compositions contained has about 45% to about 70%w/w to be released in preceding 4 hours after on-test, and/or

The fumarate total amount that wherein compositions contained has about 65% to about 85%w/w to be released in preceding 5 hours after on-test, and/or

The fumarate total amount that wherein compositions contained has about 75% to about 90%w/w to be released in preceding 6 hours after on-test.

The present invention provides controlled release pharmaceutical compositions on the other hand, comprises one or more fumarates as active substance, is selected from two of fumaric acid-(C ₁-C ₅) the list-(C of Arrcostab and fumaric acid ₁-C ₅) Arrcostab or its pharmaceutically acceptable salt, it is characterized in that it is made up of controlled release form, when in 0.1N hydrochloric acid, measuring during 2 hours according to the USP pro-, in 0.05M phosphate buffer pH6.5 or 6.8 outside the measuring body during solubility curve, this dosage form is gone through the two-(C that the scheduled time discharges fumaric acid then ₁-C ₅) Arrcostab and/or list-(C ₁-C ₅) Arrcostab or its pharmaceutically acceptable salt, the fumarate total amount that wherein compositions contained has 5%w/w to be released in preceding 2 hours after on-test at the most, the fumarate total amount that wherein compositions contained has about 20% to about 50%w/w to be released in preceding 3 hours after on-test, the fumarate total amount that wherein compositions contained has about 45% to about 70%w/w to be released in preceding 4 hours after on-test, the fumarate total amount that wherein compositions contained has about 65% to about 85%w/w to be released in preceding 5 hours after on-test, the fumarate total amount that wherein compositions contained has about 75% to about 90%w/w to be released in preceding 6 hours after on-test, and the fumarate total amount that wherein compositions contained has at least 80%w/w to be released in preceding 7 hours after on-test.

The fumarate total amount that wherein compositions contained has about 50% to about 75%w/w to be released in preceding 3 hours after on-test, and/or

The fumarate total amount that wherein compositions contained has about 70% to about 90%w/w to be released in preceding 4 hours after on-test, and/or

The fumarate total amount that wherein compositions contained has about 80% to about 90%w/w to be released in preceding 5 hours after on-test.

The present invention provides controlled release pharmaceutical compositions on the other hand, comprises one or more fumarates as active substance, is selected from two of fumaric acid-(C ₁-C ₅) the list-(C of Arrcostab and fumaric acid ₁-C ₅) Arrcostab or its pharmaceutically acceptable salt, it is characterized in that it is made up of controlled release form, when in 0.1N hydrochloric acid, measuring during 2 hours according to the USP pro-, in 0.05M phosphate buffer pH6.5 or 6.8 outside the measuring body during solubility curve, this dosage form is gone through the two-(C that the scheduled time discharges fumaric acid then ₁-C ₅) Arrcostab and/or list-(C ₁-C ₅) Arrcostab or its pharmaceutically acceptable salt, the fumarate total amount that wherein compositions contained has 5%w/w to be released in preceding 2 hours after on-test at the most, the fumarate total amount that wherein compositions contained has about 50% to about 75%w/w to be released in preceding 3 hours after on-test, the fumarate total amount that wherein compositions contained has about 70% to about 90%w/w to be released in preceding 4 hours after on-test, the fumarate total amount that wherein compositions contained has about 80% to about 90%w/w to be released in preceding 5 hours after on-test, and the fumarate total amount that wherein compositions contained has at least about 90%w/w to be released in preceding 6 hours after on-test.

With the release of the pH of conversion gradually (" half variation " method)

" half variation " method is for enteric coating or continue to discharge prepared product specifically developed.This method per hour contains and replaces half dissolve medium (with the GI passage of simulation from duodenum to the slight conversion of ileum pH value) with the neutral dissolve medium of equal portions.This method is as described in the following table:

Time after the beginning (hour)	The ratio of simulated gastric fluid/simulated intestinal fluid (%)	PH value
Time after the beginning (hour)		PH value	0-1	100/0	1.3
1-2	50/50	2.4	0-1	100/0	1.3
1-2	50/50	2.4	2-3	25/75	6.2
3-4	12.5/87.5	6.8	2-3	25/75	6.2
3-4	12.5/87.5	6.8	4-5	6.25/93.75	7.1
5-6	～3/97	7.2	4-5	6.25/93.75	7.1
5-6	～3/97	7.2	6-7	～1/99	7.3
7-8	～0/100	7.3	6-7	～1/99	7.3

The composition of simulated gastric fluid for example can be referring to American Pharmacopeia (USP) 2005:

Is that 800 to 2500 units every mg protein purification pepsin is dissolved in 7.0mL hydrochloric acid and enough water with 2.0g NaCl and 3.2g from Gaster Sus domestica mucosa, activity, to 1000mL.Gained testing liquid has about 1.2 pH.

The composition of another kind of simulated gastric fluid is referring to German E DIN 19738 (DeutscheIndustrie Norm):

100mL is synthetic/and simulated gastric fluid contains 290mg NaCl, 70mg KCl, 27mg KH ₂PO ₄With capacity HCl, to regulate pH to 2.0.In addition, it contains 100mg pepsin and 300mg mucin.

The composition of simulated intestinal fluid for example can be referring to American Pharmacopeia (USP) 2005:

The 6.8g potassium dihydrogen phosphate is dissolved in 250mL water.Mix, add 77mL 0.2N sodium hydroxide and 500mL water.Add the 10.0g pancreatin, mix this solution, adding 0.2N sodium hydroxide or 0.2N hydrochloric acid adjusting pH is 6.8 ± 0.1.The gained solution with water is diluted to 1000mL.

The composition of another kind of simulated intestinal fluid is referring to German E DIN 19738 (DeutscheIndustrie Norm):

100mL is synthetic/and simulated intestinal fluid contains 30mg KCl, 50mg CaCl ₂, 20mg MgCl ₂With capacity NaHCO ₃, to regulate pH to 7.5.In addition, it contains 30mg trypsin, 900mg pancreatin, 900mg lyophilizing bile and 30mg carbamide.

In preferred implementation of the present invention, the utilization of " half variation " method is carried out as USP 2005 defined simulated gastric fluid and simulated intestinal fluid.

In another embodiment of the invention, the utilization of " half variation " method is carried out as USP 2005 defined simulated gastric fluid and simulated intestinal fluid, but there is not protein (just in simulated gastric fluid, do not have pepsin, in simulated intestinal fluid, do not have pancreatin).

Therefore, the present invention relates to mouth on the one hand and uses controlled release pharmaceutical compositions, comprises one or more fumarates as active substance, is selected from two of fumaric acid-(C ₁-C ₅) the list-(C of Arrcostab and fumaric acid ₁-C ₅) Arrcostab or its pharmaceutically acceptable salt, wherein fumarate is as follows according to " half variation " release when method is carried out extracorporeal dissoluting test:

After on-test in preceding 3 hours, the total amount of fumarate have about 20% to about 40%w/w, about 20% to about 35%w/w or approximately 30%w/w be released, and/or

After on-test in preceding 3 hours, the total amount of fumarate has at least about 12%w/w to be released, for example about 12% to about 50%w/w, about 15% to about 45%w/w, about 20% to about 40%w/w, about 20% to about 35%w/w, about 22% to about 35%w/w or approximately 25%w/w or approximately 30%w/w, and/or

After on-test in preceding 4 hours, the total amount of fumarate have about 25% to about 40%w/w, about 30% to about 40%w/w or approximately 40%w/w be released, and/or

In preceding 4 hours, the total amount of fumarate has at least about 76%w/w to be released after on-test, and for example about 76% to about 95%w/w, about 80% to about 90%w/w or approximately 80%w/w or approximately 85%w/w, and/or

After on-test in preceding 4 hours, the total amount of fumarate has about 40%w/w to be released at the most, for example about 10% to about 40%w/w, about 15% to about 35%w/w, about 20% to about 30%w/w or approximately 25%w/w or approximately 30%w/w, and/or

After on-test in preceding 6 hours, the fumarate total amount that said composition contained has at least about 81%w/w to be released, for example about 81% to about 96%w/w, about 85% to about 95%w/w, about 85% to about 90%w/w or approximately 80%w/w or approximately 85%w/w or approximately 90%w/w, and/or

After on-test in preceding 6 hours, the fumarate total amount that said composition contained has about 50%w/w to be released at the most, for example about 20% to about 50%w/w, about 25% to about 45%w/w, about 30% to about 45%w/w or approximately 40%w/w or approximately 45%w/w, and/or

After on-test in preceding 7 hours, the fumarate total amount that said composition contained has at least about 82%w/w to be released, for example about 82% to about 99%w/w, about 85% to about 99%w/w, about 85% to about 95%w/w or about 90%w/w, and/or

After on-test in preceding 7 hours, the fumarate total amount that said composition contained has about 65%w/w to be released at the most, for example about 25% to about 65%w/w, about 30% to about 65%w/w, about 35% to about 60%w/w, about 40% to about 60%w/w, about 50% to about 60%w/w or approximately 55%w/w or approximately 60%w/w, and/or

In preceding 8 hours, the fumarate total amount that said composition contained has about 85%w/w to be released at the most after on-test, and for example about 50% to about 85%w/w, about 60% to about 80%w/w or about 75%w/w, and/or

After on-test in preceding 8 hours, the fumarate total amount that said composition contained has about 92%w/w to be released at the most, for example about 30% to about 92%w/w, about 35% to about 90%w/w, about 40% to about 85%w/w, about 45% to about 80%w/w, about 50% to about 75%w/w, about 55% to about 75%w/w, about 60% to about 75%w/w or approximately 65%w/w or approximately 70%w/w, and/or

In preceding 12 hours, the fumarate total amount that said composition contained has at least about 80%w/w to be released after on-test, for example approximately 80%w/w or above, about 85%w/w or above, about 90%w/w or above or about 95%w/w or more than.

Slowly discharge

Provide the explanation of specific implementations below, wherein fumarate with slowly or the mode that postpones be released, wherein release mode is suitable for that be administered twice every day or compositions repeatedly.The preparation principle example that is fit to be above-mentioned arbitrarily those.

In preceding 6 hours, the fumarate total amount that said composition contained has about 35%w/w to be released at the most after on-test, and for example about 15% to about 35%w/w, about 20% to about 30%w/w or about 25%w/w, and/or

In preceding 8 hours, the fumarate total amount that said composition contained has about 60%w/w to be released at the most after on-test, and for example about 30% to about 60%w/w, about 40% to about 55%w/w or about 50%w/w, and/or

In preceding 10 hours, the fumarate total amount that said composition contained has about 85%w/w to be released at the most after on-test, and for example about 50% to about 85%w/w, about 60% to about 80%w/w or about 75%w/w, and/or

Be designed to the compositions that is administered once every day

PH independence discharges

Provide the explanation of specific implementations below, wherein fumarate is released with being independent of pH, and wherein release mode is suitable for the compositions that is administered once every day.The preparation principle example that is fit to for example be the compositions, matrix particles or the substrate tablet that have diffusion coating, for example controlled release diffusion coating, hydrogel, pulsed dosage drug delivery system, with the common preparation of vitamin E concentrate or ethanol, TPGS, Semen Maydis oil and wax etc., comprise any above-mentioned preparation principle.

In preceding 9 hours, the fumarate total amount that said composition contained has about 60%w/w to be released at the most after on-test, and for example about 30% to about 60%w/w, about 40% to about 55%w/w or about 50%w/w, and/or

In preceding 13.5 hours, the fumarate total amount that said composition contained has about 85%w/w to be released at the most after on-test, and for example about 50% to about 85%w/w, about 60% to about 80%w/w or about 75%w/w, and/or

After on-test in preceding 18 hours, the fumarate total amount that said composition contained has at least about 80%w/w to be released, for example approximately 80%w/w or above, about 85%w/w or above, about 90%w/w or above or about 95%w/w or more than, and/or

The fumarate total amount that compositions contained was released in preceding 18 hours after on-test.

The controlled release of pH

Provide the explanation of specific implementations below, wherein fumarate is released with depending on pH, and wherein release mode is suitable for the compositions that is administered once every day.The preparation principle example that is fit to for example is the compositions that has the described type hydrogels of (US 6,537,584) and Bae (US5,484,610) such as enteric coating or Zentner.Other preparation principle example that are fit to for example be the compositions, matrix particles or the substrate tablet that have diffusion coating, for example controlled release diffusion coating, hydrogel, pulsed dosage drug delivery system, with the common preparation of vitamin E concentrate or ethanol, TPGS, Semen Maydis oil and wax etc.; comprise any above-mentioned preparation principle, have enteric coating alternatively.

After on-test in preceding 4 hours, the total amount of fumarate has about 90%w/w to be released at the most, for example about 5% to about 90%w/w, about 5% to about 85%w/w, about 10% to about 80%w/w, about 10% to about 70%w/w, about 10% to about 65%w/w, about 10% to about 60%w/w, about 15% to about 50%w/w, about 15% to about 35%w/w, about 20% to about 30%w/w or approximately 20%w/w or approximately 25%w/w, and/or

In preceding 4.5 hours, the total amount of fumarate has about 35%w/w to be released at the most after on-test, and for example about 15% to about 35%w/w, about 20% to about 30%w/w or about 25%w/w, and/or

After on-test in preceding 5 hours, the total amount of fumarate has about 92%w/w to be released at the most, for example about 10% to about 92%w/w, about 20% to about 85%w/w, about 20% to about 80%w/w, about 20% to about 70%w/w, about 25% to about 60%w/w, about 25% to about 55%w/w, about 30% to about 50%w/w or approximately 35%w/w or approximately 40%w/w or approximately 45%w/w, and/or

After on-test in preceding 6 hours, the total amount of fumarate has about 94%w/w to be released at the most, for example about 15% to about 94%w/w, about 25% to about 90%w/w, about 30% to about 85%w/w, about 35% to about 80%w/w, about 35% to about 75%w/w, about 40% to about 70%w/w, about 45% to about 70%w/w, about 55% to about 70%w/w, about 60% to about 70%w/w or approximately 45%w/w or approximately 50%w/w or approximately 55%w/w or approximately 60%w/w or approximately 65%w/w, and/or

After on-test in preceding 7 hours, the fumarate total amount that said composition contained has about 95%w/w to be released at the most, for example about 35% to about 95%w/w, about 40% to about 90%w/w, about 45% to about 85%w/w, about 50% to about 85%w/w, about 55% to about 85%w/w, about 60% to about 85%w/w, about 65% to about 85%w/w, about 70% to about 85%w/w, about 75% to about 85%w/w or approximately 65%w/w or approximately 70%w/w or approximately 75%w/w or approximately 80%w/w, and/or

After on-test in preceding 9 hours, the fumarate total amount that said composition contained has about 98%w/w to be released at the most, for example about 45% to about 98%w/w, about 50% to about 98%w/w, about 55% to about 98%w/w, about 60% to about 98%w/w, about 65% to about 98%w/w, about 70% to about 98%w/w, about 75% to about 95%w/w, about 80% to about 95%w/w, about 85% to about 95%w/w or approximately 75%w/w or approximately 80%w/w or approximately 85%w/w or approximately 90%w/w, and/or

After on-test in preceding 12 hours, the fumarate total amount that said composition contained has about 99%w/w to be released at the most, for example about 60% to about 99%w/w, about 70% to about 99%w/w, about 80% to about 99%w/w, about 90% to about 99%w/w or about 95%w/w, and/or

In preceding 13.5 hours, the fumarate total amount that said composition contained has about 85%w/w to be released at the most after on-test, and for example about 50% to about 85%w/w, about 60% to about 80%w/w or about 75%w/w.

With the release of the pH of conversion gradually (" half variation " method)

Provide the explanation of specific implementations below, wherein fumarate is released with depending on pH, and wherein release mode is suitable for the compositions that is administered once every day.The preparation principle example that is fit to for example is the compositions that has the described type hydrogels of (US 6,537,584) and Bae (US5,484,610) such as enteric coating or Zentner, quotes at this as a reference.Other preparation principle example that are fit to for example be the compositions, matrix particles or the substrate tablet that have diffusion coating, for example controlled release diffusion coating, hydrogel, pulsed dosage drug delivery system, with the common preparation of vitamin E concentrate or ethanol, TPGS, Semen Maydis oil and wax etc.; comprise any above-mentioned preparation principle, have enteric coating alternatively.

After on-test in preceding 3 hours, the total amount of fumarate has at least about 12%w/w to be released, for example about 12% to about 60%w/w, about 15% to about 50%w/w, about 20% to about 40%w/w, about 20% to about 35%w/w or approximately 25%w/w or approximately 30%w/w, and/or

In preceding 4 hours, the total amount of fumarate has about 35%w/w to be released at the most after on-test, and for example about 15% to about 35%w/w, about 20% to about 30%w/w or about 25%w/w, and/or

After on-test in preceding 5 hours, the total amount of fumarate has about 45%w/w to be released at the most, for example about 10% to about 45%w/w, about 15% to about 40%w/w, about 15% to about 35%w/w, about 20% to about 30%w/w or approximately 25%w/w or approximately 30%w/w, and/or

After on-test in preceding 7 hours, the total amount of fumarate has about 65%w/w to be released at the most, for example about 20% to about 65%w/w, about 20% to about 60%w/w, about 20% to about 50%w/w, about 25% to about 45%w/w, about 30% to about 45%w/w or approximately 40%w/w or approximately 45%w/w, and/or

After on-test in preceding 8 hours, the fumarate total amount that said composition contained has about 92%w/w to be released at the most, for example about 25% to about 92%w/w, about 25% to about 90%w/w, about 30% to about 80%w/w, about 35% to about 70%w/w, about 40% to about 65%w/w, about 45% to about 60%w/w, about 50% to about 60%w/w or approximately 55%w/w or approximately 60%w/w, and/or

After on-test in preceding 12 hours, the fumarate total amount that said composition contained has about 99%w/w to be released at the most, for example about 30% to about 99%w/w, about 30% to about 95%w/w, about 35% to about 90%w/w, about 40% to about 85%w/w, about 45% to about 80%w/w, about 50% to about 75%w/w, about 55% to about 75%w/w, about 60% to about 75%w/w or approximately 65%w/w or approximately 70%w/w, and/or

In preceding 12.5 hours, the fumarate total amount that said composition contained has about 85%w/w to be released at the most after on-test, and for example about 50% to about 85%w/w, about 60% to about 80%w/w or about 75%w/w, and/or

In preceding 18 hours, the fumarate total amount that said composition contained has at least about 80%w/w to be released after on-test, for example approximately 80%w/w or above, about 85%w/w or above, about 90%w/w or above or about 95%w/w or more than.

Slowly discharge

Provide the explanation of specific implementations below, wherein fumarate with slowly or the mode that postpones be released, wherein release mode is suitable for the compositions that is administered once every day.The preparation principle example that is fit to be above-mentioned arbitrarily those.

In preceding 7 hours, the fumarate total amount that said composition contained has about 35%w/w to be released at the most after on-test, and for example about 15% to about 35%w/w, about 20% to about 30%w/w or about 25%w/w, and/or

In preceding 11 hours, the fumarate total amount that said composition contained has about 60%w/w to be released at the most after on-test, and for example about 30% to about 60%w/w, about 40% to about 55%w/w or about 50%w/w, and/or

In preceding 14 hours, the fumarate total amount that said composition contained has about 85%w/w to be released at the most after on-test, and for example about 50% to about 85%w/w, about 60% to about 80%w/w or about 75%w/w, and/or

Usually, as mentioned above, compositions according to the present invention is designed to extension system delivery of active substances (just the mono alkyl ester of fumaric acid, it is metabolised to fumaric acid then, eliminates process subsequently rapidly).Except the feature of release in vitro pattern described herein, a kind of like this prolongation discharges and also is reflected in after the clinical research in the gained pharmacokinetic parameters.Therefore, the C of the mono alkyl ester of imagination fumaric acid (after the hydrolysis of the dialkyl that is given or metabolism, appearing in the blood plasma) _MaxBe in the identical order of magnitude with former document is described, (that is to say the C of monomethyl fumarate as long as give similar or equal dosage _MaxIn about scope of 0.4 to about 2.0mg/L, be equivalent to the oral dose of 120 to 240mg dimethyl fumarates).But, for fear of repeatedly frequent administration every day (2-4 sheet, every day 1-3 time), have a mind to time expand, wherein concentration is in the treatment window.Therefore, imagination W ₅₀(just wherein plasma concentration is C _Max50% or above time) prolonged at least 10% than commercially available treatment, for example at least 20%, at least 30%, at least 40% or at least 50%.The W that is fit to ₅₀Believe it is at least 2 hours, for example about 2 to about 15 hours or about 2.5 to about 10 hours or about 3 to about 8 hours scope.

In addition, imagination can reduce between the individuality of curve of blood plasma and/or difference in individual according to controlled release composition of the present invention, the dependency whether minimizing takes with food for compositions (when give pharmaceutical composition with or when not having food intake, reduce the difference of monomethyl fumarate plasma concentration curve).Therefore, can reduce the frequency and/or minimizing average every day always of the dosage of taking medicine according to controlled release composition of the present invention, and/or and Fumaderm ^Compare the active substance effect that is increased under identical total every day of the dosage.

Different kinetic models can be applied to explain drug release kinetics, for example; Zero level (1), one-level (2), square root (Higuchi equation).

1：M _t＝M ₀+k ₀*t

2：lnM _t＝lnM+k ₁*t

3：M _t＝M ₀+k _H*t ^1/2

In these equations, M _tBe the cumulant that means the medicine of fixing time a little to be discharged in office, M ₀Be in the pharmaceutical composition the dosage of bonded active substance, k ₀, k ₁And k _HIt is respectively the speed constant of zero level, one-level and Higuchi equation.

The present invention relates to zero level dissolving release profiles on the one hand.Relate to one-level dissolving release profiles on the other hand.Relate to square root (Higuchi equation) dissolving release profiles on the other hand.

The present invention provides controlled release pharmaceutical compositions on the one hand, comprises one or more fumarates as 10 to 90 weight % of active substance, is selected from two of fumaric acid-(C ₁-C ₅) the list-(C of Arrcostab and fumaric acid ₁-C ₅) Arrcostab or its pharmaceutically acceptable salt, the pharmaceutically acceptable polymer of 2 to 40 weight % and the hydrophilic excipient of 1 to 40 weight % are alternatively with pharmaceutically acceptable excipient or additive.

The present invention provides controlled release pharmaceutical compositions on the other hand, comprises one or more fumarates as 40 to 60 weight % of active substance, is selected from two of fumaric acid-(C ₁-C ₅) the list-(C of Arrcostab and fumaric acid ₁-C ₅) Arrcostab or its pharmaceutically acceptable salt, the pharmaceutically acceptable polymer of 15 to 25 weight % and the hydrophilic excipient of 2 to 15 weight % are alternatively with pharmaceutically acceptable excipient or additive.

The present invention provides controlled release pharmaceutical compositions on the other hand, comprises one or more fumarates as 65 to 80 weight % of active substance, is selected from two of fumaric acid-(C ₁-C ₅) the list-(C of Arrcostab and fumaric acid ₁-C ₅) Arrcostab or its pharmaceutically acceptable salt, the pharmaceutically acceptable polymer of 10 to 25 weight % and the hydrophilic excipient of 2 to 15 weight % are alternatively with pharmaceutically acceptable excipient or additive.

The example of " pharmaceutically acceptable polymer " is including but not limited to ethyl cellulose or methacrylate/acrylic copolymer, for example ammonio methacrylate copolymer A type and Type B or methacrylic acid copolymer A and B.

The example of " hydrophilic excipient " is including but not limited to Polyethylene Glycol (PEG), polyvidone, hydroxypropyl cellulose (HPC), hetastarch (HES) or hydroxypropyl emthylcellulose (HPMC) or material with similar quality, perhaps their combination.

The present invention provides controlled release pharmaceutical compositions on the other hand, and wherein this pharmaceutically acceptable polymer is an ethyl cellulose.

The present invention provides controlled release pharmaceutical compositions on the other hand, and wherein this hydrophilic excipient is a hydroxypropyl cellulose.

The present invention provides controlled release pharmaceutical compositions on the other hand, and wherein this hydrophilic excipient is a Polyethylene Glycol.

The present invention provides controlled release pharmaceutical compositions on the other hand, comprises one or more fumarates as 10 to 90 weight % of active substance, is selected from two of fumaric acid-(C ₁-C ₅) the list-(C of Arrcostab and fumaric acid ₁-C ₅) methacrylic acid copolymer A and the B of Arrcostab or its pharmaceutically acceptable salt and 2 to 40 weight %, weight ratio is between 1: 9 and 9: 1, alternatively with pharmaceutically acceptable excipient or additive.

The present invention provides controlled release pharmaceutical compositions on the other hand, comprise 50 to 90 weight % one or more fumarates, be selected from two of fumaric acid-(C ₁-C ₅) the list-(C of Arrcostab and fumaric acid ₁-C ₅) Arrcostab or its pharmaceutically acceptable salt.

Various controlled release preparations are described below, and they do not limit the scope of the invention, only for setting forth invention (all concentration are all based on final tablet):

1) granule

Granule can be prepared as follows, and mixes and/or the pelletize active substance, and concentration about 10 is to about 90%, especially about 50 to about 70%, with the pelletize excipient, and for example pharmaceutically acceptable polymer, for example ethyl cellulose, for example Ethocel ^NF premium, perhaps methacrylate/acrylic copolymer, for example ammonio methacrylate copolymer A type and Type B (weight ratio is 1: 9 to 9: 1) or methacrylic acid copolymer A and B (weight ratio is 1: 9 to 9: 1), the bonded concentration of institute is between about 2 to about 40%.Can be combined with hydrophilic excipient, for example Polyethylene Glycol (PEG), polyvidone, hydroxypropyl cellulose (HPC), hetastarch (HES) or hydroxypropyl emthylcellulose (HPMC), concentration about 1 to about 40%, and/or pharmaceutically acceptable surfactant, the HLB value is more than 8, concentration about 0.01 to about 3%.

2) crystallite preparation

In the organic solvent that is suitable for recrystallization arbitrarily, carry out crystallization, isopropyl alcohol for example, suitable temperature is for example between+70 ℃ and-20 ℃.Can use the hydrocolloid (for example HPMC) or the surfactant (for example polysorbate) of debita spissitudo, to control the growth of crystal during recrystallization.Can use any pelletize/coating excipient, for example pharmaceutically acceptable polymer, for example ethyl cellulose, concentration about 10 to about 50%, especially about 20 to about 35%, polyisobutylene acid esters, for example ammonio methacrylate copolymer A type and Type B or methacrylic acid copolymer A and B.As hydrophilic excipient, can mention for example PEG 400.

3) capsule and medicine bag agent

Can fill coating crystallite or coated granule to capsule (for example capsule of gelatin, HPMC or starch derivatives) or medicine bag, if necessary also have an amount of filling excipient, sugar alcohol for example, for example mannitol, and/or fluidizer.

4) tablet

Tablet can be based on crystallite or granule.When the large-scale production tablet, especially on whirler, may need other excipient, to increase fluid ability or to improve the tabletting behavior.As filling and bonding excipient, if necessary, can mention for example microcrystalline Cellulose, for example Avicel ^102, and cellulose, concentration about 1 is to about 60%, through the crystallinity lactose monohydrate of spray drying or pelletize, for example Tablettose ^, and Lactis Anhydrous monohydrate, concentration about 5 is to about 60%, sugar alcohol, for example Sorbitol and mannitol, concentration about 0 is to about 40%, and modified starch, concentration about 0 to about 40%.In addition, can add disintegrating agent, for example starch and starch derivatives, Explotab (concentration about 0.2 to about 10%) for example, polyvinylpolypyrrolidone (concentration about 0.2 to about 10%), sodium carboxymethyl cellulose (concentration about 0.1 to about 10%), fluidizer, for example colloid is anhydrous and aqueous silicon dioxide (concentration about 0.2 to about 4%), and lubricant, for example magnesium stearate, behenic acid calcium and arachidic acid calcium (concentration about 0.2 to about 3%) or sodium stearyl fumarate (concentration about 1 to about 8%).

Dosage

Except the compositions with different fumaric acid content was provided, the present invention also provided the medicine box that for example contains two or more containers, for example accommodated the compositions that comprises various fumaric acid content.This class medicine box is suitable for use in need be increased in the situation of dosage in time.Provide conventional dosage specification below:

Week	Morning	Noon	Evening	Intensity
Week	Morning	Noon	Evening	Intensity	1	1	-	-	A
2	1	-	1	A	1	1	-	-	A
2	1	-	1	A	3	1	-	1	B
4	1	-	-	B	3	1	-	1	B
4	1	-	-	B	5	1	-	1	B
6	1	1	1	B	5	1	-	1	B
6	1	1	1	B	7	2	1	1	B
8	2	1	2	B	7	2	1	1	B
8	2	1	2	B	9	2	2	2	B

A is equivalent to low-intensity, for example about 30mg dimethyl fumarate (the perhaps another kind of fumarate of corresponding effective dose).

B is equivalent to high strength, for example about 120mg dimethyl fumarate (the perhaps another kind of fumarate of corresponding effective dose).

The present invention provides controlled release pharmaceutical compositions on the one hand, wherein one or more fumarates, be selected from two of fumaric acid-(C ₁-C ₅) the list-(C of Arrcostab and fumaric acid ₁-C ₅) Arrcostab or the amount of its pharmaceutically acceptable salt in dosage form be 90mg to 360mg active substance, for example 90,120,180,240 or the 360mg active substance.In another aspect of this invention, the amount of active substance is 120,180 or the 240mg active substance.In another aspect of this invention, the amount of active substance is 180 or 360mg.

Dosage every day according to controlled release pharmaceutical compositions drug treatment patient of the present invention depends on some factors, wherein comprises the cause of disease of body weight, age and the disease that will treat or disease without limitation, and the doctor has the ability to determine it.In one aspect of the invention, every day, dosage can be 240 to 360mg active substances for example, divide and give for one to three time, 360 to 480mg active substances on the other hand, divide and give for one to three time, 480 to 600mg active substances on the other hand, divide to give for one to three time, 600 to 720mg active substances divide to give for one to three time on the other hand, 720 to 840mg active substances on the other hand, divide to give for one to three time, 840 to 960mg active substances divide to give for one to three time on the other hand, 960 to 1080mg active substances divide to give for one to three time on the other hand.

In one aspect of the invention, controlled release pharmaceutical compositions is capsular form.

The present invention provides the controlled release pharmaceutical compositions of tablet form on the other hand, and for example shape makes it easily and be suitably the tablet that the patient swallows, and for example circular or excellent sample shape is without any sharp-pointed edge.

The present invention provides the pharmaceutical composition of tablet form on the other hand, and it is designed to be divided into two or more parts.

Can be according to compositions of the present invention with meals or administration before and after the meals, for example at before the meals about at least 30 minutes after meals about 2 hours, perhaps any specific time point gave compositions in whole day.

In one embodiment, h.d. give total every day dosage, for example before going to bed at the most or about 30 minutes, before going to bed at the most or about 60 minutes, before going to bed at the most or about 90 minutes, before going to bed at the most or about 120 minutes or before going to bed at the most or about 180 minutes.

Be envisaged as according to compositions of the present invention and medicine box and be suitable for treating one or more following diseases:

A. psoriasis

B. arthritic psoriasis

C. neural dermatitis

D. inflammatory bowel, for example

I. Crohn disease

Ii. ulcerative colitis

E. autoimmune disease:

I. polyarthritis

Ii. multiple sclerosis (MS)

Iii. the diabetes of teenager outbreak

Iv. struma lymphomatosa

V. Ge Leifushi disease

Vi.SLE (systemic lupus erythematosus (sle))

Vii. siogren's syndrome

Viii. pernicious anemia

Ix. chronic active type (lupoid acne) hepatitis

X. rheumatoid arthritis (RA)

Xi. optic neuritis

And, can be used for the treatment of according to novel composition of the present invention or medicine box

1. pain, for example nerve root pain, pain, neuropathy pain or the sciatic nerve/ischium pain relevant with radiculopathy

2. organ transplantation (prevention of repulsion)

3. sarcoidosis

4. necrobiosis lipoidica

5. granuloma annulare

Psoriasis has been suggested may be relevant with following disease: Crohn disease (Najarian DJ, Gottlieb AB, Connections between psoriasis and Crohn ' s disease.J Am Acad Dermatol.2003 Jun; 48 (6): 805-21), coeliac disease (OjettiV et al, High prevalence of celiac disease in psoriasis.Am JGastroenterol.2003 Nov; 98 (11): 2574-5), spirit or mental illness (for example depression or Midlife crisis) (Gupta MA, Gupta AK, Psychiatric andpsychological co-morbidity in patients with dermatologicdisorders:epidemiology and management.Am J Clin Dermatol.2003; 4 (12): 833-42.and Mallbris L et al, Psoriasis phenotypeat disease onset:clinical characterization of 400 adult cases.J Invest Dermatol.2005 Mar; 124 (3): 499-504), the excessive consumption/alcoholism and the arthritic psoriasis of overweight, diabetes, ethanol.

The present invention thereby relate to the treatment psoriasis on the one hand, arthritic psoriasis, neural dermatitis, inflammatory bowel (for example Crohn disease and ulcerative colitis), autoimmune disease (polyarthritis for example, multiple sclerosis (MS), the diabetes of teenager outbreak, struma lymphomatosa, the Ge Leifushi disease, SLE (systemic lupus erythematosus (sle)), siogren's syndrome, pernicious anemia, chronic active type (lupoid acne) hepatitis, rheumatoid arthritis (RA) and optic neuritis), pain (nerve root pain for example, the pain relevant with radiculopathy, neuropathy pain or sciatic nerve/ischium pain), organ transplantation (prevention of repulsion), sarcoidosis, the method of necrobiosis lipoidica or granuloma annulare, this method comprise to patient's orally give effective dose that needs are arranged according to controlled release pharmaceutical compositions of the present invention.

The present invention relates to the purposes that controlled release pharmaceutical compositions according to the present invention prepares medicine on the other hand, and this medicine is used for the treatment of psoriasis, arthritic psoriasis, neural dermatitis, inflammatory bowel (for example Crohn disease and ulcerative colitis), autoimmune disease (polyarthritis for example, multiple sclerosis (MS), the diabetes of teenager outbreak, struma lymphomatosa, the Ge Leifushi disease, SLE (systemic lupus erythematosus (sle)), siogren's syndrome, pernicious anemia, chronic active type (lupoid acne) hepatitis, rheumatoid arthritis (RA) and optic neuritis), pain (nerve root pain for example, the pain relevant with radiculopathy, neuropathy pain or sciatic nerve/ischium pain), organ transplantation (prevention of repulsion), sarcoidosis, necrobiosis lipoidica or granuloma annulare.

In addition, the present invention also relates to use according to compositions of the present invention or medicine box and treat the individuality of suffering from one of above-mentioned disease, more specifically is psoriasis or arthritic psoriasis, and described individuality is further accepted following treatment:

A) local psoriasis medicine, for example 1) vitamin D or derivatives thereof (bone calitriol, bone calcium triolefin), 2) corticosteroid, for example betamethasone, desoximetasone, fluocinolone acetonide, Mo Meitasong, hydrogen hydrocortisone aceponate, fluticasone, clobetasol, clobetasone, hydrocortisone butyrate, desonide, triamcinolone or hydrocortisone, 3) tazaroten, 4) ditranol, 5) tacrolimus (FK-506), with other calcineurin inhibitor, pimecrolimus for example, perhaps 6) combination of 1-5 arbitrarily, and/or

B) oral psoriasis medicine, for example 1) oral retinoic acid-like, for example acitretin or etretinate, combination or do not made up PUVA, 2) cyclosporin and other calcineurin inhibitor, for example ISA247, tacrolimus and pimecrolimus, 3) methotrexate, 4) hydroxyurea, 5) azathioprine, 6) sulfasalazine, 7) fumarate derivative, for example Fumaderm ^Or BG-12,8) rosiglitazone (Avandia) and other peroxisome proliferation-activation-γ (PPAR γ) agonist or adjusting control agent, pioglitazone for example, farglitazar, GW1929, GW7845, MC-555, MBX-102/MBX-10, MBX-1828, MBX-2044, CLX-0921, R-483, reglitazar, naveglitazar (LY-519818/LY-818), netoglitazone (MCC-555), CS-7017, troglitazone, Xi Gelie ketone, tesaglitazar, isaglitazone, balaglitazone, muraglitazar, TAK-654, LBM642, DRF4158, EML4156, T-174, TY-51501, TY-12780, VDO-52 or AMG-131 (T131), the perhaps combination of 1-8 arbitrarily, and/or

C) the psoriasis medicine of parenteral, for example 1) alefacept (Amevive), 2) etanercept (Enbrel), 3) efalizumab (Raptiva), 4) onercept, 5) adalimumab (Humira), the perhaps combination of 1-5 arbitrarily, and/or

D) at last joint c) under the TNF-alpha inhibitor (for example CDP 870 or infliximab (Remicade)) do not mentioned, via enteral or parenteral route administration, and/or

E) tisocalicitrate and/or NCX 1022 and/or IDEC-131 and/or MEDI-507, and/or

F) NSAID or COX or LOX inhibitor, for example cox 2 inhibitor or COX/5-LOX inhibitor, and/or

G) anti-diabetic or antiadipositas drug, for example biguanide, for example metformin, metformin XR; Sulfonylureas, for example chlorpropamide, glipizide, gliclazide, glibenclamide/glyburide or glimepiride; Glucovance (metformin+glibenclamide); Metaglip (glipizide+metformin); Peroxisome proliferation-activation-γ (PPAR γ) agonist or adjusting control agent, for example rosiglitazone (Avandia), pioglitazone, farglitazar, GW1929, GW7845, MC-555, MBX-102/MBX-10, MBX-1828, MBX-2044, CLX-0921, R-483, reglitazar, naveglitazar (LY-519818/LY-818), netoglitazone (MCC-555), CS-7017, troglitazone, Xi Gelie ketone, tesaglitazar, isaglitazone, balaglitazone, muraglitazar, TAK-654, LBM642, DRF4158, EML4156, T-174, TY-51501, TY-12780, VDO-52 or AMG-131 (T131); Avandamet (rosiglitazone+metformin); Actos (pioglitazone+metformin); Avandaryl (rosiglitazone maleate+glimepiride); Benzimidazole, for example FK-614; CS-917; TA-1095; ONO-5129; TAK-559; TAK-677/AJ-9667; D-phenylalanine derivant, for example senaglinide; C-3347; NBI-6024; Ingliforib; BVT3498; LY929; The SGLT2 inhibitor; CS011; BIM51077; R1438; R1439; R1440; R1498; R1499; AVE0847; AVE2268; AVE5688; AVE8134; TA-6666; AZD6370; SSR162369; TLK-17411; NN2501; MK431; KGA-2727; MK-767; CS-872; Beta-3 receptor antagonist, for example N-5984; Alpha-glucosidase inhibitor, for example acarbose, voglibose or miglitol; Glinitide/meglitinide analog or carbamyl methyl bensoeicacid derivant, for example Mitiglinide, repaglinide or Nateglinide; DPP-IV inhibitor, for example LAF237 (vildagliptin), DPP728, P93/01, P32/98, PT-630 or saxagliptin; GLP-1 or GLP-1 analog, for example exenatide, Exenatide-LAR, liraglutide (NN2211), ZP10/AVE0010, LY307161, betatropin, CJC-1131, GTP-010, SUN E7001 or AZM134; Pramlinitideacetate; Insulin or insulin analog, for example Humalog (insulin lispro), Humulin, Novolin, Novolog/NovoRapid (insulin aspart), Apidra (insulin glulisine), Lantus (insulin glargine), Exubera, Levemir/NN 304 (insulin detemir), AERx/NN 1998, Insuman, Pulmonary insulin or NN344; Sibutramine or other serotonins and norepinephrine presynaptic reuptake blocker; Orlistat and other GI lipase inhibitors; The β3-Shen Shangxiansunengshouti agonist; Uncoupling protein; (specificity) antagonist of PPAR γ (peroxisome vegetation-activated receptor γ); The insulin succagoga; Class cannabinoid receptor antagonist in rimonabant and other CB1; Amfebutamone; Topiramate; The leptin agonist; Ciliary neurotrophic factor; The peptide analogues of human growth hormone's fragment 177-191; Cholecystokinin-A receptor stimulating agent; Melanocortin-3 agonist; Norepinephrine energy medicine, for example phentermine, amfepramone, the bent piperazine of benzene first or benzfetamine; , the combination of perhaps any above-mentioned anti-diabetic or antiadipositas drug, and/or

H) the potential medicine that can be used for treating psychoactive substanceabuse, for example alcohol abuse, for example naltrexone, acamprosate, disulphiram or Vivitrex (naltrexone long-acting injection), and/or

I) the potential medicine that can be used for treating Crohn disease, for example

1.5-ASA chemical compound, for example sulfasalazine, oral 5-ASA preparation or rectum 5-ASA preparation,

2. glucocorticosteroid, for example general action steroid class (for example budesonide or prednisolone) or local action steroid class (for example budesonide),

3. antibiotic, for example metronidazole or quinolinones (for example ciprofloxacin, ofloxacin, norfloxacin, levofloxacin or moxifloxacine),

4. immunosuppressant, for example azathioprine, Ismipur or methotrexate,

5. trophotherapy, for example element or polymer formulators or preceding-with short-antibiotic,

6. biotherapy, TNF-alpha inhibitor for example, for example infliximab, adalimumab, CDP870, CDP571, etanercept or onercept,

7. symptomatic drugs, for example diarrhea medicine or spasmolytic.

The NSAID example that is fit to is piroxicam, diclofenac, nabumetone, propanoic acid class (comprising naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen), fenamates (comprising mycophenolic acid), acetaminophen, indometacin, sulindac, Metro former times health, azapropazone, pyrazolone (comprising Phenylbutazone), Salicylate (comprising aspirin).

The cox 2 inhibitor example that is fit to is rofecoxib (Vioxx), valdecoxib (Bextra), celecoxib (Celebrex), etoricoxib (Arcoxia), lumiracoxib (Prexige), parecoxib (Dynastat), deracoxib (Deram), tiracoxib, Metro former times health, nimesulide, (1,1-dimethyl heptyl)-6a, 7,10,10a-tetrahydrochysene-1-hydroxyl-6,6-dimethyl-6H-dibenzo [b, d] pyrans carboxylic acid (CT-3), 2 (5H)-furanones, 5,5-dimethyl (1-methyl ethoxy) [4-(methyl sulphonyl) phenyl]-(DFP); Carprofen (RIMADYL), (acetoxyl group)-benzoic acid 3-[(nitroxyl) methyl] phenylester (NCX4016), P54 (CAS Reg.No.130996 0), 2,6-two (1, the 1-dimethyl ethyl) [(E)-(2-ethyl-1, the inferior isothiazole alkyl of 1-dioxo) methyl] phenol (S-2474), 5 (R)-sulfo-sulfonamide-3 (2H)-benzofuranone (SVT-2016) and N-[3-(formamido group) oxo phenoxy group-4H-benzopyranyl] Methanesulfomide (" T-614 "); Perhaps its pharmaceutically acceptable salt.

The COX/5-LOX inhibitor example that is fit to is licofelone (ML-3000 or [2,2-dimethyl-6-(4-chlorphenyl)-7-phenyl-2,3-dihydro-1H-pyrazine-5-yl] acetic acid), the di-tert-butyl phenols, for example (E)-(5)-(3,5-di-t-butyl-4-hydroxyl benzal)-2-ethyl-1,2-isothiazolidine-1,1-dioxide (S-2474), darbufelone or tebufelone and pharmaceutically active metabolite, and derivant, for example dihydro-dimethyl-benzofuran and PGV-20229, dihydro-dimethyl-benzofuran, thiophenes, RWJ-63556 for example, N-hydroxy-n-methyl-4-(2,3-pair-(4-methoxyphenyl)-thiophene-5-yl)-butyramide (S19812), methoxyl group tetrahydropyran derivatives, oxygenate xanthene ketone, for example 1,3,6,7-tetrahydroxy xanthone (norathyriol)-pyrazoles thiocarbamate, pyrazoles, for example contain the modified form of chemical compound of phenidone or the pyrazoline derivative BW-755C that trifluoro-benzene replaces, tepoxaline and derivant and di-t-butyl miazines.

Imagine this class combination treatment and do not compare with using the individuality according to the treatment of compositions of the present invention or medicine box, the treatment that improves described individuality is replied and/or is increased suitability.

The present invention relates to the method that reduces the side effect relevant with 1-5 with any above-mentioned disease a-e of oral medication on the other hand, uses the active pharmaceutical ingredient of the described disease of treatment in the method, and combination has one or more following ingredients:

A) antacid, for example 1) magnesium hydroxide, 2) magnesium trisilicate, 3) gel aluminum hydroxide, 4) sodium bicarbonate, 5) magaldrat, the perhaps combination of 1-5 arbitrarily, and/or

B) histamine H-2 antagonist, for example 1) cimetidine, 2) ranitidine, 3) nizatidine, 4) famotidine, 5) roxatidine, 6) lavoltidine, the perhaps combination of 1-6 arbitrarily, and/or

C) cytoprotective, for example 1) sucralfate, 2) tripotassiumdictitratobismuthate; 3) Carbenoxalone, 4) prostaglandin E2 analog, for example misoprostol; 5) ecabet; 6) cetraxate HCl, 7) teprenone, 8) troxipide; 9) bentrl hydrothloride; 10) sofalcon, the perhaps combination of 1-10 arbitrarily, and/or

D) proton pump inhibitor (PPI), for example 1) omeprazole, 2) esomeprazole, 3) lansoprazole, 4) pantoprazole, 5) the La Beila azoles, 6) CS-526/R-105266,7) AZD 0865,8) soraprazan, the perhaps combination of 1-8 arbitrarily, and/or

E) NSAID or COX or LOX inhibitor, for example cox 2 inhibitor or COX/5-LOX inhibitor, and/or

F) pentoxifylline, for example dosage range is 400 to 800mg/ days.

In specific embodiment, active substance is the chemical compound that contains fumarate.Definite, the chemical compound that contains fumarate is any and all at Fumaderm ^Or Fumaraat ^Or Panaclar ^(BG-12) or as US 6,277,882, US 6,355,676 or US6,509,376 is described or according to the salt that is contained in the preparation of the present invention.Can be at preparation according to the present invention or any Fumaderm ^Or Fumaraat ^Or Panaclar ^Preparation or as US 6,277,882, provide active pharmaceutical ingredient in US 6,355,676 or US 6,509, the 376 described preparations.

Self-evident, the invention is not restricted to described definite embodiment, they certainly have nothing in common with each other.Self-evident, term used herein does not plan to limit only for the purpose of describing definite embodiment yet, and scope of the present invention only is subjected to the restriction of claims.If the scope of numerical value is provided, intermediate value in self-evident each intermediate value between this scope bound and the scope other defineds or at defined all is encompassed in the present invention, apart from 1/10th units of lower limit, context has except the clearly instruction in addition.These bounds more among a small circle can be included in the littler scope independently, also are encompassed in the present invention, are subject to the restriction of specifically getting rid of arbitrarily in the scope of defined.If the scope of defined comprises one or two limit, get rid of one of these limits or two scope be also included within the present invention.Unless otherwise defined, all scientific and technical terminologies used herein all have one skilled in the art of the present invention the implication generally understood.Although the time also can use arbitrarily and those method similar or of equal value and materials described herein, but description preferable methods and material in practice of the present invention or test.All publications mentioned in this article are all quoted at this as a reference, method and/or the material quoted about these publications with disclosure and description.Must be noted that used singulative " a kind of ", " one " and " being somebody's turn to do " of this paper and claims comprises plural indicant, context has except the clearly instruction in addition.Patent discussed in this article and publication are only for disclosing before the application submits day to.This paper is not interpreted as allowing the present invention not have qualification in advance in this class patent or publication owing to formerly inventing.And then the date of publication that is provided may be different from actual date of publication, and they may need to confirm independently.As will be conspicuous after reading this paper by those skilled in the art, every kind of indivedual embodiments described herein and that set forth have discrete component and characteristic, they can easily separate with the characteristic of any other plurality of embodiments or make up, and do not deviate from scope of the present invention or spirit.Accompanying drawing shown in this paper needn't be drawn in proportion, has for clarity sake amplified some components and characteristic.

Although describe foregoing invention in detail by illustrating for the clear purpose of understanding, but will be it is evident that by those of ordinary skills in view of instruction of the present invention, certain changes and modifications can be carried out, and do not deviate from the spirit or scope of claims.

Embodiment

Embodiment 1

The preparation of tablet

With 200g granule and 150g microcrystalline Cellulose (Avicel for example ^102), 97.5g lactose (Tablettose for example ^), 10g sodium carboxymethyl cellulose (Ac-Di-Sol for example ^) and 25g starch mixing 30min.Add 10g magnesium stearate and 7.5g amorphous silica (Aerosil for example then ^200), with mixture of powders mixing 5min.

(sheet is 10mm directly, the about 280-300mm of surface area in flakes with this powder mixture in sheeting equipment ²).Bag is with enteric coating, as described in embodiment 4 in disc type coating or fluidized bed coating process.

Embodiment 2

The preparation of tablet

With 200g crystallite and 150g microcrystalline Cellulose (Avicel for example ^102), 130g lactose (Tablettose for example ^), 10g sodium carboxymethyl cellulose (Ac-Di-Sol for example ^) and 25mg starch mixing 30min.Add 10g magnesium stearate and 7.5g amorphous silica then, with mixture of powders mixing 5min.(sheet is 10mm directly, the about 280-300mm of surface area in flakes with this powder mixture in sheeting equipment ²).Bag is with enteric coating, as described in embodiment 4 in disc type coating or fluidized bed coating process.

Embodiment 3

The preparation of capsule

Granule or crystallite are filled in the HPMC capsule, and bag as described below is with enteric coating.In disc type coating machine, spray is with Eudragit on capsule ^L30D-55,60 ℃ to 80 ℃ of baking temperatures, the every mm of consumption 20mg polymeric material ²Add an amount of pigment and Talcum.

Embodiment 4

Tablet is enteric coated

In disc type coating machine, spray is with Eudragit on tablet ^L30D-55,60 ℃ to 80 ℃ of baking temperatures, the every mm of consumption 6mg polymeric material ²Add an amount of pigment and Talcum.

Embodiment 5

The preparation of capsule

To be filled in as the 156mg crystallite of preparation as described in the embodiment 15 in No. 0 hard gelatin capsule.Capsule is immersed 5%HPMCP (Pharmacoat HP50 ^) acetone soln in, every side capsule four times, the bag with enteric coating.

Embodiment 6

Particulate preparation

In granulation process, with 50g dimethyl fumarate (calling DMF in the following text) and the 1g ethyl cellulose that is dissolved in 10ml ethanol 96% (Ethocel for example ^NF premium) mixes, by 1.0mm sieve, dry 30min under 50 ℃ to 60 ℃.Utilize embodiment 1 and 3 described processes that these granules are made tablet and capsule.

Embodiment 7

Particulate preparation

In granulation process, with 50g DMF and the 1g polyvinyl acetate (PVA) that is dissolved in 10ml ethanol 96% (Kollicoat for example ^SR30) mix, by 1.00mm sieve, dry 30min under 50 ℃ to 60 ℃.

Embodiment 8

Particulate preparation

In granulation process, with the Eudragit of 50g DMF and 15g pulverizing ^RL100 mixes.Add an amount of 2-propanol and by behind the 1.00mm sieve, at 60 ℃ of following dried particles.Utilize embodiment 1 and 3 described processes that these granules are made tablet or capsule.

Embodiment 9

The preparation of coated granule

In granulation process, the direct and 5g Eudragit with 50g DMF ^RL30D mixes, and sieve (1.00mm) is dry down at 80 ℃.After sieving, in fluidized-bed coating machine (Mini-Glatt), use 15g Eudragit ^1: 1 mixture coating of RL30D/RS30D.Can utilize embodiment 1 and 3 described processes that these coated granules are made tablet or capsule.

Embodiment 10

The preparation of coated granule

In granulation process, with 50g DMF and 20% ethyl cellulose that is dissolved in an amount of ethanol 96% (Ethocel for example ^NF premium) mixes.Add 15% polyethylene glycol 6000 to granulation liquid.Mixture is sieved, dry 30min under 50 ℃ to 60 ℃ by 1.00mm.After sieving, with 2: 1 mixture coatings of ethyl cellulose and polyethylene glycol 6000, consumption is the every mm of 20mg in fluidized-bed coating machine (Mini-Glatt) ²Granule surface area.Can utilize embodiment 1 and 3 described processes that these granules are made tablet or capsule.

Embodiment 11

The preparation of coated granule

In granulation process, with 50g DMF and 10% ethyl cellulose that is dissolved in an amount of ethanol 96% (Ethocel for example ^NF premium) mixes.Add 6% polyvidone (Kollidon for example to granulation liquid ^25).Mixture is sieved, dry 30min under 50 ℃ to 60 ℃ by 1.00mm.After sieving, with 3: 2 mixture coatings of ethyl cellulose and polyvidone, consumption is the every mm of 20mg in fluidized-bed coating machine (Mini-Glatt) ²Granule surface area.

Can utilize embodiment 1 and 3 described processes that these granules are made tablet or capsule.

Embodiment 12

The preparation of coated granule

In granulation process, with 50g DMF and 10% ethyl cellulose that is dissolved in an amount of ethanol 96% (Ethocel for example ^NF premium) mixes.Add 5% hydroxypropyl cellulose (HPC) (Klucel for example to granulation liquid ^).Mixture is sieved, dry 30min under 50 ℃ to 60 ℃ by 1.00mm.After sieving, with 2: 1 mixture coatings of ethyl cellulose and HPC, consumption is the every mm of 20mg in fluidized-bed coating machine (Mini-Glatt) ²Granule surface area.

Embodiment 13

The preparation of coated granule

In granulation process, with the direct and an amount of Eudragit of 50g DMF ^The aqueous dispersion of NE30D mixes, and sieve (1.00mm) is dry down at 80 ℃.After sieving, in fluidized-bed coating machine (Mini-Glatt), use 15g Eudragit ^1: 1 mixture coating of RL30D/RS30D.Can utilize embodiment 1 and 3 described processes that coated granule is made tablet and capsule.

Embodiment 14

The preparation of coated granule

In granulation process, with the direct and an amount of Eudragit of 50g DMF ^The aqueous dispersion of RL30D mixes, and sieve (1.00mm) is dry down at 80 ℃.After sieving, in fluidized-bed coating machine (Mini-Glatt), use Eudragit ^The NE30D coating.Can utilize embodiment 1 and 3 described processes that coated granule is made tablet and capsule.

Embodiment 15

The preparation of coating crystallite

Prepare the saturated solution of 50g DMF in 300ml 2-propanol down at 60 ℃, slowly cooling under magnetic stirs.Leach sedimentary crystal, dry down at 50 ℃.Crystal is sieved, use 315-710 μ m fraction in disc type coating machine or fluidized-bed coating machine (Mini-Glatt), to carry out the coating process.Under 60 ℃ to powder surface spray with 12g ethyl cellulose (Ethocel for example ^NF premium) with the coating solution of 3g PEG400 in 500g ethanol.After the drying, the coating crystal is sieved by 1.00mm.Can utilize embodiment 2 and 3 described processes that coating DMF crystal is made tablet and capsule.

Embodiment 16

The preparation of tablet

In granulation process, with 50g DMF and 12g ethyl cellulose (Ethocel for example ^NFpremium) and 150ml ethanol 96% solution of 3g PEG400 mix, by the 1.0mm sieve,, sieve by 1.0mm once more at 50 ℃ to 60 ℃ dry 30min down.Be prepared as follows the comfort granule: with Tablettose ^And Avicel ^102 equal portions mix, with 2% polyvidone (Kollidon for example ^25) pelletize of water (q.s.) solution, by the 1.0mm sieve, dry 30min under 50 ℃ to 60 ℃ sieves by 1.0mm once more.60 parts of DMF-granules were mixed 30 minutes in Turbula Shaker mixer with 38 parts of comfort-granules.Add a Aerosil ^200 and a magnesium stearate, mixed once more 5 minutes.With the admixture compacting in flakes, diameter 10mm, the great about 260mg of sheet, the about 50N of hardness.Utilize embodiment 4 described process bags with enteric coating.

Embodiment 17

The preparation of tablet

In granulation process, with 50g DMF and 12g ethyl cellulose (Ethocel for example ^NFpremium) and 150ml ethanol 96% solution of 3g PEG400 mix, by the 1.0mm sieve,, sieve by 1.0mm once more at 50 ℃ to 60 ℃ dry 30min down.Be prepared as follows the comfort granule: with Tablettose ^And Avicel ^102 equal portions mix, with 2% polyvidone (Kollidon for example ^25) pelletize of water (q.s.) solution, by the 1.0mm sieve, dry 30min under 50 ℃ to 60 ℃ sieves by 1.0mm once more.60 parts of DMF-granules were mixed 30 minutes in Turbula Shaker mixer with 37 parts of comfort-granules.Add a carboxymethyl cellulose (Ac-Di-Sol for example ^), a Aerosil ^200 and a magnesium stearate, mixed this admixture once more 5 minutes.With the admixture compacting in flakes, diameter 10mm, the great about 260mg of sheet, the about 50N of hardness.Utilize embodiment 4 described process bags with enteric coating.

Embodiment 18

The preparation of coating crystallite

Prepare the saturated solution of 50g DMF in 300ml 2-propanol down at 60 ℃, slowly cooling under magnetic stirs.Leach sedimentary crystal, dry down at 50 ℃.Crystal is sieved, use 315-710 μ m fraction in disc type coating machine or fluidized-bed coating machine (Mini-Glatt), to carry out the coating process.Under 60 ℃ to plane of crystal spray with 12g ethyl cellulose (Ethocel for example ^NF premium) with the coating solution of 3g polyvidone (PVP) in 500g ethanol.After the drying, the coating crystal is sieved by 1.00mm.Can utilize embodiment 2 and 3 described processes that coating DMF crystal is made tablet and capsule.

Embodiment 19

The preparation of coating crystallite

Prepare the saturated solution of 50g DMF in 300ml 2-propanol down at 60 ℃, slowly cooling under magnetic stirs.Leach sedimentary crystal, dry down at 50 ℃.Crystal is sieved, use 315-710 μ m fraction in disc type coating machine or fluidized-bed coating machine (Mini-Glatt), to carry out the coating process.Under 60 ℃ to powder surface spray with 12g ethyl cellulose (Ethocel for example ^NF premium) with the coating solution of 3g hydroxypropyl cellulose (HPC) in 500g ethanol.After the drying, the coating crystal is sieved by 1.00mm.Can utilize embodiment 2 and 3 described processes that coating DMF crystal is made tablet and capsule.

Embodiment 20

The preparation of crystallite

As described in embodiment 15, prepare the DMF-crystal, but before crystalline precipitation, directly add 2% ethyl cellulose, for crystalline quality to the 2-propanol.

Embodiment 21

The preparation of coating crystallite

As described in embodiment 15, prepare 50g DMF crystal, in fluidized-bed coating machine (Mini-Glatt), use Eudragit ^The 20g aqueous dispersion coating of 1: 1 mixture of RL30D/RS30D, 80 ℃ of temperature.Utilize embodiment 2 and 3 described processes that these coatings DMF crystal is made tablet and capsule.

Embodiment 22

The preparation of tablet

As described in embodiment 15, prepare the DMF crystal, directly with 25% solid Eudragit ^RSPO/RL PO mixes at 1: 2, makes tablet as described in embodiment 2.

Embodiment 23

The preparation of coating crystallite

As preparation DMF crystal as described in the embodiment 15, in fluidized-bed coating machine (Mini-Glatt) with 5% (for crystal mass) polyvinyl acetate (Kollicoat for example ^SR30D) aqueous dispersion coating.Utilize embodiment 2 and 3 described processes that these coatings DMF crystal is made tablet and capsule.

Embodiment 24

Particulate preparation

In granulation process, with 50g DMF and 15% ethyl cellulose that is dissolved in an amount of ethanol 96% (Ethocel for example ^NF premium) mixes.Add 10% polyethylene glycol 6000 to granulation liquid.Mixture is sieved, dry 30min under 50 ℃ to 60 ℃ by 1.00mm.Can utilize embodiment 1 and 3 described processes that these granules are made tablet or capsule.

Embodiment 25

Particulate preparation

In granulation process, with 50g DEF (DEF) and 15% ethyl cellulose that is dissolved in an amount of ethanol 96% (Ethocel for example ^NF premium) mixes.Add 10% polyethylene glycol 6000 to granulation liquid.Mixture is sieved, dry 30min under 50 ℃ to 60 ℃ by 1.00mm.Can utilize embodiment 1 and 3 described processes that these granules are made tablet or capsule.

Embodiment 26

The preparation of tablet

As preparation granule as described in the embodiment 24, but add 10% polyvidone (Kollidon for example ^25) replace PEG 6000.Can utilize embodiment 1 and 3 described processes that this mixture is made tablet or capsule.

Embodiment 27

The preparation of tablet

As preparation granule as described in the embodiment 24, replace PEG6000 but add 10% hydroxypropyl emthylcellulose.Can utilize embodiment 1 and 3 described processes that this mixture is made tablet or capsule.

Embodiment 28

As described in embodiment 15, prepare 50g DMF crystal, in fluidized-bed coating machine (Mini-Glatt), use Eudragit ^The 20g aqueous dispersion coating of 1: 1 mixture of RL30D/RS30D, 80 ℃ of temperature.As described below in disc type coating machine to coating crystal bag with enteric coating.Spray with Eudragit to the coating crystal ^L30D-55,60 ℃ to 80 ℃ of baking temperatures, consumption are the every mm of 6mg polymeric material ²

These dual coating DMF crystal are filled in glutoid or the Perle, perhaps utilize embodiment 2 described processes to make tablet.

Embodiment 29

The preparation of tablet

In granulation process, with 50g DMF and 12g ethyl cellulose (Ethocel for example ^NFpremium) and 3g hydroxypropyl cellulose (Klucel for example ^) 150ml ethanol 96% solution mix, by the 1.0mm sieve,, sieve by 1.0mm once more at 50 ℃ to 60 ℃ dry 30min down.With Tablettose ^And Avicel ^102 equal portions mix, with 2% polyvidone (Kollidon for example ^25) pelletize of water (q.s.) solution.60 parts of DMF-granules were mixed 30 minutes in Turbula Shaker mixer with 38 parts of comfort-granules.Add a Aerosil ^200 and a magnesium stearate, mixed once more 5 minutes.With the admixture compacting in flakes, diameter 10mm, the great about 260mg of sheet, the about 50N of hardness.Utilize embodiment 4 described process bags with enteric coating.

Embodiment 30

The mensuration of the controlled release solubility curve of the pH of capsule

As mensuration solubility curve as described in the American Pharmacopeia, use the rotation basket, 6 so-called Levy-glasses containers, 1 liter and 6 basket agitating elements of capacity are by Motor Drive (100rpm).To Levy-glasses container perfusion 0.1N HCl (bath temperature is 37 ℃+/-0.5 ℃), put into capsule to basket.After 2 hours, remove disacidify from container, replace, tested other 6 hours with dissolve medium (USP phosphate buffer pH6.5).After replacing dissolve medium with the USP buffer, sampling (5ml) from acid medium after 0,60 and 120 minute was taken a sample from the buffering liquid medium after 30,60,90,120,180,240,300 and 360 minutes.The amount that after each sampling, is extracted without the buffer solution replacement, but calculating the loss of considering buffer when the DMF that is discharged measures.By the amount of HPLC (Kontron XXX) mensuration DMF, use Merck LiChroCART RP8 5 μ M, 20cm post, 25 ℃ of temperature.Mobile phase is by acetonitrile and 0.0725mol/l NaH ₂PO ₄* H ₂The mixture of O-buffer (35: 65) is formed, and is adjusted to pH3.2 with phosphoric acid.The UV detector be set to wavelength 230nm, flow velocity 1.0ml per minute.Approximately after the retention time of 5min, the DMF peak is detectable.

Embodiment 31

The mensuration of the controlled release solubility curve of the pH of non-enteric coated tablet

Following mensuration solubility curve uses 6 so-called Levy-glasses containers, and 1 liter and 6 oars of capacity are as agitating element, by Motor Drive.The rotating speed of oar is 100rpm.To Levy-glasses container perfusion USP phosphate buffer pH6.5 (bath temperature is 37 ℃+/-0.5 ℃), put into tablet to the Levy-glasses container.After replacing dissolve medium with the USP buffer, sampling (5ml) from the buffering liquid medium after 0,30,60,90,120,180,240,300 and 360 minute.The amount that after each sampling, is extracted without the buffer solution replacement, but calculating the loss of considering buffer when the DMF that is discharged measures.By the amount of HPLC (Kontron XXX) mensuration DMF, use Merck LiChroCART RP8 5 μ M, 20cm post, 25 ℃ of temperature.Mobile phase is by acetonitrile and 0.0725mol/l NaH ₂PO ₄* H ₂The mixture of O-buffer (35: 65) is formed, and is adjusted to pH3.2 with phosphoric acid.The UV detector be set to wavelength 230nm, flow velocity 1.0ml per minute.Approximately after the retention time of 5min, the DMF peak is detectable.

Embodiment 32

As preparation capsule as described in the embodiment 5, as mensuration solubility curve as described in the embodiment 30.Solubility curve as shown in Figure 1.

Embodiment 33

As preparation tablet as described in the embodiment 16 (before bag is with enteric coating), as mensuration solubility curve as described in the embodiment 31.Solubility curve as shown in Figure 2.

Embodiment 34

As preparation tablet as described in the embodiment 17 (before bag is with enteric coating), as mensuration solubility curve as described in the embodiment 31.Solubility curve as shown in Figure 3.

Claims

1, pharmaceutical composition comprises one or more fumarates as active substance, is selected from two of fumaric acid-(C ₁-C ₅) the list-(C of Arrcostab and fumaric acid ₁-C ₅) Arrcostab or its pharmaceutically acceptable salt, it is behind oral administration, with Isodose Fumaderm ^Compare behind the sheet oral administration, reduce the GI side effect.

2, according to the pharmaceutical composition of claim 1, be the form of controlled release composition.

3, mouthful use controlled release pharmaceutical compositions, comprise one or more fumarates, be selected from two of fumaric acid-(C as active substance ₁-C ₅) the list-(C of Arrcostab and fumaric acid ₁-C ₅) Arrcostab or its pharmaceutically acceptable salt, wherein the release of fumarate when carrying out extracorporeal dissoluting test is as follows, this test pro-adopts 0.1N hydrochloric acid as dissolve medium during 2 hours, then with 0.05M phosphate buffer pH 6.5 as dissolve medium:

In preceding 3 hours, the fumarate total amount that said composition contained has about 70%w/w to be released at the most after on-test.

4, mouthful use controlled release pharmaceutical compositions, comprise one or more fumarates, be selected from two of fumaric acid-(C as active substance ₁-C ₅) the list-(C of Arrcostab and fumaric acid ₁-C ₅) Arrcostab or its pharmaceutically acceptable salt, wherein the release of fumarate when carrying out extracorporeal dissoluting test is as follows, this test pro-adopts 0.1N hydrochloric acid as dissolve medium during 2 hours, then with 0.05M phosphate buffer pH 6.5 as dissolve medium:

In preceding 4 hours, the total amount of fumarate has about 92%w/w to be released at the most after on-test.

5, according to the controlled release composition of claim 3, wherein the release of fumarate is as follows:

6, the controlled release composition any according to claim 3-5, wherein the release of fumarate is as follows:

In preceding 5 hours, the total amount of fumarate has about 94%w/w to be released at the most after on-test.

7, the controlled release composition any according to claim 3-6, wherein the release of fumarate is as follows:

In preceding 6 hours, the fumarate total amount that said composition contained has about 95%w/w to be released at the most after on-test.

8, the controlled release composition any according to claim 3-7, wherein the release of fumarate is as follows:

In preceding 7 hours, the fumarate total amount that said composition contained has about 98%w/w to be released at the most after on-test.

9, the controlled release composition any according to claim 3-8, wherein the release of fumarate is as follows:

In preceding 9 hours, the fumarate total amount that said composition contained has about 99%w/w to be released at the most after on-test.

10, the controlled release composition any according to claim 3-9, wherein the release of fumarate is as follows:

11, according to any one controlled release pharmaceutical compositions of claim formerly, wherein this release has zero level, one-level or square root (Higuchi equation) kinetics release profiles.

12, according to the controlled release pharmaceutical compositions of claim 11, wherein this release has square root (Higuchi equation) kinetics release profiles.

13, the controlled release composition any according to claim 3-12, it is behind oral administration, with Isodose Fumaderm ^Compare behind the sheet oral administration, reduce the GI side effect.

14, controlled release pharmaceutical compositions comprises one or more fumarates as 10 to 90 weight % of active substance, is selected from two of fumaric acid-(C ₁-C ₅) the list-(C of Arrcostab and fumaric acid ₁-C ₅) Arrcostab or its pharmaceutically acceptable salt, the pharmaceutically acceptable polymer of 2 to 40 weight % and the hydrophilic excipient of 1 to 40 weight % are alternatively with pharmaceutically acceptable excipient or additive.

15,, comprise one or more fumarates, be selected from two of fumaric acid-(C as 40 to 60 weight % of active substance according to the controlled release pharmaceutical compositions of claim 14 ₁-C ₅) the list-(C of Arrcostab and fumaric acid ₁-C ₅) Arrcostab or its pharmaceutically acceptable salt, the pharmaceutically acceptable polymer of 15 to 25 weight % and the hydrophilic excipient of 2 to 15 weight % are alternatively with pharmaceutically acceptable excipient or additive.

16,, comprise one or more fumarates, be selected from two of fumaric acid-(C as 65 to 80 weight % of active substance according to the controlled release pharmaceutical compositions of claim 14 ₁-C ₅) the list-(C of Arrcostab and fumaric acid ₁-C ₅) Arrcostab or its pharmaceutically acceptable salt, the pharmaceutically acceptable polymer of 10 to 25 weight % and the hydrophilic excipient of 2 to 15 weight % are alternatively with pharmaceutically acceptable excipient or additive.

17, the controlled release pharmaceutical compositions any according to claim 14-16, wherein this pharmaceutically acceptable polymer is an ethyl cellulose.

18, the controlled release pharmaceutical compositions any according to claim 14-17, wherein this hydrophilic excipient is a Polyethylene Glycol.

19, the controlled release pharmaceutical compositions any according to claim 14-17, wherein this hydrophilic excipient is a hydroxypropyl cellulose.

20, controlled release pharmaceutical compositions comprises one or more fumarates as 10 to 90 weight % of active substance, is selected from two of fumaric acid-(C ₁-C ₅) the list-(C of Arrcostab and fumaric acid ₁-C ₅) methacrylic acid copolymer A and the B of Arrcostab or its pharmaceutically acceptable salt and 2 to 40 weight %, weight ratio is between 1: 9 and 9: 1, alternatively with pharmaceutically acceptable excipient or additive.

21, according to claim 14 and any one controlled release pharmaceutical compositions of 16-20, comprise 50 to 90 weight % one or more fumarates, be selected from two of fumaric acid-(C ₁-C ₅) the list-(C of Arrcostab and fumaric acid ₁-C ₅) Arrcostab or its pharmaceutically acceptable salt.

22, the controlled release pharmaceutical compositions any according to claim 14-21 has the solubility curve any according to claim 3-13.

23, according to any one controlled release pharmaceutical compositions of claim formerly, wherein this fumarate is selected from the group of being made up of dimethyl fumarate, DEF, fumaric acid dipropyl, dibutyl fumarate, fumaric acid diamyl ester, fumaric acid Methylethyl ester, fumaric acid methyl-propyl ester, fumaric acid methyl butyl ester, fumaric acid methyl amyl ester, fumaric acid monomethyl ester, fumaric acid list ethyl ester, fumaric acid list propyl diester, fumaric acid monobutyl ester and fumaric acid list amyl group ester, comprises its pharmaceutically acceptable salt.

24, according to any one controlled release pharmaceutical compositions of claim formerly, wherein this fumarate is the list-(C of fumaric acid ₁-C ₅) Arrcostab, exist with the pharmaceutically acceptable salt form.

25, according to the controlled release composition of claim 24, wherein this salt is slaine, for example is selected from the salt of alkali metal salt and alkali salt

26, according to claim 24 or 25 any one controlled release compositions, wherein this salt is sodium, potassium, calcium, magnesium or zinc salt.

27, according to any one controlled release pharmaceutical compositions of claim formerly, comprise dimethyl fumarate as active substance.

28, according to any one controlled release pharmaceutical compositions of claim formerly, comprise monomethyl fumarate as active substance.

29, according to the controlled release pharmaceutical compositions of claim 28, wherein monomethyl fumarate exists with the form of its sodium, potassium, calcium, magnesium and/or zinc salt.

30,, be used for being administered once every day, twice or three times according to any one controlled release composition of claim formerly.

31,, be used for being administered once every day according to the controlled release composition of claim 30.

32,, be used for being administered twice every day according to the controlled release composition of claim 30.

33, according to any one controlled release pharmaceutical compositions of claim formerly, wherein one or more fumarates, be selected from two of fumaric acid-(C ₁-C ₅) the list-(C of Arrcostab and fumaric acid ₁-C ₅) Arrcostab or the amount of its pharmaceutically acceptable salt in dosage form be 90mg to 360mg active substance.

34, according to the controlled release pharmaceutical compositions of claim 33, wherein the amount in dosage form is 90,120,180,240 or the 360mg active substance.

35, according to the controlled release pharmaceutical compositions of claim 33, wherein the amount in dosage form is the 120mg active substance.

36, according to the controlled release pharmaceutical compositions of claim 33, wherein the amount in dosage form is the 180mg active substance.

37, according to the controlled release pharmaceutical compositions of claim 33, wherein the amount in dosage form is the 240mg active substance.

38, according to the controlled release pharmaceutical compositions of claim 33, wherein the amount in dosage form is the 360mg active substance.

39, according to any one controlled release pharmaceutical compositions of claim formerly, be the form of tablet.

40, according to the controlled release pharmaceutical compositions of claim 39, wherein the shape of this tablet makes it easily and be suitably the patient and swallow.

41, the controlled release pharmaceutical compositions any according to claim 39-40, wherein this tablet is circular or excellent sample shape, without any sharp-pointed edge.

42, the controlled release pharmaceutical compositions any according to claim 39-41, wherein this tablet is designed to be divided into two or more parts.

43, the controlled release pharmaceutical compositions any according to claim 1-38 is the form of capsule.

44, the treatment psoriasis, arthritic psoriasis, neural dermatitis, inflammatory bowel (for example Crohn disease and ulcerative colitis), autoimmune disease (polyarthritis for example, multiple sclerosis (MS), the diabetes of teenager outbreak, struma lymphomatosa, the Ge Leifushi disease, SLE (systemic lupus erythematosus (sle)), siogren's syndrome, pernicious anemia, chronic active type (lupoid acne) hepatitis, rheumatoid arthritis (RA) and optic neuritis), pain (nerve root pain for example, the pain relevant with radiculopathy, neuropathy pain or sciatic nerve/ischium pain), organ transplantation (prevention of repulsion), sarcoidosis, the method of necrobiosis lipoidica or granuloma annulare, this method comprise the pharmaceutical composition any according to claim 1-43 to patient's orally give effective dose that needs are arranged.

45, according to the purposes of any one the preparation of pharmaceutical compositions medicine of claim 1-43, this medicine is used for the treatment of psoriasis, arthritic psoriasis, neural dermatitis, inflammatory bowel (for example Crohn disease and ulcerative colitis), autoimmune disease (polyarthritis for example, multiple sclerosis (MS), the diabetes of teenager outbreak, struma lymphomatosa, the Ge Leifushi disease, SLE (systemic lupus erythematosus (sle)), siogren's syndrome, pernicious anemia, chronic active type (lupoid acne) hepatitis, rheumatoid arthritis (RA) and optic neuritis), pain (nerve root pain for example, the pain relevant with radiculopathy, neuropathy pain or sciatic nerve/ischium pain), organ transplantation (prevention of repulsion), sarcoidosis, necrobiosis lipoidica or granuloma annulare.