EP1901722A1 - Compositions de nanoparticules à libération contrôlée comprenant des composés d'aryle hétérocyclique - Google Patents

Compositions de nanoparticules à libération contrôlée comprenant des composés d'aryle hétérocyclique

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Publication number
EP1901722A1
EP1901722A1 EP06773467A EP06773467A EP1901722A1 EP 1901722 A1 EP1901722 A1 EP 1901722A1 EP 06773467 A EP06773467 A EP 06773467A EP 06773467 A EP06773467 A EP 06773467A EP 1901722 A1 EP1901722 A1 EP 1901722A1
Authority
EP
European Patent Office
Prior art keywords
composition
less
ziprasidone
release
particles
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Withdrawn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
EP06773467A
Other languages
German (de)
English (en)
Other versions
EP1901722A4 (fr
Inventor
John Devane
Paul Stark
Niall Fanning
Gurvinder Rekhi
Scott Jenkins
Gary Liversidge
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.)
Elan Pharma International Ltd
Original Assignee
Elan Pharma International Ltd
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
Priority claimed from US11/372,857 external-priority patent/US20060240105A1/en
Application filed by Elan Pharma International Ltd filed Critical Elan Pharma International Ltd
Publication of EP1901722A1 publication Critical patent/EP1901722A1/fr
Publication of EP1901722A4 publication Critical patent/EP1901722A4/fr
Withdrawn legal-status Critical Current

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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
    • 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
    • A61K31/495—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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular 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
    • 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
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • 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
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • 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

  • Nanoparticulate and Controlled Release Compositions Comprising Aryl-Heterocyclic Compounds
  • Ziprasidone chemically known as 5-[2-[4-(l,2-benzisothiazol-3-yl)-l-piper- azinyl]ethyl]-6-chloro-l,3-dihydro-2H-indol-2-one, is a benzothiazolylpiperazine derivative that is used as an antipsychotic agent to treat psychiatric conditions such as schizophrenia, hallucinations, delusions, hostility and other bipolar disorder without increase of lipids and other blood fats.
  • Ziprasidone has an empirical formula of C 2 i ⁇ 2 iClN 4 OS and molecular weight of 412.94 (free base).
  • ziprasidone The chemical structure of ziprasidone is shown below:
  • Ziprasidone may be administered as part of a dosage form offered under the registered trademark name Geodon ® in the United States by Pfizer Inc. Ziprasidone is present in Geodon ® Capsules in the form of the hydrochloride salt of ziprasidone, 5-(2-(4- (l,2-benzisothiazol-3-yl)piperazinyl)ethyl)-6-chloro-l,3-dihydro-2H-indole-2-one monohydrochloride monohydrate.
  • This salt is a white to slightly pink powder, having a melting point of 300 0 C, an empirical formula Of C 2I H 2I ClN 4 OS-HCl-H 2 O and molecular weight of 467.42.
  • Geodon ® for Injection contains a lyophilized form of ziprasidone mesylate trihydrate (5-(4-(l,2-benzisothiazol-3- yl)piperazinyl)ethyl)-6-chloro-l,3-dihydro-2H-indole-2-one, methanesulfonate, trihydrate (empirical formula: C 2I H 2 ICIN 4 OS-CH 3 SO 3 H-SH 2 O; molecular weight: 563.09).
  • Ziprasidone is highly effective in the therapeutic treatment of patients suffering from schizophrenia and similar mental disorders. However, given the need to take ziprasidone two times a day and the further need to take ziprasidone after meals, strict patient compliance is a critical factor in the efficacy of ziprasidone in the treatment of schizophrenia and similar mental disorders. Moreover, such frequent administration often requires the attention of health care workers and contributes to the high cost associated with treatments involving ziprasidone. Thus, there is a need in the art for ziprasidone compositions which overcome these and other problems associated with their use in the treatment of schizophrenia and similar psychoses.
  • One embodiment of the invention encompasses a nanoparticulate composition
  • a nanoparticulate composition comprising: (A) ziprasidone; and (B) at least one surface stabilizer.
  • the surface stabilizer can be adsorbed on or associated with the surface of the nanoparticulate particles.
  • the nanoparticulate particles have an effective average particle size of less than about 2,000 nm.
  • the nanoparticulate composition may optionally comprise one or more additional active ingredients useful in the prevention and treatment of schizophrenia and similar psychiatric disorders and/or one or more pharmaceutically acceptable excipients.
  • the administration of the nanoparticulate composition to a subject in a fed or fasted state may be bioequivalent and may exhibit similar pharmacokinetics.
  • Such modified release compositions may comprise a nanoparticulate form of ziprasidone and at least one surface stabilizer, and may optionally comprise one or more additional active ingredients useful in the prevention and treatment of schizophrenia and similar psychiatric disorders and/or one or more pharmaceutically acceptable excipients.
  • the release profile of the active ingredients from the composition is bimodal.
  • the first component exhibits an immediate release profile and the second component exhibits a delayed release profile
  • the duration of the lag time may be varied by altering the amount and/or composition of the modified release coating or by altering the amount and/or composition of the modified release matrix material utilized to achieve the desired release profile.
  • the duration of the lag time can be designed to mimic a desired plasma profile.
  • the dosage form is an injectable depot formulation comprising a nanoparticulate composition comprising ziprasidone.
  • the depot formulation slowly dissolves and releases the drug into the patient's circulation.
  • a single injection of the formulation can provide effective therapeutic plasma concentrations of ziprasidone for up to 3 months.
  • the present invention further relates to methods of treatment including but not limited to, the prevention and treatment of schizophrenia and similar mental disorders.
  • Such methods comprise the step of administering to a subject a therapeutically effective amount of a composition, for example, a nanoparticulate composition, comprising ziprasidone.
  • ziprasidone includes ziprasidone, its pharmaceutically acceptable salts, acids, esters, metabolites, complexes or other derivatives and thereof, and each of their respective stereoisomers including mixtures, racemic or otherwise, of two or more such stereoisomers.
  • stable refers to, but is not limited to, one or more of the following parameters: (1) the particles do not appreciably flocculate or agglomerate due to interparticle attractive forces or otherwise significantly increase in particle size over time; (2) the physical structure of the particles is not altered over time, such as by conversion from an amorphous phase to a crystalline phase; (3) the particles are chemically stable; and/or (4) where the active ingredient has not been subject to a heating step at or above the melting point of the particles in the preparation of the nanoparticles of the present invention.
  • “poorly water soluble drug” refers to a drug that has a solubility in water of less than about 30 mg/ml, less than about 20 mg/ml, less than about 10 mg/ml, or less than about 1 mg/ml.
  • modified release includes a release which is not immediate and includes controlled release, extended release, sustained release and delayed release.
  • time delay refers to the period of time between the administration of a dosage form comprising the composition of the invention and the release of the active ingredient from a particular component thereof.
  • lag time refers to the time between the release of the active ingredient from one component of the composition and the release of the active ingredient from another component of the composition.
  • electrode refers to formulations which may be worn away, diminished, or deteriorated by the action of substances within the body.
  • diffusion controlled refers to formulations which may spread as the result of their spontaneous movement, for example, from a region of higher to one of lower concentration.
  • osmotic controlled refers to formulations which may spread as the result of their movement through a semi-permeable membrane into a solution of higher concentration that tends to equalize the concentrations of the formulation on the two sides of the membrane.
  • the present invention provides a nanoparticulate composition
  • a nanoparticulate composition comprising particles which comprise: (A) ziprasidone, or a salt or derivative thereof; and (B) at least one surface stabilizer.
  • Nanoparticulate compositions were first described in U.S. Patent No.
  • Nanoparticulate active agent compositions are described also in, for example,
  • the effective average particle size of the particles in the nanoparticulate composition of the present invention is less than about 2000 nm (i.e., 2 microns) in diameter.
  • the effective average particle size may be, for example, less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, or less than about 50 nm in
  • a nanoparticulate composition of the present invention exhibits, for example, a T ma ⁇ for ziprasidone contained therein which is not greater than about 90% of the T max for the same ziprasidone delivered at the same dosage by a non-nanoparticulate composition.
  • the nanoparticulate composition of the present invention may exhibit, for example, a T max for ziprasidone contained therein which is not greater than about 80%, not greater than about 70%, not greater than about 60%, not greater than about 50%, not greater than about 30%, not greater than about 25%, not greater than about 20%, not greater than about 15%, not greater than about 10%, or not greater than about 5% of the T m a x for the same ziprasidone delivered at the same dosage by a non-nanoparticulate composition.
  • the T max of ziprasidone when assayed in the plasma of the mammalian subject is less than about 6 to about 8 hours after administration.
  • the T max of ziprasidone is less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour, or less than about 30 minutes after administration.
  • the nanoparticulate composition of the present invention may exhibit, for example, a C max for ziprasidone contained therein which is at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%, at least about 1100%, at least about 1200%, at least about 1300%, at least about 1400%, at least about 1500%, at least about 1600%, at least about 1700%, at least about 1800%, or at least about 1900% greater than the C max for the same ziprasidone delivered at the same dosage by a non-nanoparticulate composition.
  • a C max for ziprasidone contained therein which is at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%, at least about 1100%
  • the nanoparticulate composition of the present invention may exhibit, for example, an AUC for ziprasidone contained therein which is at least about 50%, at least about 75%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200%, at least about 225%, at least about 250%, at least about 275%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 550%, at least about 600%, at least about 750%, at least about 700%, at least about 750%, at least about 800%, at least about 850%, at least about 900%, at least about 950%, at least about 1000%, at least about 1050%, at least about 1100%, at least about 1150%, or at least about 1200% greater than the AUC for the same ziprasidone delivered at the same dosage by a non-nanoparticulate composition.
  • an AUC for ziprasidone contained therein which is at least about 50%, at
  • Benefits of a dosage form which substantially eliminates the effect of food include an increase in subject convenience, thereby increasing subject compliance, as the subject does not need to ensure that they are taking a dose either with or without food. This is significant as, with poor subject compliance, an increase in the medical condition for which the ziprasidone is being prescribed may be observed.
  • the difference in absorption of the composition of the invention, when administered in the fed versus the fasted state, preferably is less than about 100%, less than bout 95%, less than about 90%, less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 3%.
  • the nanoparticulate composition of the invention is proposed to have an unexpectedly dramatic dissolution profile. Rapid dissolution of ziprasidone is preferable, as faster dissolution generally leads to faster onset of action and greater bioavailability. To improve the dissolution profile and bioavailability of the ziprasidone, it would be useful to increase the drug's dissolution so that it could attain a level close to 100%.
  • Dissolution is preferably measured in a medium which is discriminating. Such a dissolution medium will produce two very different dissolution curves for two products having very different dissolution profiles in gastric juices; i.e., the dissolution medium is predictive of in vivo dissolution of a composition.
  • An exemplary dissolution medium is an aqueous medium containing the surfactant sodium lauryl sulfate at 0.025 M. Determination of the amount dissolved can be carried out by spectrophotometry. The rotating blade method (European Pharmacopoeia) can be used to measure dissolution.
  • Biorelevant pH is well known in the art.
  • the pH ranges from slightly less than 2 (but typically greater than 1) up to 4 or 5.
  • the pH can range from 4 to 6, and in the colon it can range from 6 to 8.
  • Biorelevant ionic strength is also well known in the art. Fasted state gastric fluid has an ionic strength of about 0.1M while fasted state intestinal fluid has an ionic strength of about 0.14. See e.g., Lindahl et al., "Characterization of Fluids from the Stomach and Proximal Jejunum in Men and Women," Pharm. Res., 14 (4): 497-502 (1997).
  • pH and ionic strength of the test solution is more critical than the specific chemical content. Accordingly, appropriate pH and ionic strength values can be obtained through numerous combinations of strong acids, strong bases, salts, single or multiple conjugate acid-base pairs (i.e., weak acids and corresponding salts of that acid), monoprotic and polyprotic electrolytes, etc.
  • the relative amounts of the ziprasidone and surface stabilizer present in the composition of the present invention can vary widely.
  • the optional amount of the individual components can depend, upon, among other things, the particular drug selected, the hydrophilic-lipophilic balance (HLB), melting point, and the surface tension of water solutions of the stabilizer.
  • the concentration of the ziprasidone can vary from about 99.5% to about 0.001%, from about 95% to about 0.1%, or from about 90% to about 0.5%, by weight, based on the total combined weight of the ziprasidone and surface stabilizer(s), not including other excipients.
  • Such exemplary cationic surface stabilizers and other useful cationic surface stabilizers are described in J. Cross and E. Singer, Cationic Surfactants: Analytical and Biological Evaluation (Marcel Dekker, 1994); P. and D. Rubingh (Editor), Cationic Surfactants: Physical Chemistry (Marcel Dekker, 1991); and J. Richmond, Cationic Surfactants: Organic Chemistry, (Marcel Dekker, 1990).
  • Such compounds include, but are not limited to, behenalkonium chloride, benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride, lauralkonium chloride, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cethylamine hydrofluoride, chlorallylmethenamine chloride (Quaternium-15), distearyldimonium chloride (Quaternium-5), dodecyl dimethyl ethylbenzyl ammonium chloride(Quaterniv ⁇ m- 14), Quaternium-22, Quaternium-26, Quaternium-18 hectorite, dimethylaminoethyl- chloride hydrochloride, cysteine hydrochloride, diethanolammom ' um POE (10) oletyl ether phosphate, diethanolammonium POE (3)oleyl ether phosphate, tallow alkonium chloride, dimethyl dioctade
  • Suitable disintegrants include lightly crosslinked polyvinyl pyrrolidone, corn starch, potato starch, maize starch, and modified starches, croscarmellose sodium, cross- povidone, sodium starch glycolate, and mixtures thereof.
  • effervescent agents are effervescent couples such as an organic acid and a carbonate or bicarbonate.
  • Suitable organic acids include, for example, citric, tartaric, malic, fumaric, adipic, succinic, and alginic acids and anhydrides and acid salts.
  • Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate.
  • sodium bicarbonate component of the effervescent couple may be present.
  • composition of the present invention may comprise also a carrier, adjuvant, or a vehicle (hereafter, collectively, “carriers”).
  • the nanoparticulate compositions can be made using, for example, milling, homogenization, precipitation, freezing, or template emulsion techniques. Exemplary methods of making nanoparticulate compositions are described in the '684 patent. Methods of making nanoparticulate compositions are described also in U.S. Patent Nos. 5,518,187; 5,718,388; 5,862,999; 5,665,331; 5,662,883; 5,560,932; 5,543,133; 5,534,270; 5,510,118; and 5,470,583.
  • Dispersions can be manufactured continuously or in a batch mode. One skilled in the art would understand that it may be the case that, following milling, not all particles may be reduced to the desired size. In such an event, the particles of the desired size may be separated and used in the practice of the present invention.
  • a nanoparticulate composition may be formed also by homogenization.
  • Exemplary homogenization methods are described in U.S. Patent No. 5,510,118, for "Process of Preparing Therapeutic Compositions Containing Nanoparticles.”
  • Such a method comprises dispersing particles comprising ziprasidone in a liquid dispersion medium, followed by subjecting the dispersion to homogenization to reduce the particle size to the desired effective average particle size.
  • the particles can be reduced in size in the presence of at least one surface stabilizer.
  • the particles can be contacted with one or more surface stabilizers either before or after attrition.
  • Other compounds, such as a diluent can be added to the composition before, during, or after the size reduction process.
  • Dispersions can be manufactured continuously or in a batch mode.
  • the active agent is admixed with at least one of the following: (a) one or more inert excipients (or carriers), such as sodium citrate or dicalcium phosphate; (b) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (c) binders, such as carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (d) humectants, such as glycerol; (e) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (f) solution retarders, such as paraffin; (g) absorption accelerators, such as quaternary ammonium compounds; (h) wetting agents, such as cetyl alcohol and glycerol monostearate; ( ⁇ ) adsorbent
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may comprise inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers.
  • the release profiles of dosage fo ⁇ ns may exhibit different rates and durations of release and may be continuous or pulsatile.
  • Continuous release profiles include release profiles in which a quantity of one or more pharmaceutical compounds is released continuously throughout the dosing interval at either a constant or variable rate.
  • Pulsatile release profiles include release profiles in which at least two discrete quantities of one or more pharmaceutical compounds are released at different rates and/or over different time frames. For any given pharmaceutical compound or combination of such compounds, the release profile for a given dosage form gives rise to an associated plasma profile in a patient.
  • the release profile of the dosage form as a whole is a combination of the individual release profiles and may be described generally as "multimodal.”
  • the release profile of a two-component dosage form in which each component has a different release profile may described as "bimodal," and the release profile of a three-component dosage form in which each component has a different release profile may described as "trimodal.”
  • the associated plasma profile in a patient may exhibit constant or variable blood plasma concentration levels of the pharmaceutical compounds over the duration of action and may be continuous or pulsatile.
  • Continuous plasma profiles include plasma profiles of all rates and duration which exhibit a single plasma concentration maximum.
  • Pulsatile plasma profiles include plasma profiles in which at least two higher blood plasma concentration levels of pharmaceutical compound are separated by a lower blood plasma concentration level and may be described generally as “multimodal.” Pulsatile plasma profiles exhibiting two peaks may be described as “bimodal” and plasma profiles exhibiting three peaks may be described as “trimodal.” Depending on, at least in part, the pharmacokinetics of the pharmaceutical compounds included in the dosage form as well as the release profiles of the individual components of the dosage form, a multimodal release profile may result in either a continuous or a pulsatile plasma profile upon administration to a patient.
  • the present invention provides a multiparticulate modified release composition which delivers ziprasidone, or nanoparticles containing ziprasidone, in a pulsatile manner.
  • the nanoparticles are of the type described above and comprise also at least one surface stabilizer.
  • the present invention provides a multiparticulate modified release composition which delivers ziprasidone, or nanoparticles containing ziprasidone, in a continuous manner.
  • the nanoparticles are of the type described above and comprise also at least one surface stabilizer.
  • the present invention provides a multiparticulate modified release composition in which a first portion of ziprasidone, or nanoparticles containing ziprasidone, is released immediately upon administration and one or more subsequent portions of ziprasidone, or nanoparticles containing ziprasidone, are released after an initial time delay.
  • the present invention provides solid oral dosage forms for once-daily or twice-daily administration comprising the multiparticulate modified release composition of the present invention.
  • the present invention provides a method for the prevention and/or treatment of schizophrenia and similar psychiatric disorders comprising the administration of a composition of the present invention.
  • the present invention provides a multiparticulate modified release composition in which the particles forming the multiparticulate are nanoparticulate particles of the type described above.
  • the nanoparticulate particles may, as desired, contain a modified release coating and/or a modified release matrix material.
  • a pharmaceutical composition having a first component comprising active ingredient- containing particles, and at least one subsequent component comprising active ingredient- containing particles, each subsequent component having a rate and/or duration of release different from the first component wherein at least one of said components comprises particles containing ziprasidone.
  • ziprasidone- containing particles that form the multiparticulate may themselves contain nanoparticulate particles of the type described above which comprise ziprasidone and also at least one surface stabilizer.
  • nanoparticulate particles of the type described above which comprise ziprasidone and also at least one surface stabilizer themselves are the drug-containing particles of the multiparticulate.
  • the drug-containing particles may be coated with a modified release coating.
  • the drug-containing particles may comprise a modified release matrix material.
  • the composition delivers ziprasidone, or nanoparticles containing ziprasidone, in a pulsatile manner.
  • the first component provides an immediate release of ziprasidone, or nanoparticles containing ziprasidone
  • the one or more subsequent components provide a modified release of ziprasidone, or nanoparticles containing ziprasidone.
  • the immediate release component serves to hasten the onset of action by minimizing the time from administration to a therapeutically effective plasma concentration level, and the one or more subsequent components serve to minimize the variation in plasma concentration levels and/or maintain a therapeutically effective plasma concentration throughout the dosing interval.
  • the modified release composition of the present invention is particularly useful for administering ziprasidone.
  • the proportion of ziprasidone contained in each component may be the same or different depending on the desired dosing regime.
  • the ziprasidone present in the first component and in subsequent components may be any amount sufficient to produce a therapeutically effective plasma concentration level.
  • the ziprasidone when applicable, may be present either in the form of one substantially optically pure stereoisomer or as a mixture, racemic or otherwise, of two or more stereoisomers.
  • the ziprasidone is present in the composition in an amount of from about 0.1 to about 500 mg. In another embodiment, the ziprasidone is present in the composition in an amount of from about 1 to about 100 mg.
  • the plasma profile may be continuous (i.e., having a single maximum) or pulsatile in which the peaks in the plasma profile may be well separated and clearly defined (e.g. when the lag time is long) or superimposed to a degree (e.g. when the lag time is short).
  • coating materials suitable for use in the practice of the present invention include but are not limited to polymer coating materials, such as cellulose acetate phthalate, cellulose acetate trimaletate, hydroxy propyl methylcellulose phthalate, polyvinyl acetate phthalate, ammonio methacrylate copolymers such as those sold under the trademark Eudragit RS and RL, poly acrylic acid and poly acrylate and methacrylate copolymers such as those sold under the trademark Eudragit ® S and L, polyvinyl acetaldiethylamino acetate, hydroxypropyl methylcellulose acetate succinate, shellac; hydrogels and gel-forming materials, such as carboxyvinyl polymers, sodium alginate, sodium carmellose, calcium carmellose, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, gelatin, starch, and
  • Polyox ® Union Carbide
  • Eudragit ® Rohm and Haas
  • other acrylic acid derivatives other acrylic acid derivatives
  • sorbitan esters natural gums, lecithins, pectin, alginates, ammonia alginate, sodium, calcium, potassium alginates, propylene glycol alginate, agar, and gums such as arabic, karaya, locust bean, tragacanth, carrageens, guar, xanthan, scleroglucan and mixtures and blends thereof.
  • excipients such as plasticisers, lubricants, solvents and the like may be added to the coating.
  • modified release component comprises a modified release matrix material
  • any suitable modified release matrix material or suitable combination of modified release matrix materials may be used. Such materials are known to those skilled in the art.
  • modified release matrix material includes hydrophilic polymers, hydrophobic polymers and mixtures thereof which are capable of modifying the release of ziprasidone, or a salt or derivative thereof, dispersed therein in vitro or in vivo.
  • a modified release composition according to the present invention may be incorporated into any suitable dosage form which facilitates release of the active ingredient in a pulsatile manner.
  • the dosage form comprises a blend of different populations of active ingredient-containing particles which make up the immediate release and the modified release components, the blend being filled into suitable capsules, such as hard or soft gelatin capsules.
  • suitable capsules such as hard or soft gelatin capsules.
  • the different individual populations of active ingredient-containing particles may be compressed (optionally with additional excipients) into mini-tablets which may be subsequently filled into capsules in the appropriate proportions.
  • Another suitable dosage form is that of a multilayer tablet. In this instance the first component of the modified release composition may be compressed into one layer, with the second component being subsequently added as a second layer of the multilayer tablet.
  • the plasma profile produced by the administration of dosage forms of the present invention which comprise an immediate release component comprising ziprasidone, or nanoparticles containing ziprasidone, and at least one modified release component comprising ziprasidone, or nanoparticles containing ziprasidone, can be substantially similar to the plasma profile produced by the administration of two or more IR dosage forms given sequentially, or to the plasma profile produced by the administration of separate IR and modified release dosage forms. Accordingly, the dosage forms of the present invention can be particularly useful for administering ziprasidone where the maintenance of pharmacokinetic parameters may be desired but is problematic.
  • release of ziprasidone from subsequent components may be delayed until substantially all of the ziprasidone contained in the first component has been released, and further delayed until at least a portion of the ziprasidone released from the first component has been cleared from the patient's system.
  • release of the ziprasidone from subsequent components of the composition is substantially, if not completely, delayed for a period of at least about two hours after administration of the composition.
  • the release of ziprasidone from subsequent components of the composition is substantially, if not completely, delayed for a period of at least about four hours after administration of the composition.
  • the present invention also includes various types of modified release systems by which ziprasidone may be delivered in either a pulsatile or continuous manner.
  • These systems include but are not limited to: films with ziprasidone, or nanoparticles containing ziprasidone, in a polymer matrix (monolithic devices); systems in which ziprasidone, or nanoparticles containing ziprasidone, is contained by a polymer (reservoir devices); polymeric colloidal particles or microencapsulates (microparticles, microspheres or nanoparticles) in the form of reservoir and matrix devices; systems in which ziprasidone, or nanoparticles containing ziprasidone, is contained by a polymer which contains a hydrophilic and/or leachable additive e.g., a second polymer, surfactant or plasticizer, etc.
  • a hydrophilic and/or leachable additive e.g., a second polymer, surfactant or plasticizer, etc.
  • the delivery mechanism of the present invention can control the rate of release of ziprasidone. While some mechanisms will release ziprasidone at a constant rate, others will vary as a function of time depending on factors such as changing concentration gradients or additive leaching leading to porosity, etc.
  • Polymers used in sustained release coatings are necessarily biocompatible, and ideally biodegradable.
  • examples of both naturally occurring polymers such as Aquacoat ® (FMC Corporation, Food & Pharmaceutical Products Division, Philadelphia, USA) (ethylcellulose mechanically spheronised to sub-micron sized, aqueous based, pseudo-latex dispersions), and also synthetic polymers such as the Eudragit ® (Rohm Pharma, Rothstadt.) range of poly(acrylate, methacrylate) copolymers are known in the art.
  • Transport properties of coated tablets may be enhanced compared to free- polymer films, due to the enclosed nature of the tablet core (permeant) which may enable the internal build-up of an osmotic pressure which will then act to force the permeant out of the tablet.
  • Monolithic Devices Monolithic (matrix) devices may be used for controlling the release of a drug.
  • nanoparticulate ziprasidone composition may be prepared.
  • An aqueous dispersion of 5% (w/w) ziprasidone, combined with one or more surface stabilizers, such as hydroxypropyl cellulose (HPC-SL) and dioctylsulfosuccinate (DOSS), may be milled in a 10 ml chamber of a NanoMill ® 0.01 (NanoMill Systems, King of Prussia, PA; see e.g., U.S. Patent No. 6,431,478), along with 500 micron PolyMill ® attrition media (Dow Chemical Co.) (e.g., at an 89% media load).
  • the mixture may be milled at a speed of 2500 rpms for 60 minutes.
  • the particle size of the milled ziprasidone particles can be measured, in deionized distilled water, using a Horiba LA 910 particle size analyzer.
  • the initial mean and/or D50 milled ziprasidone particle size is expected to be less than 2000 run.

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Abstract

La présente invention concerne une composition comprenant de la ziprasidone utilisée pour le traitement et la prévention de la schizophrénie et de troubles psychiatriques similaires. Dans un mode de réalisation, la composition inclut des nanoparticules comprenant de la ziprasidone et au moins un agent stabilisant de surface. Les nanoparticules ont une taille effective moyenne inférieure à 2000 nm environ. Dans un autre mode de réalisation, la composition comprend une composition de libération modifiée qui, après administration à un patient, délivre la ziprasidone de manière bimodale, multimodale ou continue. L'invention concerne également des formes galéniques contenant de telles compositions et des procédés de traitement et de prévention de la schizophrénie et de troubles psychiatriques similaires.
EP06773467A 2005-06-20 2006-06-19 Compositions de nanoparticules à libération contrôlée comprenant des composés d'aryle hétérocyclique Withdrawn EP1901722A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US69209605P 2005-06-20 2005-06-20
US11/372,857 US20060240105A1 (en) 1998-11-02 2006-03-10 Multiparticulate modified release composition
PCT/US2006/023695 WO2007027273A1 (fr) 2005-06-20 2006-06-19 Compositions de nanoparticules à libération contrôlée comprenant des composés d'aryle hétérocyclique

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EP1901722A1 true EP1901722A1 (fr) 2008-03-26
EP1901722A4 EP1901722A4 (fr) 2011-06-15

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EP (1) EP1901722A4 (fr)
KR (1) KR20080024206A (fr)
CN (1) CN101879140A (fr)
AU (1) AU2006285349A1 (fr)
BR (1) BRPI0612297A2 (fr)
CA (1) CA2613474A1 (fr)
EA (1) EA200800092A1 (fr)
HK (1) HK1117060A1 (fr)
IL (1) IL188093A0 (fr)
NO (1) NO20076628L (fr)
SG (1) SG162811A1 (fr)
WO (1) WO2007027273A1 (fr)

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BRPI0909818A2 (pt) * 2008-03-07 2015-10-06 Pfizer métodos, formas de dosagem e conjunto para administrar ziprasidona sem alimentos
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
US20130108701A1 (en) 2010-05-25 2013-05-02 Krishna Murthy Bhavanasi Solid Dosage Forms of Antipsychotics
MX2016007786A (es) 2013-12-16 2017-03-03 Massachusetts Inst Technology Formulaciones de sal de micronutrientes fortificadas.
WO2015095230A1 (fr) * 2013-12-16 2015-06-25 Massachusetts Institute Of Technology Formulations de vaccin micro-moulées ou imprimées en trois dimensions (3d) à libération pulsatile
MA41611A (fr) * 2015-02-23 2018-01-02 Omthera Pharmaceuticals Inc Préparations en milli-capsules comprenant des acides gras polyinsaturés libres

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EP0499299A2 (fr) * 1991-01-25 1992-08-19 NanoSystems L.L.C. Nanoparticules de médicaments à surface modifiée
EP0965343A2 (fr) * 1998-06-15 1999-12-22 Pfizer Products Inc. Formulations de ziprasidone
WO2000072847A1 (fr) * 1999-05-27 2000-12-07 Pfizer Products Inc. Suspension de ziprasidone
US20020012675A1 (en) * 1998-10-01 2002-01-31 Rajeev A. Jain Controlled-release nanoparticulate compositions
WO2005020929A2 (fr) * 2003-09-02 2005-03-10 Imran Ahmed Formes posologiques a liberation prolongee de ziprasidone
WO2006109183A1 (fr) * 2005-04-13 2006-10-19 Pfizer Products Inc. Formulations de depot injectables et procedes destines a assurer une liberation prolongee de compositions de nanoparticules

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AU660852B2 (en) * 1992-11-25 1995-07-06 Elan Pharma International Limited Method of grinding pharmaceutical substances
JP4613275B2 (ja) * 1998-11-02 2011-01-12 エラン ファーマ インターナショナル，リミティド 多粒子改質放出組成物
PL377679A1 (pl) * 2002-10-25 2006-02-06 Pfizer Products Inc. Nowe preparaty typu depot do wstrzykiwania

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Publication number Priority date Publication date Assignee Title
EP0499299A2 (fr) * 1991-01-25 1992-08-19 NanoSystems L.L.C. Nanoparticules de médicaments à surface modifiée
EP0965343A2 (fr) * 1998-06-15 1999-12-22 Pfizer Products Inc. Formulations de ziprasidone
US20020012675A1 (en) * 1998-10-01 2002-01-31 Rajeev A. Jain Controlled-release nanoparticulate compositions
WO2000072847A1 (fr) * 1999-05-27 2000-12-07 Pfizer Products Inc. Suspension de ziprasidone
WO2005020929A2 (fr) * 2003-09-02 2005-03-10 Imran Ahmed Formes posologiques a liberation prolongee de ziprasidone
WO2006109183A1 (fr) * 2005-04-13 2006-10-19 Pfizer Products Inc. Formulations de depot injectables et procedes destines a assurer une liberation prolongee de compositions de nanoparticules

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EA200800092A1 (ru) 2008-06-30
CN101879140A (zh) 2010-11-10
CA2613474A1 (fr) 2007-03-08
KR20080024206A (ko) 2008-03-17
NO20076628L (no) 2008-03-12
BRPI0612297A2 (pt) 2010-11-03
WO2007027273A1 (fr) 2007-03-08
AU2006285349A1 (en) 2007-03-08
SG162811A1 (en) 2010-07-29
HK1117060A1 (en) 2009-01-09
IL188093A0 (en) 2008-03-20
EP1901722A4 (fr) 2011-06-15

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