WO2009105023A1

WO2009105023A1 - Pharmaceutical formulation comprising oxabispidines / 236

Info

Publication number: WO2009105023A1
Application number: PCT/SE2009/050184
Authority: WO
Inventors: Anders R Berggren; Hans Carlsson; Hans JÖNSSON; Kristina Roos; Erik SÖDERLIND
Original assignee: Astrazeneca Ab
Priority date: 2008-02-22
Filing date: 2009-02-19
Publication date: 2009-08-27
Also published as: TW200940110A; AR070617A1; UY31669A1; PE20091464A1

Abstract

The present invention relates to modified release formulations comprising oxapispidines, such as the compound tert-butyl (2- {7- [2- (4-cyano-2-fluorophenoxy) ethyl] -9-oxa-3, 7-diazabicyclo- [3.3.1] non-3-yl} ethyl) carbamate. Said formulations are preferably in the form of multiple unit systems providing for an immediate release of drug in combination with an extended release of drug during a period of time of up to 24 hours. The compositions are useful in the treatment of cardiac arrhythmias and additionally providing the possibility for early detection of patients responding with an unfavourable QT prolongation.

Description

PHARMACEUTICAL FORMULATION COMPRISING OXABISPIDINES /236

Field of the Invention

This invention relates to modified release pharmaceutical formulations, to the manufacture of such formulations, and to the use of such a formulation in the treatment or prevention of cardiac arrhythmias.

Background

Cardiac arrhythmias may be defined as abnormalities in the rate, regularity, or site of origin of the cardiac impulse or as disturbances in conduction which causes an abnormal sequence of activation. Arrhythmias may be classified clinically by means of the presumed site of origin (i.e. as supraventricular, including atrial and atrioventricular, arrhythmias and ventricular arrhythmias) and/or by means of rate (i.e. bradyarrhythmias (slow) and tachyarrhythmias (fast)).

The oxabispidines of interest for the present invention are so called Class III antiarrhythmic drugs which may be defined as drugs which prolong the trans-membrane action potential duration (which can be caused by a block of outward K⁺ currents or from an increase of inward ion currents) and refractoriness, without affecting cardiac conduction.

Compounds which are indicated as being useful in the treatment of cardiac arrhythmias are known from the following international patent applications WO 01/28992, WO2005/123747, WO2005/123748, WO2006/135316 and WO2007/069986.

It is often necessary to administer pharmaceutically active compounds frequently throughout the day in order to maintain a desired therapeutic level of active principle in plasma, body tissues and/or the gastrointestinal tract. This is particularly the case where it is intended to deliver the drug orally and to provide a uniform response over an extended period of time.

Over the last thirty or so years, modified release dosage forms have increasingly become a preferred method of delivering certain drugs to patients, particularly via the oral route. Such forms may e.g. provide for release of drug over an extended period of time, thus reducing the number of required daily doses, and during which time the rate of release may be substantially uniform and/or constant, within a specific part of the gastrointestinal tract.

Oral pharmaceutical dosage forms for pulsatile administration of antiarrhythmic agents are described in WO02/13794.

Pharmaceutical formulations comprising an oxabispidine as active ingredient are previously known by WO02/083687 and WO02/083689. Formulations for modified release and for immediate release are described. However, there is still a need for formulations comprising oxabispidines for administering the active ingredient substantially uniformly and/or constantly during a time period of up to 24 hours. Also, the modified release formulation of the invention is suitable for incorporating a high dose of the active ingredient.

Description of the Invention

The compositions of the invention provide for a delayed release or, more preferably, a sustained (i.e. prolonged or extended) release of drug over a period of time including provision for an initial amount of drug being made available within a predetermined time following administration to cause an initial desired therapeutic response. Thus, we prefer that the compositions of the invention provide for an immediate release of drug in combination with an extended release of drug during a period of time.

According to a first aspect of the invention, there is provided a modified release pharmaceutical formulation comprising oxabispidines, or a pharmaceutically acceptable salt thereof, formulated into pellets having different release properties, immediate release and extended release, respectively.

One embodiment of the invention is a modified release pharmaceutical formulation which releases the active ingredient in an even manner during a period of time of up to 24 hours after administration, after the initial release of active ingredient by the immediate release pellets. One embodiment of the invention is a modified release pharmaceutical formulation comprising oxabispidines (as active ingredient), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable diluent or carrier; for use in the treatment of cardiac arrhythmia.

The active ingredient of the modified release pharmaceutical formulation according to the invention is preferably selected from the group tert-butyl (2-{7-[(2S)-3-(4-cyanophenoxy) -2 -hydroxypropyl] -9-oxa-3,7-diazabicyclo- [3.3.1]non-3-yl}ethyl)carbamate; N-(4-cyanobenzyl)-2-[7-(2-phenethyl)-9-oxa-3,7- diazabicyclo[3.3.1]non-3-yl}acetamide; tert-butyl(2-{7-[2-(4-cyano-2- fluorophenoxy)ethyl]-9-oxa-3,7-diazabicyclo-[3.3. l]non-3-yl}ethyl)carbamate; and 4-({3- [7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3- yl]propyl}amino)benzonitrile. The list of compounds is not exhaustive.

According to one aspect of the invention, there is provided a modified release pharmaceutical formulation comprising the compound tert-butyl(2-{7-[2-(4-cyano-2- fluorophenoxy)ethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}ethyl)carbamate (hereinafter denoted as Compound A), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

The oxabispidines of interest for the present invention also show properties such as stickiness and adhesion. By the present invention such substances can be formulated into a modified release formulation which simultaneously also incorporates a high dose of the active ingredient. Also, the present invention provides a formulation, in parellel with the properties of active ingredient, for administering the active ingredient with an even release during a determined time period and without significant food interactions.

In one embodiment of the present invention there is provided a modified release pharmaceutical formulation in the form of a multiple unit system comprising:

I) immediate release pellets comprising Compound A, or a pharmaceutically acceptable salt thereof; II) extended release pellets comprising Compound A, or a pharmaceutically acceptable salt thereof, coated with one or more polymer coating layer(s); with a ratio between the pellets according to I and II ranging from 10:90 to 90:10 (with respect to weight of active ingredient of the pellets according to I and II, respectively).

In one embodiment of the present invention there is provided a modified release pharmaceutical formulation in the form of a multiple unit system comprising: I) immediate release pellets comprising Compound A, or a pharmaceutically acceptable salt thereof; II) extended release pellets comprising Compound A, or a pharmaceutically acceptable salt thereof, coated with one or more polymer coating layer(s); with a ratio between the pellets according to I and II ranging from 10:90 to 90:10 (with respect to weight of active ingredient of the pellets according to I and II, respectively); for use in cardiac arrhytmia.

I) immediate release pellets comprising Compound A, or a pharmaceutically acceptable salt thereof;

II) extended release pellets comprising Compound A, or a pharmaceutically acceptable salt thereof, coated with one or more polymer coating layer(s); with a ratio between the pellets according to I and II ranging from 10:90 to 90:10 (with respect to weight of active ingredient of the pellets according to I and II, respectively), for use in a) providing a therapeutic effect against cardiac arrhythmia primarily provided by the extended release pellets (II) , and, additionally, b) providing the possibility for the early detection of patients responding with unfavorable QT-prolongation primarily provided by the immediate release pellets (I).

In one embodiment of the present invention there is provided a modified release pharmaceutical formulation in the form of a multiple unit system comprising extended release pellets coated with one or more polymer coating layer(s). In one embodiment of the present invention the polymeric materials of the polymer coating layer(s) are selected from ethylcellulose in combination with one or more of the group consisting of hydroxypropylcellulose and methacrylic acid copolymers.

The term "modified release" pharmaceutical formulation will be well understood by the skilled person to include any composition/formulation in which the onset and/or rate of release of the active ingredient is altered by galenic manipulations, and thus includes the definition provided in the United States Pharmacopeia (USP XXII) at pages xliii and xliv of the preface/preamble part, the relevant disclosure in which document is hereby incorporated by reference.

The modified release pharmaceutical formulation of the invention comprises pellets in specified amounts for administering the active ingredient to cause a desired therapeutic response. By using an appropriate pharmaceutically-acceptable carrier, and/or other means, which carrier or means (as appropriate) gives rise to an alteration of the onset and/or rate of release of active ingredient. Thus, the term "modified release" will be understood by those skilled in the art to include compositions which are adapted (for example as described herein) to provide for a "sustained", a "prolonged" or an "extended" release of drug (in which drug is released at a sufficiently retarded rate to produce a therapeutic response over a required period of time, optionally including provision for an initial amount of drug being made available within a predetermined time following administration to cause an initial desired therapeutic response); compositions which provide for a "delayed" release of drug (in which the release of drug is delayed, for example, until a specific region of the gastrointestinal tract is reached, following which drug release may be either pulsatile or further modified as indicated above).

In one embodiment of the invention a multiple unit system comprises one part comprising of immediate release pellets and a second part comprising of extended release pellets wherein the ratio between the parts ranges from 10:90 to 90:10 (with respect to weight of active ingredient of the respective parts).

In one embodiment of the invention a multiple unit system comprises one part comprising immediate release pellets and a second part comprising extended release pellets wherein the ratio between the two parts is about 10:90; 15:85; 20:80; 25:75; 30:70; 35:65; 40:60; 45:55; 50:50; 60:40; 70:30; 75:25; 80:20 and 90: 10 (with respect to weight of active ingredient of the respective parts).

In one embodiment of the invention a multiple unit system comprises one part comprising immediate release pellets and a second part comprising extended release pellets wherein the weight of active ingredient of the immediate release pellets is around one third of the total weight of active ingredient, thus around 33:66.

The final dosage form of the modified release pharmaceutical formulation, the multiple unit system, may be in, for example, capsule, sachet or tablet form. The units of these multiple unit systems include microparticles, microspheres, microtablets, pellets and the like. Examples are pellets, which may be coated with one or more polymer coating layer(s). Examples further include coated pellets, which may be designed to release at least some of the drug when the formulation in question reaches a particular region of the gastrointestinal tract. The polymer coating layer(s) may be enteric coating layer(s), providing for release of at least part of the drug present in the formulation in a specific part of the gastrointestinal tract, such as the intestinal regions.

The units of these multiple unit systems may further be based on solid dispersions or solid solutions of active compound in a matrix, which may be in the form of a wax, gum or fat, or, particularly, in the form of a polymer.

The above principles are discussed at length in numerous prior art references including Pharmaceutisch Weekblad Scientific Edition, 6, 57 (1984); Medical Applications of

Controlled Release, VoI II, eds. Langer and Wise (1984) Bocaraton, Florida, at pages 1 to 34; Industrial Aspects of Pharmaceuticals, ed. Sandel, Swedish Pharmaceutical Press (1993) at pages 93 to 104; and pages 191 to 211 of "Pharmaceutics: The Science of Dosage Form Design", ed. M. E. Aulton (1988) (Churchill Livingstone); as well as the references cited in the above-mentioned documents. Suitable modified release pharmaceutical formulations may be prepared by the skilled person in accordance with standard techniques in pharmacy, as described herein or in the above-mentioned documents, and/or which are well known.

We prefer that the compositions of the invention be provided for oral administration in the form of pellets formed into multiple unit systems as the final dosage form. The pellets can be produced by a number of processes, including spray layering or spray crystallization in a fluidised bed, melt spheronization, extrusion/spheronization, powder layering and rotor granulation. In the case of pellets produced by the spray layering technique, the active ingredient is dispersed in an aqueous medium and sprayed onto inert cores in a fluid bed equipment. The inert cores can, for example, be made of micro crystalline cellulose. The pellets thus formed may then be coated by spraying a solution or a dispersion of one or more polymeric materials on top of the substance layer in order to control the release of active substance. The polymer coating (or coatings if there are a number of polymer layers) thus obtained may comprise one or more polymers which may, for example, possess different physicochemical properties such as solubility in aqueous media. The choice of polymeric material and ratio between the included polymeric materials will be determined by the nature of the active ingredient/drug as well as the desired rate of release.

In one embodiment of the invention the drug is released from the extended release pellets by diffusion through membranes.

Examples of suitable polymeric materials are ethyl cellulose (EC) in combination with one or more additional polymer(s). The additional polymer may be selected from the following polymers hydroxypropyl cellulose (HPC); polyvinyl pyrrolidone (PVP K30); hydroxypropyl methylcellulose (HPMC); preferably a HPMC having low viscosity, for example 6 cps; and pH dependent soluble polymers such as methacrylic acid copolymer and hydroxypropyl methylcellulose phtalate acrylic acid. The additional polymer is present in an amount of around 20% to around 60% by weight, for example in an amount of around 20% to around 40% by weight of the total amount of polymeric material. The methacrylic acid copolymers are filmcoating substances on an acrylic resin basis. Eudragit is the trade name for a number of such filmcoating polymers produced by Evonik

TM

Degussa. For example, Eudragit L30D is a dispersion based on copolymer of

TM methacrylic acid and ethyl acrylate (1:1); Eudragit L100-55 is based on the same

TM copolymer but in a solid state (powder); Eudragit LlOO is copolymer of methacrylic acid

TM and methyl methacrylate (1:1); finally Eudragit S-IOO is copolymer of methacrylic acid

TM and methyl metacrylate (1:2). Kollicoat is the trade name for a number of filmcoating

TM substances produced by BASF wherein Kollicoat MAE 30 D, which is a copolymer of methacrylic acid and ethyl acrylate (1:1), is one example.

Ethyl cellulose is available in variants having different grades of viscosity. According to the invention it is suitable to use ethyl cellulose having a viscosity between 9-11 mPas but also other types of ethyl cellulose may be used.

In one embodiment of the invention the polymeric materials selected from the ones described above form a coating which may give a reduced release of the active ingredient in the pH range of 1.0-8.0, for example within the pH range of 1.0-5.0; or 1.0-3.0; or 1.0- 2.5; especially at around pH 1.0, such as the pH range presented by the gastric environment in the stomach.

The units/pellets may be formed around an inert core. Examples of inert core are

TM TM particles/seeds of microcrystalline cellulose, for example Celphere 203 or Celphere

305; silica; or non-pareil. The size of the inert core particles may, for example, be between 0.15 and 0.30 mm or between 0.20 and 0.50 mm.

Compositions of the invention, whether in the form of a pellet system or otherwise, may contain one or more further excipients to further modify drug release, to improve the physical and/or chemical properties of the final composition, and/or to facilitate the process of manufacture. Such excipients are conventional in the formulation of modified release compositions.

For example, compositions of the invention may contain one or more of the following diluents: calcium phosphate (monocalcium phosphate, dicalcium phosphate and tricalcium phosphate), lactose, microcrystalline cellulose, mannitol, sorbitol, titanium dioxide, aluminium silicate and the like. Preferred diluents include microcrystalline cellulose.

Compositions of the invention may contain one or more of the following lubricants: magnesium stearate, sodium stearyl fumarate and the like.

Compositions of the invention may contain a glidant, such as colloidal silica.

Compositions of the invention may contain one or more of the following binders: polyvinylpyrrolidone, lactose, mannitol, microcrystalline cellulose, a polyethylene glycol (PEG), a hydroxypropyl methylcellulose (HPMC) of a low molecular weight, a methyl cellulose (MC) of a low molecular weight, a hydroxypropyl cellulose (HPC) of a low molecular weight and the like.

Compositions of the invention may contain one or more of the following pH controlling agents: organic acids (e.g. citric acid and the like) or alkali metal (e.g. sodium) salts thereof, pharmaceutically acceptable salts (e.g. sodium, magnesium or calcium salts) of inorganic acids (such as carbonic acid or phosphoric acid), oxides of magnesium, as well as alkali, and alkaline earth, metal (e.g. sodium, calcium, potassium and the like) sulphates, metabisulphates, propionates and sorbates.

Other further excipients may include colorants, flavourings, tonicity-modifying agents, coating agents, preservatives, etc.

Combinations of the above-stated further excipients may be employed. It will be appreciated by the skilled person that some of the above mentioned further excipients, which may be present in the final form of the modified release pharmaceutical formulation of the invention, may have more than one of the above-stated functions.

The total amount of further excipients that may be present in the modified release pharmaceutical formulation of the invention will depend upon the nature of the composition, as well as the nature, and amounts of, the other constituents of that composition, and may be an amount of up to 85%, for example between 0.1 to 75%, such as 0.2 to 65%, preferably 0.3 to 55%, more preferably 0.5 to 45% and especially 1 to 40%, such as 2 to 35% w/w of the total amount of excipient. In any event, the choice, and amount, of these excipient(s) may be determined routinely (i.e. without recourse to inventive input) by the skilled person.

The active ingredient may be present in form of a salt. Salts, which may be mentioned include acid addition salts. Pharmaceutically acceptable derivatives also include, at the oxabispidine C_1-4 alkyl quaternary ammonium salts and iV-oxides. Examples of salts of the compound are benzoic acid salts, hydroxy- substituted benzenesulphonic acid salts, 1- or 2- naphthalenesulphonic acid salts, 1,5-naphthalenedisulphonic acid salts, particularly, toluenesulphonic acid salts, or, especially, benzenesulphonic acid salts, methanesulphonic acid salts, hippuric acid salts, toluenesulphonic acid salts, pamoic acid salts, 1,5- naphthalenedisulphonic acid salts, terephthalic acid salts, succinic acid salts, or tartaric acid salts. Particular salts that may be mentioned include salts with fumaric acid or maleic acid.

Suitable amounts of active ingredient in the modified release pharmaceutical formulation of the invention, depend upon many factors, such as the nature of that ingredient (free base/salt etc), the dose that is required, and the nature, and amounts, of other constituents of the composition. However, they may be in the range 0.5 to 80%, for example 1 to 75%, such as 3 to 70%, preferably 5 to 65%, more preferably 10 to 60% and especially 15 to 55% w/w. The final dosage form of the modified release pharmaceutical formulation of the invention may be dosed one or more times daily (e.g. up to six times, but preferably no more than twice, daily), irrespective of the number of individual units (e.g. capsules, tablets) that are administered as part of one "dose" .

Typical daily doses of Compound A, or of pharmaceutically-acceptable salts thereof, are in the range 10 to 1000 mg of free base (i.e., in the case of a salt, excluding any weight resulting from the presence of a counter ion), irrespective of the number of compositions (e.g. tablets) that are administered during the course of that day. Examples of daily doses are in the range 50 to 1000 mg, such as 100 to 500 mg. Typical doses in individual compositions of the invention (e.g. tablets) are thus in the range 15 to 500 mg, for example 40 to 400 mg. Doses of Compound A in the individual composition may be such as 15, 20, 25, 30, 40, 50, 60, 70, 75, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, or 400 mg.

The final dosage forms of the invention such as those described hereinbefore may be made in accordance with well-known techniques such as those described in the references mentioned hereinbefore.

In one embodiment of the present invention there is provided a use of the modified release formulation for the treatment of cardiac arrhythmia.

The compositions of the invention are useful in the delivery of the active ingredient and pharmaceutically acceptable salts thereof to patients. As Compound A and pharmaceutically- acceptable salts thereof are useful in both the prophylaxis and the treatment of cardiac arrhythmias, in particular atrial arrhythmias (such as atrial fibrillation or atrial flutter) and ventricular arrhythmias, the compositions of the invention are also expected to be useful in the treatment of such disorders.

The compositions of the invention are thus indicated in the treatment or prophylaxis of cardiac diseases, or in indications related to cardiac diseases, in which arrhythmias are believed to play a major role, including ischaemic heart disease, sudden heart attack, myocardial infarction, heart failure, cardiac surgery and thromboembolic events.

According to a further aspect of the invention, there is provided a method of treatment of an arrhythmia which method comprises administration of a composition of the invention to a person suffering from, or susceptible to, such a condition.

For the avoidance of doubt, by "treatment" we include the therapeutic treatment, as well as the prophylaxis, of a condition.

The formulation provided by the present invention has the advantage that it may provide an even and prolonged effect of Compound A against cardiac arrhythmias and may thus provide efficient dosing of active ingredient preferably no more than once or twice daily. By the administration of the composition according to the present invention an even concentration profile during up to 24 hours after administration may be obtained. Further, the dose released may give an onset in time of about 5 minutes from time for administering. Preferably, the desired plasma concentration is achieved within a time period of around 4 hours after administration.

The QT segment of an electrocardiogram (ECG) includes the time interval from the beginning of ventricular depolarization, the Q wave, to the end of the T wave, at which point the repolarisation is complete. Prolongation of the QT interval is known to increase the risk of arrhythmias. QT prolongation is a possible adverse effect for several antiarrhythmic drugs, but is reported also for non-cardiac drugs.

In clinical practice, adverse effects of QT prolonging drugs can be prevented by not exceeding the recommended dose and by avoiding their use at certain conditions or in certain patients or patient groups. It is therefore of interest to as early as possible identify patients unsuitable for using such drugs in order to prevent clinically undesireable effects. One way of identifying such patients could be the use of a high, initial dose of Compound A with a formulation that achieves a similar concentration as expected at steady state concentration of the drug within hours and thereby allowing a prediction of the QT interval at steady state.

One embodiment of the invention is a modified release pharmaceutical formulation comprising oxabispidines (as active ingredient), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable diluent or carrier; for use in treatment of cardiac arrhythmia effect and additionally providing the possibility for early detection of patients responding with excessive/unfavorable QT prolongation.

One embodiment of the invention provides a modified release pharmaceutical formulation comprising (as active ingredient), Compound A or a pharmaceutically acceptable salt thereof ; and a pharmaceutically acceptable diluent or carrier; for use in providing a therapeutic anti-arrhythmic effect and additionally providing the possibility for early detection of patients unsuitable for treatment with Compound A by responding with an excessive/unfavorable QT prolongation.

One embodiment of the invention is the use of the modified release pharmaceutical formulation as herein described for use in a) providing a therapeutic effect, primarily provided by the extended release pellets (II), against cardiac arrhythmia, and, additionally, b) providing the possibility for the early detection, primarily provided by the immediate release pellets (I), of patients responding with unfavourable QT-prolongation.

The term "early detection of patients responding with unfavorable QT-prolongation" describes the advantage of having the possibility to, within a short period of time after administering the formulation, monitor the QT response at plasma concentrations corresponding to those later seen during steady state and thereby being able to immediately exclude from therapy, patients unsuitable for treatment. An early exclusion from further treatment will increase the safety for the patient unsuitable for the treatment and will also affect the patient compliance by avoiding unnecessary hospitalisation, as well as the requirements of hospital resources. Preparation of the modified release formulation

The pellets to be included in the formulation may be prepared in accordance with the following, but this is in no way a limitation of the present invention.

A suspension of Compound A was prepared by first dissolving the binder (10-20 mg/ capsule (final composition)) in water and then by adding the Compound A (125 mg / capsule) to the solution . The mixture was homogenised into suspension. The suspension thus obtained was sprayed onto the inert cores (for example, microcrystalline cellulose spheres) (10-20 mg/capsule) in a fluidised bed with subsequent drying. Aggregates of pellets were removed (sieved). The weight of the product was determined.

The pellets obtained according to the above are also referred to as "immediate release pellets".

The immediate release pellets were then further treated by applying one or more polymer coating layer(s) to obtain pellets with extended release. These extended release pellets may be obtained by coating the immediate release pellets with : i): a mixture of polymers suitable for providing extended release of the active ingredient, such as, for example ethylcellulose and hydroxypropylcellulose; or ii): a first layer comprising a mixture of polymers, suitable for providing extended release of the active ingredient, such as, for example ethylcellulose and hydroxypropylcellulose, and a second layer comprising enteric coating polymer(s), such as methacrylic acid copolymer (for example methacrylic acid-methyl metacrylate copolymer, methacrylic acid-methyl metacrylate copolymer, or mixtures thereof); or iii): a mixture of polymers suitable for providing extended release of the active ingredient, such as, for example ethylcellulose, hydroxypropylcellulose, together with enteric coating polymer(s), such as methacrylic acid copolymer (for example methacrylic acid-methyl metacrylate copolymer, methacrylic acid-methyl metacrylate copolymer, or mixtures thereof).

In one embodiment of the invention the extended release pellets (II) are coated with: a first polymer coating layer comprising a mixture of polymers suitable for providing extended release of the active ingredient (in particular ethylcellulose and hydroxypropylcellulose); and a second polymer coating layer comprising enteric coating polymer(s) ( in particular methacrylic acid copolymer(s) (in particular methacrylic acid-methyl metacrylate copolymer, methacrylic acid-methyl metacrylate copolymer, or mixtures thereof)).

In one embodiment of the invention the extended release pellets (II) are coated with: a first polymer coating layer comprising enteric coating polymer(s) (in particular methacrylic acid copolymer(s) (in particular methacrylic acid-methyl metacrylate copolymer, methacrylic acid- methyl metacrylate copolymer, or mixtures thereof)); and a second polymer coating layer comprising a mixture of polymers suitable for providing extended release of the active ingredient (in particular ethylcellulose and hydroxypropylcellulose).

In one embodiment of the invention the extended release pellets (II) comprise a mixture of polymers suitable for providing extended release of the active ingredient (in particular ethylcellulose and hydroxypropylcellulose) and enteric coating polymer(s) (in particular methacrylic acid copolymer(s) (of, in particular methacrylic acid-methyl metacrylate copolymer, methacrylic acid-methyl metacrylate copolymer, or mixtures thereof)).

In one embodiment the modified release pharmaceutical formulation as described herein is for use in cardiac arrhythmia.

In one embodiment the modified release pharmaceutical formulation as described herein is for use in a) providing a therapeutic effect, primarily provided by the extended release pellets (II), against cardiac arrhythmia, and, additionally, b) providing the possibility for the early detection, primarily provided by the immediate release pellets (I), of patients responding with unfavourable QT-prolongation.

These coating layers can be applied by coating or layering procedures in suitable equipments such as a coating pan, a coating granulator or in a fluidized bed apparatus using water and/or organic solvents for the coating process. As an alternative the coating layer(s) can be applied to the core material by using a powder coating technique. In one embodiment of the invention the composition in i) comprises 65-80 % (w/w) ethyl cellulose and 20-35 % (w/w) hydroxypropyl cellulose. Examples are 73 % (w/w) ethylcellulose and 27 % (w/w) hydroxypropyl cellulose, or 75 % (w/w) ethylcellulose and 25 % (w/w) hydroxypropyl cellulose.

In one embodiment of the invention the composition in iii) comprises 60-70% (w/w) ethylcellulose; 10-20 % (w/w) hydroxypropyl cellulose; and 10-20 % (w/w) enteric coating polymer.

The pellets obtained as described above and in the examples are then further formulated into the final dosage form of the modified release pharmaceutical formulation.

In one embodiment, the final dosage form of the modified release pharmaceutical formulation thus obtained comprises a combination of the immediate release pellets together with the extended release pellets with polymer coating layer(s) according to i) above; or with extended release pellets with polymer coating layer(s) according to ii) above; or with extended release pellets with polymer coating layer(s) according to iii) above; or a mixture of extended release pellets with polymer coating layer(s) according to i), ii) or iii) above.

An embodiment of the invention is a final dosage form of the modified release pharmaceutical formulation comprising solely the extended release pellets with polymer coating layer(s) according to i), ii) or iii) above.

The modified release pharmaceutical formulation according to the present invention is further shown by the Examples below. The immediate release pellets may be produced by the process as described in any of Examples 1. The extended release pellets may be produced by any of the processes as described in Examples 2, 3 and 4. The final dosage form of the modified release pharmaceutical formulation comprises at least two types of pellets comprising compound A, one part of the pellets is obtained according to any of Examples 1, the second according to any of Examples 2, 3 or 4. In one embodiment of the invention, the immediate release pellets are coated with enteric coating polymer(s). A final dosage form comprises a combination of the enteric coated immediate release pellets together with the extended release pellets with polymer coating layer(s) according to i) above; or with extended release pellets with polymer coating layer(s) according to ii) above; or with extended release pellets with polymer coating layer(s) according to iii) above.

Before applying enteric coating layer(s) onto the core material in the form of individual pellets, said pellets may optionally be covered with one or more separating layers. The separating layer(s) may comprise pharmaceutical excipients optionally including alkaline compounds such as for instance pH-buffering compounds. This/these separating layer(s) separate(s) the core material from the outer layer(s) being enteric coating layer(s).

The separating layer(s) can be applied to the core material by coating or layering procedures in suitable equipments such as a coating pan, a coating granulator or in a fluidized bed apparatus using water and/or organic solvents for the coating process. As an alternative the separating layer(s) can be applied to the core material by using powder coating technique. The materials for separating layers are pharmaceutically acceptable compounds such as, for instance, sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose sodium and others, used alone or in mixtures. Further additives, such as plasticizers, colorants, pigments, fillers, anti-tacking and anti-static agents, such as for instance magnesium stearate, titanium dioxide, talc and other additives may also be included into the separating layer(s). The separating layer may have a variable thickness, and is only limited by processing conditions.

By applying an enteric coating layer to the units/pellets the degradation of the active ingredient due to the gastric pH may be decreased, or avoided, by that the exposure of the active ingredient to the conditions in the gastric environment is reduced. Examples

The invention is illustrated, but in no way limited, by the following Examples.

Example 1-A Immediate release pellets

The drug-containing suspension was made according to the composition below: Compound A 960 g

Hydroxypropyl methylcellulose (HPMC) 6cps 120 g

Water, purified 1683 g The HPMC was dissolved in water and compound A was added to the solution which was homogenised using a suitable mixer. The suspension of Compound A was sprayed onto

TM

120 g of microcrystalline cellulose spheres (Celphere 203) in a fluidised bed with subsequent drying. Aggregates of pellets were removed (sieved). The weight of the product was 1087g.

Example 1-B Immediate release pellets

The drug-containing suspension was made according to the composition below: Compound A 2557 g Hydroxypropyl methylcellulose (HPMC) 6cps 192 g

Water, purified 5105 g

The HPMC was dissolved in water and compound A was added to the solution which was homogenised using a suitable mixer. The suspension of Compound A was sprayed onto

TM

733 g of microcrystalline cellulose spheres (Celphere 305) in a fluidised bed with subsequent drying. Aggregates of pellets were removed (sieved). The weight of the product was 3405g.

Example 2- A Extended release pellets Pellets were produced according to Example 1-A. A solution of ethylcellulose (10 cps CR)/hydroxypropylcellulose (HPC LF) in ratio 73/27 with respect to weight in 95% ethanol (solid content of solution: 8%(w/w)) was applied to the pellets in a fluidised bed according to the following: Pellets (ace. Example 1-A) 200 g

Filmcoating polymer 30 g The coated pellets were subsequently dried in the fluidised bed. Aggregates of extended release pellets were removed (sieved).

Example 2-B

Extended release pellets Pellets were produced according to Example 1-A. A solution of ethylcellulose (lOcps

CR)/hydroxypropylcellulose (HPC LF) in ratio 75/25 with respect to weight in 95% ethanol (solid content of solution: 8%(w/w)) was applied to the pellets in a fluidised bed according to the following:

Pellets (ace. Example 1-A) 200 g Filmcoating polymer 40 g

The coated pellets were subsequently dried in the fluidised bed. Aggregates of extended release pellets were removed (sieved).

Example 2-C Extended release pellets

Pellets were produced according to Example 1-A. A solution of ethylcellulose (lOcps

CR)/hydroxypropylcellulose (HPC LF) in ratio 76.5/23.5 with respect to weight in 95% ethanol (solid content of solution: 8%(w/w)) was applied to the pellets in a fluidised bed according to the following: Pellets (ace. Example 1-A) 200 g

Filmcoating polymer 30 g

Example 2-D Extended release pellets

Pellets were produced according to Example 1-A. A solution of ethylcellulose (lOcps CR)/hydroxypropylcellulose (HPC LF) in ratio 75/25 with respect to weight in 95% ethanol (solid content of solution: 8%(w/w)) was applied to the pellets in a fluidised bed according to the following:

Pellets (ace. Example 1-A) 200 g

Filmcoating polymer 40 g

Example 2-E

Extended release pellets

Pellets were produced according to Example 1-B. A solution of ethylcellulose (10 cps

CR)/hydroxypropylcellulose (HPC LF) in ratio 72.5/27.5 with respect to weight in 95% ethanol (solid content of solution: 8%(w/w)) was applied to the pellets in a fluidised bed according to the following:

Pellets (ace. Example 1-B) 2000 g

Filmcoating polymers 300 g

Example 3-A

Extended release pellets coated with enteric coating layer

Pellets were produced according to Example 2- A. A solution of Eudragit L30D (solid content 30 %) was applied in a fluidised bed according the following: Pellets (ace. Example 2- A) 200 g Enteric coating polymer 50 g

The coated pellets were subsequently dried. Aggregates of the pellets were removed (sieved).

Example 3-B

Extended release pellets coated with enteric coating layer Pellets were produced according to Example 2-B.

A solution of Eudragit L30D (solid content 30 %) was applied in a fluidised bed according the following:

Pellets (ace. Example 2-B) 200 g Enteric coating polymer 50 g

Example 3-C Extended release pellets coated with enteric coating layer

Pellets were produced according to Example 2- A. A solution of Eudragit L30D (solid content 30 %) was applied in a fluidised bed according the following:

Pellets (ace. Example 2- A) 200 g

Enteric coating polymer 30 g The coated pellets were subsequently dried. Aggregates of the pellets were removed

(sieved).

Example 3-D

Extended release pellets coated with enteric coating layer Pellets were produced according to Example 2-E.

A solution of Eudragit L30D (solid content 30%) was applied in a fluidised bed according to the following:

The pellets (ace. Example 2-E) 2000 g

Enteric coating polymer (Eudragit L30D (solid content 30%)) 400 g The pellets were subsequently dried. Aggregates of the pellets were removed (sieved).

Example 4- A

Pellets with mixed extended/enteric coating. Pellets were produced according to Example 1-A. A filmcoating solution comprising solution of etylcellulose (lOcps CR), hydroxypropylcellulose (HPC LF) and Eudragit LlOO in a ratio 68.6/15.7/15.7 with respect to weight in 95 % ethanol (solid content of 8%(w/w)) was applied in a fluidised bed according the following:

Pellets (ace. Example 1-A) 200 g

Enteric coating polymer 30 g

The coated pellets were subsequently dried in a fluidised bed. Aggregates of the coated pellets were removed (sieved).

Example 4-B

Pellets with mixed extended/enteric coating.

Pellets were produced according to Example 1-A. A filmcoating solution comprising solution of etylcellulose (lOcps CR), hydroxypropylcellulose (HPC LF) and Eudragit LlOO in a ratio 67/16.5/16.5 with respect to weight in 95 % ethanol (solid content of 8%(w/w)) was applied in a fluidised bed according to the following:

Pellets (ace. Example 1-A) 200 g pellets

Enteric coating polymer 30 g

The coated pellets were subsequently dried in a fluidised bed. Aggregates of coated pellets were removed (sieved).

Example 5 A - 5 F Capsules (gelatin) were filled with the pellets produced according to Examples 1 -

Example 4 (separately). The amounts mentioned in the table denotes amount of Compound A in (mg). In Examples 5D-5F, two capsule containing pellets according to Example 1 (total 125mg) were added. Drug release profiles were determined (pH 1.0 and 6.8).

Figure 1 shows the amount Compound A released (amount released drug (% w/w) versus time (h)) at pH 6.8, from capsule comprising the pellets according to Examples 5-A, 5-B and 5-C; Figure 2 shows the amount Compound A released (amount released drug (% w/w) versus time (h)) at pH 6.8, from capsule comprising the pellets according to Examples 5-D, 5-E and 5-F.

Example 6 The modified release formulations according to the invention were administered to healthy male volunteers (in a phase I, two-part, randomised, open, single-centre, crossover clinical study) as single oral doses. The result is shown in Figure 3 and Figure 4. Figure 3 shows the mean concentration of Compound A in plasma (concentration in plasma (C_p (μmol/L) versus time (h)). Compound A was administered by a modified release pharmaceutical formulation according to Example 5-C.

Figure 4 shows the mean concentration of Compound A in plasma (concentration in plasma (Cp (μmol/L) versus time (h)). Compound A was administered by a modified release pharmaceutical formulation according to Example 5-F.

Example 7

Comparison of pellets comprising en extended release coating (ER) and pellets comprising a combination of extended release coating (ER) and enteric coating (EC).

The effect of the enteric coating layer of the pellets was studied in a food interaction study.

Pellet formulations according to Examples 2-D, 3-A, 3-B and 4- A were administered to healthy male volunteers (in a phase I, two-part, randomised, open, single-centre, crossover clinical study) as single oral doses.

After administration, blood was collected and the plasma concentration of Compound A was determined. Pellets according to Example 3-A (coated with enteric coating layer) were administered to participants in the fed and fasting state, respectively.

The ratio Mean plasma concentration (C_max, fed) / Mean plasma concentration (C_max, fasting) was determined to 0.89. SD=O.32 Pellets according to Example 3-B (coated with enteric coating layer) were administered to participants in the fed and fasting state, respectively.

The ratio Mean plasma concentration (C_max, fed) / Mean plasma concentration (C_max, fasting) was determined to 1.4. SD=O.36

Pellets according to Example 2-D (coated only with extended release coating layer) were administered to participants in the fed and fasting state, respectively.

The ratio Mean plasma concentration (C_max, fed) / Mean plasma concentration (C_max, fasting) was determined to 2.1. SD=O.79

Pellets according to Example 4-A (coated with a layer comprising a combination of extended release polymeric coating material and enteric coating polymeric material) were administered to participants in the fed and fasting state, respectively.

The ratio Mean plasma concentration (C_max, fed) / Mean plasma concentration (C_max, fasting) was determined to 1.12. SD=O.24

Also the variability caused by the food was determined, indicated by the SD value above.

Claims

1. A modified release pharmaceutical formulation in the form of a multiple unit system comprising I) immediate release pellets comprising Compound A, or a pharmacuetically acceptable salt thereof;

II) extended release pellets comprising Compound A, or a pharmacuetically acceptable salt thereof, coated with one or more polymer coating layer(s), with a ratio between the pellets according to I and II ranging from 10:90 to 90:10 (with respect to weight of active ingredient of the pellets according to I and II, respectively).

2. A modified release pharmaceutical formulation according to claim 1 wherein the polymer coating of the extended release pellets (II) comprises a mixture of polymers suitable for providing extended release of the active ingredient (of, in particular ethylcellulose and hydroxypropylcellulose).

3. A modified release pharmaceutical formulation according to claim 1 wherein the extended release pellets (II) are coated with: a first polymer coating layer comprising a mixture of polymers suitable for providing extended release of the active ingredient ( in particular ethylcellulose and hydroxypropylcellulose); and a second polymer coating layer comprising enteric coating polymer(s) (of, in particular methacrylic acid copolymer(s) (of, in particular methacrylic acid-methyl metacrylate copolymer, methacrylic acid-methyl metacrylate copolymer, or mixtures thereof)).

4. A modified release pharmaceutical formulation according to claim 1 wherein the polymer coating of the extended release pellets (II) comprises a mixture of polymers suitable for providing extended release of the active ingredient (of, in particular ethylcellulose and hydroxypropylcellulose) and enteric coating polymer(s) (of, in particular methacrylic acid copolymer(s) (of, in particular methacrylic acid-methyl metacrylate copolymer, methacrylic acid-methyl metacrylate copolymer, or mixtures thereof)).

5. A modified release pharmaceutical formulation according to any of claims 1 to 4 for use in cardiac arrhythmia.

6. A modified release pharmaceutical formulation according to any of claims 1 to 4 for use in a) providing a therapeutic effect, primarily provided by the extended release pellets (II), against cardiac arrhythmia , and, additionally, b) providing the possibility for the early detection, primarily provided by the immediate release pellets (I), of patients responding with unfavourable QT-prolongation .

7. A modified release pharmaceutical formulation according to claim 1 wherein the polymers of the polymer coating(s) are selected from ethylcellulose in mixture with a polymer selected from the group consisting of hydroxypropyl cellulose (HPC); polyvinyl pyrrolidone; hydroxypropyl methylcellulose; or polymer(s) with pH dependent solubility (of, in particular methacrylic acid copolymer).

8. A modified release pharmaceutical formulation according to any of claims 1 to 7 wherein the multiple unit system is in sachet, capsule or tablet form.

9. Use of the modified release pharmaceutical formulation according to any of claims 1 to 8 for the treatment of cardiac arrhythmia.

10. Use of the modified release pharmaceutical formulation according to any of claims 1 to 8 for the treatment of cardiac arrhythmia, and additionally, for providing the possibility for early detection of patients responding with unfavourable QT-prolongation.

11. Use of the modified release pharmaceutical formulation according to any of claims 1 to 8 for use in a) providing a therapeutic effect, primarily provided by the extended release pellets (II), against cardiac arrhythmia, and, additionally, b) providing the possibility for early detection, primarily provided by the immediate release pellets (I), of patients responding with unfavourable QT-prolongation .

12. A method of treating an arrhythmic disorder in a patient suffering from said disorder, which comprises administering to the patient a therapeutically effective amount of Compound A in a modified release pharmaceutical formulation according to any of the preceeding claims.