WO2019025934A1 - Composition pharmaceutique orale stable de pimavansérine - Google Patents

Composition pharmaceutique orale stable de pimavansérine Download PDF

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Publication number
WO2019025934A1
WO2019025934A1 PCT/IB2018/055667 IB2018055667W WO2019025934A1 WO 2019025934 A1 WO2019025934 A1 WO 2019025934A1 IB 2018055667 W IB2018055667 W IB 2018055667W WO 2019025934 A1 WO2019025934 A1 WO 2019025934A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
pimavanserin
pharmaceutically acceptable
composition according
present
Prior art date
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PCT/IB2018/055667
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English (en)
Inventor
Jitendra Shantilal PATEL
Suhag Mayankkumar PATEL
Nehal Mayur BHATT
Dhaval Mukeshbhai DHULIA
Parva Yogeshchandra Purohit
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Kashiv Pharma Llc
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Publication of WO2019025934A1 publication Critical patent/WO2019025934A1/fr

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4465—Non condensed piperidines, e.g. piperocaine only substituted in position 4
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to a stable orally disintegrating composition comprising pimavanserin or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  • the present invention further relates to a stable dispersible pharmaceutical formulation comprising pimavanserin or a pharmaceutically acceptable salt thereof, and a one or more pharmaceutically acceptable excipients.
  • the present invention also relates to a novel pharmaceutical sachet formulation comprising pimavanserin or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • Parkinson’s disease is a chronic, progressive neurodegenerative disease characterized by bradykinesia, rigidity, tremor, and postural instability, and is second only to Alzheimer’s disease as the most common neurodegenerative disorder. Parkinson's disease is more common in the elderly, the average age of onset of about 60 years old. Hallucinations and delusions are common psychiatric symptoms of Parkinson's disease, affecting approximately 50% of patients in the course of the disease.
  • US7601740 patent first disclosed pimavanserin hemi-tartrate as serotonin 2A/2C receptor inverse agonists to treat a variety of human neurodegenerative diseases including parkinson's disease, huntington's disease, lewy body dementia, and alzheimer's disease.
  • WO2007/133802 patent application disclosed a stable pharmaceutical composition
  • pimavanserin and at least one pharmaceutically acceptable excipient selected from the group consisting of a sugar, a starch, a cellulose preparation, silicon dioxide aerosol, gelatin, calcium phosphate dibasic, sodium lauryl sulfate, magnesium stearate, sodium stearyl fumarate, talc, polyethylene glycol, and polyvinylpyrrolidone, and combinations thereof.
  • CN106265605A patent application disclosed fast dissolving oral film formulation of pimavanserin tartrate.
  • Oral film formulations have some drawbacks. Oral film formulation is temperature and moisture sensitive and therefore requires expensive packaging. Furthermore, Oral film formulation has inability of high drug loading.
  • Swallowing difficulties can arise from either psychological aversion, which can occur at any age, or from dysphagia, which is a physical impairment in the swallowing process.
  • Dysphagia can be acute, for example, in patients with a sore throat or those with an exacerbation of gastro-oesophageal reflux disease, or chronic disease, for example, in patients who have experienced a stroke, patients with parkinson’s disease or huntingdon’s chorea, or those with muscular dystrophy.
  • Dysphagia in parkinson’s disease is associated with increased morbidity and mortality. Some form of swallowing difficulty is believed to be found in between 70 and 90 per cent of the elderly. This can result from a reduction in the production of saliva and weakening of the muscles involved in swallowing.
  • parkinson s disease and psychosis associated with parkinson’s disease mainly occurs in elder patient population and such patients have swallowing problems. So, orally disintegrating, dispersible or sachet formulation is better option for such patient population.
  • Pimavanserin has a pronounced bitter taste. So, the inventors have also addressed the bitter taste problem associated with pimavanserin active ingredient by incorporating taste masking agents.
  • the present invention relates to a stable orally disintegrating pharmaceutical formulation comprising pimavanserin or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • the present invention also relates to a stable dispersible pharmaceutical formulation of pimavanserin or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • the present invention relates a novel sachet pharmaceutical formulation comprising an effective amount of pimavanserin or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • the present invention relates to a stable orally disintegrating tablet of pimavanserin or a pharmaceutically acceptable salt thereof, which disintegrates in about 60 second or less in oral cavity.
  • the present invention relates to a process of preparing a stable orally disintegrating, dispersible or sachet pharmaceutical formulation of pimavanserin or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a stable oral pharmaceutical formulation comprising pimavanserin or a pharmaceutically acceptable salt thereof and a process for preparing thereof.
  • the present invention relates to a stable orally disintegrating, dispersible or sachet pharmaceutical formulation comprising pimavanserin or a pharmaceutically acceptable salt thereof, and a one or more pharmaceutically acceptable excipients.
  • the present invention relates to a stable orally disintegrating and dispersible pharmaceutical formulation is in tablet form.
  • pimavanserin includes the compound pimavanserin, pharmaceutically acceptable salts, esters and prodrugs thereof, the active metabolites of pimavanserin, and any of their polymorphs, solvates, hydrates, and combinations thereof.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • a “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.
  • Acid salts include, but not limited to, for example, mineral acid salts, such as a hydrochloride, hydrobromide, sulfate, etc.
  • Salts with organic acids include, for example, a tartrate, succinate, maleate, fumarate, malate etc.
  • orally disintegrating refer to a solid dosage form which disintegrates rapidly in the oral cavity of a patient, without chewing.
  • the rate of disintegration can vary, but it is faster than the rate of disintegration of conventional solid dosage forms or chewable solid dosage forms which are intended to be swallowed immediately after administration.
  • dispenser tablet refers to a tablet, which may be dispersed in water before administration, providing a homogeneous dispersion. Dispersible tablets disintegrate within 3 minutes using water at 15 - 25°C. The fineness of dispersion should comply with a test comprising placing two tablets in 100 ml water and stirring until completely dispersed. A smooth dispersion is produced, which passes through a sieve screen with a nominal mesh aperture of 710 ⁇ m.
  • homogeneous dispersion means that the dispersion produced upon contact with water which ensures the uniformity of pharmacologically active ingredient content for a reasonable period of time.
  • the term “sedimentation rate” means the rate at which the pharmacologically active ingredients settle from the dispersion.
  • stable means a drug substance and/or pharmaceutical composition for pharmaceutical use which remains stable as per ICH guidelines.
  • the present invention provides a novel approach of an orally disintegrating formulation of 34 mg pimavanserin for solving the problem by reducing pill burden and do not causes difficulties in swallowing in parkinson’s patients.
  • a stable orally disintegrating composition of the present invention is palatable with good disintegration characteristics and pharmacokinetics property, which provide greater compliance to patients who have difficulty in swallowing conventional pimavanserin tablet.
  • the dispersible tablet as per present invention rapidly disperses in water to produce a homogeneous dispersion that ensures uniformity of dose and desired therapeutic outcome.
  • the present invention particularly relates to the selective use of excipients that reduce the sedimentation rate which interact ionically with the active ingredient or which acts to reduce the surface tension between the aqueous media and the insoluble active, thereby facilitating the active's maintenance in the aqueous media.
  • the present invention provides aspects for a sachet formulation which can be reconstituted with a diluent just before use.
  • the sachet formulation of present invention may be introduced by a patient into a suitable amount of liquid, preferably water, as pimavanserin is soluble in water.
  • the present invention provides a pharmaceutical composition of pimavanserin or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients selected from fillers, super-disintegrants, binders, taste masking agents selected from water soluble/water in-soluble polymers, sweeteners, flavouring agents and mixture thereof, lubricants, glidants, sedimentation rate reducing agents, solvents and mixtures thereof.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising pimavanserin or a pharmaceutically acceptable salt thereof and one or more other pharmaceutically acceptable excipients.
  • a stable orally disintegrating composition comprises pimavanserin or a pharmaceutically acceptable salt thereof in an amount of about 1% to 80%.
  • a stable orally disintegrating composition comprises pimavanserin or a pharmaceutically acceptable salt thereof in an amount of about 10 mg to 50 mg, more preferably 10 mg to 40 mg.
  • the present invention relates to, a stable oral pharmaceutical composition comprising pimavanserin tartrate.
  • the present invention relates to, a stable oral pharmaceutical composition
  • a stable oral pharmaceutical composition comprising 11.8 mg pimavanserin tartrate which is equivalent to 10 mg pimavanserin base.
  • the present invention relates to, a stable oral pharmaceutical composition
  • a stable oral pharmaceutical composition comprising 20 mg pimavanserin tartrate which is equivalent to 17 mg pimavanserin base.
  • the present invention relates to, a stable oral pharmaceutical composition
  • a stable oral pharmaceutical composition comprising 40 mg pimavanserin tartrate which is equivalent to 34 mg pimavanserin base.
  • the present invention relates to, a stable orally disintegrating composition
  • a stable orally disintegrating composition comprising 10 mg pimavanserin is biologically equivalent to 10 mg immediate release marketed tablet, NUPLAZID®.
  • the present invention relates to, a stable orally disintegrating composition
  • a stable orally disintegrating composition comprising 17 mg pimavanserin is biologically equivalent to 17 mg immediate release marketed tablet, NUPLAZID®.
  • the present invention relates to, a stable orally disintegrating composition
  • a stable orally disintegrating composition comprising 34 mg pimavanserin is biologically equivalent to two units of 17 mg immediate release marketed tablet, NUPLAZID® taken together.
  • the fillers used in the pharmaceutical composition of the present invention are selected from the group comprising of lactose, microcrystalline cellulose, starch, pre-gelatinized starch, calcium phosphate, calcium sulfate, calcium carbonate, mannitol, sorbitol, xylitol, sucrose, maltose, fructose, dextrose, maltodextrin, dextrates, dextrin, and the like.
  • the fillers can be used in an amount from about 1% to 80% by weight of the composition, preferably from about 10% to 70% by weight of composition.
  • super-disintegrants referred as a substance which facilitates rapid disintegration of the present oral dosage forms following introduction into the oral cavity.
  • the super-disintegrants used in the pharmaceutical composition of the present invention are selected from the group comprising of cross-linked polymer such as crospovidone (crosslinked PVP), modified starches such as sodium starch glycolate, cross-linked cellulose such as crosslinked sodium carboxymethyl cellulose (croscarmellose sodium), low substituted hydroxypropyl cellulose, cross-linked alginic acid, natural polymer such as soy polysaccharides, ion-exchange resins, calcium silicate and mixtures thereof.
  • cross-linked polymer such as crospovidone (crosslinked PVP)
  • modified starches such as sodium starch glycolate
  • cross-linked cellulose such as crosslinked sodium carboxymethyl cellulose (croscarmellose sodium)
  • low substituted hydroxypropyl cellulose cross-linked alginic acid
  • natural polymer such as soy polysaccharides, i
  • preferable disintegrants are crospovidone, croscarmellose sodium and sodium starch glycolate.
  • the super-disintegrants can be used in an amount from about 1% to 30% by weight of composition, preferably from about 1% to 25% by weight of composition, and more preferably employed in an amount in a range of from about 5% to 20% by weight of composition.
  • the pharmaceutical composition can be taste-masked with taste masking agents.
  • the taste masking agents selected from group comprising of water-insoluble/water soluble polymers, flavouring agents and sweeteners.
  • the taste masking agents can be used in an amount from about 1% to 50% by weight of composition.
  • Non-limiting examples of suitable water-insoluble polymers for the taste-masking layer include ethylcellulose, polyvinyl acetate (PVA), cellulose acetate (CA), cellulose acetate butyrate (CAB), methacrylate copolymers, such as those available under the tradename “EUDRAGIT” (e.g., type RL, RS, and NE30D), and combinations thereof.
  • Non-limiting examples of water-soluble polymer include, e.g. sodium chloride, sucrose, povidone, and mixtures thereof. The water-insoluble/water soluble polymers can be used in an amount from about 1% to 30% by weight of composition.
  • the sweeteners used in the pharmaceutical composition of the present invention are selected from the group comprising of alitame, acesulfame potassium, aspartame, D-tryptophan, dextrose, erythritol, fructose, galactose, glycerol, glycyrrhizin, glucose, isomalt, xylitol, xylose, lactitol, lactose, levulose, maltitol, maltodextrin, maltol, maltose, corn syrup, neohesperidin dihydrochalcone, neotame, sodium saccharin, siclamate, sorbitol, sucralose, sucrose, tagatose, taumatin, trehalose, and the like.
  • the sweeteners can be used in an amount about 10% or less by weight of composition, preferably from about 5% or less by weight of composition.
  • the flavouring agents used in the pharmaceutical composition of the present invention are selected from the group comprising of natural flavoring oils, anethole, acetic acid, ascorbic acid, phosphoric acid, fumaric acid, lactic acid, lemon, linalool, malic acid, menthol, eucalyptol, orange, citric acid, cinnamone, tartaric acid, thymol, vanilla, strawberry, cherry Flavor (spray dried naturaltype), chocolate aroma or peppermint aroma and the like.
  • the flavouring agents can be used in an amount less than about 5% by weight of composition, preferably less than about 2% by weight of composition.
  • the binders used in the pharmaceutical composition of the present invention are selected from the group comprising of starches, natural and synthetic gums, cellulose derivatives, gelatin, povidone, copovidone, polyethylene glycol, waxes, sodium alginate, and the like .
  • the binders can be used in an amount from about 0 % to 15% by weight of composition, preferably from about 0.05% to 10 % by weight of composition.
  • the lubricants used in the pharmaceutical composition of the present invention are selected from the group comprising of calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, stearic acid, zinc stearate, and sodium stearyl fumarate and a combination thereof.
  • a preferred lubricant is magnesium stearate and sodium stearyl fumarate and can be used in amount from about 0% to 10% by weight of composition, preferably from about 0.5 to 5% and more preferably from about 1% to 2% by weight of composition.
  • the glidants used in the pharmaceutical composition of the present invention are selected from the group comprising of starch, talc, lactose, stearates, dibasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, and colloidal silicon dioxide (Aerosil) and the like.
  • the Glidants can be used in an amount from about 0% to 10% by weight of composition, preferably from about 0.5 to 5% and more preferably from about 1% to 2% by weight of composition.
  • excipients used in the pharmaceutical composition of the present invention which reduce the sedimentation rate of the active ingredient may include polymers, waxes, wetting agents or others that interact ionically with the active ingredient.
  • the wetting agent acts by reducing the surface tension between the aqueous media and the insoluble active, thereby facilitating the active's maintenance in the aqueous media.
  • the preferred excipients for reducing sedimentation rate are hydrophilic polymers. They increase the viscosity of the medium and maintain the wetted particles of the active substance(s) in homogeneous suspension, leading to reduction in their sedimentation rate.
  • the preferred hydrophilic polymers are polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, sodium carboxy methylcellulose, microcrystalline cellulose, guar gum, xanthan gum, alginates and combinations thereof.
  • the hydrophilic polymer can be used in an amount from about 0 to 50% by weight of composition, preferably from about with amounts of about 1% to 20%.
  • composition of the present invention may be in the form of orally disintegrating tablets, orally dispersible tablets, granules, pellets, minitablets, sachets, chewable tablets, powder for reconstitution, orally disintegrating films, or a like thereof which can be easily disintegrate after administration or dispersed/reconstituted in a suitable medium during administration.
  • the present invention provides an orally disintegrating tablet comprising from about 1% to 80% w/w of pimavanserin or a pharmaceutically acceptable salt thereof, from about 1% to 80% w/w fillers, from about 1% to 30% w/w of super-disintegrants, from about 0% to 20% w/w of binders, from about 1% to 50% w/w of taste masking agents selected from water soluble/water in-soluble polymers, sweeteners and flavouring agents or mixture thereof, from about 0% to 10% w/w of lubricants, from about 0% to 10% w/w of glidants.
  • the orally disintegration formulations disintegrate in the oral cavity of a patients about 60 seconds or less, about 50 seconds or less, about 40 seconds or less, about 30 seconds or less, about 20 seconds or less.
  • Disintegration time in the mouth can be measured by observing the dissolution time of the tablet in purified water at about 37 °C using the USP basket-rack assembly method.
  • the present invention provides an dispersible tablet comprising from about 1% to 80% w/w of pimavanserin or a pharmaceutically acceptable salt thereof, from about 1% to 80% w/w fillers, from about 1% to 30% w/w of super-disintegrants, from about 0% to 20% w/w of binders, from about 1 to 50% of taste masking agents selected from water soluble/water in-soluble polymers, sweeteners and flavouring agents or mixture thereof, from about 0% to 50% w/w sedimentation rate reducing agents, from about 0% to 10% w/w of lubricants, from about 0% to 10% w/w of glidants.
  • the dispersible formulations disintegrate within 3 minutes when dispersed in water before administration giving homogenous dispersion.
  • the dispersible formulation in present invention disintegrates in about 3 minutes or less, in about 2 minutes or less, in about 1 minute or less.
  • Disintegration time can be measured by observing the dissolution time of the tablet in purified water at about 37 °C using the USP basket-rack assembly method.
  • the pharmaceutical composition of the present invention can be obtained by a known conventional methods like dry granulation, wet granulation, direct compression, roller compaction, fluidized bed granulation, rapid mixture granulation, spray drying, freeze drying, solvent evaporation, hot-melt extrusion, extrusion spheronization, melt granulation or a like that.
  • the present invention relates to process for the preparation of the pharmaceutical composition, comprising the steps of –
  • the present invention relates to a process for the preparation of a pharmaceutical composition of the present invention, comprising the steps of: a. preparing a dry mixture of pimavanserin or a pharmaceutically acceptable salt thereof and fillers/diluents; b. blending said dry mixture with one or more pharmaceutical excipients specifically super-disintegrants; c. further solvent is slowly sprayed onto the powder for the granulation purpose; d. blending the obtained granules with extragranular excipients and lubricating the blend; e. at last compressing/filling the blend obtained to form a composition.
  • the present invention relates a process for the preparation of the pharmaceutical composition of the present invention, comprising the steps of: a. blending pimavanserin or a pharmaceutically acceptable salt thereof, one or more fillers, binders, and super-disintegrants, and one or more pharmaceutical excipients; b. compacting the blend to obtain granules or flakes; c. further blending with a one or more pharmaceutically acceptable excipients specifically super-disintegrants; d. subsequently lubricating the granules/flakes using the additional lubricants; and compressing the lubricated granules into tablets or filling into sachets.
  • solvents used for granulating solution are selected from methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water, or mixtures thereof.
  • the pharmaceutical composition of the present invention can be used in the treatment of hallucinations and delusions associated with Parkinson's disease psychosis.
  • ODT Oral Disintegrating Tablets
  • Example 1 Example 2
  • Example 3 mg/dose mg/dose mg/dose Pimavanserin tartrate 11.8 (equivalent to 10 mg pimavanserin) 20(equivalent to 17 mg pimavanserin) 40(equivalent to 34 mg pimavanserin) Mannitol 125.00 150.00 225.00
  • Procedure 1) In a high shear mixer, about half of the required quantity of mannitol (sift using screen # 25) is added, followed by pimavanserin (sift using screen # 25) and the remaining mannitol and mixed for about 5 minutes. 2) To the blend from step 1, crospovidone, pregelatinized starch, sucralose and cherry flavor (sift excipients using screen # 25) are added and mixed for 5 minutes to achieve a uniform blend. 3) The blend from step 2 is transferred to V-blender and magnesium stearate and colloidal silicon dioxide (sift using screen # 30) are added and blended for about 3 minutes. 4) The lubricated blend from step 3 is then compressed into tablets using tablet press.
  • ODT Oral Disintegrating Tablets
  • Example 4 Example 6 mg/dose mg/dose mg/dose Wet Granulation Pimavanserin tartrate 11.8 (equivalent to 10 mg pimavanserin) 20(equivalent to 17 mg pimavanserin) 40(equivalent to 34 mg pimavanserin) Microcystalline cellulose 30.00 34.00 68.00 Eudragit E 10 17 34 Povidone K 30 5.00 7.00 10.00 Crospovidone 7.00 15.00 20.00 Isopropyl alcohol* NA NA NA Final Blending Mannitol (Parteck M100) 50.00 50.00 75.00 Crospovidone (Polyplasdone XL) 7.00 15.00 20.00 Colloidal Silicon Dioxide 1.00 1.00 1.5 Sucralose 0.7 1.50 1.50 Cherry Flavor (Spray Dried Natural Type) 0.50 0.50 0.75 Magnesium Stearate 1.00 1.00 1.25 Total 124.00 162.00 272.00
  • step 5 The dried granules from step 4 are taken in a high shear mixer and mannitol, crospovidone, sucralose (sift excipients using screen # 25) and cherry flavor are added and mixed for 5 minutes to achieve a uniform blend. 6) The blend from step 5 is transferred to V-blender followed by addition of magnesium stearate and colloidal silicon dioxide (sift using screen # 30) and blended for about 3 minutes. 7) The lubricated blend from step 6 is then compressed into tablets using tablet press.
  • Example 7 Example 8 mg/dose mg/dose Wet granulation Pimavanserin 20(equivalent to 17 mg pimavanserin) 40(equivalent to 34 mg pimavanserin) Eudragit E 17.00 30.00 Lactose 20.00 40.00 Isopropyl alcohol * NA NA Final Blending Maltodextrin 70.00 100.00 Hydroxyethyl cellulose 20.00 20.00 Crospovidone 10.00 15.00 Sucralose 1.00 1.50 Flavor 1.00 1.50 Magnesium Stearate 2.00 2.50 Total 161.00 250
  • step 4 Dried milled granules are taken in a V-blender and maltodextrin, crospovidone, hydroxyethyl cellulose, sucralose and flavour (sift excipients using screen # 25) are added and mixed for 5 minutes to achieve a uniform blend. 5) To the blend from step 5, magnesium stearate (sift using screen # 30) is added and blended for about 3 minutes. 6) The lubricated blend from step 6 is then compressed into tablets using tablet press.

Abstract

La présente invention concerne une formulation pharmaceutique stable se délitant oralement comprenant de la pimavansérine ou un sel pharmaceutiquement acceptable de celle-ci et un ou plusieurs excipients pharmaceutiquement acceptables. La présente invention concerne en outre une composition pharmaceutique dispersible stable comprenant de la pimavansérine ou un sel pharmaceutiquement acceptable de celle-ci et un ou plusieurs excipients pharmaceutiquement acceptables. De plus, la présente invention concerne également un nouvelle formulation pharmaceutique en sachet comprenant une quantité efficace de pimavansérine ou d'un sel pharmaceutiquement acceptable de celle-ci et un ou plusieurs excipients pharmaceutiquement acceptables.
PCT/IB2018/055667 2017-08-02 2018-07-30 Composition pharmaceutique orale stable de pimavansérine WO2019025934A1 (fr)

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