Patent Publication Number: US-2023147712-A1

Title: Oleyl phosphocholine containing granulates

Description:
FIELD OF THE INVENTION 
     The present invention relates to process for the production of oleyl phosphocholine (C18:1-PC or OlPC) containing granulates, to the granulates obtainable by said process, dosage forms comprising said grantulates and to use of said dosage forms in therapeutic and/or prhophylactic methods of treatment. 
     BACKGROUND OF THE INVENTION 
     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 WO 99/37289 describes and addresses some of the problems associated with miltefosine formulations. 
     An alternative for miltefosine is the alkylphosphocholine oleyl phosphocholine (C18:1-PC or OlPC) 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 (56.3° C.), high hygroscopicity (absorbing 41.67 weight percent of water when exposed to 90% RH at 25° C.) 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 WO 2012/069427 A1 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 WO 2012/069427 A1 was only tested for a period of twelve months at a temperature of 30° C. and a relative humidity (RH) of 65%. 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 (30° C.) and humid conditions (75% RH) for a period of at least 24 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. 
     SUMMARY OF THE INVENTION 
     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 24 months at 30° C. and 75% 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 (OlPC) containing granulate, said process comprising the consecutive steps of:
         a) preparing a mixture of olelyl 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).       

     In a further aspect, the invention provides OlPC 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 OlPC 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 WO 2012/069427. In another particularly advantageous embodiment, the granulation process is based on the technology described in international application no. PCT/EP2020/060324 (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. 
     DETAILED DESCRIPTION OF THE INVENTION 
     Definitions 
     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 (Remington&#39;s Pharmaceutical Sciences 18th ed. 1990, page 1641). 
     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 0.1 N aqueous HCl solution. Disintegration of a tablet dosage formulation may be determined using the European Pharmacopoeia 2.9.1 standard disintegration test (900 ml HCl 0.1 N) or USP &lt;701&gt;. 
     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 2.9.3 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 2.9.3 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 60, 65, 70, 75 or 80 weight percent of oleyl phospocholine has been dissolved after 60 minutes, preferably at least 70 weight percent of oleyl phospocholine, more preferably at least 75 weight percent of oleyl phospocholine, most preferably at least 80 weight percent of oleyl phospocholine, as determined by the European Pharmacopoeia 2.9.3 standard dissolution test, for all tablet dosage formulations stored up to 24 months under warm and humid conditions. Preferably, said warm and humid conditions are 25° C. and 60% RH, 30° C. and 65% RH or 30° C. and 75% RH, more preferably 30° C. and 75% 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 24 months at a temperature of 30° C. and a relative humidity of 75%,
         the concentration of each active pharmaceutical ingredient in said tablet dosage formulation does not change by more than 5 weight percent, preferably by not more than 2.5 weight percent, more preferably by not more than 1 weight percent; and   each active pharmaceutical ingredient in said tablet dosage formulation has a stable dissolution release profile.       

     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, 1, 2, 3, 6, 12, 18, 24 or 36 months in a temperature range from 20° C. to 60° C. and a relative humidity range from 20% to 100%. Preferred temperature ranges are, in the order of increasing preference, from 25° C. to 60° C., from 30° C. to 60° C., from 35° C. to 60° C., and from 40° C. to 60° C. Preferred relative humidity ranges are, in the order of increasing preference, from 50% to 100%, from 60% to 100%, from 65% to 100%, from 70% to 100%, and from 75% to 100%. Preferred warm and humid storage conditions in this context are at 25° C. and 60% RH or at 30° C. and 65% RH or at 30° C. and 75% RH or at 40° C. and 75% RH for 12 or 24 months; even more preferably at 25° C. and 60% RH or at 30° C. and 65% RH or at 30° C. and 75% RH or at 40° C. and 75% RH for 24 months; even more preferably at 30° C. and 75% RH or at 40° C. and 75% RH for 24 months; even more preferably at 30° C. and 75% RH for 24 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. 
     Processes for Preparing OlPC Containing Granulate 
     In a first aspect, the invention provides a process for preparing an olelyl phosphocholine (OlPC) containing granulate, said process comprising the consecutive steps of:
         a) preparing a mixture of olelyl 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 dry granulate produced in step b).       

     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 tocophero. 
     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 OlPC so as to produce granules. This step is carried out at a temperature above the melting temperature of OlPC so that OlPC 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 OlPC 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 50° C., e.g. at a temperature of at least 60° C., at least 65° C., at least 70° C. or at least 75° C. Preferably the hot melyt extrusion step, is carried out at a temperature below 120° C., e.g. at a temperature below 100° C., preferably below 90° C. A particularly preferred embodiment of the invention concerns a process with a melt-agglomeration step based on the technology disclosed in PCT/EP2020/060324, 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 40° C. and 60° C. 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 WO 2012/069427. 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 WO 2012/069427, 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 OlPC 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 OlPC 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 OlPC, 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-(2-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 4000 (PEG 4000, macrogol 4000) and polyethylene glycol 6000 (PEG 6000, macrogol 6000), polyvinyl pyrrolidone (PVP), poly-(2-oxazoline)s (PDX) and polyacrylic acid (PAA). More preferably, the granulation spacer in a process for agglomeration is polyethylene glycol 4000 or polyethylene glycol 6000, more preferably polyethylene glycol 6000. 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 50/13, 44/14, 48/,16, 55/18, 35/10 and 48/09, 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 concentration of oleyl phosphocholine in the OlPC containing granulate is between 10 and 50 weight percent, preferably between 25 and 35 weight percent;   the concentration of the antioxidant in the OlPC containing granulate is between 0.05 and 5 weight percent, preferably between 0.1 and 1 weight percent, preferably wherein said antioxidant is selected from the group consisting of alpha tocopherol, vitamin E, alpha tocopherolacetate, ascorbic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butylhydroquinone (TBHQ), propyl gallate and ethoxyquin and mixtures thereof, most preferably wherein said antioxidant is alpha tocopherol or Vitamin E;   if a binder is added as a granulation excipient, the concentration of the binder in the extrudated OlPC containing granulate is between 10 and 50 weight percent, preferably between 25 and 35 weight percent, preferably wherein said binder is 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, magnesium aluminum silicate, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, copovidone, sodium alginate, starch paste, pregelatinized starch, sucrose (syrup) and mixtures thereof, most preferably wherein said binder is microcrystalline cellulose;   if a spacer is added as a granulation excipient, the concentration of the spacer in the OlPC containing granulate is between 10 and 50 weight percent, preferably between 25 and 35 weight percent, preferably wherein said spacer is selected from the group consisting of polyethylene glycol 4000, polyethylene glycol 6000, polyvinyl pyrrolidone, poly-(2-oxazoline)s and polyacrylic acid and mixtures thereof, most preferably wherein said spacer is polyethylene glycol 6000;   if a disintegrant is added as a granulation excipient, the concentration of the disintegrant in the OlPC containing granulate is between 1 and 20 weight percent, preferably between 1 and 10 weight percent, preferably wherein said disintegrant is selected from the group consisting of starch, microcrystalline cellulose, alginic acid, methyl cellulose, sodium starch glycolate, croscarmellose sodium, crospovidone, calcium silicate and mixtures thereof, most preferably wherein said disintegrant is croscarmellose sodium; and   if a lubricant is added as a granulation excipient, the concentration of the lubricant in the ICP containing granulate is between 1 and 20 weight percent, preferably between 1 and 10 weight percent, preferably wherein said lubricant is 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, most preferably wherein said lubricant is selected from the group consisting of magnesium stearate and mixtures thereof.       

     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. 
     Granulate Obtaine by the Processes of the Present Invention and Dosage Formulations Containing Saud Granulate 
     A further aspect of the invention concerns the olelyl phosphocholine (OlPC) 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:
         i. a process for making an OLPC containing granulate according to the invention;   ii. preparing a compression mixture by mixing an OlPC containing granulate prepared by the process according to the invention with compression excipients,herein said compression excipients comprise at least a filler and a lubricant, and optionally a binder and/or a disintegrant;   iii. compressing the mixture produced in step ii) into a tablet; and, optionally   iv. coating the compressed tablet obtained in step iii).       

     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:
         sealing with a seal coating, wherein the seal coating is selected from the group consisting of shellac, zinc oxide, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxylpropylcellulose, hydroxypropylmethylcellulose or mixtures thereof;   optionally subcoating with a subcoating comprising a sugar coating and a powder until the desired shape and consistency is achieved, wherein the sugar coating is a sucrose based solution or syrup and the powder is talc, a talc-calcium mixture, calcium carbonate or a mixture thereof;   optionally smoothing of the tablet formulation to remove irregular features or areas of the table formulation to the required dimension;   optionally colouring with a colour coating, wherein the colour coating is a dye or a pigment; and   optionally polishing of the tablet formulation with a wax, wherein the wax is Montanglycolwax, beeswax or carnauba wax       

     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 6000; 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;
         wherein between 30 and 60 weight percent of OlPC containing granulate is added during the compression blending step;   wherein the concentration of the filler in the compression mixture is between 10 and 40 weight percent, preferably between 25 and 35 weight percent, preferably wherein said 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 and mixtures thereof, most preferably wherein said filler is lactose monohydrate;   wherein the concentration of the lubricant in the compression mixture is between 10 and 30 weight percent, preferably between 15 and 25 weight percent, preferably wherein said lubricant is 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, most preferably wherein said lubricant is selected from the group consisting of magnesium stearate, and mixtures thereof;   wherein the concentrations in this embodiment are relative to the compression mixture.       

     In an embodiment of the invention is provided a process for preparing a tablet dosage formulation as defined herein:
         wherein the concentration of oleyl phosphocholine in the tablet dosage formulation is between 5 and 40 weight percent, preferably between 15 and 30 weight percent;   wherein the concentration of the filler in the tablet dosage formulation is between 20 and 70 weight percent, preferably between 30 and 60 weight percent, preferably wherein said 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, 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, silica gel, mesoporous silica or nanoporous silica, and mixtures thereof, most preferably wherein said filler is lactose and colloidal silicone dioxide;   wherein the concentration of the binder in the tablet dosage formulation is between 10 and 40 weight percent, preferably between 15 and 30 weight percent, preferably wherein said binder is 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, magnesium aluminum silicate, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, copovidone, sodium alginate, starch paste, pregelatinized starch, sucrose (syrup) and mixtures thereof, most preferably wherein said binder is microcrystalline cellulose and hydroxypropylmethyl cellulose;   wherein the concentration of the disintegrant in the tablet dosage formulation is between 1 and 5 weight percent, preferably between 2 and 4 weight percent, preferably wherein said disintegrant is selected from the group consisting of starch, microcrystalline cellulose, alginic acid, methyl cellulose, sodium starch glycolate, croscarmellose sodium, crospovidone, calcium silicate and mixtures thereof, most preferably wherein said disintegrant is croscarmellose sodium;   wherein the concentration of the lubricant in the tablet dosage formulation is between 0.1 and 2 weight percent, preferably between 0.5 and 1 weight percent, preferably wherein said lubricant is 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, most preferably wherein said lubricant is magnesium stearate;   wherein the concentration of the antioxidant in the tablet dosage formulation is between 0.1 and 2 weight percent, preferably between 0.5 and 1 weight percent, preferably wherein said antioxidant is selected from the group consisting of alpha tocopherolacetate, ascorbic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butylhydroquinone (TBHQ), propyl gallate and ethoxyquin and mixtures thereof, most preferably wherein said antioxidant is vitamin E;   wherein the concentrations in this embodiment are relative to the tablet dosage formulation.       

     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:
         wherein the concentration of oleyl phosphocholine in the tablet dosage formulation is between 5 and 40 weight percent, preferably between 15 and 30 weight percent;   wherein the concentration of the lactose in the tablet dosage formulation is between 5 and 25%, preferably between 10 and 20%;   wherein the concentration of the colloidal silica in the table dosage formulation is between 15 and 45%, preferably between 20 and 40%;   wherein the concentration of the microcrystalline cellulose in the tablet dosage formulation is between 5 and 25 weight percent, preferably between 10 and 20 weight percent;   wherein the concentration of the hydroxypropylmethyl cellulose in the tablet dosage formulation is between 5 and 15 weight percent, preferably between 5 and 10 weight percent;   wherein the concentration of the croscarmellose sodium in the tablet dosage formulation is between 1 and 5 weight percent, preferably between 2 and 4 weight percent;   wherein the concentration of the magnesium stearate in the tablet dosage formulation is between 0.1 and 2 weight percent, preferably between 0.5 and 1 weight percent;   wherein the concentration of the vitamin E in the tablet dosage formulation is between 0.1 and 2 weight percent, preferably between 0.5 and 1 weight percent;   wherein the concentrations in this embodiment are relative to the tablet dosage formulation.
 
always
       

     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:
         wherein the concentration of oleyl phosphocholine in the tablet dosage formulation is between 5 and 30 weight percent, preferably between 5 and 15 weight percent;   wherein the concentration of the filler in the tablet dosage formulation is between 10 and 30 weight percent, preferably between 15 and 25 weight percent, preferably wherein said 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 and mixtures thereof, most preferably wherein said filler is lactose monohydrate;   wherein, if a binder is added during the process for preparing said tablet dosage formulation, the concentration of the binder in the tablet dosage formulation is between 10 and 30 weight percent, preferably between 15 and 25 weight percent, preferably wherein said binder is 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, magnesium aluminum silicate, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, copovidone, sodium alginate, starch paste, pregelatinized starch, sucrose (syrup) and mixtures thereof, most preferably wherein said binder is microcrystalline cellulose;   wherein the concentration of the spacer in the tablet dosage formulation is between 10 and 30 weight percent, preferably between 15 and 25 weight percent, preferably wherein said spacer is selected from the group consisting of polyethylene glycol 4000, polyethylene glycol 6000, polyvinyl pyrrolidone, poly-(2-oxazoline)s and polyacrylic acid and mixtures thereof, most preferably wherein said spacer is polyethylene glycol 6000;   wherein the concentration of the disintegrant in the tablet dosage formulation is between 1 and 10 weight percent, preferably between 1 and 5 weight percent, preferably wherein said disintegrant is selected from the group consisting of starch, microcrystalline cellulose, alginic acid, methyl cellulose, sodium starch glycolate, croscarmellose sodium, crospovidone, calcium silicate and mixtures thereof, most preferably wherein said disintegrant is croscarmellose sodium;   wherein the concentration of the lubricant in the tablet dosage formulation is between 5 and 20 weight percent, preferably between 5 and 15 weight percent, preferably wherein said lubricant is 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, most preferably wherein said lubricant is selected from the group consisting of magnesium stearate, and mixtures thereof;   wherein the concentration of the antioxidant in the tablet dosage formulation is between 0.05 and 5 weight percent, preferably between 0.1 and 1 weight percent, preferably wherein said antioxidant is selected from the group consisting of alpha tocopherolacetate, ascorbic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butylhydroquinone (TBHQ), propyl gallate and ethoxyquin and mixtures thereof, most preferably wherein said antioxidant is alpha tocopherolacetate;   wherein the concentrations in this embodiment are relative to the tablet dosage formulation.       

     In a preferred embodiment a tablet dosage formulation according to the invention is provided:
         wherein the concentration of oleyl phosphocholine in the tablet dosage formulation is between 5 and 40 weight percent, preferably between 15 and 30 weight percent;   wherein the concentration of the filler in the tablet dosage formulation is between 20 and 70 weight percent, preferably between 30 and 60 weight percent, preferably wherein said 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, 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, silica gel, mesoporous silica or nanoporous silica, and mixtures thereof, most preferably wherein said filler is lactose and colloidal silicone dioxide;   wherein, the concentration of the binder in the tablet dosage formulation is between 10 and 40 weight percent, preferably between 15 and 30 weight percent, preferably wherein said binder is 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, magnesium aluminum silicate, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, copovidone, sodium alginate, starch paste, pregelatinized starch, sucrose (syrup) and mixtures thereof, most preferably wherein said binder is microcrystalline cellulose and hydroxypropylmethyl cellulose;   wherein the concentration of the disintegrant in the tablet dosage formulation is between 1 and 5 weight percent, preferably between 2 and 4 weight percent, preferably wherein said disintegrant is selected from the group consisting of starch, microcrystalline cellulose, alginic acid, methyl cellulose, sodium starch glycolate, croscarmellose sodium, crospovidone, calcium silicate and mixtures thereof, most preferably wherein said disintegrant is croscarmellose sodium;   wherein the concentration of the lubricant in the tablet dosage formulation is between 0.1 and 2 weight percent, preferably between 0.5 and 1 weight percent, preferably wherein said lubricant is 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, most preferably wherein said lubricant is magnesium stearate;   wherein the concentration of the antioxidant in the tablet dosage formulation is between 0.1 and 2 weight percent, preferably between 0.5 and 1 weight percent, preferably wherein said antioxidant is selected from the group consisting of alpha tocopherolacetate, ascorbic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butylhydroquinone (TBHQ), propyl gallate and ethoxyquin and mixtures thereof, most preferably wherein said antioxidant is vitamin E;   wherein the concentrations in this embodiment are relative to the tablet dosage formulation.       

     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:
         wherein the concentration of oleyl phosphocholine in the tablet dosage formulation is between 5 and 40 weight percent, preferably between 15 and 30 weight percent;   wherein the concentration of the lactose in the tablet dosage formulation is between 5 and 25%, preferably between 10 and 20%;   wherein the concentration of the colloidal silica in the table dosage formulation is between 15 and 45%, preferably between 20 and 40%;   wherein the concentration of the microcrystalline cellulose in the tablet dosage formulation is between 5 and 25 weight percent, preferably between 10 and 20 weight percent;   wherein the concentration of the hydroxypropylmethyl cellulose in the tablet dosage formulation is between 5 and 15 weight percent, preferably between 5 and 10 weight percent;   wherein the concentration of the croscarmellose sodium in the tablet dosage formulation is between 1 and 5 weight percent, preferably between 2 and 4 weight percent;   wherein the concentration of the magnesium stearate in the tablet dosage formulation is between 0.1 and 2 weight percent, preferably between 0.5 and 1 weight percent;   wherein the concentration of the vitamin E in the tablet dosage formulation is between 0.1 and 2 weight percent, preferably between 0.5 and 1 weight percent;   wherein the concentrations in this embodiment are relative to the tablet dosage formulation.       

     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;
         wherein the seal coating is selected from the group consisting of shellac, zinc oxide, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxylpropylcellulose, hydroxypropylmethylcellulose and mixtures thereof and wherein the concentration of the seal coating is between 1 and 3 weight percent;   wherein the subcoating comprises a sugar coating and a powder, wherein the sugar coating is a sucrose based solution or syrup, wherein the powder is talc, talc-calcium mixture, calcium carbonate or mixtures thereof and wherein the concentration of the subcoating is between 70 and 80 weight percent;   wherein the colour coating is a dye or a pigment and wherein the concentration of the colour coating is between 20 and 30 weight percent;   wherein the wax is Montanglycolwax, beeswax or carnauba wax and wherein the concentration of the wax is less than 0.01 weight percent;   wherein the concentrations in this embodiment are relative to the tablet coating.       

     The preparation and composition of tablet dosage formulations according to the invention is shown in Examples 1 and 2. 
     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 concentration of each active pharmaceutical ingredient in said tablet dosage formulation does not change by more than 5 weight percent, preferably by not more than 2.5 weight percent, more preferably by not more than 1 weight percent; and/or   each active pharmaceutical ingredient in said tablet dosage formulation has a stable dissolution release profile;   wherein storage, in the order of increasing preference, is for 1, 2, 3, 6, 12, 18, 24 or 36 months;   wherein warm conditions correspond to a temperature range from 20° C. to 60° C., wherein more preferred temperature ranges are, in the order of increasing preference, from 25° C. to 60° C., from 30° C. to 60° C., from 35° C. to 60° C., and from 40° C. to 60° C.,   wherein humid conditions correspond to a relative humidity range from 20% to 100%, wherein more preferred relative humidity ranges are, in the order of increasing preference, are from 50% to 100%, from 60% to 100%, from 65% to 100%, from 70% to 100%, and from 75% to 100%,   preferably wherein warm and humid conditions correspond to 25° C. and 60% RH or 30° C. and 65% RH or 30° C. and 75% RH or 40° C. and 75% RH for 12 or 24 months; more preferably 25° C. and 60% RH or 30° C. and 65% RH or 30° C. and 75% RH or 40° C. and 75% RH for 24 months; more preferably 30° C. and 75% RH or 40° C. and 75% RH for 24 months; most preferably 30° C. and 75% RH for 24 months.       

     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 3 and 4, 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:
         I. a process for making an OlPC containing granulate according to any one of claims  1 - 8 ;   II. optionally mixing the OlPC containing granulate with one or more excipients;   III. filling of the mixture produced in step II) into hollow capsules.       

     Medical Uses of Dosage Formulations 
     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. 
    
    
     
       LEGEND OF THE FIGURES 
         FIG.  1   : Process for preparing the tablet core of the tablet dosage formulation in Example 1. 
     
    
    
     EXAMPLES 
     The following examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way. 
     Example 1 
     Granulate 
     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 1. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Composition of milled extrudate 
               
            
           
           
               
               
               
               
            
               
                   
                   
                   
                 % in the  
               
               
                   
                   
                   
                 milled extrudate 
               
               
                   
                   
                 mass  
                 (157.730 mg  
               
               
                   
                   
                 (mg per  
                 milled extrudate 
               
               
                   
                   
                 tablet) 
                 per tablet) 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 API 
                 oleyl phosphocholine 
                 50.000 
                 31.700 
               
               
                 Granulation 
                 alpha tocopherolacetate 
                 1.000 
                 0.634 
               
               
                 excipient 
                   
                   
                   
               
               
                   
                 microcrystalline cellulose 
                 49.000 
                 31.066 
               
               
                   
                 macrogol 6000 
                 50.000 
                 31.700 
               
               
                   
                 sodium croscarmellose 
                 7.730 
                 4.901 
               
               
                 Sum 
                   
                 157.730 
                 100.000 
               
               
                   
               
            
           
         
       
     
     Example 2 
     Tablet Dosage Formulation 
     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 1 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 2. 
     The composition of the tablet dosage formulation in this example is given in Table 3. The composition of the tablet coating of the tablet dosage formulation in this example is given in Table 4. 
     The tablet core of the tablet dosage formulation in this example was prepared via the process steps as described in  FIG.  1   . 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Composition of the compression mixture 
               
            
           
           
               
               
               
            
               
                   
                   
                 mass (mg  
               
               
                   
                   
                 per tablet) 
               
               
                   
               
            
           
           
               
               
               
            
               
                 Compression 
                 lactose monohydrate 
                 97.920 
               
               
                 excipient 
                   
                   
               
               
                   
                 microcrystalline cellulose 
                 47.250 
               
               
                   
                 sodium croscarmellose 
                 9.350 
               
               
                   
                 magnesium stearate 
                 3.150 
               
               
                 Sum 
                   
                 157.670 
               
               
                 Milled extrudate 
                   
                 157.730 
               
               
                 Compression 
                   
                 315.400 
               
               
                 mixture 
                   
                   
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Composition of tablet dosage formulation 
               
            
           
           
               
               
               
               
            
               
                   
                   
                   
                 % in the  
               
               
                   
                   
                   
                 tablet dosage 
               
               
                   
                   
                 mass 
                 formulation  
               
               
                   
                   
                 (mg per  
                 (557.700 mg 
               
               
                   
                   
                 tablet) 
                 per tablet) 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 API 
                 oleyl phosphocholine 
                 50.000 
                 8.965 
               
               
                 Excipient 
                 alpha tocopherolacetate 
                 1.000 
                 0.180 
               
               
                   
                 microcrystalline cellulose 
                 96.250 
                 17.258 
               
               
                   
                 macrogo 16000 
                 50.000 
                 8.965 
               
               
                   
                 sodium croscarmellose 
                 17.080 
                 3.062 
               
               
                   
                 lactose monohydrate 
                 97.920 
                 17.558 
               
               
                   
                 magnesium stearate 
                 3.150 
                 0.565 
               
               
                 Coating 
                   
                 242.300 
                 43.446 
               
               
                 Sum 
                   
                 557.700 
                 100.00 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Composition of the tablet coating 
               
            
           
           
               
               
               
            
               
                   
                   
                 mass (mg per tablet) 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 Seal coating 
                 3.976 
               
               
                   
                 Talc 
                 0.904 
               
               
                   
                 Sugar coating 
                 19.605 
               
               
                   
                 Talc-calcium mixture 
                 31.679 
               
               
                   
                 Sugar coating 
                 129.870 
               
               
                   
                 Colour coating 
                 56.112 
               
               
                   
                 Motanylglycolwax 
                 0.160 
               
               
                   
                 Sum 
                 234.600 
               
               
                   
                   
               
            
           
         
       
     
     Example 3 
     Stability of a Tablet Dosage Formulation 
     The change of the concentration of oleyl phosphocholine in the tablet dosage formulation described in Example 2 upon storage under different conditions can be found in Table 5. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Change of oleyl phosphocholine concentration 
               
            
           
           
               
               
            
               
                   
                 OIPC concentration in the tablet dosage formulation 
               
               
                 Conditions 
                 (mg/tablet) after X months of storage 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 T 
                 RH 
                 X = 0 
                 X = 3 
                 X = 6 
                 X = 18 
                 X = 24 
                 X = 36 
               
               
                   
               
               
                 25° C. 
                 60% 
                 50.2 
                 48.1 
                 48.1 
                 49.15 
                 47.10 
                 50.14 
               
               
                 30° C. 
                 75% 
                 50.2 
                 47.5 
                 49.7 
                 50.17 
                 47.46 
                 49.30 
               
               
                 40° C. 
                 75% 
                 50.2 
                 48.9 
                 49.9 
               
               
                   
               
            
           
         
       
     
     Example 4 
     Dissolution of Oleyl Phosphocholine 
     The dissolution of oleyl phosphocholine comprised in the tablet dosage formulation described in Example 2, which has been stored for different time periods (18 months, 24 months, 36 months) under different conditions, has been determined by the European Pharmacopoeia 2.9.3 standard dissolution test after 60 minutes. The results can be found in Table 6. 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Dissolution of oleyl phosphocholine concentration 
               
            
           
           
               
               
               
            
               
                   
                   
                 Dissolved weight percentage of oleyl  
               
               
                   
                   
                 phosphocholine after 60 minutes, 
               
               
                   
                   
                 relative to the tablet dosage formulation 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Conditions 
                 storage of  
                 storage of  
                 storage of  
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 T 
                 RH 
                 18 months 
                 24 months 
                 36 months 
               
               
                   
                   
               
               
                   
                 25° C. 
                 60% 
                 78.4 
                 83.2 
                 96.4 
               
               
                   
                 30° C. 
                 75% 
                 89.9 
                 80.9 
                 83.3