WO2007126322A1 - Procédé servant à obtenir une composition pharmaceutique comprenant un agent actif de type ziprasidone ou un sel de celui-ci acceptable pharmaceutiquement - Google Patents

Procédé servant à obtenir une composition pharmaceutique comprenant un agent actif de type ziprasidone ou un sel de celui-ci acceptable pharmaceutiquement Download PDF

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Publication number
WO2007126322A1
WO2007126322A1 PCT/PL2006/000058 PL2006000058W WO2007126322A1 WO 2007126322 A1 WO2007126322 A1 WO 2007126322A1 PL 2006000058 W PL2006000058 W PL 2006000058W WO 2007126322 A1 WO2007126322 A1 WO 2007126322A1
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Prior art keywords
ziprasidone
active agent
pharmaceutically acceptable
derivatives
pharmaceutical composition
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PCT/PL2006/000058
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English (en)
Inventor
Elzbieta Turczyn
Agnieszka Cieplucha
M. Zahirul I. Khan
Teresa Wloch
Robert Dyba
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Plivakraków, Zaklady Farmaceutyczne S.A.
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Application filed by Plivakraków, Zaklady Farmaceutyczne S.A. filed Critical Plivakraków, Zaklady Farmaceutyczne S.A.
Publication of WO2007126322A1 publication Critical patent/WO2007126322A1/fr

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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
    • A61K9/14—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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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

Definitions

  • a method for obtaining a pharmaceutical composition comprising an active agent ziprasidone or a pharmaceutically acceptable salt thereof.
  • the subject of this invention is a method for obtaining a pharmaceutical composition comprising an active agent ziprasidone or a pharmaceutically active salt thereof, to improve solubility and thus bioavailability of the drug, a pharmaceutical composition and use of hydrophilic excipients.
  • Ziprasidone a chemical compound known as 5- ⁇ 2-[4-(l,2- benzisothiazol-3-yl)-l-piperazinyl]ethyl ⁇ -6-chloro-l,3-dihydro-2H-indol- 2-one, having the structure presented below,
  • ziprasidone shows neuroleptic action and is used in preparation of a medicament for the treatment of schizophrenia.
  • the drug ziprasidone is commonly used in the pharmaceutically accepted forms: crystalline ziprasidone itself, ziprasidone hydrochloride and ziprasidone monochloride monohydrate.
  • Formulation of pharmaceutical dosage forms is frequently hampered by poor aqueous solubility and/or stability of the drug of interest, which in turn can severely limit its therapeutic application. Conversely, increasing drug solubility and stability through appropriate formulation can accordingly lead to increased therapeutic efficacy of the drug.
  • Low-solubility drugs often show poor bioavailability or irregular absorption, the degree of irregularity being affected by factors such as dose level, fed state of the patient, and form of the drug.
  • ziprasidone is typically administered as the hydrochloric acid addition salt.
  • the hydrochloride salt is advantageous in that it is high permeability drug, a factor that favorably affects bioavailability.
  • the hydrochloride salt does, however, posses relatively poor aqueous solubility, a factor that unfavorably affects bioavailability.
  • US patent No. 6399777 teaches improvements to the solubility of ziprasidone hydrochloride salts by preparing inclusion complexes of ziprasidone hydrochloride.
  • the patent teaches the use of cyclodextrins to form complexes with the poorly soluble drugs to improve the bioavailability of the drugs.
  • the disclosed composition comprises a pharmaceutically acceptable salt of an arylheterocyclic compound, such as ziprasidone, and cyclodextrins.
  • the composition can comprise a dry mixture of an active substance and cyclodextrins, a dry inclusion complex or an aqueous solution.
  • An inclusion complex of a pharmaceutically acceptable acid addition salt of ziprasidone can be formed conventionally by known methodology. That is, a desired inclusion complex of a pharmaceutically acceptable ziprasidone salt can be formed in situ by adding a ziprasidone salt, in an amount up to the amount corresponding to its equilibrium solubility (or less depending on the desired strength of the product solution), directly to a pre-made solution of cyclodextrins dissolved in water (or other suitable pharmaceutically acceptable aqueous medium). Alternatively, the inclusion complex of ziprasidone in cyclodextrins can first be isolated by drying, usually by lyophilization. The isolated dry inclusion complex can be stored at room temperature for periods up to two years and longer, and reconstituted into a product solution as needed.
  • the molecular structure, the polarity, the size and the possibility for interactions with the cyclodextrins molecules are important factors determining the success of cyclodextrins-preparations.
  • compositions containing ziprasidone includes patent EP 0 965 343, which describes a composition comprising crystalline ziprasidone free base or crystalline ziprasidone hydrochloride particles having a mean particle size equal to or less than about 85 ⁇ m and a pharmaceutically acceptable diluent or carrier.
  • the composition in addition to ziprasidone free base or ziprasidone hydrochloride, can contain conventional pharmaceutically acceptable excipients such as, for example: fillers and diluents; binders; disintegrating agents; lubricants.
  • Composition comprising ziprasidone free base or ziprasidone hydrochloride having a mean particle size less than 85 ⁇ m can be formulated into conventional, usually dry, pharmaceutical dosage forms such as tablets, powders for oral suspension, unit dosage packets, and capsules for oral administration, and such dosage forms can be made by conventional methodology and employing conventional equipment.
  • the patent EP 0965 343 states that the reduced particle size approach to increase the surface area of the drug to facilitate more rapid dissolution can present difficult and expensive formulation and quality control challenges.
  • Patent application US 2005/0163858 describes a formulation comprising an active agent, wherein the active agent is ziprasidone or a pharmaceutically acceptable salt thereof, wherein the active agent has a mean particle size greater than 85 ⁇ m, and a pharmaceutically acceptable carrier.
  • the formulation contains ziprasidone hydrochloride or ziprasidone mono-hydrochloride monohydrate as the active agent.
  • the formulation can contain pharmaceutically acceptable fillers and excipients such as binders, disintegrants, lubricants, glidants, compression aids, colors, sweeteners, preservatives, suspending agents, dispersing agents, film formers, flavors, printing inks etc.
  • pharmaceutically acceptable fillers and excipients such as binders, disintegrants, lubricants, glidants, compression aids, colors, sweeteners, preservatives, suspending agents, dispersing agents, film formers, flavors, printing inks etc.
  • Immediate - release dosage form according to the US 2005/0163858 releases greater than or equal to 75% of the active agent within 2 hours (preferably within 1 hour of administration).
  • Pharmaceutical dosage forms can be made, according to US 2005/0163858, by conventional methodology used in pharmacy, including blending, filling, granulation and compressing.
  • a pharmaceutical composition comprising ziprasidone hydrochloride having a mean particle size greater than 85 ⁇ m and less than about 300 ⁇ m and a pharmaceutically acceptable carrier is claimed in patent application US 2005/0049295.
  • a dosage form comprising ziprasidone or a salt thereof in the form of particles having a mean size at least about 90 ⁇ m, and having a ziprasidone bioavailability equal to or greater than the bioavailability of a dosage form where ziprasidone or a salt thereof is present as particles having a mean size less than 85 ⁇ m.
  • ziprasidone is present as ziprasidone hydrochloride in the dosage form.
  • the dosage form further comprises a hydrophilic excipient, preferably a surfactant, more preferably a sorbitan derivative surfactant, most preferably a polysorbate.
  • Dosage forms of the invention disclosed in the WO 2005/123086 can be produced using any of the customary procedures. These include simply mixing the desired components, then filling the mixtures into capsules or compressing the mixtures into tablets of a desired size and shape. Alternatively, the component mixtures can be granulated, either in the dry form or using a binder solution, then dried (if necessary) and filled into capsules or compressed into tablets.
  • International patent application WO 2004/039411 presents another invention improving aqueous solubility of pharmaceutical compounds.
  • the invention pertains to a solid ionic conjugate comprising a pharmaceutical compound and a functional polymer.
  • the solid ionic conjugate of the invention has an aqueous solubility greater than that of the pharmaceutical compound.
  • the pharmaceutical compound used in the solid ionic conjugate is by itself insoluble or poorly soluble in water.
  • the subject ionic conjugate imparts water solubility, enabling e.g. the otherwise insoluble or poorly soluble pharmaceutical compound to be incorporated into pharmaceutical formulations.
  • the pharmaceutical compound is ziprasidone in the form of free base or a salt thereof.
  • the invention provides with a process for preparing the solid ionic conjugate wherein pharmaceutical compound and a functional polymer are dissolved in an organic solvent and the ionic conjugate in substantially dry form is obtained after removing the solvent by distillation or sublimation under reduced pressure.
  • the water-soluble clathrates of ziprasidone and its salts according to the invention comprise effective amount of ziprasidone and its salts as active principle, and derivatives of cyclodextrins as clathration materials.
  • the preparation methods of water-soluble clathrates according to the WO 2004/054621 comprise the steps: ziprasidone or the salts thereof is added into the organic solvent containing cyclodextrins.
  • the aim of the present invention was to improve solubility of poorly water-soluble drug, namely ziprasidone or its salt. This objective has been achieved by developing a non conventional method for obtaining a pharmaceutical composition comprising an active agent ziprasidone or a pharmaceutically active salt thereof.
  • the present invention relates to a method for obtaining a pharmaceutical composition comprising an active agent ziprasidone or a pharmaceutically acceptable salt thereof, improving solubility and thus bioavailability of the drug, whereby the active agent is slugged together with one or more pharmaceutically acceptable excipients.
  • the active agent is slugged with solubilizing agent and optionally with additional diluent and/or lubricant.
  • ziprasidone hydrochloride or ziprasidone hydrochloride monohydrate are used as the active agent.
  • hydrophilic excipient is used as the solubilizing agent.
  • the preferred solubilizing agents are: alkyl cellulose derivatives, starch derivatives, poly(oxy)ethylene derivatives, polyvinyl derivatives, glyceryl derivatives.
  • the active agent after slugging is further processed into a pharmaceutical composition.
  • the composition obtained by the inventive method is a solid dosage form of a drug.
  • composition obtained by the inventive method is an oral dosage form, preferably a capsule.
  • the present invention relates to a pharmaceutical composition which is producible by the inventive method according to any of its embodiments.
  • the composition comprises 100 mg or less of active substance ziprasidone or the equivalent of its pharmaceutically acceptable salt and is placed in a USP-2 apparatus containing 900 ml of aqueous NaH 2 PO 4 buffer, pH 7.5, containing 2 % (w/v) sodium dodecyl sulfate, and equipped with paddles stirring at 75 rpm, at least 60%, preferably at least 65%, still preferred at least 70%, more preferred at least 75%, and most preferred at least 80% of the active substance dissolves within 45 minutes of analysis.
  • the dissolution medium is maintained at 37 0 C during the test.
  • Such conditions are equivalent to an environment of ziprasidone absorption in a human body; since drug absorption occurs primarily in the intestines, such dosage forms that do not sustain high concentration of the drug in an intestinal solutions will also present poor bioavailability. It is important to obtain good dissolution rate of the active substance in a solution that accurately simulates intestinal fluid properties, typically with pH-range about 6,8-7,5.
  • hydrophilic excipients for increasing the solubility of ziprasidone or a pharmaceutically acceptable salt thereof.
  • hydrophilic excipients are chosen from alkyl cellulose derivatives, starch derivatives, poly(oxy)ethylene derivatives, polyvinyl derivatives and/or glyceryl derivatives.
  • the slugging technique can be described as follows:
  • the active substance and pharmaceutically acceptable excipients are blended, for example by dry blending or wet granulation and compressed into slugs on a tablet press. Thus formed slugs are milled to form granular powder with active agent therein. Many trials proved that this method used for formulation comprising ziprasidone free base or pharmaceutically acceptable salt thereof as active substance, together with solubilizing agent and optionally other excipients effectively enhances solubility of active pharmaceutical ingredient (API).
  • the amount of solubilizing substance should be optimized according to the properties of active substance.
  • at least 10wt% solubilizing agent per API is present in the pharmaceutical composition, still preferred at least 30wt%, more preferred at least 50wt%, most preferred at least 80wt%.
  • Preferably less than 99wt% solubilizing agent per API is present in the pharmaceutical composition, still preferred less than 98wt%, more preferred less than 95wt%, most preferred about 90wt%.
  • solubilisation process can be characterized as the possibility of dissolving ziprasidone as a poorly soluble active substance in water solutions at concentration above the established value.
  • the mechanism for dissolution enhancement is believed to be a microenvironment effect facilitated by keeping solubilizing substance particles together with drug particles in close proximity during dissolution process.
  • solubilizing agent is a mediator in drug dissolution, and is able to form weak associates with active substance molecules, which become better soluble because of the presence of hydrophilic groups therein.
  • this invention relates to be an example of hydrotropic solubilization of poorly water soluble substance.
  • the compaction process is believed to be particularly effective, because of direct contact with solubilizing agent during drug dissolution, in contrast to physical mixture where the drug and solubilizing agent particles may quickly disperse and separate in dissolution medium.
  • the final form of ziprasidone (capsules preferably) was produced in two-step process.
  • ziprasidone hydrochloride was blended with pharmaceutically acceptable excipients.
  • ziprasidone hydrochloride was mixed with solubilizing agent, optionally with additional diluent and/or lubricant.
  • solubilizing agent optionally with additional diluent and/or lubricant.
  • Such a mixture was compressed on a tableting machine into slugs.
  • slugs There is no detailed characterization of slugs: they may have wide-ranging shape and surface, as well as diameter and mass.
  • slugs were milled and sieved preferably through sieves under 5mm, still preferred through sieves under 3mm, more preferred through 1.5mm sieves und most preferred through 0.4mm sieves.
  • such milled granulate was blended with additional capsule components and samples of final mix were filled into hard gelatin capsules, preferably of size one.
  • the present invention is based on the surprising observation that formulations produced with the use of the slugging technique dissolve with acceptable and satisfactory rates in the whole range of ziprasidone particle sizing. Since for micronised ziprasidone it is sufficient to formulate API as a capsule containing physical mixture, it became particularly important to prepare good formulation method for compositions with ziprasidone having a mean particle size greater than 85 ⁇ m.
  • Average particle size was determined by a light scattering method, with the use of Mie theory.
  • particles refers to individual particles of API used in a composition obtained according to the inventive method, whether the particles exist singly or are agglomerated.
  • the particle size of ziprasidone hydrochloride was measured using a Malvern Mastersizer 2000 analyser (Malvern Instruments Ltd. Enigma Business Park Grovewood Road Malvern Worcestershire United Kingdom WRl 4 IXZ) with a Hydro 2000S accessory attached. This unit allows the Mastersizer to be used for particle-in-liquid particle sizing. Prior to analysis of the sample a tank and measurement cell were filled with 150 ml of hexane containing 1% Span 85. Samples for analysis were prepared by adding a weighed amount of ziprasidone hydrochloride (300 ⁇ 50mg) to a small glass beaker.
  • suspending media hexane containing 1% Span 85
  • SOP Standard Operating Procedure
  • the row data contained in the measurement can be analysed by the Malvern software (version 5.22). Upon measurement completion, the sample cell was emptied and cleaned, refilled with suspending medium (hexane containing 1% Span 85) and sampling procedure repeated for a total of three measurements.
  • suspending medium hexane containing 1% Span 85
  • compositions obtained according to the inventive method can be formulated into conventional, usually dry, pharmaceutical dosage forms such as granules, powders, tablets, capsules etc. Such dosage forms can be made with the use of described methodology employing conventional equipment.
  • compositions for particular doses of the active substance can be wide- ranging; preferably mass of particular dosage forms strengths is proportional.
  • Contents of a slugged granulate (comprising API) in a final mix can be wide-ranging; preferably it is about 50 % of capsule filling.
  • compositions obtained by the method according to this invention comprise pharmaceutically acceptable solubilizing substance, which in direct compression process with a drug substance enables better solubility of API.
  • solubilizing substance which in direct compression process with a drug substance enables better solubility of API.
  • the preferred solubilizers are chosen from, but not restricted to:
  • HPC hydroxypropylcellulose
  • MC methyl cellulose
  • EC ethyl cellulose
  • - starch derivatives which can be cyclodextrins
  • poly(oxy)ethylene derivatives which can be selected from polyethylene- propylene glycol copolymers (poloxamers) or polyoxyethylene alkyl esters;
  • polyvinyl derivative which can be polyvinylpyrrolidone (PVP) or polyvinylpolypyrrolidone (PVPP); - glyceryl derivatives, which can be glyceryl monostearate.
  • Other pharmaceutically acceptable excipients used for the purpose of this invention can be, for example: diluents, binders, lubricants and/or disintegrants.
  • the most suitable diluents can be chosen from microcrystalline cellulose, calcium hydrogen carbonate, starch, mannitol, sorbitol, lactose, saccharose and others.
  • Binders can be cellulose and its derivatives: ( MC, EC, HPC, etc.), starch and its derivatives and others.
  • Suitable lubricants are: stearic acid, polyethylene glycol, talc, sodium lauryl sulfate, calcium and magnesium stearate, and others.
  • Pharmaceutically acceptable disintegrants include: cellulose, starch and their derivatives, and others.
  • excipients can serve more than one function.
  • an active substance should exhibit relatively high plasma level at the acceptable time after administration.
  • Main factor that influences oral bioavailability of API is its rate of dissolution at physiologic pH.
  • compositions comprising ziprasidone (or salts thereof) having a mean particle size equal to or less than about 85 ⁇ m exhibit good dissolution properties at physiologic pH.
  • formulations were made comprising crystalline ziprasidone or pharmaceutically acceptable salt thereof, wherein the active agent particles have a mean particle size D[4,3] greater than 85 ⁇ m.
  • the advantage of this invention is providing a new and inventive specific manufacturing process which causes great increase in dissolution rate of ziprasidone or a pharmaceutically acceptable salt thereof in comparison to drug form produced by physical mixing of appropriate components as typical technology of capsules preparation.
  • Fig.1. Ziprasidone dissolution for capsules containing physical mixture and slugged granulate with the presence of HPC (Klucel EXF);
  • Fig.2. Ziprasidone dissolution for capsules containing physical mixture and slugged granulate with the presence of ⁇ -cyclodextrins (Kleptose DC);
  • Fig.3. Ziprasidone dissolution for capsules containing physical mixture and slugged granulate with the presence of poloxamer (Lutrol F 68);
  • Fig.4. Ziprasidone dissolution for capsules containing physical mixture and slugged granulate with the presence of PVP K30;
  • Fig.5. Ziprasidone dissolution for capsules containing physical mixture and slugged granulate without the presence of solubilizing agent
  • Fig.6 Ziprasidone dissolution for capsules containing physical mixture and slugged granulate with the presence of HPC as 10% (by weight) of the active substance
  • Fig.7 Ziprasidone dissolution for capsules containing physical mixture and slugged granulate with the presence of HPC as 50% (by weight) of the active substance;
  • Fig.9. Ziprasidone dissolution for capsules containing slugged granulate with the presence of HPC as 10% (by weight) of the active substance supplied from manufacturers "A" and "B";
  • Ziprasidone capsules were prepared in a two-step process. At the first stage ziprasidone granulate was prepared by dry blending following by slugging. In order to obtain a mixture for direct compression ziprasidone hydrochloride was blended for 15 min with solubilizing agent (HPC, ⁇ - cyclodextrins, Lutrol or PVP, respectively), cellulose Avicel PH 200 and sodium lauryl sulfate (quantities in Table 1).
  • solubilizing agent HPC, ⁇ - cyclodextrins, Lutrol or PVP, respectively
  • cellulose Avicel PH 200 cellulose Avicel PH 200
  • sodium lauryl sulfate quantities in Table 1.
  • Rotation speed of a blender was kept constant at 20 rpm. Then magnesium stearate was added and mixing was continued for additional 5 min with the same rotation speed. Such a physical mixture was compressed into tablets on a Korsch Press and the resulting tablets were comminuted and sieved through 1,5 and 0,4 mm sieves to produce a free-flowing powder (ziprasidone granulate) .
  • ziprasidone granulate was mixed with Lactose Pharmatose DCLI l and starch pregelatinised Lycatab C (Table 2). After 15 min of mixing additional amount of magnesium stearate was added to obtain a mixture with good flowing properties (magnesium stearate was mixed in the same conditions as above). Samples were than filled with 360 mg of the mixture into hard gelatin capsules of size one. Such a dosage form comprises 87,06 mg of ziprasidone hydrochloride, equivalent to 80 mg of ziprasidone.
  • Dissolution analysis was established in a USP-2 apparatus containing 900 ml of aqueous NaH 2 PO 4 buffer of pH 7.5, containing 2 % (w/v) sodium dodecyl sulfate, and equipped with paddles stirring at 75 rpm.
  • the dissolution medium was maintained at 37 0 C during the test. Capsules were added directly to the aqueous medium.
  • the active substance dissolution rate was tested after 5, 10, 15, 30, 45, 60, 75 and 90 rnin, than the agitation rate was increased up to 250 rpm and the amount of ziprasidone hydrochloride finally dissolved was checked (about 90-100 % of API was than dissolved).
  • Fig.1-4 ziprasidone dissolution rates for capsules prepared from slugged ziprasidone granulate and capsules containing qualitative and quantitative physical mixtures were compared.
  • Fig.l. ziprasidone dissolution for capsules containing physical mixture and slugged granulate with the presence of HPC (Klucel EXF) is presented
  • Fig. 2-4 shows enhancement o dissolution rate of ziprasidone in the presence of ⁇ -cyclodextrins (Kleptose DC), poloxamer (Lutrol F 68) and PVP K30, respectively.
  • compositions without solubilizing agent were prepared and tested as well.
  • Fig. 5 dissolution of ziprasidone compositions lacking a solubilizing agent obtained with slugging technique and as physical mixtures is shown. Obtained profiles confirm that compression with other excipients only cannot significantly increase the rate of dissolution of active substance with particles greater than 85 ⁇ m. Therefore the presence of solubilizing agent in formulations comprising solid ziprasidone or a salt thereof with particles greater that about 85 ⁇ m is strongly recommended.
  • Fig. 6 and 7 present ziprasidone dissolution rates for capsules containing physical mixture and slugged granulate with the presence of HPC as 10 % and 50 % (by weight) of the active substance. These trials show how the ratio of solubilizer influences a dissolution rate: as expected the higher amount of solubilizing agent present in the composition the higher rate of dissolution can be obtained.
  • the extension of dissolution rate is additionally summarized in Fig. 8.
  • the rate of ziprasidone dissolution is largely dependent on a solubilizer presence in a composition.
  • the amount of solubilizing agent in the dosage form should be optimized and adjusted to provide suitable active substance dissolution parameters.
  • Fig. 7 solubilizing agent
  • 10 % ratio of solubilizer in proportion to API quantity
  • mean particle size values are comparable for active substance supplied from manufacturer "A" and "B".

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Abstract

La présente invention concerne un procédé servant à obtenir une composition pharmaceutique comprenant un agent actif de type ziprasidone ou un sel de celui-ci acceptable pharmaceutiquement, pour améliorer la solubilité et donc la biodisponibilité du médicament, lequel procédé consiste à former à pastiller l'ingrédient actif avec un ou plusieurs excipients acceptables pharmaceutiquement. Dans un mode de réalisation préféré, l'agent actif est pastillé avec un agent de solubilisation et éventuellement avec un diluant et/ou un lubrifiant supplémentaires. De préférence, le chlorhydrate de ziprasidone ou le chlorhydrate de ziprasidone monohydraté est utilisé en tant qu'agent actif. De préférence, un excipient hydrophile choisi parmi des dérivés d'alkylcellulose, des dérivés d'amidon, des dérivés de poly(oxy)éthylène, des dérivés polyvinyliques ou des dérivés glycéryliques est utilisé en tant qu'agent de solubilisation. De préférence, après pastillage, l'agent actif est mis sous la forme d'une composition pharmaceutique. Dans un mode de réalisation préféré, la composition pharmaceutique est une forme de dosage solide, de préférence une forme de dosage orale d'un médicament, de préférence une gélule. L'invention concerne également une composition pharmaceutique qui peut être produite selon le procédé de l'invention. Dans un autre aspect, l'invention concerne l'utilisation d'excipients hydrophiles pour augmenter la solubilité de la ziprasidone ou de son sel actif pharmaceutiquement.
PCT/PL2006/000058 2006-04-28 2006-08-30 Procédé servant à obtenir une composition pharmaceutique comprenant un agent actif de type ziprasidone ou un sel de celui-ci acceptable pharmaceutiquement WO2007126322A1 (fr)

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PL379569A PL379569A1 (pl) 2006-04-28 2006-04-28 Sposób wytwarzania kompozycji farmaceutycznej zawierającej substancję aktywną ziprasidone lub jego farmaceutycznie dopuszczalną sól zwiększający rozpuszczalność i biodostępność tego leku, kompozycja farmaceutyczna i zastosowanie hydrofilowych substancji pomocniczych

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102008045854A1 (de) 2008-09-05 2010-03-11 Tiefenbacher Pharmachemikalien Alfred E. Tiefenbacher Gmbh & Co. Kg Partikel aus Ziprasidone und einem Sprengmittel enthaltende Pharmazeutische Zusammensetzung
WO2010082855A1 (fr) * 2009-01-15 2010-07-22 Zaklady Farmaceutyczne Polpharma Sa Compositions pharmaceutiques comprenant de la ziprasidone sous forme de base libre ou de chlorhydrate et leur méthode d'élaboration
EP2340834A1 (fr) 2009-12-30 2011-07-06 Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi Solubilité améliorée de la ziprasidone
WO2011148253A2 (fr) 2010-05-25 2011-12-01 Aurobindo Pharma Limited Formes posologiques solides d'antipsychotiques

Citations (4)

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Publication number Priority date Publication date Assignee Title
EP0965343A2 (fr) * 1998-06-15 1999-12-22 Pfizer Products Inc. Formulations de ziprasidone
US20030219489A1 (en) * 1997-08-11 2003-11-27 Pfizer Inc. Solid pharmaceutical dispersions with enhanced bioavailability
US20050163858A1 (en) * 2003-12-31 2005-07-28 Garth Boehm Ziprasidone formulations
WO2005123086A2 (fr) * 2004-06-11 2005-12-29 Dr. Reddy's Laboratories Ltd. Forme de dosage de ziprasidone

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030219489A1 (en) * 1997-08-11 2003-11-27 Pfizer Inc. Solid pharmaceutical dispersions with enhanced bioavailability
EP0965343A2 (fr) * 1998-06-15 1999-12-22 Pfizer Products Inc. Formulations de ziprasidone
US20050163858A1 (en) * 2003-12-31 2005-07-28 Garth Boehm Ziprasidone formulations
WO2005123086A2 (fr) * 2004-06-11 2005-12-29 Dr. Reddy's Laboratories Ltd. Forme de dosage de ziprasidone

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102008045854A1 (de) 2008-09-05 2010-03-11 Tiefenbacher Pharmachemikalien Alfred E. Tiefenbacher Gmbh & Co. Kg Partikel aus Ziprasidone und einem Sprengmittel enthaltende Pharmazeutische Zusammensetzung
WO2010025848A1 (fr) * 2008-09-05 2010-03-11 Alfred E. Tiefenbacher Gmbh & Co. Kg Composition pharmaceutique contenant des particules qui se composent de ziprasidone et d'un délitant
WO2010082855A1 (fr) * 2009-01-15 2010-07-22 Zaklady Farmaceutyczne Polpharma Sa Compositions pharmaceutiques comprenant de la ziprasidone sous forme de base libre ou de chlorhydrate et leur méthode d'élaboration
EP2340834A1 (fr) 2009-12-30 2011-07-06 Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi Solubilité améliorée de la ziprasidone
WO2011080706A1 (fr) 2009-12-30 2011-07-07 Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi Solubilité améliorée de la ziprasidone
WO2011148253A2 (fr) 2010-05-25 2011-12-01 Aurobindo Pharma Limited Formes posologiques solides d'antipsychotiques

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