EP2782561A1 - Controlled release particles comprising dimethyl fumarate - Google Patents

Controlled release particles comprising dimethyl fumarate

Info

Publication number
EP2782561A1
EP2782561A1 EP12791165.9A EP12791165A EP2782561A1 EP 2782561 A1 EP2782561 A1 EP 2782561A1 EP 12791165 A EP12791165 A EP 12791165A EP 2782561 A1 EP2782561 A1 EP 2782561A1
Authority
EP
European Patent Office
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.)
Withdrawn
Application number
EP12791165.9A
Other languages
German (de)
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 EP12791165.9A priority Critical patent/EP2782561A1/en
Priority claimed from PCT/EP2012/073406 external-priority patent/WO2013076216A1/en
Publication of EP2782561A1 publication Critical patent/EP2782561A1/en
Withdrawn legal-status Critical Current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.
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.
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.
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:
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:
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.
EP12791165.9A 2011-11-24 2012-11-22 Controlled release particles comprising dimethyl fumarate Withdrawn EP2782561A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP12791165.9A EP2782561A1 (en) 2011-11-24 2012-11-22 Controlled release particles comprising dimethyl fumarate

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP2011070955 2011-11-24
PCT/EP2012/073406 WO2013076216A1 (en) 2011-11-24 2012-11-22 Controlled release particles comprising dimethyl fumarate
EP12791165.9A EP2782561A1 (en) 2011-11-24 2012-11-22 Controlled release particles comprising dimethyl fumarate

Publications (1)

Publication Number Publication Date
EP2782561A1 true EP2782561A1 (en) 2014-10-01

Family

ID=51392986

Family Applications (1)

Application Number Title Priority Date Filing Date
EP12791165.9A Withdrawn EP2782561A1 (en) 2011-11-24 2012-11-22 Controlled release particles comprising dimethyl fumarate

Country Status (1)

Country Link
EP (1) EP2782561A1 (en)

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1153927A (en) 1966-08-25 1969-06-04 Wilhelm Hoerrmann Medicinal Composition Suitable For Treating Diseases Of The Retina
US5424332A (en) 1987-10-19 1995-06-13 Speiser; Peter P. Pharmaceutical composition and process for the production thereof
US5484610A (en) 1991-01-02 1996-01-16 Macromed, Inc. pH and temperature sensitive terpolymers for oral drug delivery
US6359003B1 (en) 1998-08-31 2002-03-19 Fumapharm Ag Use of fumaric acid derivatives in transplant medicine
US6436992B1 (en) 1997-05-20 2002-08-20 Fumapharm Ag Use of fumaric acid derivatives
WO2003004001A1 (en) 2001-07-06 2003-01-16 Lifecycle Pharma A/S Controlled agglomeration
US20030013761A1 (en) 2000-01-10 2003-01-16 Joshi Rajendra Kumar Use of fumaric acid derivatives for treating mitochondrial diseases
US6537584B1 (en) 1999-11-12 2003-03-25 Macromed, Inc. Polymer blends that swell in an acidic environment and deswell in a basic environment
WO2003080034A2 (en) 2002-03-27 2003-10-02 Pharmatech Gmbh Method for the production and the use of microparticles and nanoparticles by constructive micronisation
DE10360869A1 (en) * 2003-09-09 2005-04-07 Fumapharm Ag Use of fumaric acid derivatives for the treatment of heart failure, hyperkeratosis and asthma
US20090304790A1 (en) * 2004-10-08 2009-12-10 Aditech Pharma Ab Controlled release pharmaceutical compositions comprising a fumaric acid ester

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1153927A (en) 1966-08-25 1969-06-04 Wilhelm Hoerrmann Medicinal Composition Suitable For Treating Diseases Of The Retina
US5424332A (en) 1987-10-19 1995-06-13 Speiser; Peter P. Pharmaceutical composition and process for the production thereof
US5484610A (en) 1991-01-02 1996-01-16 Macromed, Inc. pH and temperature sensitive terpolymers for oral drug delivery
US6436992B1 (en) 1997-05-20 2002-08-20 Fumapharm Ag Use of fumaric acid derivatives
US6359003B1 (en) 1998-08-31 2002-03-19 Fumapharm Ag Use of fumaric acid derivatives in transplant medicine
US6537584B1 (en) 1999-11-12 2003-03-25 Macromed, Inc. Polymer blends that swell in an acidic environment and deswell in a basic environment
US20030013761A1 (en) 2000-01-10 2003-01-16 Joshi Rajendra Kumar Use of fumaric acid derivatives for treating mitochondrial diseases
WO2003004001A1 (en) 2001-07-06 2003-01-16 Lifecycle Pharma A/S Controlled agglomeration
WO2003080034A2 (en) 2002-03-27 2003-10-02 Pharmatech Gmbh Method for the production and the use of microparticles and nanoparticles by constructive micronisation
DE10360869A1 (en) * 2003-09-09 2005-04-07 Fumapharm Ag Use of fumaric acid derivatives for the treatment of heart failure, hyperkeratosis and asthma
US20090304790A1 (en) * 2004-10-08 2009-12-10 Aditech Pharma Ab Controlled release pharmaceutical compositions comprising a fumaric acid ester

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO2013076216A1 *

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
US7955622B2 (en) Controlled-release galantamine formulations
KR101588259B1 (en) Formulation of doxylamine and pyridoxine and/or metabolites or salts thereof
US20060153925A1 (en) Novel solid pharmaceutical composition comprising amisulpride
KR102381586B1 (en) Oral pharmaceutical composition of mesalazine
RU2372893C2 (en) Coated compound containing pharmaceutical agent
JP2004521910A (en) Tramadol
CA2637444A1 (en) Coated pharmaceutical composition of tolterodine or a salt thereof having rapid dissolution at acidic conditions and slow dissolution at higher ph values
WO2012156981A1 (en) Pharmaceutical compositions of lurasidone
JP2015500853A (en) Immediate release multi-unit pellet system
US20130236544A1 (en) Stable pharmaceutical compositions of fesoterodine
AU2017348941B2 (en) Pharmaceutical compositions comprising a fumaric acid ester and method for the preparation thereof
EP2533766B1 (en) Pharmaceutical mini-tablets for sustained release of flecainide acetate
US20160074333A1 (en) Pharmaceutical compositions of tamsulosin or salts thereof
US20130202688A1 (en) Delayed release oral disintegrating pharmaceutical compositions of lansoprazole
US11202772B2 (en) Duloxetine sprinkles
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
CN108472260B (en) Process for preparing enteric coated granules comprising dimethyl fumarate
TR2023000985A2 (en) FORMULATION OF PROPIVERINE PROVIDING CONTROLLED RELEASE
WO2024200335A1 (en) Pharmaceutical dosage forms comprising (4s)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5- dioxo-14-(trifluoromethyl)-32 h-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide
AU2021265311A1 (en) Novel multiparticulate pharmaceutical composition of tamsulosin and solifenacin

Legal Events

Date Code Title Description
TPAC Observations filed by third parties

Free format text: ORIGINAL CODE: EPIDOSNTIPA

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20140624

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20160105

TPAC Observations filed by third parties

Free format text: ORIGINAL CODE: EPIDOSNTIPA

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

INTG Intention to grant announced

Effective date: 20180215

RIN1 Information on inventor provided before grant (corrected)

Inventor name: VAN DEN HEUVEL-JANSEN, KORINDE ANNEMARIE

GRAJ Information related to disapproval of communication of intention to grant by the applicant or resumption of examination proceedings by the epo deleted

Free format text: ORIGINAL CODE: EPIDOSDIGR1

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

INTC Intention to grant announced (deleted)
INTG Intention to grant announced

Effective date: 20180626

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20181107