WO2013095314A1 - Formulations pharmaceutiques comprenant de la rispéridone - Google Patents

Formulations pharmaceutiques comprenant de la rispéridone Download PDF

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Publication number
WO2013095314A1
WO2013095314A1 PCT/TR2012/000218 TR2012000218W WO2013095314A1 WO 2013095314 A1 WO2013095314 A1 WO 2013095314A1 TR 2012000218 W TR2012000218 W TR 2012000218W WO 2013095314 A1 WO2013095314 A1 WO 2013095314A1
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WO
WIPO (PCT)
Prior art keywords
risperidone
granules
active agent
excipient
optionally
Prior art date
Application number
PCT/TR2012/000218
Other languages
English (en)
Inventor
Mahmut Bilgic
Original Assignee
Mahmut Bilgic
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mahmut Bilgic filed Critical Mahmut Bilgic
Publication of WO2013095314A1 publication Critical patent/WO2013095314A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • 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

Definitions

  • the present invention relates to pharmaceutical formulations comprising risperidone that shall be used in treatment of schizophrenia, affective symptoms related to schizophrenia, manic episodes of bipolar disorder and unease associated with autistic disorder.
  • Risperidone was first disclosed in the application numbered EP 196132. In said document, it was disclosed that risperidone is effective in treatment of psychotic disorders.
  • Risperidone is available in form of effervescent tablet, film tablet, orodispersible tablet of 0,5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 6 mg; oral solution of 1 mg/ml and injection vial of 25 mg, 37,5 mg, 50 mg on the market.
  • formulation mixtures do not have proper flow due to the reasons that free flow of the obtained granules cannot be enabled and/or possible friction between granule particles cannot be reduced, therefore homogeneity cannot be provided in the pharmaceutical composition obtained and the mixture loses its homogeneity during preparation of the formulations comprising risperidone. Therefore, the abovementioned problems cause weight changes in the end product and increase in relative standard deviation values during forming the formulations into any dosage form. Weight and content uniformity cannot be provided in the end product due to these variations observed in weight of the end product obtained and failure to ensure formulation homogeneity. This situation poses problems for producers during production and quality control phases and also patients cannot take same amount of drug during the treatment, which results in decrease in treatment efficiency due to loss of weight and content uniformity observed in the dosage forms obtained.
  • the present invention relates to pharmaceutical formulations comprising risperidone and methods for preparation of these formulations.
  • the formulations wherein the granules comprising risperidone, at least one excipient and optionally a second active agent and having an average particle size in the range of 300- 2500 ⁇ , preferably in the range of 350-2000 ⁇ , more preferably in the range of 500-1750 ⁇ are formed into any solid dosage form, relative standard deviation thereof remains low, a homogeneous pharmaceutical composition is obtained, weight and content uniformity are provided by preventing weight changes.
  • the subject of the present invention is that the average particle size of the granules comprising risperidone, at least one excipient and optionally a second active agent is in the range of 300-2500 ⁇ , preferably in the range of 350-2000 ⁇ , more preferably in the range of 500-1750 ⁇ during preparation of the formulations comprising risperidone.
  • the term "average particle size" refers to volumetric average particle size and is shown with d 5 o in short. In this sense, the term d 5 o signifies that half of the said substance by volume has a particle size above the value stated with d 50 and the other half of the substance by volume has a particle size below the value stated with d 50.
  • D 50 value can be measured by one of the known measuring devices, for instance by a device measuring particle distribution by laser diffraction (for instance, Malvern Mastersizer etc.).
  • the pharmaceutical formulations prepared according to the process of the present invention can comprise various excipients in addition to the active agent risperidone.
  • the pharmaceutical formulations prepared according to the process of the present invention and comprising risperidone comprise at least one excipient selected from a group comprising disintegrant, diluent, lubricant, glidant, binder, effervescent couple comprising effervescent acid and effervescent base, colouring agent, pH regulating agent, surfactant, antiadherant, stabilizing agent, sweetener and/or taste regulating agent, flavouring agent.
  • the granules should not agglomerate during their preparations.
  • the inventors have observed that when the granules comprise risperidone, effervescent acid, effervescent base and taste regulating agent, the granules do not agglomerate during the preparation of the effervescent formulation and a more homogeneous effervescent formulation is obtained, resulting in a rapid dispersion in water and an effective treatment.
  • the present invention relates to a process that shall be used in production of granules having an average particle size in the range of 300-2500 ⁇ , preferably in the range of 350-2000 ⁇ , more preferably in the range of 500-1750 ⁇ characterized in that said granules comprise risperidone, effervescent acid, effervescent base and taste regulating agent.
  • the present invention relates to a process that shall be used in production of granules having an average particle size in the range of 300-2500 ⁇ , preferably in the range of 350-2000 ⁇ , more preferably in the range of 500-1750 ⁇ which comprise risperidone, at least one excipient and optionally a second active agent characterized in that said granules having an average particle size in the range of 300-2500 ⁇ , preferably in the range of 350- 2000 ⁇ , more preferably in the range of 500-1750 ⁇ are obtained by
  • grinding is performed by the effect of rotating hammers in the device.
  • grinding is performed by providing collision of the particles with each other with the help of high-pressured and high-speed airstream.
  • the pharmaceutical formulation of the present invention can be obtained by a method comprising the steps of; • Homogeneously mixing the granules obtained after granulating the active agent risperidone and, if available, the second active agent with the granulation solution comprising at least one of the excipients and drying the mixture obtained; if required, bringing it to an average particle size in the range of 300-2500 ⁇ by an appropriate method and optionally treating it with at least one other excipient or
  • the pharmaceutical formulation of the present invention is preferably obtained by a method comprising the steps of;
  • Step II drying and then sieving the granules obtained in Step I bringing them to an average particle size in the range of 300-2500 ⁇ ,
  • Step III mixing the granules obtained in Step II with risperidone active agent and then adding sweetener, flavouring agent and lubricant into the mixture obtained and
  • the inventors have also observed that in the case that the granules obtained in Step II is mixed with risperidone active agent portion by portion, a homogenous risperidone formulation is obtained, high solubility of risperidone and rapid dispersion of the formulation are provided, resulting in a more effective treatment.
  • the present invention relates to a process for the preparation of the quetiapine formulation wherein 50% of the amount of the granules obtained in Step II is firstly mixed with the risperidone active agent, the mixture is stirred for 0.2- 4, preferably 0.5- 2.5 minutes and then rest of the granules is added to the obtained mixture.
  • the parameters such as drying temperature and moisture content of the obtained granules are important for obtaining optimum values of hardness, brittleness and stability of the granules obtained during preparation of the formulations comprising risperidone and the end product in solid form prepared with the said granules and therefore important for preventing possible problems that can be encountered during quality control and using phases.
  • the present invention relates to drying the granules comprising risperidone, at least one excipient and optionally the second active agent in the manner that they have moisture content less than 1% by weight, preferably in the range of 0,1-0,9% by weight during preparation of the formulations comprising risperidone.
  • Risperidone comprised in the pharmaceutical formulations prepared according to the process of the present invention is in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof in terms of chemical structure; in terms of polymorphic structure, it is in amorphous form or crystalline form or the combination thereof.
  • the pharmaceutical formulations prepared according to the process of the present invention and comprising risperidone can be prepared in any solid dosage form such as tablet, effervescent tablet, effervescent granule, effervescent dry powder, film coated tablet, enterically coated tablet, dry powder, granule, capsule, prolonged release tablet, modified release tablet, delayed release tablet.
  • the pharmaceutical formulations prepared according to the process of the present invention and comprising risperidone are preferably in powder, tablet and granule forms, more preferably in film coated tablet or effervescent tablet forms.
  • the pharmaceutical formulation obtained according to the present invention can be formed into any abovementioned dosage forms.
  • the tablets obtained can be treated with film coating agents, for instance sugar based coating agents, water soluble film coating agents, enteric coating agents, delayed release coating agents or coating compositions comprising a combination thereof.
  • saccharose can be used singly or optionally with any of the agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatine, gum arabic, polyvinylpyrrolidone and pullulan or a combination thereof.
  • the enteric coating agents can be selected from cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate; acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S and natural substances such as shellac or combinations thereof.
  • cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate
  • acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S and natural substances such as shellac or combinations thereof.
  • the delayed release coating agents can be selected from cellulose derivatives such as ethyl cellulose; acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS, emulsion copolymer of ethyl acrylate-methyl methacrylate or combinations thereof.
  • the disintegrant that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising risperidone can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate.
  • the glidant that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising risperidone can be selected from a group comprising tribasic calcium phosphate, colloidal silicone dioxide, magnesium silicate, magnesium trisilicate, talc.
  • the binder that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising risperidone can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone, starch.
  • the acidic agent composing the effervescent couple comprising at least one acidic agent and at least one basic agent that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising risperidone can be selected from a group comprising organic acids such as malic acid, citric acid, tartaric acid, fumaric acid; and the basic agent composing the effervescent couple comprising at least one acidic agent and at least one basic agent that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising risperidone can be selected from a group comprising agents such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate.
  • the pH regulating agent that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising risperidone can be selected from citrate, phosphate, carbonate, tartrate, fumarate, acetate and amino acid salts.
  • the surfactant that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising risperidone can be selected from sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and similar agents.
  • the sweetener and/or taste regulating agent that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising risperidone can be selected from a group comprising acesulfame, aspartame, dextrose, fructose, maltitol, maltose, mannitol, saccharine, saccharine sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol, sodium chloride.
  • the flavouring agent that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising risperidone can be selected from flavours such as menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and similar flavours.
  • the pharmaceutical formulations prepared according to the process of the present invention and comprising risperidone can comprise risperidone in the range of 0,01 to 90 % by weight, preferably in the range of 0,02 to 80% by weight, more preferably in the range of 0,05 to 50% by weight.
  • the pharmaceutical formulations prepared according to the process of the present invention and comprising risperidone can optionally comprise a second active agent in addition to risperidone.
  • the second active agent can be selected from antacid, anticholinergic, antispasmodic, antiemetic, antidiabetic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacne, antibacterial, antimycotic, antiviral, antineoplastic, antiarrhythmic, antiadrenergic, antiepileptic, anti-parkinson, antiprotozoal, anthelmintic, anti-inflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, thiazolidinedione, biguanide, immunostimulant
  • EXAMPLE Formulation and process for preparation of effervescent tablet comprising risperidone

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des formulations pharmaceutiques comprenant de la rispéridone devant être utilisée dans le traitement de la schizophrénie, des symptômes affectifs liés à la schizophrénie, des épisodes maniaques du trouble bipolaire et des malaises associés à des troubles autistiques. La présente invention concerne également les méthodes de préparation de ces formulations.
PCT/TR2012/000218 2011-12-19 2012-12-19 Formulations pharmaceutiques comprenant de la rispéridone WO2013095314A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR201112583 2011-12-19
TR2011/12583 2011-12-19

Publications (1)

Publication Number Publication Date
WO2013095314A1 true WO2013095314A1 (fr) 2013-06-27

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0196132A2 (fr) 1985-03-27 1986-10-01 Janssen Pharmaceutica N.V. Dérivés de 1,2-benzisoxazol-3-yle et 1,2-benzisothiazol-3-yle
WO2004091585A1 (fr) * 2003-04-16 2004-10-28 Synthon B.V. Tablettes a desintegration orale
WO2005034921A1 (fr) * 2003-10-07 2005-04-21 Andrx Pharmaceuticals Llc Formulation a desintegration rapide
WO2005120463A1 (fr) * 2004-06-09 2005-12-22 Ranbaxy Laboratories Limited Comprimes de risperidone a desintegration rapide
WO2005123084A1 (fr) * 2004-06-15 2005-12-29 Krka, Tovarna Zdravil, D.D., Novo Mesto Composition pharmaceutique a base de risperidone se desintegrant oralement
WO2009043844A2 (fr) * 2007-10-01 2009-04-09 Laboratorios Lesvi, S.L. Comprimés orodispersibles

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0196132A2 (fr) 1985-03-27 1986-10-01 Janssen Pharmaceutica N.V. Dérivés de 1,2-benzisoxazol-3-yle et 1,2-benzisothiazol-3-yle
WO2004091585A1 (fr) * 2003-04-16 2004-10-28 Synthon B.V. Tablettes a desintegration orale
WO2005034921A1 (fr) * 2003-10-07 2005-04-21 Andrx Pharmaceuticals Llc Formulation a desintegration rapide
WO2005120463A1 (fr) * 2004-06-09 2005-12-22 Ranbaxy Laboratories Limited Comprimes de risperidone a desintegration rapide
WO2005123084A1 (fr) * 2004-06-15 2005-12-29 Krka, Tovarna Zdravil, D.D., Novo Mesto Composition pharmaceutique a base de risperidone se desintegrant oralement
WO2009043844A2 (fr) * 2007-10-01 2009-04-09 Laboratorios Lesvi, S.L. Comprimés orodispersibles

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BOWEN P: "Particle Size Distribution Measurement from Millimeters to Nanometers and from Rods to Platelets", JOURNAL OF DISPERSION SCIENCE AND TECHNOLOGY, TAYLOR AND FRANCIS GROUP, NEW YORK, NY, US, vol. 23, no. 5, 1 January 2002 (2002-01-01), pages 631 - 662, XP009102859, ISSN: 0193-2691, DOI: 10.1081/DIS-120015368 *

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