WO2013076216A1 - Controlled release particles comprising dimethyl fumarate - Google Patents

Controlled release particles comprising dimethyl fumarate Download PDF

Info

Publication number
WO2013076216A1
WO2013076216A1 PCT/EP2012/073406 EP2012073406W WO2013076216A1 WO 2013076216 A1 WO2013076216 A1 WO 2013076216A1 EP 2012073406 W EP2012073406 W EP 2012073406W WO 2013076216 A1 WO2013076216 A1 WO 2013076216A1
Authority
WO
WIPO (PCT)
Prior art keywords
particle
dimethyl fumarate
particles
coating
coated
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2012/073406
Other languages
French (fr)
Inventor
VAN DEN Korinde Annemarie HEUVEL-JANSEN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Synthon BV
Original Assignee
Synthon BV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Synthon BV filed Critical Synthon BV
Priority to RU2014125430/15A priority Critical patent/RU2014125430A/en
Priority to EP12791165.9A priority patent/EP2782561A1/en
Publication of WO2013076216A1 publication Critical patent/WO2013076216A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose

Definitions

  • the present invention relates to coated particles comprising dimethyl fumarate as the active pharmaceutical ingredient.
  • the particles are designed to release the active substance in a controlled manner so that, after oral administration, it is released in the upper
  • Fumaric acid esters are pharmaceutically active substances useful, e.g., for the treatment of psoriasis or other hyperproliferative, inflammatory or autoimmune disorders.
  • dimethyl fumarate in combination with metal salts of ethyl hydrogenfumarate have been used for the treatment of psoriasis for many years, e.g. under trade name Fumaderm®.
  • Fumaderm® compositions are marketed as enteric -coated tablets for oral administration.
  • compositions comprising dialkyl fumarates and/or alkyl hydrogen fumarates are known in the art.
  • EP 188 749 discloses fumaric acid derivatives and compositions comprising the same for the treatment of psoriasis.
  • US 4,959,389 discloses compositions comprising salts of monoalkyl fumarates alone or in combination with dialkyl fumarates.
  • US 6,277,882 and US 6,355,676 disclose the use of alkyl hydrogen fumarates for preparing microtablets for the treatment of psoriasis, psoriatic arthritis and other diseases.
  • US 6,509,376 discloses pharmaceutical preparations comprising one or more dialkyl fumarates in the form of enteric-coated micro-tablets and micro-pellets (filled into hard gelatine capsules), made by a conventional wet-granulation process, for use in transplantation medicine or for therapy of autoimmune diseases.
  • DE 38 34 794 discloses pharmaceutical preparations comprising one or more fumaric acid derivatives in the form of e.g. hard gelatine capsules filled with a granulate of said derivatives which are made in a conventional way with a granulation material which is either easily soluble, difficult soluble or insoluble in gastric fluid.
  • medicaments like, e.g., Fumaderm® is accompanied with various undesired gastrointestinal side-effects, such as nausea, vomiting, and diarrhea. This is due to irritation of the stomach tissue when a too-high peak concentration of the fumarate is released.
  • dialkyl fumarates e.g., dimethyl fumarate
  • sublimate already at relatively low temperatures.
  • Example 1 of the above-cited US 6,509,376 EP 1 131 065
  • Example 1 of the above-cited US 6,509,376 EP 1 131 065
  • Example 1 of the above-cited US 6,509,376 EP 1 131 065
  • Example 1 of the above-cited US 6,509,376 EP 1 131 065
  • Sublimation may also cause loss of dimethyl fumarate during long-term storage of pharmaceutical compositions comprising it.
  • the present invention relates to particles of dimethyl fumarate coated by at least one layer comprising a pharmaceutically acceptable pH-dependent entero-resistant polymer under process conditions at which sublimation of dimethyl fumarate essentially does not take place.
  • the stable coated particles may then be formulated into various pharmaceutical preparations for oral administration, whereby the release rate of the dimethyl fumarate in the patient' s body advantageously can be so-adjusted that irritation of the stomach tissue is minimized.
  • the present invention relates to a particle or a plurality of particles of dimethyl fumarate, wherein the particle is coated by at least one layer comprising a pharmaceutically acceptable pH-dependent entero-resistant polymer.
  • the present invention relates to an oral pharmaceutical preparation comprising a plurality of particles of dimethyl fumarate, wherein the particles are coated by at least one layer comprising a pharmaceutically acceptable pH-dependent entero-resistant polymer and at least one pharmaceutically acceptable excipient.
  • the present invention relates to an oral dosage form comprising a therapeutically effective amount of the above particles or preparation.
  • the present invention relates to a process for making a particle or a plurality of particles of dimethyl fumarate comprising coating the dimethyl fumarate particle(s) with at least one layer comprising a pharmaceutically acceptable pH-dependent entero-resistant polymer.
  • the temperature of coating does not exceed 40°C.
  • the present invention relates to the use of the above particle(s), preparation or dosage form in medicine, in particular for the treatment of autoimmune diseases such as multiple sclerosis.
  • Figure 1 shows in vitro dissolution profiles of the enteric-coated compositions of Example 1 according to USP method (basket, 100 rpm).
  • the present invention relates to coated dimethyl fumarate particles and to
  • pharmaceutical preparations and dosage forms comprising them which are designed for oral administration of dimethyl fumarate for the treatment of various diseases with the aim of minimizing gastrointestinal side-effects such as nausea, vomiting and diarrhoea associated therewith, caused by inherent gastro-irritating behaviour of dimethyl fumarate. Furthermore, undesired sublimation of dimethyl fumarate during making pharmaceutical preparations and dosage forms comprising dimethyl fumarate and during storage thereof are minimized as well.
  • Dimethyl fumarate is a compound which is well-known in the art and is either commercially available or is preparable by known methods.
  • the present invention solves both the problem of undesired gastrointestinal side-effects associated with oral administration of dimethyl fumarate and the problem of sublimation of dimethyl fumarate from pharmaceutical preparations by providing a particle or a plurality of particles of dimethyl fumarate coated by at least one layer comprising a pharmaceutically acceptable polymer, the aqueous solubility and degradation of which polymer is dependent on the pH. As a result, a stable and non-irritant dimethyl fumarate particle is provided.
  • Dimethyl fumarate is a solid state compound at ambient conditions. When in the solid state, it inherently exists in a particulate form.
  • the "particle" of dimethyl fumarate as used within the context of the present invention, means any particulate form of dimethyl fumarate. It may be a crystalline or an amorphous particle and may it be produced by any conventional method such as crystallization, precipitation, spray drying, etc.
  • the particle size distribution of dimethyl fumarate for making the coated particle(s) of the present invention typically is a D 50 (volume median diameter D(v,0.5)) between 50 and 1000, preferably between 300 and 900, more preferably between 500 and 900 micrometers (micron)
  • the particle or plurality of particles of dimethyl fumarate is coated by at least one layer comprising a pharmaceutically acceptable pH-dependent entero-resistant polymer.
  • a polymer is "pH-dependent entero-resistant" if the coating layer comprising it does not allow acidic gastric water to penetrate through but it allows the penetration of water to the dimethyl fumarate core (e.g., by dissolution, swelling, degradation etc.) at the essentially neutral pH of the intestines.
  • a pH-dependent entero-resistant polymer suitable for purposes of the present invention is a polymer, which dissolves, swells or degrades at a pH of 4.5 or higher, preferably pH 5.0 or higher.
  • the polymer dissolves, swells or degrades at a pH in the range of from 4.5 to 7.0, preferably from 5.0 to 6.5.
  • suitable pH-dependent entero-resistant polymers include, alone or in combination, a polymethacrylate (for instance a copolymer of methacrylic acid and methyl methacrylate or a copolymer of methacrylic acid and ethyl aery late), hydroxypropyl methyl cellulose acetate succinate (HPMC-AS), hydroxypropyl methyl cellulose phthalate (HPMC- P), polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP) and shellac.
  • a polymethacrylate for instance a copolymer of methacrylic acid and methyl methacrylate or a copolymer of methacrylic acid and ethyl aery late
  • HPMC-AS hydroxypropyl methyl cellulose acetate succinate
  • the preferred polymer is a polymethacrylate polymer.
  • suitable commercially available polymers of this kind are Eudragit® L, Eudragit® S and Eudragit® FS and other brand-name equivalents thereof such as Eastacryl® 30D and Kollicoat® 30.
  • Suitable commercially available hydroxypropyl methyl cellulose phthalate polymers are hypromellose phthalate HP-55, hypromellose phthalate HP-55S, and hypromellose phthalate HP-50.
  • Suitable commercially available hydroxypropyl methyl cellulose acetate succinate polymers are Aquoat® polymers.
  • mixtures of one or more pH-dependent entero-resistant polymers and one or more pH-independent water-insoluble polymers are used to coat the dimethyl fumarate particle(s).
  • pH-independent water-insoluble polymers such as e.g. cellulose acetate, cellulose acetate butyrate, cellulose triacetate, and ethyl cellulose.
  • cellulose acetate and ethyl cellulose are the preferred polymers for use in said combination.
  • the thickness (relative amount) of the polymer coating layer may affect the overall release rate.
  • the amount of polymer coating is from 10 to 100 wt , preferably from 20 to 70 wt , more preferably from 30 to 60 wt relative to the weight of the dimethyl fumarate particle(s). In other words, from 10 to 100% etc. weight gain.
  • the smaller the particle size the more polymer material is needed to provide a coating layer with enteric protection around the dimethyl fumarate particle(s).
  • the coating may comprise other functional excipients, e.g. plasticizers, anti-tacking agents, pH adjusters, stabilizers, pore formers or additives improving the moisture/oxygen barrier, as known in the art.
  • functional excipients e.g. plasticizers, anti-tacking agents, pH adjusters, stabilizers, pore formers or additives improving the moisture/oxygen barrier, as known in the art.
  • the dimethyl fumarate particle generally needs not to be granulated and/or mixed with any inactive excipient prior to coating, which is an advantage over other compositions known from the prior art.
  • the pH-dependent entero-resistant polymer can be advantageously applied during the coating process at temperatures, when measured on the product, not exceeding 40°C, which is below the temperatures that are routinely used in coating operations. This suppresses sublimation of dimethyl fumarate during coating.
  • the present invention also provides a process for making a stable pharmaceutical particle or a plurality of particles of dimethyl fumarate comprising coating the dimethyl fumarate particle(s) by at least one layer comprising a pharmaceutically acceptable pH- dependent entero-resistant polymer.
  • the temperature of coating does not exceed 40°C, preferably it does not exceed 30°C. More preferably, the coating temperature (as measured on the product) is between 20 and 25 °C.
  • the coating process advantageously is carried out by spraying the polymer dissolved or suspended in a coating liquid onto the surface of the particle(s).
  • the coating liquid may be water, an alcohol or a mixture thereof.
  • the coating process is performed portionwise, wherein more than one layer is applied on the particle(s).
  • the first (innermost) coating layer is applied at a product temperature not exceeding 40°C, preferably not exceeding 30°C.
  • the subsequent second (third, fourth, etc.) coating layer then may be applied at any conventionally used temperature including a temperature exceeding 40°C, as the dimethyl fumarate particles have already been sufficiently protected against sublimation by the first layer of the polymer.
  • the product temperature during coating lies in the range of from 40 to 55 °C.
  • (third, fourth, etc.) layer can be either a pH-dependent entero-resistant polymer (which is the same or different as the one of the first coating layer) or is a pH-independent water-insoluble polymer (e.g. ethyl cellulose, cellulose acetate, Eudragit® RS, Eudragit® RL, Eudragit® NE,
  • a pH-dependent entero-resistant polymer which is the same or different as the one of the first coating layer
  • a pH-independent water-insoluble polymer e.g. ethyl cellulose, cellulose acetate, Eudragit® RS, Eudragit® RL, Eudragit® NE,
  • the first (innermost) coating layer may advantageously comprise from 5 to 30 wt , in some embodiments up to 40 wt of the total amount of coating material.
  • the pH-dependent entero-resistant polymer used for the innermost coating layer may be partially neutralized as described in WO 2008/135090, whereby the second (third, fourth, etc.) coating layer is made up of a pH-dependent entero-resistant polymer which is less neutralized than the material of the innermost coating layer or not at all neutralized.
  • the pH-dependent entero-resistant polymer is not used for the innermost coating layer.
  • the innermost layer is formed from a pH-independent water- soluble polymer (e.g. PVP or polyvinylpyrrolidone, HPMC / hydroxypropyl methyl cellulose, HPC / hydroxypropyl cellulose, methyl cellulose, PVA / polyvinylalcohol, Kollicoat® IR, Kollicoat® IR white or Kollicoat® protect), and preferably is applied on the surface of the fumarate particle(s) at a product temperature not exceeding 40°C, preferably not exceeding 30°C.
  • Said innermost coating layer may comprise known excipients including a surfactant (e.g.
  • Tween SDS / sodium dodecyl sulphate or CTAB / cetyl trimethylammonium bromide
  • a disintegrant e.g. sodium starch glycolate, crosspovidone or sodium crosscarmellose
  • a sublimation decreasing compound e.g. PVP / polyvinylpyrrolidone
  • the coated particle is then coated by the required pH-dependent entero-resistant polymer, wherein the coating may be performed at any temperature including a product temperature exceeding 40°C.
  • the particle(s) may be further coated with one or more other coating layers.
  • the dimethyl fumarate particle(s) coated by a pH-dependent entero-resistant polymer allows for a controlled release of the active pharmaceutical ingredient in the gastrointestinal tract.
  • the release of the active substance in the stomach environment is minimized, whereby the majority of the amount of dimethyl fumarate is released in the intestines.
  • the desired release rate in the intestines may be modulated by choosing the right combination of coating polymer(s), relative thickness of the coating layer surrounding the dimethyl fumarate particle and, optionally, by the inclusion of other excipients known to modify the release of the active substance.
  • the coated particle(s) exhibits a release of dimethyl fumarate, when subjected to an USP or Ph.Eur. in vitro dissolution test in basket equipment at 100 rpm employing simulated gastric fluid (typically being or based on 0. IN HCl) as dissolution medium during the first two hours of the test and simulated intestinal fluid (typically being or based on a phosphate buffer pH 6.8) as the dissolution medium during next hours, as follows:
  • coated particles comprising dimethyl fumarate of the present invention may be used in therapy as such (i.e. the therapeutically effective amount of particles is filled into a suitable dosage form, e.g. a capsule, which may be a hard or a soft gel capsule, or into a sachet) or they may be formulated into oral pharmaceutical preparations, typically compressed dosage forms such as tablets or a mini-tablets.
  • a suitable dosage form e.g. a capsule, which may be a hard or a soft gel capsule, or into a sachet
  • Such pharmaceutical preparations comprise the coated particles comprising dimethyl fumarate disclosed above and at least one pharmaceutically acceptable excipient.
  • Said excipient typically is and without limitation at least one solid filler (diluent) and/or binder, for instance microcrystalline cellulose, lactose, starch etc., at least one disintegrant, for instance sodium starch glycollate, crosspovidone, croscarmellose etc., at least one lubricant, for instance magnesium stearate, sodium stearyl sulfate, etc., at least one glidant, for instance silicone dioxide etc.
  • solid filler (diluent) and/or binder for instance microcrystalline cellulose, lactose, starch etc.
  • at least one disintegrant for instance sodium starch glycollate, crosspovidone, croscarmellose etc.
  • at least one lubricant for instance magnesium stearate, sodium stearyl sulfate, etc.
  • at least one glidant for instance silicone dioxide etc.
  • the relative amount of coated dimethyl fumarate particles in the oral pharmaceutical preparation is advantageously 20-80 wt .
  • the unit amount of dimethyl fumarate to be used in the dosage form of the present invention is preferably from 10 to 300 mg of dimethyl fumarate.
  • the particles, pharmaceutical preparations, and dosage forms of the present invention do not additionally contain monoalkyl esters of fumaric acid nor metal salts thereof. This makes the compositions of the present invention simpler in comparison with the currently marketed mixtures of dialkyl- and monoalkyl fumarates.
  • the medicaments comprising coated particles, pharmaceutical preparations, and dosage forms of the invention are to be used in medicine, typically for the prevention and/or treatment of any of the diseases treatable by dialkyl fumarates, e.g. for the treatment of psoriasis, psoriatic arthritis, neurodermatitis, Crohn disease, multiple sclerosis, etc. They may also be used in combination with one or more other active substances in a combination therapy, wherein the other active substance may be administered in parallel in a separate dosage form or, together with coated dimethyl fumarate particles, in a single combination dosage form. Based on the final composition, the final dosage form comprising dimethyl fumarate may be administered once a day or several times per day, typically two or three times per day.
  • the drug substance was coated with an aqueous 36 wt% (total solids) enteric coating composition shown in Table 1 below.
  • the three batches were coated in a fluid-bed coater (GPCG2) equipped with a Wurster column.
  • the particles were coated at a temperature of the inlet air of about 34°C, the product temperature being about 22-23°C.
  • the coating liquid was water.
  • Dimethyl fumarate particles were coated with the composition shown in Table 2 below.
  • the batch of particles was coated in a fluid bed coater (GPCG2) equipped with a Wurster column.
  • the particles were coated at a temperature of the inlet air of about 35-40°C, the product temperature being about 25-26°C.
  • the coating liquid was an ethanol-water (8:2) mixture.
  • Dimethyl fumarate particles were coated with the composition shown in Table 3 below.
  • the batch of particles was coated in a fluid bed coater (GPCG2) equipped with a Wurster column.
  • the particles were coated at a temperature of the inlet air of about 35-40°C, the product temperature being about 25-26°C.
  • the coating liquid was an ethanol-water (8:2) mixture.
  • the three batches were coated in a fluid-bed coater (GPCG2) equipped with a Wurster column.
  • the particles were coated at a temperature of the inlet air of about 34°C, the product temperature being about 22-23°C.
  • the coating liquid was water.
  • the DFT particles were coated in a fluid-bed coater (GPCG2) equipped with a Wurster column.
  • the particles were coated at a temperature of the inlet air of about 34°C, the product temperature being about 22-23°C.
  • the coating liquid was water.

Landscapes

  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Emergency Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention relates to particles of dimethyl fumarate coated by at least one layer of a pH-dependent entero-resistant polymer. The particles are formulated into a pharmaceutical preparation or dosage form for oral administration of dimethyl fumarate for the treatment of autoimmune diseases, in particular multiple sclerosis.

Description

CONTROLLED RELEASE PARTICLES COMPRISING DIMETHYL
FUMARATE
The present invention relates to coated particles comprising dimethyl fumarate as the active pharmaceutical ingredient. The particles are designed to release the active substance in a controlled manner so that, after oral administration, it is released in the upper
gastrointestinal tract in a minimum amount.
BACKGROUND OF THE INVENTION
Fumaric acid esters are pharmaceutically active substances useful, e.g., for the treatment of psoriasis or other hyperproliferative, inflammatory or autoimmune disorders. For instance, dimethyl fumarate in combination with metal salts of ethyl hydrogenfumarate have been used for the treatment of psoriasis for many years, e.g. under trade name Fumaderm®.
Fumaderm® compositions are marketed as enteric -coated tablets for oral administration.
Compositions comprising dialkyl fumarates and/or alkyl hydrogen fumarates are known in the art. For instance, EP 188 749 discloses fumaric acid derivatives and compositions comprising the same for the treatment of psoriasis. US 4,959,389 discloses compositions comprising salts of monoalkyl fumarates alone or in combination with dialkyl fumarates. US 6,277,882 and US 6,355,676 disclose the use of alkyl hydrogen fumarates for preparing microtablets for the treatment of psoriasis, psoriatic arthritis and other diseases. US 6,509,376 discloses pharmaceutical preparations comprising one or more dialkyl fumarates in the form of enteric-coated micro-tablets and micro-pellets (filled into hard gelatine capsules), made by a conventional wet-granulation process, for use in transplantation medicine or for therapy of autoimmune diseases. DE 38 34 794 discloses pharmaceutical preparations comprising one or more fumaric acid derivatives in the form of e.g. hard gelatine capsules filled with a granulate of said derivatives which are made in a conventional way with a granulation material which is either easily soluble, difficult soluble or insoluble in gastric fluid.
It is well-known, however, that therapy with dimethyl fumarate-comprising
medicaments like, e.g., Fumaderm® is accompanied with various undesired gastrointestinal side-effects, such as nausea, vomiting, and diarrhea. This is due to irritation of the stomach tissue when a too-high peak concentration of the fumarate is released.
Thus, it is desirable to develop a medicament comprising dimethyl fumarate, which would provide reduction in gastro-intestinal related side-effects after oral administration.
It is also well-known that dialkyl fumarates, e.g., dimethyl fumarate, sublimate already at relatively low temperatures. For instance, when Example 1 of the above-cited US 6,509,376 (EP 1 131 065) was reproduced using a conventional wet-granulation process, about 15-20 wt of dimethyl fumarate was lost from the final formulation, most likely because of sublimation during production. Sublimation may also cause loss of dimethyl fumarate during long-term storage of pharmaceutical compositions comprising it.
Thus, it is desirable to develop a medicament comprising dimethyl fumarate which will suffer less from the problem of sublimation of the active substance during production and storage of the composition.
While various pharmaceutical preparations and dosage forms are known, which may, to a certain extent, fulfil the above criteria, an improvement in the matter is still desirable.
BRIEF DESCRIPTION OF THE PRESENT INVENTION
The present invention relates to particles of dimethyl fumarate coated by at least one layer comprising a pharmaceutically acceptable pH-dependent entero-resistant polymer under process conditions at which sublimation of dimethyl fumarate essentially does not take place. The stable coated particles may then be formulated into various pharmaceutical preparations for oral administration, whereby the release rate of the dimethyl fumarate in the patient' s body advantageously can be so-adjusted that irritation of the stomach tissue is minimized.
Thus, in a first aspect, the present invention relates to a particle or a plurality of particles of dimethyl fumarate, wherein the particle is coated by at least one layer comprising a pharmaceutically acceptable pH-dependent entero-resistant polymer.
In a second aspect, the present invention relates to an oral pharmaceutical preparation comprising a plurality of particles of dimethyl fumarate, wherein the particles are coated by at least one layer comprising a pharmaceutically acceptable pH-dependent entero-resistant polymer and at least one pharmaceutically acceptable excipient.
In a third aspect, the present invention relates to an oral dosage form comprising a therapeutically effective amount of the above particles or preparation.
In a fourth aspect, the present invention relates to a process for making a particle or a plurality of particles of dimethyl fumarate comprising coating the dimethyl fumarate particle(s) with at least one layer comprising a pharmaceutically acceptable pH-dependent entero-resistant polymer. In a particular aspect, the temperature of coating, as measured on the product, does not exceed 40°C.
In a fifth aspect, the present invention relates to the use of the above particle(s), preparation or dosage form in medicine, in particular for the treatment of autoimmune diseases such as multiple sclerosis.
BRIEF DESCRIPTION OF DRAWING
Figure 1 shows in vitro dissolution profiles of the enteric-coated compositions of Example 1 according to USP method (basket, 100 rpm). DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to coated dimethyl fumarate particles and to
pharmaceutical preparations and dosage forms comprising them, which are designed for oral administration of dimethyl fumarate for the treatment of various diseases with the aim of minimizing gastrointestinal side-effects such as nausea, vomiting and diarrhoea associated therewith, caused by inherent gastro-irritating behaviour of dimethyl fumarate. Furthermore, undesired sublimation of dimethyl fumarate during making pharmaceutical preparations and dosage forms comprising dimethyl fumarate and during storage thereof are minimized as well.
Dimethyl fumarate is a compound which is well-known in the art and is either commercially available or is preparable by known methods.
The present invention solves both the problem of undesired gastrointestinal side-effects associated with oral administration of dimethyl fumarate and the problem of sublimation of dimethyl fumarate from pharmaceutical preparations by providing a particle or a plurality of particles of dimethyl fumarate coated by at least one layer comprising a pharmaceutically acceptable polymer, the aqueous solubility and degradation of which polymer is dependent on the pH. As a result, a stable and non-irritant dimethyl fumarate particle is provided.
Dimethyl fumarate is a solid state compound at ambient conditions. When in the solid state, it inherently exists in a particulate form. The "particle" of dimethyl fumarate, as used within the context of the present invention, means any particulate form of dimethyl fumarate. It may be a crystalline or an amorphous particle and may it be produced by any conventional method such as crystallization, precipitation, spray drying, etc.
The particle size distribution of dimethyl fumarate for making the coated particle(s) of the present invention typically is a D50 (volume median diameter D(v,0.5)) between 50 and 1000, preferably between 300 and 900, more preferably between 500 and 900 micrometers (micron)
(as measured by laser diffraction using a Mastersizer 2000 (Malvern) including a dry sample dispersion unit Scirocco 2000 (Malvern) with small volume sample tray), but the invention is not limited to any specific range. Generally, it is well-known that the smaller the particle size, the faster the dissolution is of the active pharmaceutical ingredient. The proper particle size of dimethyl fumarate may be obtained in any conventional way, e.g. by milling and/or sieving.
In accordance with the present invention, the particle or plurality of particles of dimethyl fumarate is coated by at least one layer comprising a pharmaceutically acceptable pH-dependent entero-resistant polymer. A polymer is "pH-dependent entero-resistant" if the coating layer comprising it does not allow acidic gastric water to penetrate through but it allows the penetration of water to the dimethyl fumarate core (e.g., by dissolution, swelling, degradation etc.) at the essentially neutral pH of the intestines. In particular, a pH-dependent entero-resistant polymer suitable for purposes of the present invention is a polymer, which dissolves, swells or degrades at a pH of 4.5 or higher, preferably pH 5.0 or higher. In a typical embodiment, the polymer dissolves, swells or degrades at a pH in the range of from 4.5 to 7.0, preferably from 5.0 to 6.5. Non- limiting examples of suitable pH-dependent entero-resistant polymers useful as the coating material for purpose of the present invention include, alone or in combination, a polymethacrylate (for instance a copolymer of methacrylic acid and methyl methacrylate or a copolymer of methacrylic acid and ethyl aery late), hydroxypropyl methyl cellulose acetate succinate (HPMC-AS), hydroxypropyl methyl cellulose phthalate (HPMC- P), polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP) and shellac. The preferred polymer is a polymethacrylate polymer. Examples of suitable commercially available polymers of this kind are Eudragit® L, Eudragit® S and Eudragit® FS and other brand-name equivalents thereof such as Eastacryl® 30D and Kollicoat® 30. Suitable commercially available hydroxypropyl methyl cellulose phthalate polymers are hypromellose phthalate HP-55, hypromellose phthalate HP-55S, and hypromellose phthalate HP-50. Suitable commercially available hydroxypropyl methyl cellulose acetate succinate polymers are Aquoat® polymers.
In an embodiment of the present invention, mixtures of one or more pH-dependent entero-resistant polymers and one or more pH-independent water-insoluble polymers, such as e.g. cellulose acetate, cellulose acetate butyrate, cellulose triacetate, and ethyl cellulose, are used to coat the dimethyl fumarate particle(s). Such combination is generally described in WO 2004/022037. In said embodiment, cellulose acetate and ethyl cellulose are the preferred polymers for use in said combination.
The thickness (relative amount) of the polymer coating layer may affect the overall release rate. For practical purposes, the amount of polymer coating is from 10 to 100 wt , preferably from 20 to 70 wt , more preferably from 30 to 60 wt relative to the weight of the dimethyl fumarate particle(s). In other words, from 10 to 100% etc. weight gain. As is well-known to the person skilled in the art, the smaller the particle size, the more polymer material is needed to provide a coating layer with enteric protection around the dimethyl fumarate particle(s).
Apart from the pharmaceutically acceptable pH-dependent entero-resistant polymer, the coating may comprise other functional excipients, e.g. plasticizers, anti-tacking agents, pH adjusters, stabilizers, pore formers or additives improving the moisture/oxygen barrier, as known in the art.
The dimethyl fumarate particle generally needs not to be granulated and/or mixed with any inactive excipient prior to coating, which is an advantage over other compositions known from the prior art.
Importantly, it was found that the pH-dependent entero-resistant polymer can be advantageously applied during the coating process at temperatures, when measured on the product, not exceeding 40°C, which is below the temperatures that are routinely used in coating operations. This suppresses sublimation of dimethyl fumarate during coating.
Thus, the present invention also provides a process for making a stable pharmaceutical particle or a plurality of particles of dimethyl fumarate comprising coating the dimethyl fumarate particle(s) by at least one layer comprising a pharmaceutically acceptable pH- dependent entero-resistant polymer. In an important aspect, the temperature of coating (as measured on the product) does not exceed 40°C, preferably it does not exceed 30°C. More preferably, the coating temperature (as measured on the product) is between 20 and 25 °C. The coating process advantageously is carried out by spraying the polymer dissolved or suspended in a coating liquid onto the surface of the particle(s). The coating liquid may be water, an alcohol or a mixture thereof.
In an advantageous embodiment of the present invention, the coating process is performed portionwise, wherein more than one layer is applied on the particle(s). In one embodiment, the first (innermost) coating layer is applied at a product temperature not exceeding 40°C, preferably not exceeding 30°C. The subsequent second (third, fourth, etc.) coating layer then may be applied at any conventionally used temperature including a temperature exceeding 40°C, as the dimethyl fumarate particles have already been sufficiently protected against sublimation by the first layer of the polymer. Typically, the product temperature during coating lies in the range of from 40 to 55 °C. The polymer in the second
(third, fourth, etc.) layer can be either a pH-dependent entero-resistant polymer (which is the same or different as the one of the first coating layer) or is a pH-independent water-insoluble polymer (e.g. ethyl cellulose, cellulose acetate, Eudragit® RS, Eudragit® RL, Eudragit® NE,
Eudragit® NM or polyvinyl acetate). The first (innermost) coating layer may advantageously comprise from 5 to 30 wt , in some embodiments up to 40 wt of the total amount of coating material. The pH-dependent entero-resistant polymer used for the innermost coating layer may be partially neutralized as described in WO 2008/135090, whereby the second (third, fourth, etc.) coating layer is made up of a pH-dependent entero-resistant polymer which is less neutralized than the material of the innermost coating layer or not at all neutralized.
In another embodiment, the pH-dependent entero-resistant polymer is not used for the innermost coating layer. Instead, the innermost layer is formed from a pH-independent water- soluble polymer (e.g. PVP or polyvinylpyrrolidone, HPMC / hydroxypropyl methyl cellulose, HPC / hydroxypropyl cellulose, methyl cellulose, PVA / polyvinylalcohol, Kollicoat® IR, Kollicoat® IR white or Kollicoat® protect), and preferably is applied on the surface of the fumarate particle(s) at a product temperature not exceeding 40°C, preferably not exceeding 30°C. Said innermost coating layer may comprise known excipients including a surfactant (e.g. Tween, SDS / sodium dodecyl sulphate or CTAB / cetyl trimethylammonium bromide), a disintegrant (e.g. sodium starch glycolate, crosspovidone or sodium crosscarmellose), and/or a sublimation decreasing compound (e.g. PVP / polyvinylpyrrolidone). The coated particle is then coated by the required pH-dependent entero-resistant polymer, wherein the coating may be performed at any temperature including a product temperature exceeding 40°C. Similarly as described above, the particle(s) may be further coated with one or more other coating layers.
In accordance with the present invention, the dimethyl fumarate particle(s) coated by a pH-dependent entero-resistant polymer allows for a controlled release of the active pharmaceutical ingredient in the gastrointestinal tract. In particular, the release of the active substance in the stomach environment is minimized, whereby the majority of the amount of dimethyl fumarate is released in the intestines. The desired release rate in the intestines may be modulated by choosing the right combination of coating polymer(s), relative thickness of the coating layer surrounding the dimethyl fumarate particle and, optionally, by the inclusion of other excipients known to modify the release of the active substance.
In an embodiment of the present invention, the coated particle(s) exhibits a release of dimethyl fumarate, when subjected to an USP or Ph.Eur. in vitro dissolution test in basket equipment at 100 rpm employing simulated gastric fluid (typically being or based on 0. IN HCl) as dissolution medium during the first two hours of the test and simulated intestinal fluid (typically being or based on a phosphate buffer pH 6.8) as the dissolution medium during next hours, as follows:
within the first two hours after start of the test max. 10 wt of the total amount of dimethyl fumarate is released; and
within the first three hours after start of the test min. 50 wt , preferably min. 60 wt of the total amount of dimethyl fumarate is released.
Alternatively, both tests may be performed separately. The advantageous characteristics of the coated particles of the present invention are then as follows:
in one test, within the first two hours after start of the test in simulated gastric fluid max. 10 wt of the total amount of dimethyl fumarate is released; and
in the other test, within the first one hour after start of the test in simulated intestinal fluid min. 50 wt , preferably min. 60 wt of the total amount of the dimethyl fumarate is released.
The coated particles comprising dimethyl fumarate of the present invention may be used in therapy as such (i.e. the therapeutically effective amount of particles is filled into a suitable dosage form, e.g. a capsule, which may be a hard or a soft gel capsule, or into a sachet) or they may be formulated into oral pharmaceutical preparations, typically compressed dosage forms such as tablets or a mini-tablets. Such pharmaceutical preparations comprise the coated particles comprising dimethyl fumarate disclosed above and at least one pharmaceutically acceptable excipient. Said excipient typically is and without limitation at least one solid filler (diluent) and/or binder, for instance microcrystalline cellulose, lactose, starch etc., at least one disintegrant, for instance sodium starch glycollate, crosspovidone, croscarmellose etc., at least one lubricant, for instance magnesium stearate, sodium stearyl sulfate, etc., at least one glidant, for instance silicone dioxide etc.
The relative amount of coated dimethyl fumarate particles in the oral pharmaceutical preparation is advantageously 20-80 wt .
The unit amount of dimethyl fumarate to be used in the dosage form of the present invention is preferably from 10 to 300 mg of dimethyl fumarate.
In a particular aspect, the particles, pharmaceutical preparations, and dosage forms of the present invention do not additionally contain monoalkyl esters of fumaric acid nor metal salts thereof. This makes the compositions of the present invention simpler in comparison with the currently marketed mixtures of dialkyl- and monoalkyl fumarates.
The medicaments comprising coated particles, pharmaceutical preparations, and dosage forms of the invention are to be used in medicine, typically for the prevention and/or treatment of any of the diseases treatable by dialkyl fumarates, e.g. for the treatment of psoriasis, psoriatic arthritis, neurodermatitis, Crohn disease, multiple sclerosis, etc. They may also be used in combination with one or more other active substances in a combination therapy, wherein the other active substance may be administered in parallel in a separate dosage form or, together with coated dimethyl fumarate particles, in a single combination dosage form. Based on the final composition, the final dosage form comprising dimethyl fumarate may be administered once a day or several times per day, typically two or three times per day.
The invention will be further described with reference to the following non-limiting examples. EXAMPLES
Example 1
Dimethyl fumarate having three different particle size distributions was coated (PSD was based on sieve fractionation):
[A] -smaller than 500 micron (82% between 150-500 micron),
[B] - larger than 500 micron (82% between 500-900 micron), and
[C] - unsieved (82% between 150-900 micron).
The drug substance was coated with an aqueous 36 wt% (total solids) enteric coating composition shown in Table 1 below.
Figure imgf000012_0001
The three batches were coated in a fluid-bed coater (GPCG2) equipped with a Wurster column. The particles were coated at a temperature of the inlet air of about 34°C, the product temperature being about 22-23°C. The coating liquid was water.
The in vitro dissolution profiles of A, B and C are shown in Figure 1 according to USP method (basket, 100 rpm).
Example 2
Dimethyl fumarate particles were coated with the composition shown in Table 2 below.
Figure imgf000013_0001
The batch of particles was coated in a fluid bed coater (GPCG2) equipped with a Wurster column. The particles were coated at a temperature of the inlet air of about 35-40°C, the product temperature being about 25-26°C. When the first part of the coating was applied the inlet temperature was increased to higher temperatures and the remaining coating was coated at 35-37°C. The coating liquid was an ethanol-water (8:2) mixture.
Example 3
Dimethyl fumarate particles were coated with the composition shown in Table 3 below.
Figure imgf000013_0002
The batch of particles was coated in a fluid bed coater (GPCG2) equipped with a Wurster column. The particles were coated at a temperature of the inlet air of about 35-40°C, the product temperature being about 25-26°C. When the first part of the coating was applied the inlet temperature was increased to higher temperatures and the remaining coating was coated at 35-37°C. The coating liquid was an ethanol-water (8:2) mixture.
Example 4
Dimethyl fumarate D50 -325 micron was coated with the composition of Table 4:
Figure imgf000014_0001
The three batches were coated in a fluid-bed coater (GPCG2) equipped with a Wurster column. The particles were coated at a temperature of the inlet air of about 34°C, the product temperature being about 22-23°C. The coating liquid was water.
Example 5
Dimethyl fumarate D50 -850 micron was coated with the composition of Table 5:
Figure imgf000014_0002
The DFT particles were coated in a fluid-bed coater (GPCG2) equipped with a Wurster column. The particles were coated at a temperature of the inlet air of about 34°C, the product temperature being about 22-23°C. The coating liquid was water.

Claims

A particle or a plurality of particles of dimethyl fumarate, wherein each particle is coated by at least one layer comprising a pharmaceutically acceptable pH-dependent entero-resistant polymer.
The particle(s) according to claim 1, having a particle size distribution D50 of between 50 and 1000 micrometers.
The particle(s) according to claim 1 or 2, wherein the pH-dependent entero-resistant polymer is, alone or in combination, a polymethacrylate, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate or shellac.
The particle(s) according to any one of claims 1-3, wherein the polymer is a copolymer of methacrylic acid and methyl methacrylate or a copolymer of methacrylic acid and ethyl acrylate.
The particle(s) according to any one of claims 1-4, wherein the amount of polymer coating is from 10 to 100 wt relative to the weight of the dimethyl fumarate particle(s).
The particle(s) according to any one of claims 1-5, which exhibit a release of dimethyl fumarate, when subjected to an USP or Ph. Eur. in vitro dissolution test in basket equipment at 100 rpm employing simulated gastric fluid as dissolution medium during the first two hours of the test and simulated intestinal fluid as the dissolution medium during the next hours, as follows:
within the first two hours after start of the test max. 10 wt of the total amount of dimethyl fumarate is released; and
within the first three hours after start of the test min. 50 wt of the total amount of dimethyl fumarate is released.
7. An oral pharmaceutical preparation comprising particle(s) of dimethyl fumarate according to any one of claims 1-6 and at least one pharmaceutically acceptable excipient.
8. An oral dosage form comprising a therapeutically effective amount of particles
according to any one of claims 1-6 or a preparation according to claim 7.
9. A process for making a particle or a plurality of particles of dimethyl fumarate
according to any one of claims 1-6 comprising coating the dimethyl fumarate particle(s) with at least one layer comprising a pharmaceutically acceptable pH-dependent entero- resistant polymer.
10. The process according to claim 9, wherein the temperature of coating, as measured on the product, does not exceed 40°C.
11. The process according to claim 9 or 10, wherein the coating liquid is water, an alcohol or a mixture thereof.
12. The particle(s) according to any one of claims 1-6, the pharmaceutical preparation according to claim 7 or the dosage form according to claim 8 for use in medicine.
13. The particle(s), preparation or dosage form according to claim 12 for the treatment of autoimmune diseases, in particular multiple sclerosis.
PCT/EP2012/073406 2011-11-24 2012-11-22 Controlled release particles comprising dimethyl fumarate Ceased WO2013076216A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
RU2014125430/15A RU2014125430A (en) 2011-11-24 2012-11-22 CONTROLLED RELEASE OF PARTICLES CONTAINING DIMETHYLFUMARATE
EP12791165.9A EP2782561A1 (en) 2011-11-24 2012-11-22 Controlled release particles comprising dimethyl fumarate

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP2011070955 2011-11-24
EPPCT/EP2011/070955 2011-11-24

Publications (1)

Publication Number Publication Date
WO2013076216A1 true WO2013076216A1 (en) 2013-05-30

Family

ID=47226159

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2012/073406 Ceased WO2013076216A1 (en) 2011-11-24 2012-11-22 Controlled release particles comprising dimethyl fumarate

Country Status (2)

Country Link
RU (1) RU2014125430A (en)
WO (1) WO2013076216A1 (en)

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8669281B1 (en) 2013-03-14 2014-03-11 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases
US20150079180A1 (en) * 2013-09-18 2015-03-19 Xenoport, Inc. Nanoparticle compositions of dimethyl fumarate
US9302977B2 (en) 2013-06-07 2016-04-05 Xenoport, Inc. Method of making monomethyl fumarate
US9326947B1 (en) 2014-02-28 2016-05-03 Banner Life Sciences Llc Controlled release fumarate esters
US9326965B2 (en) 2014-02-28 2016-05-03 Banner Life Sciences Llc Controlled release fumarate esters
WO2016081676A1 (en) * 2014-11-19 2016-05-26 Biogen Ma Inc. Pharmaceutical bead formulations comprising dimethyl fumarate
US9416096B2 (en) 2013-09-06 2016-08-16 Xenoport, Inc. Crystalline forms of (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, methods of synthesis and use
US9421182B2 (en) 2013-06-21 2016-08-23 Xenoport, Inc. Cocrystals of dimethyl fumarate
US9452972B2 (en) 2008-08-19 2016-09-27 Xenoport, Inc. Methods of using prodrugs of methyl hydrogen fumarate and pharmaceutical compositions thereof
US9505776B2 (en) 2013-03-14 2016-11-29 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases
WO2016205270A1 (en) * 2015-06-17 2016-12-22 Biogen Ma Inc. Dimethyl fumarate particles and pharmaceutical compositions thereof
US9566259B1 (en) 2015-08-31 2017-02-14 Banner Life Sciences Llc Fumarate ester dosage forms
US9597292B2 (en) 2012-08-22 2017-03-21 Xenoport, Inc. Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof
US9604922B2 (en) 2014-02-24 2017-03-28 Alkermes Pharma Ireland Limited Sulfonamide and sulfinamide prodrugs of fumarates and their use in treating various diseases
WO2017114593A1 (en) * 2015-12-31 2017-07-06 Zaklady Farmaceutyczne Polpharma S.A. Process for preparation of an enteric coated granulate comprising dimethyl fumarate
WO2017129370A1 (en) * 2016-01-28 2017-08-03 Zaklady Farmaceutyczne Polpharma S.A. Process for preparation of a granulate comprising dimethyl fumarate
EP3326653A1 (en) * 2016-11-23 2018-05-30 Sanovel Ilac Sanayi ve Ticaret A.S. Delayed release dosage forms comprising dimethyl fumarate
US9999672B2 (en) 2014-03-24 2018-06-19 Xenoport, Inc. Pharmaceutical compositions of fumaric acid esters
US10085961B2 (en) 2015-06-01 2018-10-02 Sun Pharmaceutical Industries Limited Pharmaceutical compositions of dimethyl fumarate
US10098863B2 (en) 2014-02-28 2018-10-16 Banner Life Sciences Llc Fumarate esters
US10172794B2 (en) * 2013-12-13 2019-01-08 Biogen Ma Inc. Controlled release dosage form for once daily administration of dimethyl fumarate
US10179118B2 (en) 2013-03-24 2019-01-15 Arbor Pharmaceuticals, Llc Pharmaceutical compositions of dimethyl fumarate
EP3656379A1 (en) 2013-12-12 2020-05-27 Almirall S.A. Pharmaceutical compositions comprising dimethyl fumarate
US10945984B2 (en) 2012-08-22 2021-03-16 Arbor Pharmaceuticals, Llc Methods of administering monomethyl fumarate and prodrugs thereof having reduced side effects
US11052062B2 (en) 2004-10-08 2021-07-06 Biogen Swiss Manufacturing Gmbh Controlled release pharmaceutical compositions comprising a fumaric acid ester
US11446055B1 (en) 2018-10-18 2022-09-20 Lumoptik, Inc. Light assisted needle placement system and method
US11903918B2 (en) 2020-01-10 2024-02-20 Banner Life Sciences Llc Fumarate ester dosage forms with enhanced gastrointestinal tolerability

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0188749A2 (en) 1985-01-15 1986-07-30 Peter Paul Prof. Dr. Speiser Derivatives of fumaric acid, process for their preparation and pharmaceutical compositions containing them
DE3834794A1 (en) 1988-10-12 1990-04-19 F Schielein Composition for oral administration to treat psoriasis
US4959389A (en) 1987-10-19 1990-09-25 Speiser Peter P Pharmaceutical preparation for the treatment of psoriatic arthritis
US6277882B1 (en) 1998-03-31 2001-08-21 Fumapharm Ag Utilization of alkyl hydrogen fumarates for treating psoriasis, psoriatic arthritis, neurodermatitis and regional enteritis
EP1131065A2 (en) 1998-11-19 2001-09-12 Fumapharm AG Utilisation of dialkylfumarates
US6355676B1 (en) 1998-10-20 2002-03-12 Fumapharm Ag Fumaric acid micro tablets
WO2004022037A1 (en) 2002-09-04 2004-03-18 Ranbaxy Laboratories Limited Taste masked dosage forms and processes for their preparation
WO2008135090A1 (en) 2007-05-07 2008-11-13 Evonik Röhm Gmbh Solid dosage forms comprising an enteric coating with accelerated drug release
US20080299196A1 (en) * 2005-10-07 2008-12-04 Aditech Pharma Ab Controlled Release Pharmaceutical Compositions Comprising a Fumaric Acid Ester
US20090304790A1 (en) 2004-10-08 2009-12-10 Aditech Pharma Ab Controlled release pharmaceutical compositions comprising a fumaric acid ester
WO2010079221A1 (en) * 2009-01-09 2010-07-15 Forward Pharma A/S Pharmaceutical composition comprising one or more fumaric acid esters

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0188749A2 (en) 1985-01-15 1986-07-30 Peter Paul Prof. Dr. Speiser Derivatives of fumaric acid, process for their preparation and pharmaceutical compositions containing them
US4959389A (en) 1987-10-19 1990-09-25 Speiser Peter P Pharmaceutical preparation for the treatment of psoriatic arthritis
DE3834794A1 (en) 1988-10-12 1990-04-19 F Schielein Composition for oral administration to treat psoriasis
US6277882B1 (en) 1998-03-31 2001-08-21 Fumapharm Ag Utilization of alkyl hydrogen fumarates for treating psoriasis, psoriatic arthritis, neurodermatitis and regional enteritis
US6355676B1 (en) 1998-10-20 2002-03-12 Fumapharm Ag Fumaric acid micro tablets
EP1131065A2 (en) 1998-11-19 2001-09-12 Fumapharm AG Utilisation of dialkylfumarates
US6509376B1 (en) 1998-11-19 2003-01-21 Fumapharm Ag Utilization of dialkyfumarates
WO2004022037A1 (en) 2002-09-04 2004-03-18 Ranbaxy Laboratories Limited Taste masked dosage forms and processes for their preparation
US20090304790A1 (en) 2004-10-08 2009-12-10 Aditech Pharma Ab Controlled release pharmaceutical compositions comprising a fumaric acid ester
US20080299196A1 (en) * 2005-10-07 2008-12-04 Aditech Pharma Ab Controlled Release Pharmaceutical Compositions Comprising a Fumaric Acid Ester
WO2008135090A1 (en) 2007-05-07 2008-11-13 Evonik Röhm Gmbh Solid dosage forms comprising an enteric coating with accelerated drug release
WO2010079221A1 (en) * 2009-01-09 2010-07-15 Forward Pharma A/S Pharmaceutical composition comprising one or more fumaric acid esters

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
EVONIK RÖHM GMBH: "It`s not Rocket Science to Reach Higher Coating Efficiency PlasACRYL ™ T20 makes it possible", EVONIK BROCHURE, August 2010 (2010-08-01), pages 1 - 6, XP055420456
See also references of EP2782561A1 *

Cited By (73)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11052062B2 (en) 2004-10-08 2021-07-06 Biogen Swiss Manufacturing Gmbh Controlled release pharmaceutical compositions comprising a fumaric acid ester
US11229619B2 (en) 2004-10-08 2022-01-25 Biogen Swiss Manufacturing Gmbh Controlled release pharmaceutical compositions comprising a fumaric acid ester
US9452972B2 (en) 2008-08-19 2016-09-27 Xenoport, Inc. Methods of using prodrugs of methyl hydrogen fumarate and pharmaceutical compositions thereof
US10940117B2 (en) 2012-08-22 2021-03-09 Arbor Pharmaceuticals, Llc Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof
US10945984B2 (en) 2012-08-22 2021-03-16 Arbor Pharmaceuticals, Llc Methods of administering monomethyl fumarate and prodrugs thereof having reduced side effects
US10716760B2 (en) 2012-08-22 2020-07-21 Arbor Pharmaceuticals, Llc Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof
US9597292B2 (en) 2012-08-22 2017-03-21 Xenoport, Inc. Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof
US11230548B2 (en) 2013-03-14 2022-01-25 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases
US11905298B2 (en) 2013-03-14 2024-02-20 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases
US8669281B1 (en) 2013-03-14 2014-03-11 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases
US9090558B2 (en) 2013-03-14 2015-07-28 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases
US9505776B2 (en) 2013-03-14 2016-11-29 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases
US11083703B2 (en) 2013-03-14 2021-08-10 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases
US10596140B2 (en) 2013-03-14 2020-03-24 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases
US12076306B2 (en) 2013-03-14 2024-09-03 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases
US11679092B2 (en) 2013-03-14 2023-06-20 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases
US10406133B2 (en) 2013-03-14 2019-09-10 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases
US11938111B2 (en) 2013-03-24 2024-03-26 Arbor Pharmaceuticals, Llc Pharmaceutical compositions of dimethyl fumarate
US10179118B2 (en) 2013-03-24 2019-01-15 Arbor Pharmaceuticals, Llc Pharmaceutical compositions of dimethyl fumarate
US12440468B2 (en) 2013-03-24 2025-10-14 Arbor Pharmaceuticals, Llc Pharmaceutical compositions of dimethyl fumarate
US9302977B2 (en) 2013-06-07 2016-04-05 Xenoport, Inc. Method of making monomethyl fumarate
US9421182B2 (en) 2013-06-21 2016-08-23 Xenoport, Inc. Cocrystals of dimethyl fumarate
US9682057B2 (en) 2013-09-06 2017-06-20 Xenoport, Inc. Crystalline forms of (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, methods of synthesis and use
US9416096B2 (en) 2013-09-06 2016-08-16 Xenoport, Inc. Crystalline forms of (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, methods of synthesis and use
WO2015042294A1 (en) * 2013-09-18 2015-03-26 Xenoport, Inc. Nanoparticle compositions of dimethyl fumarate
US20150079180A1 (en) * 2013-09-18 2015-03-19 Xenoport, Inc. Nanoparticle compositions of dimethyl fumarate
EP3656379A1 (en) 2013-12-12 2020-05-27 Almirall S.A. Pharmaceutical compositions comprising dimethyl fumarate
US10172794B2 (en) * 2013-12-13 2019-01-08 Biogen Ma Inc. Controlled release dosage form for once daily administration of dimethyl fumarate
US9604922B2 (en) 2014-02-24 2017-03-28 Alkermes Pharma Ireland Limited Sulfonamide and sulfinamide prodrugs of fumarates and their use in treating various diseases
US9820960B2 (en) 2014-02-28 2017-11-21 Banner Life Sciences Llc Fumarate ester pharmaceutical compositions
US10105336B2 (en) 2014-02-28 2018-10-23 Banner Life Sciences Llc Fumarate ester pharmaceutical compositions
US9511043B2 (en) 2014-02-28 2016-12-06 Banner Life Sciences Llc Fumarate ester pharmaceutical compositions
US10918616B2 (en) 2014-02-28 2021-02-16 Banner Life Sciences Llc Fumarate ester pharmaceutical compositions
US10918615B2 (en) 2014-02-28 2021-02-16 Banner Life Sciences Llc Fumarate esters
US10098863B2 (en) 2014-02-28 2018-10-16 Banner Life Sciences Llc Fumarate esters
US10918617B2 (en) 2014-02-28 2021-02-16 Banner Life Sciences Llc Fumarate ester pharmaceutical compositions
US9814691B2 (en) 2014-02-28 2017-11-14 Banner Life Sciences Llc Fumarate ester pharmaceutical compositions
US10105337B2 (en) 2014-02-28 2018-10-23 Banner Life Sciences Llc Fumarate ester pharmaceutical compositions
US9517209B2 (en) 2014-02-28 2016-12-13 Banner Life Sciences Llc Fumarate ester pharmaceutical compositions
US9326947B1 (en) 2014-02-28 2016-05-03 Banner Life Sciences Llc Controlled release fumarate esters
EP3501510A1 (en) 2014-02-28 2019-06-26 Banner Life Sciences LLC Controlled release enteric soft capsules of fumarate esters
EP3766487A1 (en) 2014-02-28 2021-01-20 Banner Life Sciences LLC Controlled release enteric soft capsules of fumarate esters
US9326965B2 (en) 2014-02-28 2016-05-03 Banner Life Sciences Llc Controlled release fumarate esters
US11135296B2 (en) 2014-03-24 2021-10-05 Arbor Pharmaceuticals, Llc Pharmaceutical compositions of fumaric acid esters
US9999672B2 (en) 2014-03-24 2018-06-19 Xenoport, Inc. Pharmaceutical compositions of fumaric acid esters
AU2015349896B2 (en) * 2014-11-19 2021-04-29 Biogen Ma Inc. Pharmaceutical bead formulations comprising dimethyl fumarate
IL252116B (en) * 2014-11-19 2022-08-01 Biogen Ma Inc Pharmaceutical granule formulations containing dimethyl fumarate
WO2016081676A1 (en) * 2014-11-19 2016-05-26 Biogen Ma Inc. Pharmaceutical bead formulations comprising dimethyl fumarate
US11197842B2 (en) 2014-11-19 2021-12-14 Biogen Ma Inc. Pharmaceutical bead formulations comprising dimethyl fumarate
EA039157B1 (en) * 2014-11-19 2021-12-13 Байоджен Ма Инк. Pharmaceutical bead formulations comprising dimethyl fumarate
CN107205937A (en) * 2014-11-19 2017-09-26 比奥根Ma公司 Drug bead formulation comprising dimethyl fumarate
JP2017534668A (en) * 2014-11-19 2017-11-24 バイオジェン・エムエイ・インコーポレイテッドＢｉｏｇｅｎ ＭＡ Ｉｎｃ． Pharmaceutical bead formulation containing dimethyl fumarate
US10085961B2 (en) 2015-06-01 2018-10-02 Sun Pharmaceutical Industries Limited Pharmaceutical compositions of dimethyl fumarate
JP2018517735A (en) * 2015-06-17 2018-07-05 バイオジェン・エムエイ・インコーポレイテッドＢｉｏｇｅｎ ＭＡ Ｉｎｃ． Dimethyl fumarate particles and pharmaceutical compositions thereof
WO2016205270A1 (en) * 2015-06-17 2016-12-22 Biogen Ma Inc. Dimethyl fumarate particles and pharmaceutical compositions thereof
US11291642B2 (en) 2015-06-17 2022-04-05 Biogen Ma Inc. Dimethyl fumarate particles and pharmaceutical compositions thereof
JP2022042512A (en) * 2015-06-17 2022-03-14 バイオジェン・エムエイ・インコーポレイテッド Dimethyl fumarate particles and their pharmaceutical compositions
US9636318B2 (en) 2015-08-31 2017-05-02 Banner Life Sciences Llc Fumarate ester dosage forms
US11590095B2 (en) 2015-08-31 2023-02-28 Banner Life Sciences Llc Fumarate ester dosage forms
US9814692B2 (en) 2015-08-31 2017-11-14 Banner Life Sciences Llc Fumarate ester dosage forms
US10105335B2 (en) 2015-08-31 2018-10-23 Banner Life Sciences Llc Fumarate ester dosage forms
US9566259B1 (en) 2015-08-31 2017-02-14 Banner Life Sciences Llc Fumarate ester dosage forms
US9820961B2 (en) 2015-08-31 2017-11-21 Banner Life Sciences Llc Fumarate ester dosage forms
US9636319B1 (en) 2015-08-31 2017-05-02 Banner Life Sciences Llc Fumarate ester dosage forms
US10945985B2 (en) 2015-08-31 2021-03-16 Banner Life Sciences Llc Fumarate ester dosage forms
WO2017114593A1 (en) * 2015-12-31 2017-07-06 Zaklady Farmaceutyczne Polpharma S.A. Process for preparation of an enteric coated granulate comprising dimethyl fumarate
US11013693B2 (en) 2015-12-31 2021-05-25 Zaklady Farmaceutyczne Polpharma S.A. Process for preparation of an enteric coated granulate comprising dimethyl fumarate
WO2017129370A1 (en) * 2016-01-28 2017-08-03 Zaklady Farmaceutyczne Polpharma S.A. Process for preparation of a granulate comprising dimethyl fumarate
EP3513811A1 (en) * 2016-11-23 2019-07-24 Sanovel Ilac Sanayi ve Ticaret A.S. Delayed release dosage forms comprising dimethyl fumarate
WO2018095996A1 (en) * 2016-11-23 2018-05-31 Sanovel Ilac Sanayi Ve Ticaret A.S. Delayed release dosage forms comprising dimethyl fumarate
EP3326653A1 (en) * 2016-11-23 2018-05-30 Sanovel Ilac Sanayi ve Ticaret A.S. Delayed release dosage forms comprising dimethyl fumarate
US11446055B1 (en) 2018-10-18 2022-09-20 Lumoptik, Inc. Light assisted needle placement system and method
US11903918B2 (en) 2020-01-10 2024-02-20 Banner Life Sciences Llc Fumarate ester dosage forms with enhanced gastrointestinal tolerability

Also Published As

Publication number Publication date
RU2014125430A (en) 2015-12-27

Similar Documents

Publication Publication Date Title
WO2013076216A1 (en) Controlled release particles comprising dimethyl fumarate
CA2348090C (en) Oral pulsed dose drug delivery system
KR101556797B1 (en) Pharmaceutical composition with controlled active ingredient delivery for active ingredients with good solubility in water
CN1886119B (en) Pantoprazole multiparticulate formulations
US7955622B2 (en) Controlled-release galantamine formulations
RU2372893C2 (en) Coated compound containing pharmaceutical agent
KR101588259B1 (en) Formulation of doxylamine and pyridoxine and/or metabolites or salts thereof
KR20090029830A (en) Oral pharmaceutical preparations with controlled release of active ingredient in small intestine and preparation method thereof
JP2004521910A (en) Tramadol
HUP0201687A2 (en) Oral administration form for administering a fixed tramadol and diclofenac combination
CA2637444A1 (en) Coated pharmaceutical composition of tolterodine or a salt thereof having rapid dissolution at acidic conditions and slow dissolution at higher ph values
AU2008288106A1 (en) Extended release compositions comprising mycophenolate sodium and processes thereof
US20130236544A1 (en) Stable pharmaceutical compositions of fesoterodine
JP2015500853A (en) Immediate release multi-unit pellet system
KR20180133503A (en) Oral pharmaceutical composition of mesalazine
US20060153925A1 (en) Novel solid pharmaceutical composition comprising amisulpride
EP2533766B1 (en) Pharmaceutical mini-tablets for sustained release of flecainide acetate
US20160074333A1 (en) Pharmaceutical compositions of tamsulosin or salts thereof
WO2004108117A2 (en) Extended release osmo-microsealed formulation comprising venlafaxine
US12171742B2 (en) Duloxetine sprinkles
WO2018077479A1 (en) Pharmaceutical compositions comprising a fumaric acid ester and method for the preparation thereof
US20130202688A1 (en) Delayed release oral disintegrating pharmaceutical compositions of lansoprazole
EP2782561A1 (en) Controlled release particles comprising dimethyl fumarate
RU2820820C2 (en) Pharmaceutical compositions of acotiamide and proton pump inhibitor
JP2013536832A (en) Milnacipran controlled release pharmaceutical composition

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12791165

Country of ref document: EP

Kind code of ref document: A1

DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2012791165

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2014125430

Country of ref document: RU

Kind code of ref document: A