Solid orodispersible dosage form of a cholinergic drug for the treatment of cognitive decline

Abstract

An oral form of pharmaceutical dosage in orodispersible granules, wherein the granules comprise a therapeutically effective amount of choline alfoscerate adsorbed on at least one pharmaceutically acceptable excipient comprising micronized colloidal silica.

Description

[0001] SOLID ORODISPERSIBLE DOSAGE FORM OF A CHOLINERGIC

[0002] DRUG FOR THE TREATMENT OF COGNITIVE DECLINE

[0003] The present invention relates to a solid orodispersible dosage form of a cholinergic drug for the treatment of forms of cognitive decline.

[0004] The present invention originates in the field of solid pharmaceutical dosage forms for oral and / or sublingual administration of active ingredients.

[0005] In particular, the present invention relates to a solid dosage form in orodispersible granules based on a selected cholinergic drug suitable for treating forms of cognitive decline of a human being, and to a method for its preparation.

[0006] At the level of the central nervous system, the cholinergic system of nervous transmission is involved in numerous processes that regulate the activity and major functions of the brain such as attention, learning, memory, sleep-wake rhythm, and sensory information.

[0007] As age increases, changes in cholinergic transmission occur which contribute to brain alterations that are observed in several forms of dementia, including Alzheimer's disease. Recent studies on the brains of senile dementia patients have shown a marked loss of choline acetyltransferase, an enzyme involved in acetylcholine synthesis, and of nicotinic cholinergic receptors.

[0008] Thus, acetylcholine plays an important role in cognitive processes. Its deficiency is observed in Alzheimer's disease, and the observation that central cholinergic antagonists such as atropine can induce a confusional state typical of forms of dementia supports the cholinergic hypothesis that acetylcholine deficiency is critical in the onset of symptoms of Alzheimer's disease and other forms of senile dementia.

[0009] Choline and phosphatidylcholine, a choline-containing phospholipid, are essential for maintaining the integrity and structure of the cell membrane. Choline plays a role in transport into cells and in the constitution of cell membranes and is a precursor to acetylcholine. For these reasons, choline is considered to be one of the nutrients required for optimal cognitive function.

[0010] Therefore, drugs that act on the cholinergic system are a promising therapeutic option for the treatment of patients with senile dementia and Alzheimer's disease.

[0011] The first cholinergic drugs introduced into therapy were cholinergic precursors, such as CDP-choline or citicoline. Currently, the use in therapy of most cholinergic precursors is an approach that is considered outdated to treat cholinergic dysfunction and cognitive decline in adult-onset dementia. In this scenario, choline alfoscerate, L-alpha-glycerophosphorylcholine, known by the acronym GPC, is an exception, because although it is a first- generation cholinergic precursor it has yielded positive results in some preclinical and clinical studies, as highlighted in the publication Traini E., Bramanti V., Amenta F.: Cholinealphoscerate (alpha-glyceryl- phosphorylcholine) an old choline-containing phospholipid with a still interesting profile as cognition enhancing agent. Curr Alzheimer Res 2013; 10:1070-9.

[0012] In these studies, GPC has shown moderate efficacy in the treatment of Alzheimer's disease and other forms of dementia, in particular those of vascular origin.

[0013] Moreover, GPC, as a cholinergic precursor, ensures higher plasma levels of choline and greater activity on memory and cognitive parameters than citicoline.

[0014] Subsequently, other types of compounds have been identified, such as cholinesterase inhibitors, typically donepezil, galantamine and rivastigmine, and acetylcholine Ml receptor agonists, for example xanomeline. Recently, the usefulness has been furthermore hypothesized of drugs targeting the high-affinity choline transporter CHT1 and of memantine, a noncompetitive NMD A receptor antagonist, which has some protective action on cholinergic neurons against excitotoxic destruction. Despite the availability of new drugs acting on the cholinergic system, however, the scientific world's attention on GPC in the treatment of dementia, in particular of vascular origin, and early forms of Alzheimer's disease has remained high.

[0015] The kinetics and metabolism of GPC have been evaluated in studies in animals and humans. GPC is hydrolyzed by intestinal mucosal phosphodiesterases, and its concentration is higher in the liver, kidney, lungs, and spleen than in blood, while in the brain its concentration is similar or slightly lower than in blood. After cerebral perfusion in an animal model, GPC is metabolized to choline and two other metabolites and is incorporated into brain phospholipids. In humans, when GPC is administered intramuscularly at a dose of 1 g, plasma choline levels reach a Cmax of 35.1 μM after 30 min, then decline with a half-life of approximately 2 h and return to basal values after 6 to 8 h. Orally, in pharmaceutical tablet form, GPC is hydrolyzed to choline, which is absorbed during intestinal transit. Typically, it has a Tmax (time to reach the maximum concentration Cmax of the drug) of about 3.5-4 h and a half-life of about 5-7 hours.

[0016] Typically, current commercially available choline alfoscerate-based pharmaceutical formulations in solid form for oral administration are in the form of tablets, soft capsules.

[0017] However, GPC formulations in solid form are large in size and have low compliance as they are difficult to swallow especially by aging individuals who represent the main portion of the population of individuals targeted for treatment.

[0018] Therefore, there is a need to have oral solid pharmaceutical forms containing GPC that have a higher compliance in particular for the population of individuals older than 70 years.

[0019] However, the liquid physical state of choline alfoscerate and its high viscosity and hygroscopicity complicate the provision of oral solid pharmaceutical forms that are alternative to those currently available.

[0020] In particular, identifying a suitable pharmaceutically acceptable excipient on which choline alfoscerate in liquid form can be adsorbed is a difficult problem to solve, given its high viscosity and hygroscopicity.

[0021] It is therefore a general object of the present invention to provide an orosoluble oral dosage form of choline alfoscerate having improved compliance and high absorption in the gastrointestinal tract.

[0022] Another object of the present invention is to formulate choline alfoscerate in a solid pharmaceutical form in orodispersible granules that has a rapid oral dissolution profile with sublingual absorption of the active ingredient.

[0023] The present invention originates from having observed how, by using selected excipients, it is possible to formulate choline alfoscerate in a solid form of orodispersible granules suitable for oral administration with high compliance.

[0024] In accordance with an aspect of the invention, it has been found that micronized colloidal silica, preferably mixed with mannitol, is an excipient suitable to obtain an oral solid formulation in which choline alfoscerate is in the form of orodispersible granules suitable for oral administration.

[0025] Moreover, it has been found that mannitol, when incorporated into the granule dosage form described herein, increases the mass of the granules and unexpectedly improves the disintegration of the granule dosage form, increasing the rapid release of the choline alfoscerate contained in the granules.

[0026] An object of the present invention is a solid pharmaceutical dosage form of choline alfoscerate for oral administration, characterized in that it is in the form of orodispersible granules comprising at least one excipient comprising preferably micronized colloidal silica and choline alfoscerate adsorbed on the colloidal silica-based excipient. Preferably, the excipient of the oral dosage form described here further comprises mannitol, preferably in a mixture with the colloidal silica.

[0027] Preferably, the colloidal silica is fumed.

[0028] The inventors, in carrying out activities in the field of pharmaceutical technology, have focused their attention on the study of suitable excipients for the formulation of pharmacologically active ingredients that have formulation difficulties. As part of this research project, they have unexpectedly found that it is possible to overcome some technical problems observed in the formulation of choline alfoscerate in orodispersible oral dosage forms that made this pharmaceutical formulation impractical. These technical problems are mainly correlated with the chemical and physical characteristics of the raw material, which has a liquid form that is highly viscous and hygroscopic. It was unexpectedly found that these problems can be overcome by adsorbing choline alfoscerate in liquid or semiliquid form on micronized colloidal silica as defined in claim 1.

[0029] In one embodiment, the micronized colloidal silica has an average particle size comprised between 5 and 50 nanometers, preferably a surface area comprised between 50 and 600 m2 / g, and preferably a density comprised between 160 and 190 Kg / m3.

[0030] In another embodiment, the colloidal silica has a specific surface area equal to 200 ± 25 m2 / g and an average particle size of 12 nm. Adsorption of choline alfoscerate on micronized colloidal silica as described here allows to obtain an orodispersible dosage form that can be administered as is, even without water. This specific dosage form has the additional advantage of being absorbed sublingually, avoiding or reducing the hepatic first-pass phenomenon, thus improving the pharmacokinetics and bioavailability of choline alfoscerate compared with pharmaceutical forms of the prior art. Advantageously, a surprising increase in sublingual absorption of choline alfoscerate is achieved when the orodispersible granules have an average particle size selected in the range of 200 to 1000 microns.

[0031] Advantageously, sublingual administration of the solid dosage form of choline alfoscerate with average particle size as described here limits the amount of choline alfoscerate that passes from the oral cavity into the gastrointestinal tract and is absorbed in a traditional manner. In this way the hepatic first-pass effect, in which a percentage of the amount of orally administered drug is metabolized by hepatic enzymes and thus does not reach systemic circulation in an active form, thus reducing the therapeutic effect sought, is reduced considerably.

[0032] The Applicant has found that for the same dosage of active ingredient, oral administration with sublingual absorption of the choline alfoscerate dosage form as defined in claim 1 has the following advantages over a conventional pharmaceutical form, for example a tablet, for oral administration:

[0033] - increased bioavailability of choline alfoscerate, since due to absorption through the blood vessels the active ingredient enters systemic circulation directly, bypassing the metabolic processes of hepatic first pass;

[0034] - reduced salivary metabolization, since saliva possesses reduced enzyme activity with respect to gastric juices;

[0035] - bypassing of gastric degradation by avoiding or limiting degradation of the active ingredient by the acid pH environment of the stomach.

[0036] In accordance with preferred embodiments of the invention, the solid dosage form of choline alfoscerate described herein contains mannitol as an additional excipient.

[0037] The addition of mannitol as a further excipient of the dosage form described herein also solves the problem of the low palatability of the colloidal silica contained in the orosoluble granular dosage form. Moreover, mannitol, being very soluble in water, increases the disintegration rate of the orodispersible granules once they come in contact with saliva, increasing the amount of choline alfoscerate absorbed orally and reducing the absorption time.

[0038] In accordance with one aspect, the present invention relates to a solid dosage form of choline alfoscerate for use in the prevention and / or treatment of a form of cognitive function impairment of an individual by oral and / or sublingual administration, wherein said solid dosage form is an orodispersible granulate comprising excipients based on preferably micronized colloidal silica and mannitol on which choline alfoscerate is adsorbed.

[0039] In accordance with another aspect of the invention, a method is provided for the production of an oral pharmaceutical dosage form comprising the steps of:

[0040] - mixing choline alfoscerate with an excipient comprising micronized colloidal silica and optionally mannitol, until a substantially homogeneous powder is obtained,

[0041] - drying the powder preferably by heating, for example, to a temperature below 100°C,

[0042] - screening the dried powder, preferably with a 200 to 1000 micron, more preferably 400 to 800 micron sieve, to obtain a granulate with granules having an average size of 400 to 800 microns, preferably 400 to 800 microns.

[0043] Preferably, in the method described herein choline alfoscerate and excipient are mixed in one of the following weight ratios: 1:1:4; 1:4:1; 1:4:4; 4:1:1; 4:4: 1 ; 1:1:1. Preferably, choline alfoscerate and the excipient based on colloidal silica and / or mannitol are in an amount from 1:4 to 4:1, more preferably in a 1:1 ratio.

[0044] In a preferred embodiment, said method comprises the following steps:

[0045] - adsorbing choline alfoscerate onto excipients based on micronized colloidal silica and mannitol to obtain a moist powder comprising choline alfoscerate adsorbed onto micronized colloidal silica and mannitol excipients,

[0046] - drying the powder, preferably at a temperature not exceeding 60°C,

[0047] - size filtering the dried powder, preferably with a 50 to 2000 microns, preferably 400 to 800 micron, sieve.

[0048] Some characteristics and advantages of the present invention will become evident from the following figure, in which reference is made to the experimental results described in Example 2.

[0049] Figure 1 shows two charts which illustrate the results of particle size analysis of Batches 20230803 and 20230809, in the form of granulate containing choline alfoscerate, micronized colloidal silica (Aerosil), mannitol and water in accordance with Example 2.

[0050] In accordance with some aspects of the invention, it has been found that it is possible to provide a dosage form of choline alfoscerate in the form of orodispersible granules with high bioavailability and compliance in which choline alfoscerate in liquid form is adsorbed on an excipient based on micronized silica and preferably mannitol.

[0051] In accordance with a first aspect, the present invention provides a dosage form of choline alfoscerate as defined in the appended claim 1.

[0052] Further embodiments of the dosage form of choline alfoscerate are defined in the appended dependent claims 2-8.

[0053] The dosage form of the invention contains an excipient selected from micronized colloidal silica, mannitol and preferably a mixture thereof.

[0054] Preferably, the micronized colloidal silica used as an excipient is based on silicon dioxide SiO2, preferably having a purity grade > 99% by weight.

[0055] Preferably, the colloidal silica is micronized and preferably is in granule form with an average particle size of 0.1 to 0.4 microns, preferably 0.2 to 0.3 microns.

[0056] Preferably, the particle / granule size is expressed in terms of D(10), D(50), D(90) corresponding to specific cumulative percentages of size distribution. D(10) is the diameter for which 10% (by volume or weight) of the particles are smaller than or equal in diameter. It represents the finest fraction of the material. D(50) is the median diameter, i.e., the diameter for which 50% of the particles have a smaller or equal diameter.

[0057] It indicates the median particle size, and is often used as the central representation of the distribution.

[0058] D(90) is the diameter for which 90% of the particles have a smaller or equal diameter. It represents the coarsest part of the material.

[0059] The micronized colloidal silica used as an excipient in the dosage form described herein effectively adsorbs choline alfoscerate and possesses a high surface area, preferably 200 ± 25 m2 / g, and an average particle size per particle of 12 nm, acting as a thixotropic agent. Advantageously, micronized silica increases the static viscosity of choline alfoscerate while maintaining low dynamic viscosity. Advantageously, mixing choline alfoscerate with micronized colloidal silica provides a granulate in which the active ingredient is adsorbed, as shown by the experimental evidence in Example 1.

[0060] In accordance with preferred embodiments of the invention, the oral dosage form described herein contains mannitol as an additional excipient. Advantageously, the combination of micronized silica and mannitol effectively adsorbs choline alfoscerate, providing a granulate which is not sticky and can be processed easily. Moreover, the resulting granules have a uniform appearance and high flowability that facilitates the provision of an orodispersible pharmaceutical form and its packaging, for example in sachets.

[0061] In accordance with some embodiments, the granular dosage form described herein contains granules with an average particle size of 200 to 1000 microns, preferably 400 to 800 microns, for example 600 microns.

[0062] Preferably, the selection of the granule size of the dosage form described herein is performed using sieves with meshes of the desired size, preferably in accordance with the ISO 3310-1 standard.

[0063] For example, it is possible to obtain granules with sizes from 200 to 1000 microns, preferably 400 to 800 microns, by passing the dry granulate obtained from the production process through sieves with sizes from 200 to 1000 microns, for example 400 to 800 microns as required. The particle size of the powders or granulates according to any one of the embodiments described herein can be verified by using laser beam diffractometry by means of a Mastersizer 3000, MMS17, Malvern Panalytical.

[0064] A suitable type of analysis provides for:

[0065] Sample dispersion unit: Aero S

[0066] Analysis parameters:

[0067] Scattering theory applied: Mie theory

[0068] Refractive index of the sample: 1.52

[0069] Sample assonance index : 0.01

[0070] Obscuration: 0.5-10%

[0071] Number of measurements: 1

[0072] Air pressure Air: 2 bar

[0073] Velocity: 50%

[0074] Configuration:

[0075] Standard Venturi dispersion unit, multipurpose tray (with hopper), hopper space 1 mm.

[0076] A suitable choline alfoscerate for formulating the dosage form described here is in liquid form and contains water, for example in an amount of 10 to 20% by weight, preferably 12 to 18%, more preferably 14 to 16% by weight.

[0077] Preferably, in the dosage form described here the ratio of choline alfoscerate:excipient, preferably micronized colloidal silica and / or mannitol, varies from 1:4 to 4:1, more preferably between 1:2 and 2:1, and even more preferably it is 1:1.

[0078] In certain embodiments the choline alfoscerate contained in a unit dosage form is comprised between 200 and 1200 mg, preferably 400 to 1000 mg, more preferably 400 to 800 mg, for example 600 mg.

[0079] According to some embodiments, a suitable dosage form is an orodispersible granulate that can be dissolved in water or preferably administered orally as is. In accordance with another aspect, the invention relates to an orodispersible pharmaceutical dosage form containing choline alfoscerate according to any one of the embodiments described herein for use in the treatment of a form of cognitive impairment and / or memory impairment. According to some embodiments, the granular pharmaceutical dosage form described herein is for use in the treatment or prevention of Alzheimer's disease, senile dementia.

[0080] Within the scope of the present application, the term “pharmaceutically acceptable” means edible substances that are approved by health authorities for use in pharmaceutical, herbal, nutritional or food applications, as described in detail in the Handbook of Pharmaceutical Excipients, edited by Raymond C. Rowe, Paul J. Sheshey, Martin E. Quinn, published by the Pharmaceutical Press (UK).

[0081] The compositions of the present invention comprise any composition provided by administering the combination of choline alfoscerate and at least one selected pharmaceutically acceptable carrier as described herein. These pharmaceutical dosage forms are suitable for nutritional, pharmaceutical or dietary use in mammals, in particular humans.

[0082] In accordance with another aspect, the present invention relates to a method for producing a solid dosage form in orodispersible granulate based on choline alfoscerate for oral administration as defined in claims 9-12.

[0083] Preferably, the granulation is provided using a mixer of the high shear mixer type, such as for example Trichop mgr-5, Lleal.

[0084] In accordance with certain embodiments, the method comprises the steps of:

[0085] - loading choline alfoscerate and an excipient comprising micronized colloidal silica and preferably mannitol into a mixer,

[0086] - mixing the components of step a) until a substantially uniform powder is obtained,

[0087] - drying the mixture of step (b) preferably by heating to a temperature comprised between 40 and 100°C, for a period of time necessary to obtain a powder with a relative humidity of less than 10%,

[0088] - selecting the size of the powders obtained from step c) preferably filtering the dried powder, preferably with a 200 to 1000 micron, preferably 400 to 800 micron, sieve, in order to obtain an orodispersible granulate in which the choline alfoscerate is adsorbed onto the excipient.

[0089] According to some embodiments, the particle size distribution (PSD) of the powder obtained from the method described here is as follows:

[0090] % < 600 microns = 60.2%

[0091] 600 microns < % < 850 microns = 20.3%

[0092] % > 850 microns = 19.5%.

[0093] In accordance with another aspect, the invention relates to a dosage form of choline alfoscerate in orodispersible granules in which choline alfoscerate is adsorbed onto an excipient comprising micronized colloidal silica and mannitol, obtainable with a method comprising the steps of:

[0094] - adsorbing choline alfoscerate onto an excipient comprising micronized colloidal silica and mannitol until a moist and uniform powder is obtained,

[0095] - drying the powder preferably by heating not exceeding 60°C,

[0096] - size filtering the dried powder, preferably with a 50 to 2000 micron, preferably 400 to 800 micron, sieve to obtain a granulate with a granule size of 50 to 2000 microns, preferably 400 to 800 microns.

[0097] EXAMPLE 1

[0098] Comparative tests of the adsorption of choline alfoscerate on excipients for pharmaceutical formulations and selection of excipient for a granular / powder dosage form of choline alfoscerate. Starting from the stickiness and hygroscopic characteristics of choline alfoscerate, preliminary tests were performed on conventional excipients used for pharmaceutical formulations in granule or powder form. The purpose of these tests was to identify an excipient, preferably a mixture of two excipients, that combines high adsorptive properties and overcomes the formulation problems correlated with the viscosity and hygroscopicity of choline alfoscerate.

[0099] METHOD

[0100] After an initial screening among 20 excipients commonly used in pharmaceutical technology to provide pharmaceutical formulations, the following excipients were selected, which were considered at first analysis to be the most promising: silica, anhydrous lactose, hydroxypropyl-p- cyclodextrin, mannitol, mannitol-croscarmellose sodium mixture, and micronized colloidal silica.

[0101] These excipients were subjected to tests intended to verify the adsorption of choline alfoscerate and the forming of a suitable orodispersible granular dosage form.

[0102] From the tests, it was unexpectedly found that micronized colloidal silica exhibits technical characteristics that allow to overcome the formulation problems of choline alfoscerate by producing a non-sticky granular dosage form with uniform appearance that increases the compliance of the individual in need of treatment. Preferably, this compliance is further improved by reducing the amount of colloidal silica, which confers astringency upon intake, and increasing mannitol. The latter, in addition to improving the palatability of the finished pharmaceutical form, being water- soluble, facilitates granule disintegration, release of the active ingredient from the finished product, and its sublingual absorption.

[0103] Adsorption test of choline alfoscerate on specific excipients

[0104] MATERIALS - Choline alfoscerate, (batch 2101093 Laboratorio CT Sanremo) 21 / L-a-GPCH / 012 - VAV Lipids Private Limited, Maharashtra, India.

[0105] - Aerosil 200 pharma (micronized colloidal silica), batch 159112514, Evonik.

[0106] - Hisorad (mannitol-croscarmellose sodium and cellulose), batch 61H01, Daicel Corporation.

[0107] - SuperTab 21AN (Anhydrous lactose), batch 1068WVW, dfe Pharma.

[0108] - Mannogem XL Ruby (Mannitol), batch 121910323, SPI Pharma.

[0109] - Kleptose HPB Oral Grade (Hydroxypropyl-p-Cyclodextrin), batch 0460, Roquette.

[0110] - Water, MilliQ.

[0111] - Ethanol, batch 878, Girelli Alcool.

[0112] EQUIPMENT

[0113] - Thermobalance, Mettler-Toledo PM100, Mettler-Toledo LP 16

[0114] - Water purifier, MilliQ Direct 8, Millipore.

[0115] - Oven, T 6120, Heraeus.

[0116] - Analytical balance, as 220.x2, Radwag.

[0117] - Sieves, CDL and Giuliani.

[0118] - Glassware.

[0119] Batch 78P-202305220: adsorption of choline alfoscerate on anhydrous lactose

[0120] Step 1: mixture in mortar Quantity Choline alfoscerate L02 g

[0121] Anhydrous lactose LOl g

[0122] Results: Mixing the active ingredient with the anhydrous lactose excipient resulted in the forming of a wet slurry of choline alfoscerate and dissolved anhydrous lactose. The formation of a slurry demonstrates that lactose is not suitable to effectively adsorb the active ingredient and is unsuitable to form an orodispersible granulate.

[0123] Batch 78P-20230522b: adsorption of choline alfoscerate on hydroxypropyl-P-cyclodextrin (Kleptose)

[0124] Step 1: mixture in mortar Quantity Choline alfoscerate L02 g

[0125] Kleptose 1.03 g

[0126] Results:

[0127] Mixing choline alfoscerate with Kleptose resulted in the forming of a liquid mass of choline alfoscerate and dissolved Kleptose. The forming of the liquid mass shows that Kleptose is not suitable to adequately adsorb the active ingredient and is unsuitable to form an orodispersible granulate.

[0128] Batch 78P-20230522c: choline alfoscerate adsorption on mannitol

[0129] Step 1: mixture in mortar Quantity Choline alfoscerate 1.00 g

[0130] Mannitol 0.99 g

[0131] Results:

[0132] Mixing choline alfoscerate with mannitol resulted in the forming of a sticky mass of choline alfoscerate and mannitol. The forming of the sticky mass demonstrates that mannitol is unable to adequately adsorb the active ingredient and is unsuitable to form an orodispersible granulate.

[0133] Batch 78P-20230522d: choline adsorption on mannitol-croscarmellose sodium and cellulose (Hisorad)

[0134] Step 1 : mixture in mortar

[0135] Choline alfoscerate L04 g

[0136] Hisorad L02 g

[0137] Results:

[0138] Mixing choline alfoscerate with mannitol-croscarmellose sodium and cellulose formation of a wet slurry of choline alfoscerate and Hisorad is observed. The forming of the wet slurry demonstrates that the Hisorad excipient is unable to adequately adsorb the active ingredient and is unsuitable to form an orodispersible granulate.

[0139] Batch 78P-20230522e: choline adsorption on micronized colloidal silica (aerosil)

[0140] Step 1: mixture in mortar Quantity

[0141] Choline alfoscerate 1.04 g

[0142] Aerosil 1.00 g

[0143] Results:

[0144] Aerosil is shown to be able to adsorb the active ingredient completely. A mass of powder is obtained on which the active ingredient is adsorbed, consisting of an orodispersible granulate.

[0145] Evaluating the residual water content after 3 hours in an oven at 80°C, there was a drop in weight of 8.96%, with a thermobalance loss (LOD) of 1.96%. Having obtained a total water loss (10.92%) greater than the theoretical amount present (7.71%), it was noted that during processing the sample adsorbed moisture from the environment.

[0146] EXAMPLE 2

[0147] Formulation of an orodispersible choline alfoscerate granulate in granulator.

[0148] Purpose

[0149] Formulation of an orodispersible granulate containing 692 mg of the active ingredient choline alfoscerate containing water in the amount of 15.13% (equivalent to 600 mg of choline alfoscerate with a titer of 601.24 mg). The granulate was developed in a High Shear Mixer granulator.

[0150] Materials

[0151] Micronized colloidal silica, which adsorbs choline alfoscerate in liquid form, was used as the excipient. Micronized colloidal silica (Aerosil) received the addition of mannitol as a co-formulant. After preliminary screening, the two selected excipients were tested for scalability in a High Shear Mixer granulator.

[0152] Specifically, the following materials were used:

[0153] - choline alfoscerate, batch 2101093, CT Sanremo.

[0154] - Aerosil 200 pharma (Micronized colloidal silica), batch 113062214, Evonik.

[0155] - Mannogem Powder EU (Mannitol), batch 05278955, SPI Pharma.

[0156] - Purified water, MilliQ.

[0157] - Orange flavor, batch 22012555, E-pharma.

[0158] EQUIPMENT

[0159] - Thermobalance, Mettler-Toledo PM100, Mettler-Toledo LP 16

[0160] - Water purifier, MilliQ Direct 8, Millipore.

[0161] - Oven, T 6120, Heraeus.

[0162] - Analytical balance, as 22O.x2, Radwag. - Sieves, CDL and Giuliani.

[0163] - Glassware.

[0164] - High Shear Mixer Granulator, Trichop mgr-5, Lleal.

[0165] - Mastersizer, MASTERSIZER MMS17, Malvern.

[0166] Tests performed

[0167] 1. Granulation of Choline Alfoscerate in High Shear Mixer Batch: 78P-20230803

[0168] Preparation of 3000 g of product - choline / Aerosil ratio 1:1 in High Shear Mixer

[0169] Dilution of choline: 10% in water.

[0170] The first test in a High Shear Mixer was carried out to evaluate the batch size and the various parameters to be taken into account during the process. A critical aspect of this formulation is the high volume occupied by Aerosil, a characteristic that leads to the need to fractionate its loading inside the chamber, with consequent process interruption. As the Aerosil is wetted and mixed, its volume is greatly reduced. For this reason, a starting batch size of 3 kg of formulation, with a 10% by weight dilution of choline with purified water, was selected. The dilution took place inside a beaker with the use of a turbine to promote its mixing.

[0171] Starting from the small-scale tests performed in a mortar and described in EXAMPLE 1, the amount of mannitol indicated above was initially mixed with a similar volume of Aerosil at a blade speed of 250 rpm and a chopper speed of 1000 rpm, resulting in a binary mixture. At the end of this step, the chamber was opened to load an additional fraction of Aerosil. Through the spray nozzle, choline, diluted with 10 wt% water, was loaded at an average rate of about 10 g / m. The operation was repeated five times. It was noted that a batch size of 3 kg was excessive and how difficult choline is to spray; for these reasons, for the subsequent steps, it was chosen to load choline directly from a vertical opening of the chamber.

[0172] At the end of the test, the granulate, which was dry to the touch, was dried further in an oven in order to assess the moisture lost, which was found to be 6.48%. Afterwards, it was analyzed in a thermobalance, obtaining a LOD (Loss on Drying) value of -1.02%. This confirms that water is easily stripped from the granule, which however tends to regain moisture from the environment.

[0173] The granulate was screened using different mesh sizes, such as 850 microns and 600 microns, in accordance with ISO 3310-1; the obtained powder distribution is as follows:

[0174] - % < 600 microns = 60.2%

[0175] - 600 microns < % < 850 microns = 20.3%

[0176] - % > 850 microns = 19.5%

[0177] The highest fraction passes through the 600-micron sieve.

[0178] At the end of the test, we found that a reduction in batch size (from 3 kg to 2 kg) could facilitate Aerosil loading operations, thus decreasing the number of process interruptions. Moreover, a fraction of granules larger than the preset target (over 850 microns in diameter) was obtained. This was hypothesized to be due to mannitol, which, by partially solubilizing, may have promoted powder adhesion, leading to granules with a larger diameter. For this reason, in order to improve the process, the solution we devised for the next test was to adsorb the active ingredient initially only on Aerosil (always complying with the 1:1 loading ratio with the active ingredient). After loading the full amount of choline and Aerosil, we proceed with the mixing of mannitol.

[0179] Finally, since choline is particularly viscous, a fraction tends to stick to the beaker walls, resulting in consequent loss. For this reason, having confirmed that water can be easily removed from the final granulate, it was decided to add an additional 5% of water in order to clean the beaker of the choline residues left on the container.

[0180] 2. Granulation of Choline Alfoscerate in High Shear Mixer

[0181] Batch: 78P-20230809

[0182] Preparation of 2000 g of product - choline / Aerosil ratio 1:1 in High Shear Mixer

[0183] Choline dilution: 10% in water (+ 5% wash water)

[0184] This second test allowed to improve in a preliminary manner the method, which included the following steps of:

[0185] - weighing a fraction of Aerosil such as to fill the chamber and place it inside the apparatus,

[0186] - loading an amount of choline to maintain the 1:1 ratio via dedicated top-loading system, mixing at a blade rotation rate of 100 rpm,

[0187] - increasing the blade speed to 300 rpm and, only after the chamber is closed, run the chopper at a speed of 1000 rpm for 10 minutes, - repeating the operation until the entire amount of active ingredient and Aerosil has been loaded,

[0188] - after the addition of choline is complete, washing the beaker with 5% water,

[0189] - mixing under the same conditions for 10 minutes (blade at 300 rpm, chopper at 1000 rpm),

[0190] - opening the chamber and adding the weighed amount of mannitol,

[0191] - mixing under the same conditions for 10 minutes (blade at 300 rpm, chopper at 1000 rpm),

[0192] - increasing chopper speed to 3000 rpm for 60 minutes,

[0193] - verifying that the appearance of the granulate is homogeneous,

[0194] - weighing the amount of product obtained,

[0195] - drying in preheated oven at 60°C overnight,

[0196] - calculating the amount of water removed,

[0197] - measuring the Loss On Drying (LOD) in a thermobalance,

[0198] - passing the dry powder through a 600-micron sieve to obtain the granulate,

[0199] - characterization (Residual humidity, PSD, disintegration and payability).

[0200] At the end of the test, the granulate, dry to the touch, was dried further in an oven in order to evaluate the moisture lost, which was found to be 4.40%. Afterwards, the sample was analyzed in a thermobalance, reporting a LOD (Loss on Drying) value of -3.86%.

[0201] The dry granulate was screened through 600-micron mesh sieves and seen to pass entirely.

[0202] Characterization

[0203] The granulate fraction obtained by screening the product through 600- micron meshes was analyzed by laser beam diffractometry using a Mastersizer 3000, MMS17, Malvern Panalytical, in order to evaluate the particle distribution.

[0204] The results of particle size analysis of the two Batches - 20230803 vs. 20230809 - are shown in the accompanying figure.

[0205] It is observed that by increasing the rotation rate of the chopper and mixing the mannitol only after the adsorption of choline on Aerosil (batch 20230809), the particle size of the obtained granules decreases.

[0206] The entire product passes through the 600-micron sieve, entailing a very high process yield (>95%); however, in contrast, the PSD is not uniform and does not have the typical Gaussian shape that is obtained from the previous test. Advantageously, the sample exhibited rapid disintegration in water. Therefore, the non-uniform particle size distribution does not constitute a limitation for the preset target.

[0207] Disintegration and palatabilitv

[0208] The obtained products were tested to produce an orodispersible granulated product that can be administered as is, preferably without the aid of water, ensuring good compliance and rapid disintegration.

[0209] In order to evaluate the disintegration time, a dose of finished granular product equal to 2 grams was weighed. 20 ml of water were added under gentle motion, observing a very short disintegration time, well below 10 seconds for both granulates obtained from the respective tests.

[0210] Finally, the products were tasted to assess palatability, which is found to be good.

[0211] The product is tasteless, faintly sweet due to the mannitol present.

[0212] Results and Conclusions

[0213] The two preliminary tests show that a batch size of 2 kg is suitable to provide a continuous process. The addition of mannitol during final mixing substantially reduces the possibility of it passing into solution, hindering excessive powder aggregation with consequent forming of large granules; this allows to improve process yield (typically >95%) and ensures rapid dissolution of the resulting granules. The final product, consisting of an oral solid dosage form in granules, is soluble in 20 ml of water. The granules can be taken as they are.

[0214] EXAMPLE 3

[0215] Orodispersible granules containing

[0216] Choline alfoscerate 600 mg

[0217] Aerosil 600 mg

[0218] Choline alfoscerate (99.80% titer) containing water 15.13 wt% for a total content of 692 mg

[0219] EXAMPLE 4

[0220] 2000 mg unit dosage form containing

[0221] Orodispersible granules containing

[0222] Choline alfoscerate 600 mg

[0223] Aerosil 600 mg

[0224] Mannitol as much as needed to reach 2000 mg

[0225] Choline alfoscerate (99.80% titer) containing water 15.13 wt% for a total content of 692 mg

[0226] 3. Granulation of Choline Alfoscerate in High Shear Mixer Batch: 78P-20231023

[0227] Preparation of 2000 g of product - choline / Aerosil in High Shear Mixer

[0228] Choline dilution: 10% in water (+ 5% wash water) This test provided for the following steps of:

[0229] - weighing a fraction of Aerosil such as to fill the chamber and place it inside the apparatus,

[0230] - loading a fraction of choline by means of a dedicated top-loading system, mixing at a blade rotation rate of 100 rpm,

[0231] - increasing the blade speed to 300 rpm and, only after the chamber is closed, operating the chopper at a speed of 1000 rpm for 4 minutes,

[0232] - repeating the operation until the entire amount of active ingredient and Aerosil has been loaded,

[0233] - after the addition of choline is complete, washing the beaker with 5% water,

[0234] - mixing under the same conditions for 3 minutes (blade at 300 rpm, chopper at 1000 rpm),

[0235] - opening the chamber and adding the weighed amount of mannitol,

[0236] - mixing under the same conditions for 4 minutes (blade at 300 rpm, chopper at 1000 rpm),

[0237] - allowing to dry in the oven overnight at 60°C,

[0238] - increasing chopper speed to 3000 rpm for 30 minutes,

[0239] - checking that the appearance of the granulate is homogeneous.

[0240] At the end of the test, the granulate, dry to the touch, was dried further in an oven. Then the sample was analyzed in a thermobalance, giving a LOD (Loss on Drying) value of -1.07%.

[0241] Finally, to assess palatability, 100 grams of sample were flavored with orange flavor powder (2.5%) and citric acid monohydrate (1%), which increased taste and palatability.

[0242] The disclosures in Italian Patent Application No. 102023000025095, from which this application claims priority, are incorporated herein by reference.

Claims

CLAIMS1. An oral form of pharmaceutical dosage of choline alfoscerate in orodispersible granules, wherein the granules comprise choline alfoscerate adsorbed on at least one pharmaceutically acceptable excipient comprising micronized colloidal silica and mannitol, wherein the orodispersible granules have an average particle size selected in the range between 200 and 1000 microns in order to increase the absorption of choline alfoscerate by the oral administration route.

2. The dosage form according to claim 1, wherein the micronized colloidal silica has a particle size comprised between 5 and 50 nanometers.

3. The dosage form according to claim 1 or 2, wherein the orodispersible granules have an average particle size selected in the range between 400 and 800 microns.

4. The dosage form according to any one of claims 1-3, wherein the micronized colloidal silica has a surface area comprised between 50 and 600 m2 / g and a density comprised between 160 and 190 Kg / m3.

5. The dosage form according to any one of claims 1-4, wherein the choline alfoscerate, the excipient comprising colloidal silica and mannitol are in a ratio of1:1: 41:4:11:4:44:1:14:1:44:4:1,6. The dosage form according to any one of claims 1 to 5, wherein the choline alfoscerate is diluted in water, preferably in an amount of 10 to 50% by weight, preferably 14 to 16% by weight.

7. The dosage form according to any one of claims 1 to 6, for use in the treatment of a form of cognitive impairment and / or memory impairment.

8. The dosage form for use according to claim 7, wherein said form of cognitive impairment comprises Alzheimer's disease, senile dementia.

9. A method for producing a dosage form of choline alfoscerate in orodispersible granules according to any one of claims 1-8, comprising the steps of:- adsorbing choline alfoscerate on excipients based on micronized colloidal silica and mannitol so as to obtain a moist powder comprising choline alfoscerate adsorbed on the excipients micronized colloid and mannitol,- drying the powder,- size filtering the dried powder, preferably with a 50 to 2000 micron sieve.

10. The method according to claim 9, wherein the drying step occurs at a temperature that does not exceed 60°C.

11. The method according to any one of claims 9 and 10, wherein the obtained choline alfoscerate granules have an average particle size of 200 to 1000 microns, preferably 400 to 800 microns.

12. The method according to any one of claims 9 to 11, comprising a mixing step in which the choline alfoscerate and the excipients are mixed in a ratio that varies from 1 :4 to 4: 1 , preferably in a 1 : 1 ratio.

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