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WO2025114888A1 - Forme posologique orodispersible solide d'un médicament cholinergique pour le traitement du déclin cognitif - Google Patents

Forme posologique orodispersible solide d'un médicament cholinergique pour le traitement du déclin cognitif Download PDF

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Publication number
WO2025114888A1
WO2025114888A1 PCT/IB2024/061865 IB2024061865W WO2025114888A1 WO 2025114888 A1 WO2025114888 A1 WO 2025114888A1 IB 2024061865 W IB2024061865 W IB 2024061865W WO 2025114888 A1 WO2025114888 A1 WO 2025114888A1
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Prior art keywords
choline alfoscerate
dosage form
choline
mannitol
granules
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PCT/IB2024/061865
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Inventor
Mattia GHISOLFI
Davide Ruggeri
Federica Ronchi
Deborah CREMIEUX
Roberto Cacciaglia
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Laboratorio Farmaceutico CT SRL
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Laboratorio Farmaceutico CT SRL
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Publication of WO2025114888A1 publication Critical patent/WO2025114888A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches

Definitions

  • the present invention relates to a solid orodispersible dosage form of a cholinergic drug for the treatment of forms of cognitive decline.
  • the present invention originates in the field of solid pharmaceutical dosage forms for oral and/or sublingual administration of active ingredients.
  • 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.
  • 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.
  • 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.
  • Choline and phosphatidylcholine 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.
  • drugs that act on the cholinergic system are a promising therapeutic option for the treatment of patients with senile dementia and Alzheimer's disease.
  • the first cholinergic drugs introduced into therapy were cholinergic precursors, such as CDP-choline or citicoline.
  • cholinergic precursors such as CDP-choline or citicoline.
  • CDP-choline or citicoline cholinergic precursors
  • citicoline cholinergic precursors
  • choline alfoscerate L-alpha-glycerophosphorylcholine, known by the acronym GPC
  • GPC choline alfoscerate
  • GPC has shown moderate efficacy in the treatment of Alzheimer's disease and other forms of dementia, in particular those of vascular origin.
  • GPC as a cholinergic precursor, ensures higher plasma levels of choline and greater activity on memory and cognitive parameters than citicoline.
  • cholinesterase inhibitors typically donepezil, galantamine and rivastigmine
  • acetylcholine Ml receptor agonists for example xanomeline.
  • 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.
  • NMD A receptor antagonist a noncompetitive NMD A receptor antagonist
  • GPC 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.
  • GPC is metabolized to choline and two other metabolites and is incorporated into brain phospholipids.
  • plasma choline levels reach a Cmax of 35.1 ⁇ M after 30 min, then decline with a half-life of approximately 2 h and return to basal values after 6 to 8 h.
  • choline alfoscerate-based pharmaceutical formulations in solid form for oral administration are in the form of tablets, soft capsules.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the excipient of the oral dosage form described here further comprises mannitol, preferably in a mixture with the colloidal silica.
  • the colloidal silica is fumed.
  • 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.
  • the colloidal silica has a specific surface area equal to 200 ⁇ 25 m 2 /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.
  • 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.
  • 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.
  • 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.
  • the solid dosage form of choline alfoscerate described herein contains mannitol as an additional excipient.
  • 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.
  • 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.
  • an oral pharmaceutical dosage form comprising the steps of:
  • 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.
  • 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.
  • 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.
  • said method comprises the following steps:
  • 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.
  • 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.
  • the present invention provides a dosage form of choline alfoscerate as defined in the appended claim 1.
  • the dosage form of the invention contains an excipient selected from micronized colloidal silica, mannitol and preferably a mixture thereof.
  • the micronized colloidal silica used as an excipient is based on silicon dioxide SiO 2 , preferably having a purity grade > 99% by weight.
  • 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.
  • 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.
  • 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.
  • 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 m 2 /g, and an average particle size per particle of 12 nm, acting as a thixotropic agent.
  • micronized silica increases the static viscosity of choline alfoscerate while maintaining low dynamic viscosity.
  • 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.
  • the oral dosage form described herein contains mannitol as an additional excipient.
  • mannitol as an additional excipient.
  • the combination of micronized silica and mannitol effectively adsorbs choline alfoscerate, providing a granulate which is not sticky and can be processed easily.
  • 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.
  • 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.
  • 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.
  • granules with sizes from 200 to 1000 microns preferably 400 to 800 microns
  • 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.
  • a suitable type of analysis provides for:
  • Air pressure Air 2 bar
  • Standard Venturi dispersion unit multipurpose tray (with hopper), hopper space 1 mm.
  • 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.
  • 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.
  • 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.
  • a suitable dosage form is an orodispersible granulate that can be dissolved in water or preferably administered orally as is.
  • 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.
  • the granular pharmaceutical dosage form described herein is for use in the treatment or prevention of Alzheimer's disease, senile dementia.
  • 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).
  • 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.
  • 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.
  • the granulation is provided using a mixer of the high shear mixer type, such as for example Trichop mgr-5, Lleal.
  • the method comprises the steps of:
  • step a) mixing the components of step a) until a substantially uniform powder is obtained
  • step (b) 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%,
  • step c) 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.
  • the particle size distribution (PSD) of the powder obtained from the method described here is as follows:
  • 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:
  • 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.
  • 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.
  • 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.
  • Aerosil 200 pharma (micronized colloidal silica), batch 159112514, Evonik.
  • Step 1 mixture in mortar Quantity Choline alfoscerate L02 g
  • Batch 78P-20230522b adsorption of choline alfoscerate on hydroxypropyl-P-cyclodextrin (Kleptose)
  • Step 1 mixture in mortar Quantity Choline alfoscerate L02 g
  • Step 1 mixture in mortar
  • 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.
  • Formulation of an orodispersible choline alfoscerate granulate in granulator Formulation of an orodispersible choline alfoscerate granulate in granulator.
  • the granulate was developed in a High Shear Mixer granulator.
  • 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.
  • Aerosil 200 pharma (Micronized colloidal silica), batch 113062214, Evonik.
  • 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.
  • 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.
  • the chamber was opened to load an additional fraction of Aerosil.
  • 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.
  • 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.
  • 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:
  • the highest fraction passes through the 600-micron sieve.
  • 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%.
  • the dry granulate was screened through 600-micron mesh sieves and seen to pass entirely.
  • 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.
  • 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.
  • the sample exhibited rapid disintegration in water. Therefore, the non-uniform particle size distribution does not constitute a limitation for the preset target.
  • 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.
  • the product is tasteless, faintly sweet due to the mannitol present.
  • 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.

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Abstract

L'invention concerne une forme orale de dosage pharmaceutique dans des granules orodispersibles, les granules comprenant une quantité thérapeutiquement efficace d'alfoscérate de choline adsorbée sur au moins un excipient pharmaceutiquement acceptable comprenant de la silice colloïdale micronisée.
PCT/IB2024/061865 2023-11-27 2024-11-26 Forme posologique orodispersible solide d'un médicament cholinergique pour le traitement du déclin cognitif Pending WO2025114888A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT102023000025095A IT202300025095A1 (it) 2023-11-27 2023-11-27 Forma solida di dosaggio orodispersibile di un farmaco colinergico per il trattamento del declino cognitivo.
IT102023000025095 2023-11-27

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PCT/IB2024/061865 Pending WO2025114888A1 (fr) 2023-11-27 2024-11-26 Forme posologique orodispersible solide d'un médicament cholinergique pour le traitement du déclin cognitif

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100311692A1 (en) * 2008-02-15 2010-12-09 Ctc Bio, Inc. Pharmaceutical Formulation Containing Choline Alfoscerate
KR20230096434A (ko) * 2021-12-23 2023-06-30 주식회사 다산제약 콜린알포세레이트를 포함하는 약학 제제

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100311692A1 (en) * 2008-02-15 2010-12-09 Ctc Bio, Inc. Pharmaceutical Formulation Containing Choline Alfoscerate
KR20230096434A (ko) * 2021-12-23 2023-06-30 주식회사 다산제약 콜린알포세레이트를 포함하는 약학 제제

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Handbook of Pharmaceutical Excipients", 3 February 2009, PHARMACEUTICAL PRESS, article HAPGOOD K P: "Colloidal Silicon Dioxide", pages: 185 - 188, XP055959239 *

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