WO2020025579A1 - Solid dosage form of quetiapine fumarate - Google Patents

Solid dosage form of quetiapine fumarate Download PDF

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Publication number
WO2020025579A1
WO2020025579A1 PCT/EP2019/070433 EP2019070433W WO2020025579A1 WO 2020025579 A1 WO2020025579 A1 WO 2020025579A1 EP 2019070433 W EP2019070433 W EP 2019070433W WO 2020025579 A1 WO2020025579 A1 WO 2020025579A1
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WO
WIPO (PCT)
Prior art keywords
immediate release
discrete units
coated
coated discrete
quetiapine
Prior art date
Application number
PCT/EP2019/070433
Other languages
French (fr)
Inventor
Gemma Casadevall Pujals
Montserrat Garcia Rovira
Original Assignee
Medichem, S.A.
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Application filed by Medichem, S.A. filed Critical Medichem, S.A.
Publication of WO2020025579A1 publication Critical patent/WO2020025579A1/en

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    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the present invention refers to the field of pharmacy. More specifically, it relates to oral pharmaceutical compositions comprising quetiapine fumarate.
  • Quetiapine is the generic name of compound 2-[2-(4-benzo[b][1 ,4]benzothiazepin-6- ylpiperazin-1 -yl)ethoxy]ethanol, the chemical structure of which is the following:
  • Quetiapine acts as an antagonist at several neurotransmitter receptors including the dopamine Di and D 2 receptors, the serotonin 5HT A I and 5HT2 receptors, the histamine Hi receptor, and adrenergic oti and a 2 receptors. Quetiapine is thought to exert its antipsychotic effects primarily via antagonism of the dopamine D 2 receptor and the serotonin 5HT 2 receptor.
  • the inventors of the present invention have surprisingly developed immediate release quetiapine fumarate coated discrete units, which are chemically and physically stable, has a good in vitro dissolution rate and is bioequivalent to the marketed Seroquel® tablet.
  • the coated discrete units of the invention can be contained in a dosage form (e.g. a capsule or sachet) which can be sprinkled onto food to ease administration to patients who have difficulty swallowing tablets, e.g., paediatric patients and geriatrics.
  • the coated discrete units of the invention can be administered through a feeding tube in a long- term care setting to critically ill patients.
  • coated discrete units may be comprised within a capsule which is cost-effective in terms of manufacturing since it offers a clear manufacturing advantage over e.g. a tablet dosage form, as there is no need for further processing steps (such as a compression step) apart from a standard encapsulation.
  • the dosage form of the invention requires the addition of fewer excipients than the tablet dosage form.
  • a first aspect of the invention relates to immediate release coated discrete units, each discrete unit comprising: a) an inert core, b) a drug layer over the inert cores comprising quetiapine fumarate and one hydrophilic polymer, and c) an outer layer.
  • the invention also relates to an immediate release capsule dosage form of quetiapine fumarate comprising coated discrete units, each discrete unit comprising: a) an inert core, b) a drug layer over the inert cores comprising quetiapine fumarate and one hydrophilic polymer and c) an outer layer.
  • the invention relates to a method for the preparation of the immediate release quetiapine fumarate coated discrete units according to the invention, the method comprising the steps of:
  • step a) coating inert cores with a solution or dispersion comprising quetiapine fumarate and a hydrophilic polymer to obtain drug-layer coated cores; and b) coating the drug-layer coated cores of step a) with a solution or dispersion of a polymer to obtain outer-layer coated units.
  • Another aspect of the invention refers to the immediate release quetiapine fumarate dosage form comprising coated discrete units of the invention, in particular comprising 12.5 mg of quetiapine calculated on quetiapine base, for use as a medicament.
  • Another aspect of the invention refers to the immediate release quetiapine fumarate dosage form comprising coated discrete units of the invention, in particular comprising 25 mg of quetiapine calculated on quetiapine base, for use as a medicament.
  • Another aspect of the invention refers to the immediate release quetiapine fumarate dosage form comprising coated discrete units of the invention, in particular comprising 50 mg of quetiapine calculated on quetiapine base, for use as a medicament.
  • the invention relates to the immediate release quetiapine fumarate coated discrete units of the invention, for use in the treatment of schizophrenia.
  • the technical problem of the present invention is to provide an alternative oral solid pharmaceutical composition comprising quetiapine fumarate that is chemically and physically stable, has a good in vitro dissolution rate which exhibits good bioavailability and results bioequivalent to the marketed Seroquel® tablet.
  • the solution is provided by the immediate release quetiapine fumarate dosage form comprising coated discrete units of the invention.
  • the invention provides novel immediate release coated discrete units, each discrete unit comprising: a) an inert core, b) a drug layer over the inert core comprising quetiapine fumarate and one hydrophilic polymer, and c) an outer layer, more particularly an outer protective layer.
  • the immediate release coated discrete units of the invention may be conveniently contained within a capsule.
  • This capsule dosage form e.g. in the form of a sprinkle capsule
  • This composition has been found to be not only patient compliant but also chemically stable throughout the shelf life of the product.
  • a stable, immediate release quetiapine fumarate coated discrete units, optionally contained within a capsule, which is very patient compliant is presented.
  • the present invention provides coated discrete units which are capable of being administered through a feeding tube by dispersing in an aqueous media before administration.
  • the immediate release quetiapine fumarate coated discrete units of the invention are contained in a capsule dosage form. More particularly, the capsule dosage form is in the form of a sprinkle capsule.
  • an "immediate release formulation” refers to a formulation having a dissolution profile where an amount greater than or equal to about 80% of the pharmaceutical agent is released in less than or equal to about 1 hour.
  • the pharmaceutical composition as herein disclosed releases at least 80 % of the active agent in 30 min and at least a 90% of the active agent in 60 min.
  • the pharmaceutical composition as herein disclosed releases not less than (NLT) 80% of the active agent in 45 minutes, preferably it releases at least 80% of the active agent in 15 min.
  • the dissolution test for an immediate release pharmaceutical composition comprising the active agent as herein disclosed is performed in the following conditions: USP Apparatus: II (Paddles).
  • the term“weight gain” is used to describe the weight of a layer added to a pellet relative to the pellet’s weight prior to that layer’s addition.
  • the weight gain of a layer added to a pellet is expressed as a percentage and is defined as 100% times the ratio of (i) the weight of the added layer to (ii) the pellet’s weight prior to the layer’s addition.
  • the weight gain of a seal layer added to a pellet is 100% times the ratio of (i) the weight of the added seal layer to (ii) the pellet’s weight prior to the layer’s addition (i.e., the combined weight of the core and the drug layer).
  • the term“weight gain” is used as an alternative to describing the weight of a given pellet layer relative to the total pellet weight.
  • pharmaceutically acceptable excipients or carriers refers to pharmaceutically acceptable materials, solid dosage forms or vehicles for pharmaceutical or medical uses in humans. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the solid dosage form. It must also be suitable for use in contact with tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications consistent with a reasonable benefit/risk ratio.
  • cores are synonymous and may be used interchangeably.
  • bioequivalence is established by comparing pharmacokinetic parameters, for example AUC and Cmax of the present invention with Seroquel® tablets in healthy human subjects.
  • AUC refers to the area under the time/plasma concentration curve after the administration of the quetiapine fumarate immediate release dosage form to healthy human subjects.
  • Cmax refers to the maximum concentration of quetiapine fumarate in the blood following the administration of the quetiapine fumarate immediate release dosage form to healthy human subjects.
  • the invention relates to immediate release coated discrete units comprising: a) inert cores, b) a drug layer over the inert cores comprising quetiapine fumarate and one hydrophilic polymer, and c) an outer layer, more particularly an outer protective layer.
  • the immediate release quetiapine fumarate coated discrete units of the invention are contained in a capsule dosage form. More particularly, the capsule dosage form is in the form of sprinkle capsules.
  • the sprinkle capsule dosage form may be opened and sprinkled onto soft food, for example, applesauce, yogurt, cottage cheese, custard, or pudding, at the time of administration.
  • the molecular ratio of quetiapine base with respect to fumaric acid in quetiapine fumarate salt is 2:1 (quetiapine hemifumarate).
  • quetiapine fumarate may be in crystalline form either as free solvation compound or as solvate, e.g. hydrate. It is intended that both forms are within the scope of the present invention. Methods of solvation are generally known within the art.
  • the immediate release dosage form comprising coated discrete units of the invention comprises 12.5 mg, 25 mg or 50 mg of quetiapine calculated on quetiapine base.
  • Inert cores may be selected from the group comprising of water-soluble or water-swellable cores.
  • water-soluble or water-swellable inert cores are made up of sugar, microcrystalline cellulose, cellulose starch, modified starch, or mixtures thereof.
  • the inert core is made of microcrystalline cellulose.
  • the size (i.e. diameter) of the inert core is from 400 to 900 mhh, preferably from 500 to 800 mp ⁇ .
  • the drug layer over the inert cores comprises quetiapine fumarate and one hydrophilic polymer.
  • the drug coating layer comprises other pharmaceutically acceptable excipients.
  • suitable pharmaceutically acceptable excipients include plasticizers and lubricants.
  • the drug layer further comprises one or more pharmaceutically acceptable excipients or carriers, more particularly it comprises one or more plasticizers and one or more lubricants or anti-tacking agents.
  • the drug layer over the inert core does not comprise other coating polymers apart from the hydrophilic polymer.
  • the drug layer over the inert core is free from other coating polymers.
  • Hydrophilic/water-soluble/swellable polymers act as binders.
  • Hydrophilic polymers to be used in the present invention include hydroxypropyl methylcellulose (hypromellose) having a low apparent viscosity (e.g., HPMC E3, E5, E6 or E15), polyvinyl pyrrolidone (povidone) or mixtures thereof.
  • the hydrophilic polymer is a cellulose based polymer.
  • the hydrophilic polymer is selected from the group consisting of hydroxypropyl methylcellulose, polyvinyl pyrrolidone, and mixtures thereof, more preferably, the hydrophilic polymer is hydroxypropyl methylcellulose.
  • the weight to weight ratio (w/w) between the hydrophilic polymer to the active ingredient (quetiapine fumarate) in the drug layer is from 0.05:1 to 0.50:1 , more particularly from 0.10:1 to 0.45:1 , even more particularly from 0.35:1 to 0.40:1 , and even more particularly is 0.35:1 or 0.40:1 .
  • the weight to weight ratio (w/w) between the hydrophilic polymer to the active ingredient (quetiapine fumarate) in the drug layer is equal to or more than 0.35.
  • plasticizers may be comprised in the drug layer.
  • plasticizers that may be employed in this invention are without limitation triethyl citrate (TEC), triacetin, tributyl citrate, acetyl triethyl citrate (ATEC), acetyl tributyl citrate (ATBC), dibutyl phthalate, dibutyl sebacate (DBS), diethyl phthalate, vinyl pyrrolidone glycol triacetate, polyethylene glycol, polyoxyethylene sorbitan monolaurate, propylene glycol, propylene carbonate or castor oil; and combinations or mixtures thereof.
  • the amount of plasticizers in the drug layer composition may be from about 0.5 to about 10, more particularly from about 0.5 to about 5, percent by weight of the total drug layer composition.
  • the plasticizer is triethyl citrate.
  • Anti-tacking agents or processing lubricants may be also comprised in the drug layer.
  • Exemplary agents and lubricants include stearyl alcohol, stearic acid, glycerol monostearate (GMS), talc, magnesium stearate, silicon dioxide, amorphous silicic acid, and fumed silica; and combinations or mixtures thereof.
  • the amount of anti-tacking agent or processing lubricant may be from about 0.1 percent to about 10, more particularly from about 0.1 to about 5, percent by weight of the composition (i.e. weight of the discrete unit).
  • the anti-tacking agent is talc.
  • quetiapine fumarate coated discrete units of the invention are in the form of particles having a particle size distribution wherein approximately 90% by volume of the particles (d90) have a diameter equal to or below 20 pm (d90 ⁇ 20 pm), preferably equal to or below 15 pm (d90 ⁇ 15 pm), and more preferably equal to or below 10 pm (d90 ⁇ 10 pm).
  • d90 ⁇ x means that at least 90% by volume of the particles have a particle size equal to or below x.
  • the particle size can be determined by laser light scattering for instance using a Malvern Mastersizer Apparatus MS 2000 equipped with a Hydro S dispersion unit. Silicon fluid F10 may be used as dispersion medium.
  • Micronized active ingredient, preferably quetiapine fumarate, according to the present invention means the active substance having d90 equal to or less than 10 pm.
  • micronized active ingredient to be used in the present invention may be obtained by means of any micronization or comminution process of reducing primary or crystalline particle size by any method known from the state of the art such as for example dry or wet mills such as for example air jet and/or ball milling, high shear mill or high pressure homogenizer or dry mills such as cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills and ball mills or Hosokawa Alpine agitated ball mill, ultrasound processors, or wet mills such as Hielscher ultrasonic processor, and in particular high shear mixers and colloid mills, such as Turrax and colloid mills produced by Fryma.
  • dry or wet mills such as for example air jet and/or ball milling
  • high shear mill or high pressure homogenizer or dry mills such as cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills and ball mills or Hosokawa Alpine
  • compositions may be prepared which exhibit for their active ingredient both a consistent in vitro dissolution profile and in vivo bioavailability.
  • control of particle size to a narrow range has also resulted in significant improvements in manufacturing capabilities.
  • the weight to weight ratio (w/w) between the hydrophilic polymer to the active ingredient in the drug layer is from 0.05:1 to 0.50:1 ; and the quetiapine fumarate used is in the form of particles having d90 ⁇ 20 pm, more particularly d90 ⁇ 15 pm, and even more particularly d90 ⁇ 10 pm.
  • the weight to weight ratio (w/w) between the hydrophilic polymer to the active ingredient (quetiapine fumarate) in the drug layer is from 0.10:1 to 0.45:1 ; and the quetiapine fumarate used is in the form of particles having d90 ⁇ 20 pm, more particularly d90 ⁇ 15 pm, and even more particularly d90 ⁇ 10 pm.
  • the weight to weight ratio (w/w) between the hydrophilic polymer to the active ingredient (quetiapine fumarate) in the drug layer is equal to or more than 0.35; and the quetiapine fumarate used is in the form of particles having d90 ⁇ 20 pm, more particularly d90 ⁇ 15 pm, and even more particularly d90 ⁇ 10 pm.
  • the weight gain of the drug layer with respect to the inert core i.e., the ratio of (i) the weight of the drug layer to (ii) the weight of the inert core prior to the drug layer’s addition
  • the drug layer presents a weight gain of from 20% to 25%.
  • the coated discrete units are coated with an outer layer, more particularly an outer protective coating layer, disposed over the drug- layer.
  • This outer layer which may comprise at least one polymer, is free from any active ingredient and, in addition to the coating polymer, it may optionally include other pharmaceutically acceptable excipients, in particular, plasticizers, pigments and/or anti- tacking agents.
  • Anti-tacking agents or processing lubricants may be also comprised in the drug layer.
  • Exemplary agents and lubricants include stearyl alcohol, stearic acid, glycerol monostearate (GMS), talc, magnesium stearate, silicon dioxide, amorphous silicic acid, and fumed silica; and combinations or mixtures thereof.
  • the amount of anti-tacking agent or processing lubricant may be from about 0.1 percent to about 10, more particularly from about 0.1 to about 5, percent by weight of the composition (i.e. weight of the discrete unit).
  • the anti-tacking agent is talc.
  • the drug layer and the outer layer may be formed of the same or different polymers.
  • the outer coating of the pellet composition substantially (i.e. equal or more than 90% of the total surface) entirely covers the drug coating of each individual unit. This prevents direct contact between individual units, assists in protecting the integrity of the drug coating of the units, increases flowability, prevents segregation, and provides excellent protection against humidity. Additionally, the outer coating enables a good in vitro dissolution rate.
  • the outer layer is free from any extended release polymers.
  • the outer coating of the present invention comprises commercially available coating compositions comprising film-forming polymers marketed under various trade names such as Opadry® manufactured by Colorcon. This coating contains polymers, plasticizers and pigments.
  • the weight gain of the outer layer, more particularly the outer protective layer, with respect to the drug-coated inert cores is from 1 % to 20% (e.g., 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1 1 %, 12%, 13%, 14%, 15%, 16%, 17%, 17.5%, 18%, 19%, or 20%), and preferably from 5% to 10% (e.g., 5%, 6%, 7%, 8%, 9% or 10%) .
  • the outer-layer coated discrete units have an average size which is in the range from about 0.2 mm to about 2 mm, in particular from about 0.5 mm to about 1 .5 mm. Size in this respect is determined by whether a pellet passes through, or is retained, as a result of agitation on a sieve or screen having a mesh opening size as stated. If the pellet passes through the sieve or screen, it is described as having a size which is equal to or less than that of the mesh opening, and if the pellet is retained, it is described as having a size that is greater than the mesh opening.
  • the outer-layer coated discrete units are free from any extended release polymers.
  • the outer-layer coated discrete units and optionally one or more excipients or carriers, such as a lubricant have the suitable flowability to be encapsulated.
  • the desired flowability is defined as no clogging or aggregation is observed while the dispersion flows through the feeding tube.
  • Another embodiment of the present invention provides immediate release quetiapine fumarate coated discrete units having d90 value between about 0.2 mm and 1.2 mm, wherein the coated discrete units, after being dispersed in an aqueous media and delivered through a feeding tube size NLT 10 F, at least 85% of quetiapine fumarate was recovered at the exit of the feeding tube after holding for 10 minutes.
  • the coated discrete units are in the form of plurality of pellets, granules, minitablets, or beads.
  • the coated discrete units can be applied in the formulation as tablets, ODT (Orally dispersable tablets), MUPS (Multiple Unit Pellet System), capsules, caplets, sachets or other solid dosage forms of an active ingredient having stability problems.
  • the solid dosage form is a capsule.
  • the coated discrete units of the invention when the immediate release quetiapine fumarate coated discrete units of the invention are contained in a capsule dosage form, the coated discrete units are optionally lubricated before filling into the capsule.
  • a capsule containing the coated discrete units of the invention and a lubricant when the immediate release quetiapine fumarate coated discrete units of the invention are contained in a capsule dosage form, the coated discrete units are optionally lubricated before filling into the capsule.
  • a capsule containing the coated discrete units of the invention and a lubricant.
  • the lubricant is preferably selected from sodium stearylfumarate, magnesium stearate, hydrogenated vegetable oil, stearic acid, calcium stearate, glyceryl behenate, sodium lauryl sulphate and talc, the latter being preferred.
  • the combination of above-mentioned lubricants can also be used.
  • the lubricant(s) is present in less than 5% by weight with respect to the total weight of the composition.
  • the immediate release composition of the invention is stable when subjected to stability conditions of 40 °C and 75% Relative Humidity (RH) for 6 months. Further, the coated discrete units are stable when sprinkled onto soft foods of different pH levels for at least 60 minutes. Also, the dispersion of the multiparticulate pellets in an aqueous media is stable when administered in a feeding tube after holding for at least 10 minutes.
  • the process for the manufacture of the immediate release quetiapine fumarate coated discrete units of the invention represents a further aspect of the invention.
  • the mentioned formulations will be prepared using standard methods such as those described or referred to in the art.
  • the pharmaceutical processes can preferably be completely water-based.
  • the method for the preparation of the immediate release quetiapine fumarate coated discrete units according to the invention comprises the steps of:
  • step a) coating inert cores with a solution or dispersion comprising quetiapine fumarate and a hydrophilic polymer to obtain drug-layer coated cores; and b) coating the drug-layer coated cores of step a) with a solution or dispersion of a polymer to obtain outer-layer coated units.
  • the process for the preparation of the resulting immediate release capsule of the invention comprises the steps of:
  • step b) coating the drug-layer coated cores of step a) with a solution or dispersion of a polymer to obtain outer-layer coated units
  • step b) blending the coated units of step b) optionally with lubricant;
  • Another aspect of the invention relates to the immediate release quetiapine fumarate coated discrete units according to the invention for use in the treatment of schizophrenia, wherein the treatment comprises administering the said immediate release quetiapine fumarate coated discrete units.
  • Another aspect of the invention relates to the use of quetiapine fumarate for the preparation of immediate release coated discrete units as defined above for the treatment of schizophrenia. It also forms part of the invention a method for the treatment of schizophrenia, comprising administering the immediate release quetiapine fumarate coated discrete units as defined above.
  • Another aspect of the invention relates to the immediate release capsule according to the invention for use in the treatment of schizophrenia, wherein the treatment comprises administering the said immediate release capsule.
  • Another aspect of the invention relates to the use of quetiapine fumarate for the preparation of the immediate release capsule as defined above for the treatment of schizophrenia.
  • Another aspect of the invention refers to the immediate release quetiapine fumarate coated discrete units of the invention or a capsule comprising them, which comprises 12.5 mg of quetiapine calculated on quetiapine base, for use as a medicament.
  • Another aspect of the invention refers to the immediate release quetiapine fumarate coated discrete units of the invention or a capsule comprising them, which comprises 25 mg of quetiapine calculated on quetiapine base, for use as a medicament.
  • Another aspect of the invention refers to the immediate release quetiapine fumarate coated discrete units of the invention or a capsule comprising them, which comprises 50 mg of quetiapine calculated on quetiapine base, for use as a medicament.
  • Example 1 Immediate release capsules of quetiapine fumarate Immediate release quetiapine hard gelatine capsules composed by coated discrete units were prepared. The final developed composition per strength is the following:
  • Hypromellose 3CP (Methocel E3) 1 1.51 5.76
  • Opadry is a commercial one-step film coating system which combines polymer, plasticizer and pigment (in this case: HPMC, Titanium dioxide, PEG 400, Iron oxide red, Iron oxide yellow)
  • FC1 first film coating
  • FC1 Spraying of FC1 : the inert cores of microcrystalline cellulose are charged in the fluid bed system (bottom spraying wurster) and adequate air volume pressure (from 1 to 1.5 bar) is applied to move the pellets inside. Pellets are heated using the needed inlet air temperature to achieve a product temperature about 47 °C. Then the spraying process with the first film coating solution (FC1 ) is started using an adequate spraying pressure (from 1 to 3 bar) and the flow rate is adjusted to maintain the product temperature constant between 41-45 °C.
  • FC2 Spraying of FC2: the FC1 pellets obtained in step 3 are charged in the fluid bed system (bottom spraying wurster) and adequate air volume pressure (from 1 to 1.5 bar) is applied to move the pellets inside. Pellets are heated using the needed inlet air temperature to achieve a product temperature about 47 °C. Then the spraying process with the second film coating solution (FC2) is started using an adequate spraying pressure (from 1 to 3 bar) and the flow rate is adjusted to maintain the product temperature constant between 41 -45 °C.
  • FC2 second film coating solution
  • step 6 Drying of FC2: once the spraying process of step 5 is finished (all the FC2 dispersion has been applied), the pellets are dried until reach a product temperature of 47°C. After that, the inlet air temperature is turned off and the final FC2 pellets are discharged when the product temperature is ⁇ 30 °C.
  • Encapsulation process the blend obtained in the previous step is encapsulated using a dosing-chamber device in tamping-pin encapsulation equipment. The amount of pellets to fill into the capsules is adjusted accordingly for each strength. Capsule size for 25 mg strength is n°2 and for 12.5 mg strength is n°4.
  • micronized API consistently showed assay values (% of quetiapine finally absorbed in the pellet) within specifications.
  • FC2 outer protective layer
  • the qualitative-quantitative composition of the outer protective layer in the different batches was the following:
  • Dissolution profiles obtained from the resulting capsules compared with RLD (Seroquel®) are shown in the next table and graph. Dissolution method is done using the USP Apparatus II (paddles at 50 rpm) and dissolution media is buffer at pH 1.2 (500 ml_).
  • Coated discrete units comprising a weight percentage of the outer protective layer of 10% or less show a dissolution profile where at least 80% of the active agent is released in 15 minutes.
  • Hypromellose 3CP (Methocel E3) 23.02 1 1.51 5.76
  • FC1 first film coating
  • hypromellose is dispersed in hot water (>60 °C). Once the temperature is about 20-30 °C, triethyl citrate, Quetiapine fumarate and talc are incorporated.
  • the FC1 dispersion is stirred during the spraying process described in the next step of the process (step 2 below).
  • Spraying of FC1 the inert cores of microcrystalline cellulose are charged in the fluid bed system (bottom spraying wurster) and adequate air volume pressure (from 1 to 1.5 bar) is applied to move the pellets inside. Pellets are heated using the needed inlet air temperature to achieve a product temperature about 47 °C. Then the spraying process with the first film coating solution (FC1 ) is started using an adequate spraying pressure (from 1 to 3 bar) and the flow rate is adjusted to maintain the product temperature constant between 41-45 °C.
  • FC2 suspension hypromellose is solubilized in hot water (>60 °C). Once the temperature is about 20-30 °C, stirr during 45-60 min until the hypromellose is completely dissolved. A suspension of talc micronized is prepared, adding the talc to some amount of water and stirred during 15 minutes. The talc micronized dispersion is added over the solution of hypromellose previously prepared. The FC2 dispersion is stirred during the spraying process described in the next step of the process (step 5 below).
  • FC2 the FC1 pellets obtained in step 3 are charged in the fluid bed system (bottom spraying wurster) and adequate air volume pressure (from 1 to 1.5 bar) is applied to move the pellets inside. Pellets are heated using the needed inlet air temperature to achieve a product temperature about 47 °C. Then the spraying process with the second film coating dispersion (FC2) is started using an adequate spraying pressure (from 1 to 3 bar) and the flow rate is adjusted to maintain the product temperature constant between 41-45 °C.
  • FC2 second film coating dispersion
  • step 6 Drying of FC2: once the spraying process of step 5 is finished (all the FC2 dispersion has been applied), the pellets are dried until reach a product temperature of 47°C. After that, the inlet air temperature is turned off and the final FC2 pellets are discharged when the product temperature is ⁇ 30 °C.
  • Encapsulation process the blend obtained in the previous step is encapsulated using a dosing-chamber device in tamping-pin encapsulation equipment. The amount of pellets to fill into the capsules is adjusted accordingly for each strength. Capsule size for 25 mg strength is n°2, for 12.5 mg strength is n°4 and for 50 mg is n°0.
  • Example 6 Effect of the outer protective layer (FC2) on the dissolution profile The effect of the outer protective layer (FC2) on the dissolution profile was studied.
  • the tested batches were prepared as described in example 5 and differed on the amount of outer protective layers shown in the following table:
  • the qualitative-quantitative composition of the outer protective layer in the different batches was the following:
  • Dissolution profiles obtained from the resulting capsules compared with RLD (Seroquel®) are shown in the next table and graph. Dissolution method is done using the USP Apparatus II (paddles at 50 rpm) and dissolution media is buffer at pH 1.2 (500 ml_).
  • each discrete unit comprising: a) an inert core, b) a drug layer over the inert core comprising quetiapine fumarate and one hydrophilic polymer, and c) an outer layer.
  • Clause 2 The immediate release coated discrete units according to clause 1 , wherein the weight ratio of the hydrophilic polymer to the quetiapine fumarate in the drug layer is equal to or more than 0.35.
  • Clause 3 The immediate release coated discrete units according to any of the clauses 1 -2, wherein the hydrophilic polymer is selected from the group consisting of hydroxypropyl methylcellulose, polyvinyl pyrrolidone, and mixtures thereof.
  • Clause 4 The immediate release coated discrete units according to any of the clauses 1 -3, wherein the drug layer further comprises one or more plasticizers and one or more lubricants.
  • Clause 5 The immediate release coated discrete units according to any of clauses 1 to 4, wherein quetiapine fumarate is in the form of particles having a particle size distribution wherein approximately 90% by volume of the particles have a diameter (d90) equal to or below 10 mp ⁇ .
  • outer protective layer further comprises plasticizers and optionally pigments.
  • the inert core is made up of sugar, microcrystalline cellulose, cellulose starch, modified starch, or mixtures thereof.
  • weight gain of the outer layer with respect to the drug-coated inert cores is equal to or less than 15%.
  • weight gain of the drug layer with respect to the inert core is from 15% to 30%.
  • Clause 10 The immediate release coated discrete units according to any of the clauses 1 to 9, wherein each coated discrete unit has a d90 value of from about 0.2 mm to 1 .2 mm.
  • Clause 1 1.
  • Clause 12 The immediate release coated discrete units according to any of the clauses 1 to 1 1 , which are comprised within a capsule.
  • Clause 13 The immediate release capsule according to any of the clauses 12, wherein the capsule is a sprinkle capsule. Clause 14. A method for the preparation of the immediate release coated discrete units as defined in any of the clauses 1 to 13, the method comprising the steps of:
  • step b) coating the drug-layer coated cores of step a) with a solution of dispersion of a polymer to obtain outer-layer coated units.

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Abstract

The present invention relates to oral pharmaceutical compositions comprising quetiapine fumarate which comprise coated discrete units. The composition of the invention is chemically and physically stable, has a good in vitro dissolution rate thereby showing good bioavailability and resulting bioequivalent to marketed Seroquel® tablets.

Description

Solid Dosage Form of Quetiapine Fumarate
This application claims the benefit of European Patent Application EP18382580.1 filed on July 31 , 2018.
Technical Field
The present invention refers to the field of pharmacy. More specifically, it relates to oral pharmaceutical compositions comprising quetiapine fumarate.
Background Art
Quetiapine is the generic name of compound 2-[2-(4-benzo[b][1 ,4]benzothiazepin-6- ylpiperazin-1 -yl)ethoxy]ethanol, the chemical structure of which is the following:
Figure imgf000002_0001
Quetiapine, a process for its preparation, and its use as antipsychotic was firstly disclosed in the European patent EP240228. Quetiapine acts as an antagonist at several neurotransmitter receptors including the dopamine Di and D2 receptors, the serotonin 5HTAI and 5HT2 receptors, the histamine Hi receptor, and adrenergic oti and a2 receptors. Quetiapine is thought to exert its antipsychotic effects primarily via antagonism of the dopamine D2 receptor and the serotonin 5HT2 receptor.
In the form of its fumarate salt quetiapine is marketed under the name Seroquel® by Astra Zeneca and it is approved for the treatment of psychiatric conditions such as schizophrenia and bipolar disorder. Authorized dosage forms of Seroquel® in Europe include immediate release coated tablets containing 25 mg, 100 mg, 150 mg, 200 mg, and 300 mg of quetiapine. These previously described formulations of quetiapine have certain properties that are not ideal in all situations. Sometimes such solid dosage forms pose problems while swallowing as a result of, for example, their size, stickiness, taste, aftertaste or frequency of administration. Particularly, in paediatric patients or in patients suffering from dysphagia, the swallowing of solid oral dosage form may be very painful, if not impossible. Thus, there is a need to provide an alternative composition of quetiapine fumarate that is stable, easy or convenient to administrate as well as to prepare, provides the desired in vitro release profile and which is bioequivalent to the marketed Seroquel® tablet.
Summary of invention
The inventors of the present invention have surprisingly developed immediate release quetiapine fumarate coated discrete units, which are chemically and physically stable, has a good in vitro dissolution rate and is bioequivalent to the marketed Seroquel® tablet. Moreover, the coated discrete units of the invention can be contained in a dosage form (e.g. a capsule or sachet) which can be sprinkled onto food to ease administration to patients who have difficulty swallowing tablets, e.g., paediatric patients and geriatrics. Also, the coated discrete units of the invention can be administered through a feeding tube in a long- term care setting to critically ill patients.
Additionally, coated discrete units may be comprised within a capsule which is cost-effective in terms of manufacturing since it offers a clear manufacturing advantage over e.g. a tablet dosage form, as there is no need for further processing steps (such as a compression step) apart from a standard encapsulation. Further, the dosage form of the invention requires the addition of fewer excipients than the tablet dosage form.
Therefore, a first aspect of the invention relates to immediate release coated discrete units, each discrete unit comprising: a) an inert core, b) a drug layer over the inert cores comprising quetiapine fumarate and one hydrophilic polymer, and c) an outer layer.
The invention also relates to an immediate release capsule dosage form of quetiapine fumarate comprising coated discrete units, each discrete unit comprising: a) an inert core, b) a drug layer over the inert cores comprising quetiapine fumarate and one hydrophilic polymer and c) an outer layer.
In a further aspect, the invention relates to a method for the preparation of the immediate release quetiapine fumarate coated discrete units according to the invention, the method comprising the steps of:
a) coating inert cores with a solution or dispersion comprising quetiapine fumarate and a hydrophilic polymer to obtain drug-layer coated cores; and b) coating the drug-layer coated cores of step a) with a solution or dispersion of a polymer to obtain outer-layer coated units. Another aspect of the invention refers to the immediate release quetiapine fumarate dosage form comprising coated discrete units of the invention, in particular comprising 12.5 mg of quetiapine calculated on quetiapine base, for use as a medicament.
Another aspect of the invention refers to the immediate release quetiapine fumarate dosage form comprising coated discrete units of the invention, in particular comprising 25 mg of quetiapine calculated on quetiapine base, for use as a medicament. Another aspect of the invention refers to the immediate release quetiapine fumarate dosage form comprising coated discrete units of the invention, in particular comprising 50 mg of quetiapine calculated on quetiapine base, for use as a medicament.
In a further aspect, the invention relates to the immediate release quetiapine fumarate coated discrete units of the invention, for use in the treatment of schizophrenia.
These aspects and preferred embodiments thereof are additionally also defined hereinafter in the detailed description, as well as in the claims. Detailed description of the invention
The technical problem of the present invention is to provide an alternative oral solid pharmaceutical composition comprising quetiapine fumarate that is chemically and physically stable, has a good in vitro dissolution rate which exhibits good bioavailability and results bioequivalent to the marketed Seroquel® tablet. The solution is provided by the immediate release quetiapine fumarate dosage form comprising coated discrete units of the invention.
Accordingly, in a first aspect, the invention provides novel immediate release coated discrete units, each discrete unit comprising: a) an inert core, b) a drug layer over the inert core comprising quetiapine fumarate and one hydrophilic polymer, and c) an outer layer, more particularly an outer protective layer.
The immediate release coated discrete units of the invention may be conveniently contained within a capsule. This capsule dosage form (e.g. in the form of a sprinkle capsule) allows to be either swallowed or be opened and dispersed in liquid or soft food, e.g. by sprinkling onto a minimum portion, for instance, a teaspoon, of a vehicle. This composition has been found to be not only patient compliant but also chemically stable throughout the shelf life of the product. Thus, a stable, immediate release quetiapine fumarate coated discrete units, optionally contained within a capsule, which is very patient compliant is presented.
The present invention provides coated discrete units which are capable of being administered through a feeding tube by dispersing in an aqueous media before administration.
According to one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the immediate release quetiapine fumarate coated discrete units of the invention are contained in a capsule dosage form. More particularly, the capsule dosage form is in the form of a sprinkle capsule.
All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly through-out the specification and claims.
The term "about" or“around” as used herein refers to a range of values ± 10% of a specified value. For example, the expression "about 10" or“around 10” includes ± 10% of 10, i.e. from 9 to 1 1 .
All percentages referred herein are by weight. The term“percentage (%) by weight” refers to the percentage of each ingredient in relation to the total weight of the solid dosage form. The weight of the pellets must be understood as dry weight.
An "immediate release formulation" refers to a formulation having a dissolution profile where an amount greater than or equal to about 80% of the pharmaceutical agent is released in less than or equal to about 1 hour. In an embodiment, optionally in combination with one or more features of the various embodiments described above or below, the pharmaceutical composition as herein disclosed releases at least 80 % of the active agent in 30 min and at least a 90% of the active agent in 60 min. In a most preferred embodiment, the pharmaceutical composition as herein disclosed releases not less than (NLT) 80% of the active agent in 45 minutes, preferably it releases at least 80% of the active agent in 15 min. The dissolution test for an immediate release pharmaceutical composition comprising the active agent as herein disclosed is performed in the following conditions: USP Apparatus: II (Paddles). Speed: 50 rpm. Medium: buffer at pH 1 .2 (500 ml_). Wavelength: 243 nm. As used herein, the term“weight gain” is used to describe the weight of a layer added to a pellet relative to the pellet’s weight prior to that layer’s addition. The weight gain of a layer added to a pellet is expressed as a percentage and is defined as 100% times the ratio of (i) the weight of the added layer to (ii) the pellet’s weight prior to the layer’s addition. For example, the weight gain of a seal layer added to a pellet is 100% times the ratio of (i) the weight of the added seal layer to (ii) the pellet’s weight prior to the layer’s addition (i.e., the combined weight of the core and the drug layer). The term“weight gain” is used as an alternative to describing the weight of a given pellet layer relative to the total pellet weight.
The expression "pharmaceutically acceptable excipients or carriers" refers to pharmaceutically acceptable materials, solid dosage forms or vehicles for pharmaceutical or medical uses in humans. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the solid dosage form. It must also be suitable for use in contact with tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications consistent with a reasonable benefit/risk ratio.
In the present invention, the terms cores, beads, pellets, and non pareils are synonymous and may be used interchangeably.
For the purposes of the present invention, bioequivalence is established by comparing pharmacokinetic parameters, for example AUC and Cmax of the present invention with Seroquel® tablets in healthy human subjects.
The term“AUC” refers to the area under the time/plasma concentration curve after the administration of the quetiapine fumarate immediate release dosage form to healthy human subjects. The term“Cmax” refers to the maximum concentration of quetiapine fumarate in the blood following the administration of the quetiapine fumarate immediate release dosage form to healthy human subjects.
Pharmaceutical composition
In a first aspect, the invention relates to immediate release coated discrete units comprising: a) inert cores, b) a drug layer over the inert cores comprising quetiapine fumarate and one hydrophilic polymer, and c) an outer layer, more particularly an outer protective layer. According to one embodiment of this aspect, optionally in combination with one or more features of the various embodiments described above or below, the immediate release quetiapine fumarate coated discrete units of the invention are contained in a capsule dosage form. More particularly, the capsule dosage form is in the form of sprinkle capsules.
According to another embodiment of this aspect, the sprinkle capsule dosage form may be opened and sprinkled onto soft food, for example, applesauce, yogurt, cottage cheese, custard, or pudding, at the time of administration.
In one particular embodiment, optionally in combination with one or more features of the various embodiments described above or below, the molecular ratio of quetiapine base with respect to fumaric acid in quetiapine fumarate salt is 2:1 (quetiapine hemifumarate). Furthermore, quetiapine fumarate may be in crystalline form either as free solvation compound or as solvate, e.g. hydrate. It is intended that both forms are within the scope of the present invention. Methods of solvation are generally known within the art.
In one particular embodiment, optionally in combination with one or more features of the various embodiments described above or below, the immediate release dosage form comprising coated discrete units of the invention comprises 12.5 mg, 25 mg or 50 mg of quetiapine calculated on quetiapine base.
Inert cores may be selected from the group comprising of water-soluble or water-swellable cores. According to an embodiment of this aspect, optionally in combination with one or more features of the various embodiments described above or below, water-soluble or water-swellable inert cores are made up of sugar, microcrystalline cellulose, cellulose starch, modified starch, or mixtures thereof. Preferably, the inert core is made of microcrystalline cellulose. Additionally, the size (i.e. diameter) of the inert core is from 400 to 900 mhh, preferably from 500 to 800 mpΊ.
As mentioned above, the drug layer over the inert cores comprises quetiapine fumarate and one hydrophilic polymer. Optionally, the drug coating layer comprises other pharmaceutically acceptable excipients. Non-limiting examples of suitable pharmaceutically acceptable excipients that can be used include plasticizers and lubricants. Thus, in one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the drug layer further comprises one or more pharmaceutically acceptable excipients or carriers, more particularly it comprises one or more plasticizers and one or more lubricants or anti-tacking agents.
In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the drug layer over the inert core does not comprise other coating polymers apart from the hydrophilic polymer. Thus, in this embodiment, the drug layer over the inert core is free from other coating polymers.
Hydrophilic/water-soluble/swellable polymers act as binders. Hydrophilic polymers to be used in the present invention include hydroxypropyl methylcellulose (hypromellose) having a low apparent viscosity (e.g., HPMC E3, E5, E6 or E15), polyvinyl pyrrolidone (povidone) or mixtures thereof. In particular, the hydrophilic polymer is a cellulose based polymer. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the hydrophilic polymer is selected from the group consisting of hydroxypropyl methylcellulose, polyvinyl pyrrolidone, and mixtures thereof, more preferably, the hydrophilic polymer is hydroxypropyl methylcellulose.
In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the weight to weight ratio (w/w) between the hydrophilic polymer to the active ingredient (quetiapine fumarate) in the drug layer is from 0.05:1 to 0.50:1 , more particularly from 0.10:1 to 0.45:1 , even more particularly from 0.35:1 to 0.40:1 , and even more particularly is 0.35:1 or 0.40:1 .
In a preferred embodiment, optionally in combination with one or more features of the various embodiments described above or below, the weight to weight ratio (w/w) between the hydrophilic polymer to the active ingredient (quetiapine fumarate) in the drug layer is equal to or more than 0.35.
As mentioned above, plasticizers may be comprised in the drug layer. Exemplary of plasticizers that may be employed in this invention are without limitation triethyl citrate (TEC), triacetin, tributyl citrate, acetyl triethyl citrate (ATEC), acetyl tributyl citrate (ATBC), dibutyl phthalate, dibutyl sebacate (DBS), diethyl phthalate, vinyl pyrrolidone glycol triacetate, polyethylene glycol, polyoxyethylene sorbitan monolaurate, propylene glycol, propylene carbonate or castor oil; and combinations or mixtures thereof. The amount of plasticizers in the drug layer composition may be from about 0.5 to about 10, more particularly from about 0.5 to about 5, percent by weight of the total drug layer composition. In a preferred embodiment of the present invention, the plasticizer is triethyl citrate.
Anti-tacking agents or processing lubricants may be also comprised in the drug layer. Exemplary agents and lubricants include stearyl alcohol, stearic acid, glycerol monostearate (GMS), talc, magnesium stearate, silicon dioxide, amorphous silicic acid, and fumed silica; and combinations or mixtures thereof. The amount of anti-tacking agent or processing lubricant may be from about 0.1 percent to about 10, more particularly from about 0.1 to about 5, percent by weight of the composition (i.e. weight of the discrete unit). In a preferred embodiment of the present invention, the anti-tacking agent is talc.
In one particular embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the immediate release quetiapine fumarate coated discrete units of the invention quetiapine fumarate are in the form of particles having a particle size distribution wherein approximately 90% by volume of the particles (d90) have a diameter equal to or below 20 pm (d90<20 pm), preferably equal to or below 15 pm (d90<15 pm), and more preferably equal to or below 10 pm (d90<10 pm). As used herein d90<x means that at least 90% by volume of the particles have a particle size equal to or below x. The particle size can be determined by laser light scattering for instance using a Malvern Mastersizer Apparatus MS 2000 equipped with a Hydro S dispersion unit. Silicon fluid F10 may be used as dispersion medium. Micronized active ingredient, preferably quetiapine fumarate, according to the present invention means the active substance having d90 equal to or less than 10 pm. The micronized active ingredient to be used in the present invention may be obtained by means of any micronization or comminution process of reducing primary or crystalline particle size by any method known from the state of the art such as for example dry or wet mills such as for example air jet and/or ball milling, high shear mill or high pressure homogenizer or dry mills such as cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills and ball mills or Hosokawa Alpine agitated ball mill, ultrasound processors, or wet mills such as Hielscher ultrasonic processor, and in particular high shear mixers and colloid mills, such as Turrax and colloid mills produced by Fryma.
It has now been found that by processing quetiapine fumarate, to bring their particle size within a specified narrow range, pharmaceutical compositions may be prepared which exhibit for their active ingredient both a consistent in vitro dissolution profile and in vivo bioavailability. In addition to bringing about these desired dissolution/bioavailability characteristics, the control of particle size to a narrow range has also resulted in significant improvements in manufacturing capabilities.
In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the immediate release quetiapine fumarate coated discrete units of the invention, the weight to weight ratio (w/w) between the hydrophilic polymer to the active ingredient in the drug layer is from 0.05:1 to 0.50:1 ; and the quetiapine fumarate used is in the form of particles having d90<20 pm, more particularly d90<15 pm, and even more particularly d90<10 pm.
In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the immediate release quetiapine fumarate coated discrete units of the invention the weight to weight ratio (w/w) between the hydrophilic polymer to the active ingredient (quetiapine fumarate) in the drug layer is from 0.10:1 to 0.45:1 ; and the quetiapine fumarate used is in the form of particles having d90<20 pm, more particularly d90<15 pm, and even more particularly d90<10 pm.
In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the immediate release quetiapine fumarate coated discrete units of the invention the weight to weight ratio (w/w) between the hydrophilic polymer to the active ingredient (quetiapine fumarate) in the drug layer is equal to or more than 0.35; and the quetiapine fumarate used is in the form of particles having d90<20 pm, more particularly d90<15 pm, and even more particularly d90<10 pm.
In one particular embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the immediate release quetiapine fumarate coated discrete units of the invention, the weight gain of the drug layer with respect to the inert core (i.e., the ratio of (i) the weight of the drug layer to (ii) the weight of the inert core prior to the drug layer’s addition) is from 15% to 30%, preferably from 15% to 25%. Most preferably, the drug layer presents a weight gain of from 20% to 25%.
According to another embodiment of this aspect, the coated discrete units are coated with an outer layer, more particularly an outer protective coating layer, disposed over the drug- layer. This outer layer, which may comprise at least one polymer, is free from any active ingredient and, in addition to the coating polymer, it may optionally include other pharmaceutically acceptable excipients, in particular, plasticizers, pigments and/or anti- tacking agents. Anti-tacking agents or processing lubricants may be also comprised in the drug layer. Exemplary agents and lubricants include stearyl alcohol, stearic acid, glycerol monostearate (GMS), talc, magnesium stearate, silicon dioxide, amorphous silicic acid, and fumed silica; and combinations or mixtures thereof. The amount of anti-tacking agent or processing lubricant may be from about 0.1 percent to about 10, more particularly from about 0.1 to about 5, percent by weight of the composition (i.e. weight of the discrete unit). In a preferred embodiment of the present invention, the anti-tacking agent is talc. The drug layer and the outer layer may be formed of the same or different polymers.
The outer coating of the pellet composition substantially (i.e. equal or more than 90% of the total surface) entirely covers the drug coating of each individual unit. This prevents direct contact between individual units, assists in protecting the integrity of the drug coating of the units, increases flowability, prevents segregation, and provides excellent protection against humidity. Additionally, the outer coating enables a good in vitro dissolution rate.
In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the outer layer is free from any extended release polymers.
In a particular embodiment, optionally in combination with one or more features of the various embodiments described above or below, the outer coating of the present invention comprises commercially available coating compositions comprising film-forming polymers marketed under various trade names such as Opadry® manufactured by Colorcon. This coating contains polymers, plasticizers and pigments.
According to a particular embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the immediate release quetiapine fumarate coated discrete units of the invention, the weight gain of the outer layer, more particularly the outer protective layer, with respect to the drug-coated inert cores (i.e., the ratio of (i) the weight of the outer layer to (ii) the weight of the drug-coated inert cores prior to the outer layer’s addition) is from 1 % to 20% (e.g., 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1 1 %, 12%, 13%, 14%, 15%, 16%, 17%, 17.5%, 18%, 19%, or 20%), and preferably from 5% to 10% (e.g., 5%, 6%, 7%, 8%, 9% or 10%) .
In a particular embodiment, optionally in combination with one or more features of the various embodiments described above or below, the outer-layer coated discrete units have an average size which is in the range from about 0.2 mm to about 2 mm, in particular from about 0.5 mm to about 1 .5 mm. Size in this respect is determined by whether a pellet passes through, or is retained, as a result of agitation on a sieve or screen having a mesh opening size as stated. If the pellet passes through the sieve or screen, it is described as having a size which is equal to or less than that of the mesh opening, and if the pellet is retained, it is described as having a size that is greater than the mesh opening.
In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the outer-layer coated discrete units are free from any extended release polymers.
According to another embodiment of this aspect, the outer-layer coated discrete units and optionally one or more excipients or carriers, such as a lubricant have the suitable flowability to be encapsulated. For the purposes of the invention, the desired flowability is defined as no clogging or aggregation is observed while the dispersion flows through the feeding tube.
Another embodiment of the present invention provides immediate release quetiapine fumarate coated discrete units having d90 value between about 0.2 mm and 1.2 mm, wherein the coated discrete units, after being dispersed in an aqueous media and delivered through a feeding tube size NLT 10 F, at least 85% of quetiapine fumarate was recovered at the exit of the feeding tube after holding for 10 minutes.
According to one embodiment of this aspect, the coated discrete units are in the form of plurality of pellets, granules, minitablets, or beads.
In a further embodiment of the invention, optionally in combination with one or more features of the various embodiments described above or below, the coated discrete units can be applied in the formulation as tablets, ODT (Orally dispersable tablets), MUPS (Multiple Unit Pellet System), capsules, caplets, sachets or other solid dosage forms of an active ingredient having stability problems. Preferably, the solid dosage form is a capsule.
According to another embodiment of this aspect, when the immediate release quetiapine fumarate coated discrete units of the invention are contained in a capsule dosage form, the coated discrete units are optionally lubricated before filling into the capsule. Thus, it also forms part of the invention a capsule containing the coated discrete units of the invention and a lubricant.
In a preferred embodiment, the lubricant is preferably selected from sodium stearylfumarate, magnesium stearate, hydrogenated vegetable oil, stearic acid, calcium stearate, glyceryl behenate, sodium lauryl sulphate and talc, the latter being preferred. The combination of above-mentioned lubricants can also be used. Typically the lubricant(s) is present in less than 5% by weight with respect to the total weight of the composition.
The immediate release composition of the invention is stable when subjected to stability conditions of 40 °C and 75% Relative Humidity (RH) for 6 months. Further, the coated discrete units are stable when sprinkled onto soft foods of different pH levels for at least 60 minutes. Also, the dispersion of the multiparticulate pellets in an aqueous media is stable when administered in a feeding tube after holding for at least 10 minutes.
Manufacturing process
The process for the manufacture of the immediate release quetiapine fumarate coated discrete units of the invention represents a further aspect of the invention. The mentioned formulations will be prepared using standard methods such as those described or referred to in the art. The pharmaceutical processes can preferably be completely water-based.
The method for the preparation of the immediate release quetiapine fumarate coated discrete units according to the invention comprises the steps of:
a) coating inert cores with a solution or dispersion comprising quetiapine fumarate and a hydrophilic polymer to obtain drug-layer coated cores; and b) coating the drug-layer coated cores of step a) with a solution or dispersion of a polymer to obtain outer-layer coated units.
When the immediate release quetiapine fumarate coated discrete units of the invention are contained in a capsule dosage form, then the process for the preparation of the resulting immediate release capsule of the invention comprises the steps of:
a) coating inert cores with a solution or dispersion comprising quetiapine fumarate and a hydrophilic polymer to obtain drug-layer coated cores;
b) coating the drug-layer coated cores of step a) with a solution or dispersion of a polymer to obtain outer-layer coated units,
c) blending the coated units of step b) optionally with lubricant; and
d) filling the blend c) into suitable capsules.
Use of the pharmaceutical composition Another aspect of the invention relates to the immediate release quetiapine fumarate coated discrete units according to the invention for use in the treatment of schizophrenia, wherein the treatment comprises administering the said immediate release quetiapine fumarate coated discrete units. Another aspect of the invention relates to the use of quetiapine fumarate for the preparation of immediate release coated discrete units as defined above for the treatment of schizophrenia. It also forms part of the invention a method for the treatment of schizophrenia, comprising administering the immediate release quetiapine fumarate coated discrete units as defined above.
Another aspect of the invention relates to the immediate release capsule according to the invention for use in the treatment of schizophrenia, wherein the treatment comprises administering the said immediate release capsule.
Another aspect of the invention relates to the use of quetiapine fumarate for the preparation of the immediate release capsule as defined above for the treatment of schizophrenia.
It also forms part of the invention a method for the treatment of schizophrenia, comprising administering the immediate release capsule as defined above.
Another aspect of the invention refers to the immediate release quetiapine fumarate coated discrete units of the invention or a capsule comprising them, which comprises 12.5 mg of quetiapine calculated on quetiapine base, for use as a medicament.
Another aspect of the invention refers to the immediate release quetiapine fumarate coated discrete units of the invention or a capsule comprising them, which comprises 25 mg of quetiapine calculated on quetiapine base, for use as a medicament.
Another aspect of the invention refers to the immediate release quetiapine fumarate coated discrete units of the invention or a capsule comprising them, which comprises 50 mg of quetiapine calculated on quetiapine base, for use as a medicament.
Throughout the description and claims the word "comprise" and variations of the word, are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word “comprise” encompasses the case of “consisting of”. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples and drawings are provided by way of illustration, and they are not intended to be limiting of the present invention. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein.
Examples
Example 1. Immediate release capsules of quetiapine fumarate Immediate release quetiapine hard gelatine capsules composed by coated discrete units were prepared. The final developed composition per strength is the following:
Component For 25 mg dose (mg) For 12.5 mg dose (mg)
Figure imgf000015_0008
Quetiapine fumarate micronized 28.78 14.39
Hypromellose 3CP (Methocel E3) 1 1.51 5.76
Talc micronized 2.30 1.15
Triethylcitrate 2.30 1.15
Purified water 180.00 90.00
End of FC1
Figure imgf000015_0001
254.89
Figure imgf000015_0002
127.45
Figure imgf000015_0003
Opadry 03B34367 pink 50.97 25.49
Purified water 457.00 228.50
End of FC2
Figure imgf000015_0004
305.86
Figure imgf000015_0005
152.93
Figure imgf000015_0006
Talc micronized 0.92 0.46
Figure imgf000015_0007
Opadry is a commercial one-step film coating system which combines polymer, plasticizer and pigment (in this case: HPMC, Titanium dioxide, PEG 400, Iron oxide red, Iron oxide yellow)
Manufacturing procedure:
1. Preparation of the first film coating (FC1 ) solution: hypromellose is dispersed in hot water (>60 °C). Once the temperature is about 20-30 °C, triethyl citrate, Quetiapine fumarate and talc are incorporated. The FC1 dispersion is stirred during the spraying process described in the next step of the process (step 2 below).
2. Spraying of FC1 : the inert cores of microcrystalline cellulose are charged in the fluid bed system (bottom spraying wurster) and adequate air volume pressure (from 1 to 1.5 bar) is applied to move the pellets inside. Pellets are heated using the needed inlet air temperature to achieve a product temperature about 47 °C. Then the spraying process with the first film coating solution (FC1 ) is started using an adequate spraying pressure (from 1 to 3 bar) and the flow rate is adjusted to maintain the product temperature constant between 41-45 °C.
3. Drying of FC1 : once the spraying process is finished (all the FC1 dispersion has been applied) the pellets are dried until reach a product temperature of 47 °C. After that, the inlet air temperature is turned off and the final FC1 pellets are discharged when the product temperature is < 30 °C.
4. Preparation of the second film coating (FC2) solution: Opadry® is dispersed in water (20-30°C), and stirred during 45-60 min before starting the spraying process of step
5.
5. Spraying of FC2: the FC1 pellets obtained in step 3 are charged in the fluid bed system (bottom spraying wurster) and adequate air volume pressure (from 1 to 1.5 bar) is applied to move the pellets inside. Pellets are heated using the needed inlet air temperature to achieve a product temperature about 47 °C. Then the spraying process with the second film coating solution (FC2) is started using an adequate spraying pressure (from 1 to 3 bar) and the flow rate is adjusted to maintain the product temperature constant between 41 -45 °C.
6. Drying of FC2: once the spraying process of step 5 is finished (all the FC2 dispersion has been applied), the pellets are dried until reach a product temperature of 47°C. After that, the inlet air temperature is turned off and the final FC2 pellets are discharged when the product temperature is < 30 °C.
7. Blending of the pellets obtained in the previous step with 0.3 % of talc micronized.
8. Encapsulation process: the blend obtained in the previous step is encapsulated using a dosing-chamber device in tamping-pin encapsulation equipment. The amount of pellets to fill into the capsules is adjusted accordingly for each strength. Capsule size for 25 mg strength is n°2 and for 12.5 mg strength is n°4.
Example 2. Effect of the amount of the hydrophilic polymer
Several batches were manufactured to analyse the effect of the hydrophilic polymer amount in the yield of the FC1 coating process. The tested batches were prepared as described in example 1 (steps 1 -3 where identical) where the amounts of hydrophilic polymer (hypromellose) were changed, while the amounts of triethyl citrate and talc were the same as example 1 .
FC1 Yield (%)
Batch number Ratio API:HPMC
Spec: 95.0-100.0%
Figure imgf000016_0003
Figure imgf000016_0001
Figure imgf000016_0002
API = Quetiapine fumarate
The results showed that using a weight ratio of the hydrophilic polymer to the quetiapine fumarate equal or higher than 0.35 resulted in a consistently good yield of the FC1 process of 95% or more. Example 3: Effect of the particle size of quetiapine fumarate
Some batches of pellets were manufactured to analyze the effect of the particle size of the quetiapine in the coating. The tested batches were prepared as described in example 1 and differed on the particle size of the API and the ratio API: hydrophilic polymer as shown in the table below.
Assay (%)
Batch number Ratio API:HPMC API d90pm
Spec: 90.0-110.0%
06 1 :0.40 Milled (d90>20pm) 78.8
Figure imgf000017_0003
08 1 :0.40 Micronized (d90£10pm) 97.5
Figure imgf000017_0004
The use of micronized API consistently showed assay values (% of quetiapine finally absorbed in the pellet) within specifications.
Example 4: Effect of the outer protective layer (FC2) on the dissolution profile
The effect of the outer protective layer (FC2) on the dissolution profile was studied. The tested batches were prepared as described in example 1 and differed on the amount of outer protective layers shown in the following table:
Figure imgf000017_0001
The qualitative-quantitative composition of the outer protective layer in the different batches was the following:
Figure imgf000017_0005
Opadry pink 03B34367 12.75 38.23 25.49 44.61 50.97
- HPMC 7.97 23.90 15.93 27.88 31.86
- Titanium dioxide 3.75 11.24 7.50 13.12 14.99
- PEG 400 0.80 2.39 1.60 2.79 3.19
- Iron oxide red 0.12 0.35 0.24 0.41 0.47
- Iron oxide yellow 0.12 0.35 0.23 0.40 0.46 Purified water 114.32 342.77 228.54 399.98 457.00
Figure imgf000017_0002
Once coated, the final coated discrete units were blended with lubricant and encapsulated to obtain a capsule dosage form containing 25 mg of quetiapine. Dissolution profiles obtained from the resulting capsules compared with RLD (Seroquel®) are shown in the next table and graph. Dissolution method is done using the USP Apparatus II (paddles at 50 rpm) and dissolution media is buffer at pH 1.2 (500 ml_).
Figure imgf000018_0017
Coated discrete units comprising a weight percentage of the outer protective layer of 10% or less show a dissolution profile where at least 80% of the active agent is released in 15 minutes.
Example 5. Immediate release capsules of quetiapine fumarate
Immediate release quetiapine hard gelatin capsules composed by coated discrete units were prepared. The final developed composition per strength is the following:
For 50 mg For 25 mg For 12.5 mg
Component
dose (mg) dose (mg) dose (mg)
Spheres MCC (CP-507)
Figure imgf000018_0001
420.00
Figure imgf000018_0002
210.00
Figure imgf000018_0003
105.00
Figure imgf000018_0004
Quetiapine fumarate micronized 57.56 28.78 14.39
Hypromellose 3CP (Methocel E3) 23.02 1 1.51 5.76
Talc micronized 4.60 2.30 1 .15
Triethylcitrate 4.60 2.30 1 .15
Purified water 360.00 180.00 90.00
End of FC1
Figure imgf000018_0005
509.78
Figure imgf000018_0006
254.89
Figure imgf000018_0007
127.45
Figure imgf000018_0008
Hypromellose 15CP 40.78 20.39 10.20
Talc micronized 8.16 4.08 2.04
Purified water 774.80 387.40 193.70
End of FC2
Figure imgf000018_0009
558.72
Figure imgf000018_0010
279.36
Figure imgf000018_0011
139.68
Figure imgf000018_0012
Talc micronized 1 .68 0.84 0.42
TOTAL
Figure imgf000018_0013
560.40
Figure imgf000018_0014
280.20
Figure imgf000018_0015
140.10
Figure imgf000018_0016
Manufacturing procedure:
1 . Preparation of the first film coating (FC1 ) solution: hypromellose is dispersed in hot water (>60 °C). Once the temperature is about 20-30 °C, triethyl citrate, Quetiapine fumarate and talc are incorporated. The FC1 dispersion is stirred during the spraying process described in the next step of the process (step 2 below). 2. Spraying of FC1 : the inert cores of microcrystalline cellulose are charged in the fluid bed system (bottom spraying wurster) and adequate air volume pressure (from 1 to 1.5 bar) is applied to move the pellets inside. Pellets are heated using the needed inlet air temperature to achieve a product temperature about 47 °C. Then the spraying process with the first film coating solution (FC1 ) is started using an adequate spraying pressure (from 1 to 3 bar) and the flow rate is adjusted to maintain the product temperature constant between 41-45 °C.
3. Drying of FC1 : once the spraying process is finished (all the FC1 dispersion has been applied) the pellets are dried until reach a product temperature of 47 °C. After that, the inlet air temperature is turned off and the final FC1 pellets are discharged when the product temperature is < 30 °C.
4. Preparation of the second film coating (FC2) suspension: hypromellose is solubilized in hot water (>60 °C). Once the temperature is about 20-30 °C, stirr during 45-60 min until the hypromellose is completely dissolved. A suspension of talc micronized is prepared, adding the talc to some amount of water and stirred during 15 minutes. The talc micronized dispersion is added over the solution of hypromellose previously prepared. The FC2 dispersion is stirred during the spraying process described in the next step of the process (step 5 below).
5. Spraying of FC2: the FC1 pellets obtained in step 3 are charged in the fluid bed system (bottom spraying wurster) and adequate air volume pressure (from 1 to 1.5 bar) is applied to move the pellets inside. Pellets are heated using the needed inlet air temperature to achieve a product temperature about 47 °C. Then the spraying process with the second film coating dispersion (FC2) is started using an adequate spraying pressure (from 1 to 3 bar) and the flow rate is adjusted to maintain the product temperature constant between 41-45 °C.
6. Drying of FC2: once the spraying process of step 5 is finished (all the FC2 dispersion has been applied), the pellets are dried until reach a product temperature of 47°C. After that, the inlet air temperature is turned off and the final FC2 pellets are discharged when the product temperature is < 30 °C.
7. Blending of the pellets obtained in the previous step with 0.3 % of talc micronized.
8. Encapsulation process: the blend obtained in the previous step is encapsulated using a dosing-chamber device in tamping-pin encapsulation equipment. The amount of pellets to fill into the capsules is adjusted accordingly for each strength. Capsule size for 25 mg strength is n°2, for 12.5 mg strength is n°4 and for 50 mg is n°0.
Example 6: Effect of the outer protective layer (FC2) on the dissolution profile The effect of the outer protective layer (FC2) on the dissolution profile was studied. The tested batches were prepared as described in example 5 and differed on the amount of outer protective layers shown in the following table:
Figure imgf000020_0002
The qualitative-quantitative composition of the outer protective layer in the different batches was the following:
Figure imgf000020_0003
Hypromellose 15CP 20.39 25.49 30.59
Talc micronized 4.08 5.10 6.12
Purified water 387.40 484.29 581.18
Figure imgf000020_0004
Once coated, the final coated discrete units were blended with lubricant and encapsulated to obtain a capsule dosage form containing 25 mg of quetiapine. Dissolution profiles obtained from the resulting capsules compared with RLD (Seroquel®) are shown in the next table and graph. Dissolution method is done using the USP Apparatus II (paddles at 50 rpm) and dissolution media is buffer at pH 1.2 (500 ml_).
Time Seroquel 1703- 1703- 1703-
(min) © tablets 01G57 9.6% 01G57 12% 01G57 14.4%
Figure imgf000020_0001
All coated discrete units show a dissolution profile where at least 80% of the active agent is released in 45 minutes. For reasons of completeness, various aspects of the invention are set out in the following numbered clauses:
Clause 1 . Immediate release coated discrete units, each discrete unit comprising: a) an inert core, b) a drug layer over the inert core comprising quetiapine fumarate and one hydrophilic polymer, and c) an outer layer.
Clause 2. The immediate release coated discrete units according to clause 1 , wherein the weight ratio of the hydrophilic polymer to the quetiapine fumarate in the drug layer is equal to or more than 0.35.
Clause 3. The immediate release coated discrete units according to any of the clauses 1 -2, wherein the hydrophilic polymer is selected from the group consisting of hydroxypropyl methylcellulose, polyvinyl pyrrolidone, and mixtures thereof.
Clause 4. The immediate release coated discrete units according to any of the clauses 1 -3, wherein the drug layer further comprises one or more plasticizers and one or more lubricants.
Clause 5. The immediate release coated discrete units according to any of clauses 1 to 4, wherein quetiapine fumarate is in the form of particles having a particle size distribution wherein approximately 90% by volume of the particles have a diameter (d90) equal to or below 10 mpΊ.
Clause 6. The immediate release coated discrete units according to any of the clauses 1 to
5, wherein the outer protective layer further comprises plasticizers and optionally pigments.
Clause 7. The immediate release coated discrete units according to any of the clauses 1 to
6, wherein the inert core is made up of sugar, microcrystalline cellulose, cellulose starch, modified starch, or mixtures thereof.
Clause 8. The immediate release coated discrete units according to any of the clauses 1 to
7, wherein the weight gain of the outer layer with respect to the drug-coated inert cores is equal to or less than 15%.
Clause 9. The immediate release coated discrete units according to any of the clauses 1 to
8, wherein the weight gain of the drug layer with respect to the inert core is from 15% to 30%.
Clause 10. The immediate release coated discrete units according to any of the clauses 1 to 9, wherein each coated discrete unit has a d90 value of from about 0.2 mm to 1 .2 mm. Clause 1 1. The immediate release coated discrete units according to any of the clauses 1 to 10, which comprises 12.5 mg or 25 mg of quetiapine calculated on quetiapine base.
Clause 12. The immediate release coated discrete units according to any of the clauses 1 to 1 1 , which are comprised within a capsule.
Clause 13. The immediate release capsule according to any of the clauses 12, wherein the capsule is a sprinkle capsule. Clause 14. A method for the preparation of the immediate release coated discrete units as defined in any of the clauses 1 to 13, the method comprising the steps of:
a) coating inert cores with a solution or dispersion comprising quetiapine fumarate and a hydrophilic polymer to obtain drug-layer coated cores; and
b) coating the drug-layer coated cores of step a) with a solution of dispersion of a polymer to obtain outer-layer coated units.
Clause 15. Immediate release coated discrete units as defined in any of the clauses 1-13, for use in the treatment of schizophrenia.

Claims

Claims
1. Immediate release coated discrete units, each discrete unit comprising: a) an inert core, b) a drug layer over the inert core comprising quetiapine fumarate and one hydrophilic polymer, and c) an outer layer, wherein the weight ratio of the hydrophilic polymer to the quetiapine fumarate in the drug layer is equal to or more than 0.35.
2. The immediate release coated discrete units according to claim 1 , wherein the hydrophilic polymer is selected from the group consisting of hydroxypropyl methylcellulose, polyvinyl pyrrolidone, and mixtures thereof.
3. The immediate release coated discrete units according to any of the claims 1 to 2, wherein the drug layer further comprises one or more plasticizers and one or more lubricants.
4. The immediate release coated discrete units according to any of the claims 1 to 3, wherein quetiapine fumarate is in the form of particles having a particle size distribution wherein approximately 90% by volume of the particles have a diameter (d90) equal to or below 10 mpΊ.
5. The immediate release coated discrete units according to any of the claims 1 to 4, wherein the outer layer further comprises plasticizers, pigments, and/or anti-tacking agents or processing lubricants.
6. The immediate release coated discrete units according to any of the claims 1 to 5, wherein the anti-tacking agent or processing lubricant is talc.
7. The immediate release coated discrete units according to any of the claims 1 to 6, wherein the inert core is made up of sugar, microcrystalline cellulose, cellulose starch, modified starch, or mixtures thereof.
8. The immediate release coated discrete units according to any of the claims 1 to 7, wherein the weight gain of the outer layer with respect to the drug-coated inert cores is equal to or less than 15%.
9. The immediate release coated discrete units according to any of the claims 1 to 8, wherein the weight gain of the drug layer with respect to the inert core is from 15% to 30%.
10. The immediate release coated discrete units according to any of the claims 1 to 9, wherein each coated discrete unit has a d90 value of from about 0.2 mm to 1.2 mm.
1 1. Immediate release dosage form comprising the coated discrete units according to any of the claims 1 to 10, which comprises 12.5 mg or 25 mg or 50 mg of quetiapine calculated on quetiapine base.
12. The immediate release dosage form according to claim 11 , which is a capsule.
13. The immediate release capsule according to claims 12, wherein the capsule is a sprinkle capsule.
14. A method for the preparation of the immediate release coated discrete units as defined in any of the claims 1 to 10, the method comprising the steps of:
b) coating inert cores with a solution or dispersion comprising quetiapine fumarate and a hydrophilic polymer to obtain drug-layer coated cores; and
c) coating the drug-layer coated cores of step a) with a solution of dispersion of a polymer to obtain outer-layer coated units.
15. Immediate release coated discrete units as defined in any of the claims 1 -10, for use in the treatment of schizophrenia.
PCT/EP2019/070433 2018-07-31 2019-07-30 Solid dosage form of quetiapine fumarate WO2020025579A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0240228A1 (en) 1986-03-27 1987-10-07 Ici Americas Inc. Thiazepine compounds
WO2005041935A1 (en) * 2003-10-21 2005-05-12 Alpharma, Inc. Pharmaceutical formulations containing quetiapine
US20090220593A1 (en) * 2008-01-29 2009-09-03 Gulati Inder Extended release dosage forms of quetiapine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0240228A1 (en) 1986-03-27 1987-10-07 Ici Americas Inc. Thiazepine compounds
WO2005041935A1 (en) * 2003-10-21 2005-05-12 Alpharma, Inc. Pharmaceutical formulations containing quetiapine
US20090220593A1 (en) * 2008-01-29 2009-09-03 Gulati Inder Extended release dosage forms of quetiapine

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