EP3065700A1 - Im mund zerfallende pharmazeutische zusammensetzungen mit aripiprazol - Google Patents

Im mund zerfallende pharmazeutische zusammensetzungen mit aripiprazol

Info

Publication number
EP3065700A1
EP3065700A1 EP13786678.6A EP13786678A EP3065700A1 EP 3065700 A1 EP3065700 A1 EP 3065700A1 EP 13786678 A EP13786678 A EP 13786678A EP 3065700 A1 EP3065700 A1 EP 3065700A1
Authority
EP
European Patent Office
Prior art keywords
aripiprazole
composition
lactose
composition according
superdisintegrant
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP13786678.6A
Other languages
English (en)
French (fr)
Inventor
Lisa BAKKER-HOLMDAHL
Frans Henri Nicolaas HAAN DE
Deepak Murpani
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Synthon BV
Original Assignee
Synthon BV
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 Synthon BV filed Critical Synthon BV
Publication of EP3065700A1 publication Critical patent/EP3065700A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to pharmaceutically useful orodispersible tablet compositions that contain aripiprazole and pharmaceutically acceptable excipients.
  • Aripiprazole or chemically 7-[4-[4-(2,3-dichlorophenyl)-l-piperazinyl]butoxy]-3,4- dihydrocarbostyril, is a compound of the formula (1).
  • aripiprazole is present as the free base.
  • Type I aripiprazole This solid state form was designated as Type I aripiprazole and identified as an anhydrate. Aoki also teaches that the Type I aripiprazole may be converted into a Type II aripiprazole by heating at 130-140°C for 15 hours. This product is also an anhydrate. When both Type I and Type II aripiprazole were recrystallized from an alcoholic solvent containing water up to 20%, the product was an aripiprazole hydrate labeled as Type III by Aoki.
  • WO 03/26659 (EP 1330249) teaches that Type I and Type II aripiprazole are significantly hygroscopic. In an effort to find a form of aripiprazole having reduced hygroscopicity and better processing qualities, seven crystalline forms (Form A- Form G) were described.
  • PCT application WO 2006/053780 discloses crystalline alcoholates of aripiprazole.
  • Other solvates of aripiprazole have been disclosed in WO 2005/009990.
  • Aripiprazole (base) is commercially marketed, e.g., under brand name Abilify by Otsuka (in cooperation with Bristol-Myers-Squibb), in various pharmaceutical products: in tablets (of 2mg, 5mg, lOmg, 15mg, 20mg, 30 mg strengths), orodispersible tablets (of lOmg, 15 mg and 30 mg strengths), in peroral solution (lmg/ml), or in injection solution (9.75 mg/ml).
  • the orodispersible (orally disintegrating) tablets which the present invention relates to, have certain importance in treatment of patients having problems of swallowing or for immediate medication.
  • the marketed Abilify orodispersible tablets comprise aripiprazole in combination with the following inactive ingredients: calcium silicate, croscarmellose sodium, crospovidone, silicon dioxide, xylitol, microcrystalline cellulose, aspartame, acesulfame potassium, vanilla flavour, tartaric acid, magnesium stearate and colourants (Red or yellow iron oxide).
  • WO 2013/100878 teaches an orodispersible composition of aripiprazole characterized by a presence of a diluent and disintegrant in a certain ratio, which is preferablyl: l to 20:1. No example of a suitable diluent/ disintegrant combination has been provided. Such compositions have to be twice compacted in special compacting steps before compressing them into tablets.
  • the present invention provides a directly compressible orodispersible tablet composition
  • a directly compressible orodispersible tablet composition comprising aripiprazole, lactose, at least one superdisintegrant and at least one additional compressible diluent, and not comprising an alcoholic sugar or a metal silicate.
  • the amount of lactose is from about 50 to about 80 weight %, preferably from about 60 to about 70 weight .
  • the amount of a superdisintegrant is from about 5 to about 15 weight %.
  • the superdisintegrant is selected from modified starch, crosslinked polyvinylpyrrolidone, modified cellulose, crosslinked alginic acid, xanthan gum or crosslinked polyacrylate and preferably is selected from the group consisting of sodium croscarmellose, crospovidone, sodium starch glycollate and combination thereof.
  • the compressible diluent is microcrystalline cellulose, hydroxypropylcellulose, silicified cellulose, compressible calcium phosphate, starch and combination thereof.
  • the composition further comprises at least one auxiliary component and at least one lubricant.
  • the present invention provides an orodispersible tablet comprising aripiprazole, lactose, at least one superdisintegrant and at least one additional compressible diluent obtainable by the direct compression of a mixture of all components.
  • the present invention relates to a directly compressible orodispersible tablet composition comprising aripiprazole.
  • Directly compressible is a composition characterized by such selection of components that a physical mixture thereof may be, after homogenization, compressed into a tablet sufficiently hard to sustain normal conditions of treatment.
  • orodispersible in accordance with common meaning, is such composition of tablets, which can disintegrate or dissolve in the mouth, wherein the active substance may be absorbed by oral tissues without a need to enter stomach.
  • the orodispersible tablets disintegrate within 3 minutes or less in a disintegration test as described in the European Pharmacopeia.
  • composition within the present invention is a pharmaceutical composition. Accordingly, it may comprise only components that are pharmaceutically acceptable.
  • the first one is based on freeze drying of a solution resulting in a shaped wafer comprising the dose amount of the drug.
  • the basic disadvantage of these drug forms is that a solution must be made first and the process is expensive and time consuming.
  • the resulted forms are very soft and hygroscopic and must be kept in a special moisture resistant packaging.
  • the second concept is based on using special grades of sugars in a combination with superdisintegrants, which are compounds able to absorb water upon rapid swelling resulting in disintegration of the compressed composition.
  • the rapid disintegration results from the presence of an effervescent combination comprising a bicarbonate and a weak acid.
  • the aripiprazole-comprising orodispersible tablets disclosed in EP 1145711 and WO 03/030868 can be only prepared by a complicated process, comprising a pre-formulation step of blending the active ingredient, the dispersing agent, distributing agent and parts of the superdisintegrant(s) and the binder in a suitable mixer, compacting the blended mixture in a roller compactor or in a slugger and breaking the compacts or slugs by passing through a sieve forming an intragranulate. The intragranulate is then mixed with remaining
  • orodispersible tablets comprising aripiprazole may be prepared by a direct compression, i.e. by a compression of a mixture of the active
  • the present invention provides a directly compressible tablet composition of aripiprazole that is orodispersible, i.e. useful for making orodispersible tablets.
  • the tablet composition comprises aripiprazole, lactose, at least one superdisintegrant and at least one compressible diluent not comprising an alcoholic sugar or a metal silicate.
  • lactose replaces xylitol, which has negative impact on the overall hardness of the resulted tablet in case of direct compression.
  • the tablet composition of the present invention does not comprise metal silicate, such as calcium silicate, which is not useful in direct compression process due to its low flowability.
  • metal silicate such as calcium silicate
  • the replacement of metal silicate and alcoholic sugar that formed essential part of the composition of the orodispersible tablets of the prior art by a compressible lactose improves the tabletting properties of the composition while maintaining the orodispersible character of the resulting tablets.
  • This improvement results to a composition, which may be directly compressed into an orodispersible tablet without a need of any pre-formulation step, in particular that of compaction of at least part of the composition.
  • the direct compression process by which the composition of the present invention may be formulated into tablets, is simpler and cheaper than the dry granulation process of the prior art.
  • the apripiprazole useful in making the compositions of the present invention is in solid form that may be amorphous or crystalline.
  • the crystalline aripiprazole include any particular crystalline form, including mixtures of such forms, regardless the form is an anhydrate, a hydrate, or a solvate.
  • the amorphous aripiprazole includes adducts or co-precipitates of aripiprazole with various adjuvants.
  • the preferred solid state form of aripiprazole for making compositions of the present invention is a crystalline aripiprazole.
  • Crystalline Type II polymorph as defined in the above mentioned article of Aoki, is preferred. This polymorph is characterized by the XRPD pattern comprising signals at 5.4, 10.0, 10.7, 11.1, 11.6, 12.6, 14.2, 15.1, 15.6, 15.9, 16.2, 18.5, 18.9, 19.8, 20.0, 20.4, 20.7, 21.8, 22.2, 23.1, 23.3, 24.4, 25.0, 25.3, 26.0, 26.5, 27.0, 27.6, 28.4, 29.5, 30.2, 30.6, 31.0, 31.6, 32.1 ⁇ 0.2 degrees two theta, when measured at copper Ka radiation.
  • aripiprazole may be provided in particles of various particle size and particle size distribution. It is preferred that aripiprazole is used in compositions of the present invention as a particulate product of the particle size value d90 of between about 15 and about 100 micrometers, preferably between about 35 and about 80 micrometers (as determined by a laser diffraction method).
  • compositions of the present inventions preferably comprise from 5 to 15 weight % of aripiprazole, calculated on the total mass of the composition.
  • Lactose for purposes of the present invention, is preferably a directly-compressible lactose, i.e. lactose having good flow and compressibility properties.
  • spray-dried lactose is the preferred type of lactose for use in compositions of the present invention.
  • Spray-dried lactose is prepared by spraying a suspension of alpha-form of lactose monohydrate in a saturated aqueous solution of lactose in water.
  • Spray-dried lactose has, in general, spherical particles and contains approx. 85% of alpha- monohydrate crystals and 15% of amorphous lactose.
  • anhydrous beta-lactose a coprocessed mixture of beta-lactose with lactitol or a coprocessed mixture of lactose monohydrate and maize starch may be used as the "lactose" for purpose of the present invention.
  • the amount of lactose is from about 50 to about 80 weight %, preferably from about 60 to about 70 weight%, calculated on the total mass of the composition.
  • the amount of lactose corresponds to the weighed amount of the lactose, i.e. including water eventually present in the material charged in making the composition.
  • lactose is preferably used as a particulate product having the particle size value d90 of about 150-300 micrometers (as determined by laser diffraction process).
  • the amount of a superdisintegrant is from about 5 to about 15 weight %.
  • the superdisintegrant useful in compositions of the present invention is preferably modified starch, crosslinked polyvinylpyrrolidone, modified cellulose, crosslinked alginic acid, xanthan gum, or crosslinked polyacrylate, and combinations thereof.
  • the superdisintegrant is selected, alone or in combination, from the group consisting of sodium croscarmellose, crospovidone, and sodium starch glycollate.
  • Combination of two or more superdisintegrants is in some embodiments advantageous, particularly a combination of a swelling and a non-swelling superdisintegrant.
  • the superdisintegrant should be compressible.
  • the composition may further comprise at least one diluent, which is typically a directly compressible diluent. Accordingly, calcium silicate or any other silicate is not present in the composition as they suffer from low flowability.
  • Suitable compressible diluents for purposes of the present invention comprise microcrystalline cellulose, hydroxypropylcellulose, silicified cellulose, compressible calcium phosphate, starch and combination thereof. The most preferred compressible diluent is microcrystalline cellulose.
  • the composition of the invention comprises 10-25 weight % of the compressible diluent.
  • compositions comprising both lactose monohydrate and cellulose
  • the marketed Cellactose which is a co-processed product of both components in the ratio 75 : 25 (w/w)
  • 75 : 25 w/w
  • composition of the present invention may comprise auxiliary components, which improve organoleptic properties.
  • auxiliary components comprise, e.g., flavours, taste masking agents, taste enhancers, sweeteners or colourants.
  • flavours e.g., sorbitol, mannitol, mannitol, mannitol, sorbitol, mannitol, sorbitol, mannitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol,
  • the composition also comprises at least one lubricant.
  • Lubricants include, but are not limited to, magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, zinc stearate or talc.
  • the final composition has less than 2% of water, determined as loss on drying at 105°C.
  • composition of the present invention is useful in making pharmaceutical orodispersible aripiprazole tablets.
  • the composition of the present invention is compressed into a form of a tablet.
  • the present invention accordingly provides an orodispersible tablet comprising the tablet composition disclosed above.
  • the present invention accordingly provides an orodispersible tablet comprising aripiprazole, lactose, at least one superdisintegrant and at least one compressible diluent, obtainable by the compression of a mixture of all components.
  • aripiprazole lactose
  • at least one superdisintegrant at least one compressible diluent
  • the orodispersible tablet of the present invention is obtainable by a simple process comprising the steps of making the above tablet composition by blending aripiprazole, lactose, at least one superdisintegrant, at least one compressible diluent, at least one auxiliary component and at least one lubricant to form a lubricated blend, and of compressing the blend into tablets in a tablet press.
  • No specific order of mixing the components in a suitable mixer/homogenizer is prescribed except of the fact that lubricant is preferably added to the homogenized mixture as the last component.
  • any of the components may be milled, screened or sieved prior to the mixing step to obtain a population of particles of the desired particle size distribution and desired flowability.
  • the final composition to be tabletted is characterized by a flowability higher than 12 g/s, when passing through a 25 mm orifice, and/or higher than 7 g/s, when passing through a 15 mm orifice.
  • the homogenization is carried out at ambient temperature, without special precaution as to aerial oxygen and humidity.
  • the final lubricated blend may be sieved prior to compression to remove lumps.
  • the lubricated blend may be compressed on conventional tablet press, advantageously at the compression force of about 4 kN.
  • the hardness of the compressed tablets should advantageously be higher than 15N, advantageously between 19 and 27 N.
  • Orodispersibility of the tablet may be tested by a conventional pharmacopoeial test for disintegration in a basket-rack assembly, in water. Typically, the disintegration time is less than 2 minutes, advantageously less than 1 minute.
  • Each tablet represents a unit dosage form, which suitably contains between 1 and 50 mg, preferably between 2 and 30 mg of the drug substance.
  • the unit dosage form comprises 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, or 30 mg of aripiprazole.
  • Such unit dosage form is suitable for administration 1 -5 times daily, depending on the therapy and stage of the therapy.
  • a plurality of tablets may be packed in a suitable package material, which
  • blisters made from aluminium and/or hard polymer are examples of such package materials.
  • the tablet of the present invention may be used for any therapeutic or prophylactic treatment approved for aripiprazole-comprising medicaments. For instance, it may be used for the treatment of schizophrenia and bipolar disorder.
  • Example 1 Formulation and process for making 15mg orodispersible tablets comprising aripiprazole
  • Microcrystalline cellulose and iron oxide are mixed in a first container.
  • Aripiprazole and lactose are mixed in a second container.
  • Colloidal silica, croscarmellose sodium and crospovidone are mixed in a third container.
  • a bin mixer is charged with tartaric acid, vanilla flavour, acesulfame K and aspartame, the contents of the three containers are added upon stirring and the mixture is mixed for 30 minutes.
  • Magnesium stearate is added and the mixture is mixed for 3 minutes.
  • the mixture is compressed to 8 mm rounded flat tablets comprising 15 mg aripiprazole per tablet.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Zoology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
EP13786678.6A 2013-11-07 2013-11-07 Im mund zerfallende pharmazeutische zusammensetzungen mit aripiprazol Withdrawn EP3065700A1 (de)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2013/073301 WO2015067313A1 (en) 2013-11-07 2013-11-07 Orodispersible pharmaceutical compositions comprising aripiprazole

Publications (1)

Publication Number Publication Date
EP3065700A1 true EP3065700A1 (de) 2016-09-14

Family

ID=49551607

Family Applications (1)

Application Number Title Priority Date Filing Date
EP13786678.6A Withdrawn EP3065700A1 (de) 2013-11-07 2013-11-07 Im mund zerfallende pharmazeutische zusammensetzungen mit aripiprazol

Country Status (2)

Country Link
EP (1) EP3065700A1 (de)
WO (1) WO2015067313A1 (de)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TR201617675A2 (tr) * 2016-12-02 2018-06-21 Arven Ilac Sanayi Ve Ticaret Anonim Sirketi Ari̇pi̇prazole monohi̇drat formülasyonlarinin ağizda dağilan tablet formu

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5006528A (en) 1988-10-31 1991-04-09 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivatives
CA2311734C (en) 2000-04-12 2011-03-08 Bristol-Myers Squibb Company Flash-melt oral dosage formulation
WO2003030868A1 (en) 2001-10-09 2003-04-17 Bristol-Myers Squibb Company Flashmelt oral dosage formulation
AR033485A1 (es) 2001-09-25 2003-12-26 Otsuka Pharma Co Ltd Sustancia medicinal de aripiprazol de baja higroscopicidad y proceso para la preparacion de la misma
WO2005009990A1 (en) 2003-07-25 2005-02-03 Hetero Drugs Limited Aripiprazole crystalline forms
PT1613598E (pt) 2003-12-16 2012-01-13 Teva Pharma Métodos para preparar formas cristalinas de aripiprazol
WO2006053781A1 (en) 2004-11-18 2006-05-26 Synthon B.V. Process of making crystalline aripiprazole
WO2006053780A1 (en) 2004-11-18 2006-05-26 Synthon B.V. Crystalline aripiprazole solvates
AU2006224759A1 (en) 2005-03-17 2006-09-21 Synthon B.V. Process of making crystalline Type II aripiprazole
DK1808165T3 (da) * 2006-01-05 2009-08-03 Teva Pharma Törre formuleringer af aripiprazol
EP2081904B1 (de) * 2006-09-22 2011-03-02 Krka Tovarna Zdravil, D.D., Novo Mesto Aripiprazolhemifumarat und verfahren zu dessen herstellung
ES2645255T3 (es) * 2007-10-01 2017-12-04 Laboratorios Lesvi, S.L. Comprimidos orodispersables
TR201000948A1 (tr) * 2010-02-09 2011-08-22 Sanovel İlaç San.Ve Ti̇c.A.Ş. Aripiprazol formülasyonları.
WO2013100878A1 (en) 2011-12-27 2013-07-04 Mahmut Bilgic Pharmaceutical formulations comprising aripiprazole

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2015067313A1 *

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