Patent Description:
Miltefosine (MIL), an alkylphosphocholine, is a medicament for the treatment of parasitic diseases such as leishmaniasis, chagas and malaria, and cancer in humans and animals. It is generally used for the treatment of visceral leishmaniasis (VL).

The major advantage of miltefosine for the treatment of visceral leishmaniasis is that it can be administered orally and that no cross-resistance is observed with any other first and second line antileishmaniasis therapy. However, currently available drug formulations comprising miltefosine all suffer from limitations associated with cost, toxicity or the need for parenteral administration. Patent publication <CIT> describes and addresses some of the problems associated with miltefosine formulations.

An alternative for miltefosine is the alkylphosphocholine oleyl phosphocholine (C18:<NUM>-PC or OIPC) providing, amongst others, a more effective treatment of parasitic diseases such as leishmaniasis and malaria in both humans and animals. Although the use of oleyl phosphocholine for the treatment of several diseases is suggested, the currently available formulations of oleyl phosphocholine are generally solutions, suspensions or emulsions.

The development of solid dosage formulations of oleyl phosphocholine, and specifically the development of tablets, is complicated by the low melting point (<NUM>), high hygroscopicity (absorbing <NUM> weight percent of water when exposed to <NUM>% RH at <NUM>) and irregular particle size and shape of oleyl phosphocholine. These characteristics make it hard to obtain homogeneous, dry powders for tableting.

Due to these characteristics, several problems occur if a standard direct compression is used to prepare a tablet dosage formulation. As oleyl phosphocholine agglomerates upon storage due to its low melting point and high hygroscopicity, it has to be well sieved before compression. This requires a lot of energy and causes the sieves to get clogged, especially at the high temperatures which occur due to friction. During the compression, the oleyl phosphocholine tends to stick to the punches. Furthermore, the resulting tablets have a greasy appearance and are covered with non-homogeneous spots.

Patent publication <CIT> has partially addressed these problems by preparing a solid dosage formulation of oleyl phosphocholine, more specifically a tablet dosage formulation, via a modified wet granulation process, wherein OLPC is dissolved in the granulation liquid and the solution obtained is used to granulate the previously prepared dry powder mixture. This allows a homogeneous distribution of the API in the formulation and preventing segregation due to its irregular particle size/shape. The stability of the tablet dosage formulations prepared via this process as reported in <CIT> was only tested for a period of twelve months at a temperature of <NUM> and a relative humidity (RH) of <NUM>%. Since the geographic areas with high incidence of leishmaniasis are mostly tropical, this may not be sufficient, particularly because earlier stability studies have shown that oleyl phosphocholine is prone to degradation by exposure to high temperatures and humidities.

Hence, there is a need in the art for tablet dosage formulations of oleyl phosphocholine which are stable under warm (<NUM>) and humid conditions (<NUM>% RH) for a period of at least <NUM> months and can be prepared via a process which does not suffer from technical drawbacks associated with the low melting point and high hygroscopicity of oleyl phosphocholine such as agglomeration, sticking and sieve clogging.

Considering the need in the art discussed above, the present invention provides tablet dosage formulations of oleyl phosphocholine which are stable under warm and humid conditions, preferably upon storage for at least <NUM> months at <NUM> and <NUM>% RH, and the processes for their preparation, which do not suffer from technical drawbacks associated with the low melting point and high hygroscopicity of oleyl phosphocholine.

In a first aspect, the invention provides a process for preparing an olelyl phosphocholine (OIPC) containing granulate, said process comprising the consecutive steps of:.

In a further aspect, the invention provides OIPC containing granulates prepared via the process presented above.

In yet further aspects, the invention provides dosage formulations comprising OLPC containing granulate prepared via the process presented above, their uses as a medicament, and their uses in the treatment of parasitic diseases, preferably a parasitic disease selected from the group consisting of leishmaniasis, chagas and malaria, and cancer.

The processes of preparing the OIPC containing ganulate according to the invention are characterized by the fact that an anti-oxidant is present in the granulation mixture.

The processes and products of the invention do not suffer from certain technical drawbacks associated with the specific physicochemical properties of oleyl phosphocholine.

Without wishing to be be bound by theory, it is believed that the selection of the specific granulation excipients, such as a filler and/or anti-oxidant, and the specific ways in which they are combined to produce a granulate, results in a favorable granule morphology, less prone to undesirable interactions of the OLPC with other active pharmaceutical ingredient molecules, excipients, (ambient) moisture, etc. Furthermore, inclusion of the antioxidant in the granulation mixture is believed to inhibit the formation of potentially toxic OLPC degradation products during the granulation process.

In one particularly advantageous embodiment of the invention, the granulation process is based on the technology described in <CIT>. In another particularly advantageous embodiment, the granulation process is based on the technology described in international application no. <CIT> (not yet published).

These and other aspects of the invention will become apparent to the person skilled in the art, based on the following description and examples.

Tableting is the preparation of a tablet or tablet dosage formulation from the compounds comprised therein, wherein said compounds may be active pharmaceutical ingredients (APIs) or excipients.

Active pharmaceutical ingredients have a pharmaceutical activity in the field of parasitic diseases, preferably a parasitic disease selected from the group consisting of leishmaniasis, chagas, malaria, and cancer in the context of this application.

A tablet dosage formulation comprises a tablet core, comprising the active pharmaceutical ingredient(s), and optionally a tablet coating. The preparation of a tablet core comprises at least a granulation step, a compression blending step, and a compression step in the context of this application.

An excipient is any compound comprised in a tablet dosage formulation which is not an active pharmaceutical ingredient in the context of this application. Preferably, an excipient provides said tablet dosage formulation with structural integrity or a pharmacokinetical advantage over a corresponding tablet dosage formulation wherein said excipient is not present. For this reason, excipients can be classified according to their function. A non-limitative list of types of excipients are binders, spacers, fillers, lubricants, antioxidants and disintegrants. It is clear that an excipient may belong to several types of excipients. For example, microcrystalline cellulose may be at least a binder, a filler and a disintegrant.

A binder provides tablet dosage formulation with structural integrity by holding the compounds comprised therein together.

A spacer prevents the physical and/or chemical interaction between two or more other molecules in a tablet dosage formulation.

A filler increases the volume of a tablet dosage formulation.

A lubricant increases the homogeneity of the compounds in a tablet dosage formulation and prevents said tablet dosage formulation from adhering to process equipment or packaging material.

An antioxidant prevents the chemical oxidation of other compounds comprised in a tablet dosage formulation.

A disintegrant causes a tablet dosage formulation to disintegrate and release the active pharmaceutical ingredients comprised therein in the digestive track.

A solvent refers to an aqueous or organic solvent which may be added during the preparation of a tablet dosage formulation.

The expression "granulate" is generally understood to refer to aggregates of particles, sometimes called granules (<NPL>).

The term "agglomeration" refers to processes wherein compounds in particulate or powder form ('primary particles') are processed so as to produce a product composed of larger particles, called aggomerates or granules. Agglomeration usually involves the use of a liquid capable of binding primary particles. Melt agglomeration is a process employing a binder that is typically solid at ambient temperature and wherein the agglomeration is effected at an increased temperature, above the melting point of the binder.

Granulation is the process of forming grains or granules from a mixture of compounds, preferably wherein said grains or granules are homogeneous. A granulation process may be classified as a wet or a dry granulation process, depending on whether or not solvents are added during the process.

A granulation excipient is an excipient which has been added during the process for granulation of the preparation of a tablet dosage formulation.

Compression is the process of preparing a tablet core with essentially the same physical size as the tablet dosage formulation, by physically compressing a compression mixture. Said tablet core may be the tablet dosage formulation, or said tablet core may undergo several coating processes before a tablet dosage formulation is formed. During said coating processes, the physical size of the (partially coated) tablet core is essentially the same as the physical size as the tablet dosage formulation. Examples of said coating processes include sugar coating and colouring.

A compression excipient is an excipient which is added after the process for granulation of the invention and during the compression blending step and before the compression step of the process for preparing a tablet dosage formulation.

Wherever the term excipient is used in this application, reference is made to both granulation excipients and compression excipients, unless explicitly stated otherwise. Wherever granulation or compression are used as a noun modifier before a specific type of excipient, reference is made to a granulation or compression excipient of that type, respectively. For example, a granulation binder should be interpreted as a granulation excipient which is a binder.

The stability of a tablet dosage formulation refers to the change of the concentration of the active pharmaceutical ingredients comprised therein over time. In a preferred instance, stability of a tablet dosage formulation refers to stability of a tablet dosage formulation under humid and warm conditions.

The degradation of the active pharmaceutical ingredients (in a tablet dosage formulation) refers to the decrease of the concentration of the active pharmaceutical ingredients comprised in the tablet dosage formulation over time.

The disintegration of a tablet dosage formulation refers to the breaking of said tablet dosage formulation into separate parts when said tablet dosage formulation is brought into contact with a fluid. Preferably, said fluid is a buffered aqueous solution. More preferably, said fluid is a <NUM> N aqueous HCl solution. Disintegration of a tablet dosage formulation may be determined using the European Pharmacopoeia <NUM>. <NUM> standard disintegration test (<NUM> HCl <NUM> N) or USP <<NUM>>.

The dissolution of an active pharmaceutical ingredient comprised in a tablet dosage formulation refers to the dissolving of said active pharmaceutical ingredient in a fluid, when said tablet dosage formulation is brought into contact with said fluid. Preferably, said fluid is a buffered aqueous solution. For example, dissolution of oleyl phosphocholine comprised in a tablet dosage formulation according to the invention may refer to dissolving of oleyl phosphocholine in the fluids of the gastrointestinal tract after ingestion of said tablet dosage formulation. Dissolution of an active pharmaceutical ingredient comprised in a tablet dosage formulation may be determined using the European Pharmacopoeia <NUM>. <NUM> standard dissolution test and is typically expressed as the decrease of the weight percentage of the active pharmaceutical ingredient in said tablet dosage formulation over time. The dissolution release profile is determined by measuring the dissolution over time using the European Pharmacopoeia <NUM>. <NUM> standard dissolution test.

An active pharmaceutical ingredient comprised in a tablet dosage formulation has a stable dissolution release profile if the dissolution release profile of said active pharmaceutical ingredient does not change significantly upon storage under warm and humid conditions. Preferably, the dissolution release profile of oleyl phosphocholine comprised in a tablet dosage formulation according to the invention is considered to be stable if at least <NUM>, <NUM>, <NUM>, <NUM> or <NUM> weight percent of oleyl phospocholine has been dissolved after <NUM> minutes, preferably at least <NUM> weight percent of oleyl phospocholine, more preferably at least <NUM> weight percent of oleyl phospocholine, most preferably at least <NUM> weight percent of oleyl phospocholine, as determined by the European Pharmacopoeia <NUM>. <NUM> standard dissolution test, for all tablet dosage formulations stored up to <NUM> months under warm and humid conditions. Preferably, said warm and humid conditions are <NUM> and <NUM>% RH, <NUM> and <NUM>% RH or <NUM> and <NUM>% RH, more preferably <NUM> and <NUM>% RH.

A particularly stable tablet dosage formulation (under warm and humid conditions) in the context of this invention is a tablet dosage formulation, wherein, if stored under warm and humid conditions, preferably for at least <NUM> months at a temperature of <NUM> and a relative humidity of <NUM>%,.

Storage under warm and humid conditions, in the context of this application, is the storage of a tablet dosage formulation for, in the order of increasing preference, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM> months in a temperature range from <NUM> to <NUM> and a relative humidity range from <NUM>% to <NUM>%. Preferred temperature ranges are, in the order of increasing preference, from <NUM> to <NUM>, from <NUM> to <NUM>, from <NUM> to <NUM>, and from <NUM> to <NUM>. Preferred relative humidity ranges are, in the order of increasing preference, from <NUM>% to <NUM>%, from <NUM>% to <NUM>%, from <NUM>% to <NUM>%, from <NUM>% to <NUM>%, and from <NUM>% to <NUM>%. Preferred warm and humid storage conditions in this context are at <NUM> and <NUM>% RH or at <NUM> and <NUM>% RH or at <NUM> and <NUM>% RH or at <NUM> and <NUM>% RH for <NUM> or <NUM> months; even more preferably at <NUM> and <NUM>% RH or at <NUM> and <NUM>% RH or at <NUM> and <NUM>% RH or at <NUM> and <NUM>% RH for <NUM> months; even more preferably at <NUM> and <NUM>% RH or at <NUM> and <NUM>% RH for <NUM> months; even more preferably at <NUM> and <NUM>% RH for <NUM> months.

The concentration of a type of excipient in a mixture is the sum of the concentrations of the granulation excipients and the compression excipients of that type. For example, the concentration of the binder in the compression mixture in a process for preparing a tablet dosage formulation according to the invention is the sum of the weight of the granulation binder and the weight of the compression binder, divided by the weight of the compression mixture.

In an embodiement, a process for preparing an OLPC containing granulate as defined herein is provided, wherein the antioxidant is selected from the group consisting of alpha tocopherol, alpha tocopherolacetate, Vitamin E, Vitamin E TPGS, diethylhexyl syringylidene malonate, diisopropyl vanillidene malonate, tetrahydrocurcumenoids, tocopherol, carotenoids, anthocyanidins, hydroquinone monomethyl ether, ascorbic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butylhydroquinone (TBHQ), propyl gallate and ethoxyquin (EMQ) and mixtures thereof. In a particularly preferred embodiment of the invention the antioxidant is selected from the group consisting of alpha tocopherol, alpha tocopherolacetate, Vitamin E and Vitamin E TPGS. In a particularly preferred embodiment of the invention the antioxidant is Vitamin E or alpha tocopherol.

In an embodiement, a process for preparing an OLPC containing granulate as defined herein is provided, wherein the filler is selected from the group consisting of calcium carbonate, calcium phosphate (dibasic), calcium phosphate (tribasic), calcium sulphate, cellulose, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose monohydrate, magnesium carbonate, maltitol, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, sugar spheres, talc, xylitol, silicium dioxide, such as colloidal silicone dioxide (colloidal silica), silica gel, mesoporous silica or nanoporous silica; and mixtures thereof. In a particularly preferred embodiment of the invention, the filler is selected from the group consisting of cellulose, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, silicium dioxide, such as colloidal silicone dioxide (colloidal silica), silica gel, mesoporous silica or nanoporous silica; and mixtures thereof.

In an embodiement, a process for preparing an OLPC containing granulate as defined herein is provided, wherein step b) comprises a melt-agglomeration process. Melt-agglomeration results in the agglomeration/binding of primary particles of the granulation excipient and of the OIPC so as to produce granules. This step is carried out at a temperature above the melting temperature of OIPC so that OIPC is present (primarily) in a liquid state during the process. Different (wet) agglomeration techniques can be employed to accomplish this, such as extrusion granulation, high-shear granulation, low-shear granulation, or fluidized bed granulation techniques. In one particularly preferred embodiment of the invention, the melt-agglomeration step comprises hot-melt extrusion. In preferred embodiments of the invention, the temperature of the melt-agglomeration step is above the melting temperature of the OIPC and the binder. In preferred embodiments of the invention, the melt-agglomeration step, such as the hot melt extrusion step, is carried out at a temperature of at least <NUM>, e.g. at a temperature of at least <NUM>, at least <NUM>, at least <NUM> or at least <NUM>. Preferably the hot melt extrusion step, is carried out at a temperature below <NUM>, e.g. at a temperature below <NUM>, preferably below <NUM>. A particularly preferred embodiment of the invention concerns a process with a melt-agglomeration step based on the technology disclosed in <CIT>, comprising heating the mixture produced in step a), typically to a temperature above the melting point of OLPC and subjecting said heated mixture to mechanical shear force. In a preferred embodiment of the invention, step b) comprises a hot melt extrusion step, using (e.g.) a twin screw extruder, operated such that the temperature of the granulation mixture is maintained between <NUM> and <NUM>. In an embodiement, a process for preparing an OLPC containing granulate as defined herein is provided, wherein no solvent is added during any one of steps a), b) and c).

In an embodiement, a process for preparing an OLPC containing granulate as defined herein is provided, wherein steb b) does not comprise a hot-melt extrusion process wherein no solvent is added during the process.

In another embodiement, a process for preparing an OLPC containing granulate as defined herein is provided, wherein step b) comprises a wet granulation process, preferably a high-shear wet granulation process. A particularly preferred embodiment of the invention concerns a process including a wet-granulation step based on the technology disclosed in <CIT>. Hence, a process for preparing an OLPC containing granulate as defined herein is provided, wherein step a) comprises the addition to the mixture of a granulation liquid. The granulation liquid may be any liquid capable of dissolving the OLPC, such as water or certain organic solvents, to the extent suitable for use in pharmaceutical manufacturing, i. e with a view to safety/toxicity. Preferably a granulation liquid selected from the group consisting of from isopropyl alcohol (IPA), acetone, ethanol, dichloromethane, chloroform, water and mixtures thereof. In a particularly preferred embodiment of the invention, the process comnprises the step of dissolving OLPC in the granulation liquid. In a particularly preferred embodiment of the invention, the antioxidant is vitamin E or alpha tocopherol and the aniti-oxidant is added to the granulation liquid as well. Vitamin E / alpha tocopherol is an ingredient that is quite difficult to handle and process due to its specific physicochemical properties, i.e. it is a viscous oily substance at ambient temperatures. In fact, as is the case with OLPC, it is very difficult to produce a homogeneous dry mixture of the granulation excipients when Vitamin E / alpha tocopherol is added to the dry ingredients. Hence, in accordance with the teachings of <CIT>, these difficulties can be circumvented dissolving the antioxidant in the granulation liquid and using the solution obtained to granulate the dry powder mixture. Hence, in an embodiment of the invention, step a) comprises: a1) providing a dry powder (blend) of the filler and optional further granulation excipients; a2) preparing a solution of the OLPC and anti-oxidant in the granulation liquid; and adding to the dry powder (blend) of step a1), the solution prepared in step a2). In these processes, wherein a granulation liquid is used, step b) typically comprises subjecting the mixture to a mechanical operation, such as extrusion granulation, high-shear granulation, low-shear granulation, or fluidized bed granulation processes. In particularly preferred embodiments of the invention (high) shear-mixing or extrusion is carried out, e.g. by means of a high shear mixer or a twin-screw extruder, and subsequently drying the obtained granulate. Thus, in accordance with this embodiment, step b) comprises subjecting the mixture to high shear granulation or extrusion granulation, followed by drying of the obtained granulate.

All steps of a process for granulation according to the invention or a process for preparing a tablet dosage formulation according to the invention may be executed using standard equipment and methodology.

In preferred embodiments of the invention, the step a) comprises combining OIPC and the one or more granulation excipients in any order. In certain embodiments premixes of various combinations of the respective components may be made, which pre-mixes are then combined and blended. In preferred embodiments of the invention, the blending step comprises initimate blending or mixing of the OIPC and granulation excipients to produce a homoegeneous blend or mixture, employing techniques such as roller mixing, drum mixing, shear mixing, dry blending, chopping, milling, etc..

In preferred embodiments of the invention, step c) comprises cooling said granulate, typically to below the melting temperature of the OIPC, preferably to ambient temperature. In preferred embodiments of the invention, the milling step comprises milling said cooled granulate by cutting the granulate into pieces using techniques and equipment conventionally used in the field.

In preferred embodiments of the invention, the further granulation excipients comprise one, two or all of a spacer, disintegrants, binders and lubricants.

The spacer that may be used as a granulation excipient is preferably hydrophilic polymers, more preferably selected from the group consisting of polyethylene glycol, polyethylene glycol esters, polypropylene glycol, polypropylene glycol esters, polyvinyl pyrrolidone (PVP), poly-(<NUM>-oxazoline)s (POX) and polyacrylic acid (PAA) and hydroxypropylmethylcellulose. In one particularly preferred embodiment of the invention, the spacer is a hydrophilic polymer selected from the group consisting of polyethylene glycol <NUM> (PEG <NUM>, macrogol <NUM>) and polyethylene glycol <NUM> (PEG <NUM>, macrogol <NUM>), polyvinyl pyrrolidone (PVP), poly-(<NUM>-oxazoline)s (POX) and polyacrylic acid (PAA). More preferably, the granulation spacer in a process for agglomeration is polyethylene glycol <NUM> or polyethylene glycol <NUM>, more preferably polyethylene glycol <NUM>. In certain embodiments of the invention, products comprising PEG esters in combination with other components may be used as the spacer, such as the hydrophilic grades of Gelucire, e.g. Gelucire <NUM>/<NUM>, <NUM>/<NUM>, <NUM>/,<NUM>, <NUM>/<NUM>, <NUM>/<NUM> and <NUM>/<NUM>, which are based on mixtures of mono, di and triglycerides with PEG esters of fatty acids.

The disintegrant that mau be used as granulation excipient is preferably selected from the group consisting of starch, microcrystalline cellulose, alginic acid, methyl cellulose, sodium starch glycolate, croscarmellose sodium, crospovidone, calcium silicate and mixtures thereof.

The binder that may be used as granulation excipient is preferably selected from the group consisting of acacia mucilage, alginic acid, carbomer, carboxymethylcellulose calcium, carboxymethycellulose sodium, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gelatine, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose (hypromellose), magnesium aluminum silicate, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, copovidone, sodium alginate, starch paste, pregelatinized starch, sucrose (syrup), silicium dioxide and mixtures thereof. Preferably, the silicium dioxide is colloidal silicone dioxide (colloidal silica), silica gel, mesoporous silica, nanoporous silica.

The lubricant that may be used as granulation excipient is preferably selected from the group consisting of calcium stearate, fumaric acid, glyceryl behenate, glyceryl palmitostearate, hydrogenated vegetable oil, magnesium lauryl sulphate, magnesium stearate, sodium lauryl sulphate, sodium stearyl fumarate, starch, stearic acid, talc, zinc stearate and mixtures thereof. In a specific embodiment is provided a process for agglomeration according to the invention wherein the granulation lubricant is selected from said group. In a specific embodiment is provided a process for granulation according to the invention wherein the granulation lubricant is selected from said group. In another specific embodiment is provided a process for preparing a tablet dosage formulation according to the invention wherein the granulation lubricant and the compression lubricant are independently selected from said group.

In an embodiement, a process for preparing an OLPC containing granulate as defined herein is provided, wherein:.

The percentages of the various constituents of the granulate as given here above, are are based on weight of the constituent relative to the total weight of granulate.

A further aspect of the invention concerns the olelyl phosphocholine (OIPC) containing granulates obtainable by the processes as defined herein.

A further aspect of the invention concerns pharmaceutical formulations comprising an OLPC containing granulate obtainable by the processes as defined herein. In a preferred embodiment of the invention, said pharmaceutical formulation is selected from the group consisting a tablet, a filled capsule and a powder.

In a preferred embodiment is provided a process for preparing a tablet dosage formulation comprising:.

In an embodiment the invention provides a coating step iv), wherein a tablet coating is applied to the tablet dosage formulation comprising the following consecutive steps:.

Fillers (or diluents) as compression excipients are preferably selected from the group consisting of calcium carbonate, calcium phosphate (dibasic), calcium phosphate (tribasic) , calcium sulphate, cellulose, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose monohydrate (lactose), magnesium carbonate, maltitol, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, sugar spheres, talc, xylitol, silicium dioxide and mixtures thereof. Preferably, the silicium dioxide is colloidal silicone dioxide (colloidal silica), silica gel, mesoporous silica or nanoporous silicamore, more preferably mesoporous silica. More preferably, the compression filler in the process for preparing a tablet dosage formulation according to the invention is lactose monohydrate.

Binders as compression excipients are preferably selected from the group consisting of acacia mucilage, alginic acid, carbomer, carboxymethylcellulose calcium, carboxymethycellulose sodium, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gelatine, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose (hypromellose), magnesium aluminum silicate, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, copovidone, sodium alginate, starch paste, pregelatinized starch, sucrose (syrup), silicium dioxide, such as colloidal silicone dioxide, silica gel, mesoporous silica, nanoporous silicamore, more preferably mesoporous silica, and mixtures thereof. In a specific embodiment is provided a process for granulation according to the invention wherein the granulation binder is selected from said group. In another specific embodiment is provided a process for preparing a tablet dosage formulation according to the invention wherein the granulation binder and the compression binder are independently selected from said group.

More preferably, the compression binder in the process for preparing a tablet dosage formulation according to the invention is microcrystalline cellulose.

Lubricants as compression excipients are preferably selected from the group consisting of calcium stearate, fumaric acid, glyceryl behenate, glyceryl palmitostearate, hydrogenated vegetable oil, magnesium lauryl sulphate, magnesium stearate, sodium lauryl sulphate, sodium stearyl fumarate, starch, stearic acid, talc, zinc stearate and mixtures thereof.

More preferably, the compression lubricant in the process for preparing a tablet dosage formulation according to the invention is magnesium stearate.

Disintegrants as compression excipients are preferably selected from the group consisting of starch, microcrystalline cellulose, alginic acid, methyl cellulose, sodium starch glycolate, croscarmellose sodium, crospovidone, calcium silicate and mixtures thereof.

More preferably, the compression disintegrant in the process for preparing a tablet dosage formulation according to the invention is croscarmellose sodium.

Antioxidants as compression excipients are preferably selected from the group consisting of alpha tocopherolacetate, Vitamin E, Vitamin E TPGS, diethylhexyl syringylidene malonate, diisopropyl vanillidene malonate, tetrahydrocurcumenoids, tocopherol, carotenoids, anthocyanidins, hydroquinone monomethyl ether, ascorbic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butylhydroquinone (TBHQ), propyl gallate and ethoxyquin (EMQ) and mixtures thereof.

In a preferred embodiment is provided a process for preparing a tablet dosage formulation according to the invention wherein the compression filler is lactose monohydrate; wherein the granulation binder and the compression binder are microcrystalline cellulose; wherein the granulation spacer is polyethylene glycol <NUM>; wherein the compression lubricant is magnesium stearate; wherein the granulation antioxidant is alpha tocopherolacetate; and wherein the granulation disintegrant and the compression disintegrant are croscarmellose sodium.

In a preferred embodiment is provided a process for preparing a tablet dosage formulation according to the invention:.

In an embodiment of the invention is provided a process for preparing a tablet dosage formulation as defined herein:.

In a preferred embodiment a process for preparing a tablet dosage formulation according to the invention is provided, wherein the tablet dosage formulation comprises oleyl phosphocholine, lactose, colloidal silica, microcrystalline cellulose, hydroxypropylmethyl cellulose, croscarmellose sodium, magnesium stearate and vitamin E:.

The present invention also provides a tablet dosage formulation obtainable using the above described processes.

In a preferred embodiment is provided a tablet dosage formulation according to the invention:.

In a preferred embodiment a tablet dosage formulation according to the invention is provided:.

In an embodiment a tablet dosage formulation according to the invention is provided, wherein the tablet dosage formulation comprises oleyl phosphocholine, lactose, colloidal silica, microcrystalline cellulose, hydroxypropylmethyl cellulose, croscarmellose sodium, magnesium stearate and vitamin E:.

In an embodiment, the invention provides the tablet dosage formulation as defined herein further comprising a tablet coating, wherein the tablet coating comprises a seal coating, a subcoating, and a colour coating;.

The preparation and composition of tablet dosage formulations according to the invention is shown in Examples <NUM> and <NUM>.

The present invention provides tablet dosage formulations of oleyl phosphocholine which are particularly stable. Specifically, in one embodiment of the present invention is provided a tablet dosage formulation according to the invention wherein, if stored under warm and humid conditions,.

The stability of tablet dosage formulations according to the invention, and the stable dissolution release profile of oleyl phosphocholine comprised in said tablets, is demonstrated in Examples <NUM> and <NUM>, respectively.

As discussed above, a tablet dosage formulation according to the invention is more stable under warm and humid conditions than a tablet dosage formulations prepared via a direct compression or a wet granulation process and not comprising a spacer and an antioxidant, as found in the prior art.

Another preferred embodiment of the invention, concerns a process for preparing an OLPC containing capsule dosage formulation comprising:.

A tablet dosage formulation according to the invention is provided for use as a medicament. In a preferred embodiment is provided a tablet dosage formulation according to the invention for use in the treatment of parasitic diseases, preferably a parasitic disease selected from the group consisting of leishmaniasis, chagas or malaria and cancer.

<FIG>: Process for preparing the tablet core of the tablet dosage formulation in Example <NUM>.

The following examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way.

In this example a granulate according to this application is produced, using hot melt extrusion. The composition of this milled extrudate is given in Table <NUM>.

In this example is provided a tablet dosage formulation prepared via a process for preparing a tablet dosage formulation according to the invention. In this process, the milled extrudate as described in Example <NUM> was an intermediate.

The composition of the compression mixture in this example, prepared as an intermediate during the process for preparing a tablet dosage formulation according to the invention, is given in Table <NUM>.

The composition of the tablet dosage formulation in this example is given in Table <NUM>. The composition of the tablet coating of the tablet dosage formulation in this example is given in Table <NUM>.

The tablet core of the tablet dosage formulation in this example was prepared via the process steps as described in <FIG>.

The change of the concentration of oleyl phosphocholine in the tablet dosage formulation described in Example <NUM> upon storage under different conditions can be found in Table <NUM>.

The dissolution of oleyl phosphocholine comprised in the tablet dosage formulation described in Example <NUM>, which has been stored for different time periods (<NUM> months, <NUM> months, <NUM> months) under different conditions, has been determined by the European Pharmacopoeia <NUM>. <NUM> standard dissolution test after <NUM> minutes. The results can be found in Table <NUM>.

Claim 1:
A process for making an olelyl phosphocholine (OIPC) containing granulate, said process comprises the consecutive steps of:
a) preparing a mixture of oelyl phosphocholine, an anti-oxidant, a filler and, optionally, a granulation liquid and/or one or more further granulation excipients;
b) processing the mixture prepared in step a) into a dry granulate; and
c) milling the granulate produced in step b);
characterized in that the antioxidant is vitamin E, vitamin E TPGS, alpha-tocopherol acetate and/or alpha-tocopherol.