BRPI0612297A2 - stable nanoparticulate composition, method for preparing it, use thereof, pharmaceutical composition, use thereof, dosage form, controlled release composition, and use thereof - Google Patents

Abstract

STABLE NANOPARTICULATE COMPOSITION, METHOD FOR PREPARING IT, USE OF THE SAME, PHARMACEUTICAL COMPOSITION, USE OF THE SAME, FORM OF DOSAGE, CONTROLLED RELEASE COMPOSITION, AND, USE OF THE SAME. The present invention provides a composition comprising ziprasidone used in the treatment and prevention of schizophrenia and similar psychiatric disorders. In one embodiment, the composition comprises nanoparticulate particles comprising ziprasidone and at least one surface stabilizer. Nanoparticulate particles have an effective average particle size of less than about 2,000 nm. In another embodiment, the composition comprises a modified release composition which upon administration to a patient delivers ziprasidone in a bimodal, multimodal or continuous manner. The invention also relates to dosage forms containing such compositions, and methods for treating and preventing schizophrenia and similar psychiatric disorders.

Description

"STABLE NANOPARTICULATE COMPOSITION, METHOD FOR PREPARING IT, USE OF THE SAME, PHARMACEUTICAL COMPOSITION, SAME USE, DOSAGE FORM, CONTROLLED DELIBERATION COMPOSITION, AND, SAME USE"

FIELD OF INVENTION

The present invention relates to compositions which are used for the prevention and treatment of schizophrenia and similar psychiatric disorders. In particular, the present invention relates to compositions comprising a heterocyclic pharmaceutical compound, for example ziprasidone. In one aspect of the invention, the composition is in nanoparticulate form and also comprises at least one surface stabilizer. In another aspect, the present invention also relates to novel dosage forms for the controlled delivery of a heterocyclic aryl compound, e.g. ziprasidone, and methods for the prevention and treatment of schizophrenia and psychiatric-similar disorders.

BACKGROUND OF THE INVENTION

Ziprasidone, chemically known as 5- [2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] ethyl] -6-chloro-1,3-dihydro-2H-indol-2-one, It is a benzothiazolylpiperazine derivative that is used as an antipsychotic agent to treat psychiatric conditions such as schizophrenia, hallucinations, delusions, hostility and other bipolar disorders without increasing lipids and other blood fats. Ziprasidone has an empirical formula C21H21C1N4OS and molecular weight of 412.94 (free base).

The chemical structure of ziprasidone is shown below: <formula> formula see original document page 3 </formula>

Ziprasidone may be administered as part of a dosage form proposed under the registered trade name Geodon® in the United States by Pfizer Inc. Ziprasidone is present in Geodon® Capsules as the salt of ziprasidone hydrochloride, 5- (2- (4- (l 2,2-benzisothiazol-3-yl) piperazinyl) ethyl) -6-chloro-1,3-dihydro-2H-indol-2-oneamonohydrate. This salt is a white to slightly pink powder with a melting point of 300 ° C, an empirical formula of C 21 H 2 ClN 4 OSeHCleH 2 O and a weight of 467.42. Geodon® capsules are supplied for oral administration in 20 mg, 40 mg, 60 mg and 80 mg capsules. Inactive ingredients in Geodon® capsules include lactose, pregelatinized starch and magnesium stearate. General dosage for patients includes oral dosage forms (capsules) for treatment of schizophrenia in adults dosed at 20 milligrams (mg) twice daily with food. Higher dosages may include dosages of 80 mg twice daily.

Ziprasidone is available for intramuscular injection in the form of ziprasidone mesylate under the trade name Geodon® for Injection.Geodon® for injection contains a lyophilized form of trihydrate (5- (2- (4- (1,2-benzisothiazole-3-) mesiprate trihydrate il) piperazinyl) ethyl) -6-chloro-1,3-dihydro-2H-indol-2-one, methanesulfonate, trihydrate (empirical formula: C 21 H 2 ClN 4 OS-CH 3 SO 3 HeH 2 O; molecular weight: 563.09) Geodon® for injection is available from a single dose vial such as deziprasidone mesylate containing 20 mg ziprasidone / mL Ziprasidone has been approved by the US Food & Drug Administration (FDA) for schizophrenia treatment, and the intramuscular injection form daziprasidone is approved for acute agitation in schizophrenic patients.

The elimination half-life of ziprasidone is about 7 hours. Steady-state plasma concentrations are reached in one to three days. The bioavailability of ziprasidone is about 60% when taken with food. About one in twenty patients treated with high doses of Geodon® (360 mg per day) showed significant improvement in cognition.

Ziprasidone compounds have been described in U.S. Patent Nos. 4,831,031, 6,110,918, 6,245,765, 6,150,366, 6,232,304, 6,399,777 and 6,245,766. Published patents of the United States Nos. 2004/0138237 and2004 / 0146562 describe injectable ziprasidone depot formulations wherein the active ziprasidone compound is solubilized with a cyclodextrin to form a suspension.

Ziprasidone is highly effective in the therapeutic treatment of patients suffering from schizophrenia and similar mental disorders.

However, given the need to take ziprasidone twice a day and the additional need to take ziprasidone after meals, rigid patient compliance is a critical factor in the effectiveness of ziprasidonan in treating schizophrenia and similar mental disorders. In addition, such administration often requires the attention of personal care workers and contributes to the high cost associated with treatments involving Nazprasidone. Thus, there is a need in the technology of deziprasidone compositions to overcome these and other problems associated with their use of schizophrenia treatment and similar psychoses.

Additionally, ziprasidone is practically insoluble in water. This poor solubility results in poor bioavailability.

SUMMARY OF THE INVENTION

One embodiment of the invention encompasses a non-particulate composition comprising: (A) ziprasidone; and (B) at least one surface stabilizer. Surface stabilizer may be absorbed or associated with the surface of nanoparticulate particles. The particulate 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 used in the prevention and treatment of schizophrenia and similar psychiatric disorders and / or one or more pharmaceutically acceptable excipients. In such embodiments, administration of the nanoparticulate composition to an individual in a fed or fasted state may be bioequivalent and may present similar pharmacokinetics.

The present invention also relates to a first component modified deliberative composition comprising a first active ingredient-containing particle population and at least one second component comprising a second active ingredient-containing particle population, wherein each component has a different release rate and / or duration and wherein at least one of said components comprises ziprasidone. The particles of at least the second component are provided in a modified release (MR) form such as, for example, coated with a modified release coating or comprising or incorporated in a modified release matrix material. Upon oral administration to a patient, the composition releases one or more active ingredients in a bimodal or multimodal manner. Such modified release compositions may comprise a ziprasidone particulate form and at least one surface stabilizer, and may optionally comprise one or more additional active ingredients used. prevention and treatment of schizophrenia and psychiatric-similar disorders and / or one or more pharmaceutically acceptable excipients.

The first component of the modified release composition may have a variety of release profiles including profiles in which substantially all of the active ingredient contained in the first component is released rapidly upon administration of the tapping form, released rapidly, but after a delay time (delayed release), or released slowly over time. In one embodiment, the active ingredient contained in the first component of the dosage form is rapidly released upon administration to a patient. As used herein, "rapidly released" includes release profiles wherein at least about 80% of the active ingredient in a dosage form component is released within about an hour after administration, the term "delayed release" includes release profiles wherein The active ingredient of a dosage form component is released (rapidly or slowly) after a time delay, and the terms "controlled release and" extended release "include release profiles in which at least about 80% doing active ingredient contained in a component. of the dosage form is slowly released.

The second component of the modified release composition may also have a variety of release profiles including an immediate release profile, a delayed release profile or a controlled release profile. In one embodiment, the second component has a delayed release profile in which the active ingredient of the component is released after a delay time. In another embodiment, the second component has a controlled release profile in which the active ingredient of the component is released over a period of about 12 to about 24 hours after administration.

In two-component embodiments in which the components have different release profiles, the release profile of the active ingredients of the composition is bimodal. In modalities where the first component has an immediate release profile and the second component has a delayed release profile, there is a delay time between first ingredient active ingredient release and second component active ingredient release. The duration of the delay time may be varied by changing the amount and / or composition of the modified release coat or by changing the amount and / or composition of the modified release matrix material used to achieve the desired release profile. Thus, the duration of the delay time may be designed to mimic a desired plasma profile.

In modalities where the first component has an immediate release profile and the second component has a controlled deliberation profile, the active ingredients in the first and second components are released over different time periods. In such embodiments, the immediate release component serves to accelerate initiation of action by minimizing administration time to a therapeutically effective plasma concentration level, and the one or more subsequent components serve to minimize variation in plasma concentration levels and / or maintain a therapeutically plasma concentration. effective throughout the dosage range. In such a mode, the active ingredient in the first component is released rapidly and the active ingredient in the second component is released within a period of about 12 hours after administration. In another embodiment, the active ingredient in the first component is rapidly released and the active ingredient in the second component is released about 24 hours after administration. In yet another embodiment such as this, the active ingredient in the first component is released rapidly and the active ingredient in the second component is released over a period of about 12 hours after administration. In yet another embodiment such as this, the active ingredient in the first component is released rapidly and the active ingredient in the second component is released over a period of 24 hours after administration. In yet another embodiment such as this, the active ingredient in the first component is rapidly released and the active ingredient in the second component is released for a period of at least about 12 hours after administration. In yet another embodiment such as this, the active ingredient in the first component is rapidly released and the active ingredient in the second component is released for at least about 24 hours after administration.

The plasma profile produced by the administration of finger forms of the present invention comprising an immediate deliberation component and at least modified release component may be substantially similar to the plasma profile produced by the administration of two or more sequentially given IR dosage forms, or to the plasma profile produced by the present invention. administration of separate IR or MR dosage forms, the modified release composition of the present invention is particularly used for administration of ziprasidone which is usually administered twice daily. In one embodiment of the present invention, the composition distributes ziprasidone in a mannerimetric manner. Upon administration, such a composition produces a plasma profile that substantially mimics that obtained by sequential administration of two IR doses of ziprasidone according to a typical treatment regimen.

According to a further aspect of the present invention, the composition may be designed to produce a plasma profile that quimines or eliminates variations in plasma concentration levels associated with administration of two or more IR dosage forms thereafter. In such embodiments, the composition may be provided as an immediate release component to accelerate the onset of action by minimizing administration time to a therapeutically effective plasma concentration level, and at least modified release component to maintain a therapeutically effective plasma concentration level throughout the interval. Dosing Ziprasidon may be contained in nanoparticulate particles which also comprise at least one surface stabilizer.

Modified release compositions similar to those disclosed herein are disclosed and claimed in United States patent applications 6,228,398 and 6,730,325 to Devane et al.

The present invention also relates to dosage forms made of the compositions of the present invention. In one embodiment, the finger form is a solid oral dosage form comprising the modified release composition of the present invention. The oral dosage form uses, for example, erodible formulations, diffusion controlled formulations and osmotic controlled formulations. In such embodiments, the dosage form contained in the dosage form may be delivered in a pulsating or continuous manner. In such an embodiment, a portion of the total dose is released immediately to allow rapid onset of effect action, and the remainder of the total dose is released after a delay time or for a period of up to about 24 hours.

In another embodiment, the dosage form is an injectable depot formulation comprising a non-particulate 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 is also directed to a method of preparing a nanoparticulate composition comprising ziprasidone. Such a method comprises the step of bringing particulate particles comprising ziprasidone into contact with at least one surface stabilizer for a period of time and under sufficient conditions to provide a stabilized nanoparticulate composition comprising ziprasidone.

The present invention further relates to treatment methods 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.

The compositions and dosage forms of the present invention are used to reduce the required dosage frequency thereby increasing patient convenience and improving patient compliance and thus the therapeutic response for all treatments requiring ziprasidone including, but not limited to. , the prevention and treatment of schizophrenia and similar psychiatric disorders. This approach may replace conventional ziprasidon dosage forms, which are administered multiple times daily.

Both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the claimed invention. Other objects, advantages and unprecedented features will be readily apparent to those skilled in the art from the following detailed description of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is described herein using various definitions set forth below and throughout the patent application.

As used herein, "about" will be understood by those skilled in the art and will vary to some extent in the context in which it is used. If there are uses of the term that are unclear to those skilled in the technology given the context in which it is used, "about" will mean up to about 10% of the particular term. As used herein, "ziprasidone" includes ziprasidone, its salts, acids, pharmaceutically acceptable esters, metabolites, complexes or other derivatives thereof, and each of their respective stereoisomers including mixtures, racemic or otherwise, of two or more such stereoisomers.

As used herein, "therapeutically effective amount of disiprasidone" means the dosage that provides the specific pharmacological response for ziprasidone to be administered to a significant number of individuals in need of the relevant treatment. It is emphasized that a therapeutically effective amount of ziprasidone that is administered to a particular individual in a particular example will not always be effective in treating the conditions described herein, even if such dosing is considered a therapeutically effective amount by those skilled in the art.

As used herein, "particulate" refers to a state of matter which is characterized by the presence of discrete particles, precipitates, spheres or granules regardless of their size, shape or morphology.

As used herein, "multiparticulate" means a plurality of discrete or aggregated particles, precipitates, spheres or mixtures thereof regardless of their size, shape or morphology. A composition comprising a multiparticulate is described herein as a "multiparticulate composition".

As used herein, "nanoparticulate" refers to a multiparticulate where the effective average particle size of the particles thereof is less than about 2,000 nm (2 microns) in diameter. A composition comprising a nanoparticulate is described herein as a "nanoparticulate composition".

As used herein, "effective average particle size" to describe a multiparticulate (e.g., a nanoparticulate) means that at least 50% of its particles are of a specified size. Thus, "effective average particle size of less than about 2,000 nm in diameter" means that at least 50% of the particles here are less than about 2,000 nm in diameter.

As used herein, "D50" refers to the particle size below which 50% of the particles in a multiparticulate fall. Similarly, "D90" refers to the particle size below which 90% of the particles in a multiparticulate fall.

As used herein with reference to stable particles, "stable" refers to, but is not limited to, one or more of the following parameters: (1) particles do not appreciably flocculate or agglomerate due to interparticle attractive forces or otherwise significantly increase in size. of particle over time; (2) the physical structure of the particles does not change over time, such as by conversion of a phasorph to a crystalline phase; (3) the particles are chemically stable, and / or (4) where the active ingredient has not undergone a heating step at or above the melting point of the particles in the preparation of the nanoparticles of the present invention.

As used herein, "poorly water-soluble drug" refers to a drug that has a water solubility 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.

As used herein, "modified release" includes a release that is not immediate and includes controlled release, extended release, sustained release, and delayed release.

As used herein, "time delay" refers to the time period between administration of a dosage form comprising the composition of the invention and the release of the active ingredient from a particular component thereof. As used herein, "time delay" refers to the time between the release of the active ingredient from one composition component and the release of the active ingredient from another composition component.

As used herein, "erodible" refers to formulations that may be worn, diminished or deteriorated by the action of substances on the body.

As used herein, "diffusion controlled" refers to formulations that may spread as a result of their spontaneous movement, for example, from a region of higher concentration to a smaller size.

As used herein, "osmosis controlled" refers to formulations that may spread as a result of their movement across a semipermeable membrane in a higher concentration solution that tends to match the concentration of the formulation on both sides of the membrane.

I. Nanoparticulate Compositions Comprising Ziprasidone

The present invention provides a nanoparticulate composition comprising particles comprising: (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. 5,145,684. Nanoparticulate active agent compositions are also described in, for example, U.S. Pat. 5,298,262, 5,302,401.5,318,767, 5,326,552, 5,328,404, 5,336,507, 5,340,564, 5,346,702, 5,349,957,5,352,459, 5,399,363, 5,494,683, 5,401. 492, 5,429,824, 5,447,710, 5,451,393.5,466,440, 5,470,583, 5,472,683, 5,500,204, 5,518,738, 5,521,218, 5,525,328,5,543,133, 5,552,160, 5,565,188, 5,569,448, 5,571,536, 5,573,749, 5,573,750,5,573,783, 5,580,579, 5,585,108, 5,587,143, 5,591,456, 5,593,657, 5,622,938,5,628. 981, 5,643,552, 5,718,388, 5,718,919, 5,747,001, 5,834,025, 6,045,829,6,068,858, 6,153,225, 6,165,506, 6,221,400, 6,264,922, 6,267,989, 6,270,806,6,316,029, 6,375,986, 6,428,814, 6,431,478, 6,432,381, 6,582,285, 6,592,903.6,656,504, 6,742,734, 6,745,962, 6,811,767, 6,908. 626, 6,969,529, 6,976,647, and 6,991,191, and US Patent Nos. 20020012675, 20050276974,20050238725, 20050233001, 20050147664, 20050063913, 20020179758,20020012675 and 20010053664. Compositions of small amorphous particles are described, for example, in U.S. Pat. 4,783,484, 4,826,689,4,997,454, 5,741,522, 5,776,496.

As stated above, the effective mean particle size of the particles in the nanoparticulate composition of the present invention is less than about 2,000 nm (i.e. 2 microns) in diameter. In modalities of the present invention, the effective average particle size may, for example, be less than about 1,900 nm, less than about 1,800 nm, less than about 1,700 nm, less than about 1,600 nm, less than 1,500 nm, less than about 1,400 nm, less than about 1,300nm, less than about 1,200 nm, less than about 1,100 nm, less than about 1,000 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 mu, less than about 300 nm, less about 250 nm, less than about 200 nm, less than about 150 nm. nm, less than about 100 nm, less than about 75 nm, or less than about 50 nm in diameter, as measured by light scattering, microscopy, or other appropriate methods.

Nanoparticulate particles may exist in a crystalline phase, an amorphous phase, a semicrystalline phase, a semi-amorphous phase, or a mixture thereof.

In addition to allowing a smaller dosage form size, the nanoparticulate composition of the present invention has greater bioavailability, and requires lower doses of ziprasidone compared to prior conventional non-particulate compositions comprising ziprasidone. In one embodiment of the invention, the nanoparticulate composition of the present invention has a bioavailability that is about 50% greater than ziprasidone administered in a conventional dosage form. In other embodiments, the nanoparticulate composition of the present invention has a bioavailability that is about 40% greater, about 30% greater, about 20% or about 10% greater than ziprasidone administered in a conventional dosage form.

The nanoparticulate composition may also have a desirable pharmacokinetic profile measured following the initial dosage thereof to a mammalian subject. The desirable pharmacokinetic profile of the composition includes, but is not limited to: (1) a Cmax for ziprasidone when tested in a mammalian plasmid after administration which is preferably greater than the Cmax for the same ziprasidone delivered at the same dosage by a non-nanoparticulate composition; and / or (2) an AUC for ziprasidone when tested in a mammalian plasma after administration which is preferably greater than the AUC for mesmaziprasidone delivered at the same dosage by a non-particulate composition; and / or (3) a Tmax for ziprasidone when tested in a mammalian subject's plasma after administration which is preferably less than the Tmax for the same ziprasidone distributed in the same dosage by a non-nanoparticulate composition.

In one embodiment of the present invention, a non-particulate composition of the present invention has, for example, a Tmax paraziprasidone contained therein which is not greater than about 90% of the Tmax for the same ziprasidone distributed at the same dosage as a non-particulate composition. In other embodiments of the present invention, the non-particulate composition of the present invention may have, for example, a Tmax for ziprasidone contained therein which is no greater than about 80%, no greater than about 70%, no greater than about 60%, no larger that about 50%, no greater than about 30%, no greater than about 25%, no greater than about 20%, no greater than about 15%, no greater than about 10%, no greater than about 5% Tmax for the same ziprasidone distributed at the same dosage by a non-nanoparticulate composition. In one embodiment of the invention, the ziprasidone Tmax when assayed in mammalian plasma is less than about 6 to about 8 hours after administration. In other embodiments of the invention, ziprasidone Tmax 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.

In one embodiment of the present invention, a non-particulate composition of the present invention has, for example, a Cmax paraziprasidone contained therein which is at least about 50% of Cmax for the same ziprasidone distributed at the same dosage as a non-particulate composition. In other embodiments of the present invention, the non-particulate composition of the present invention may have, for example, a Cmax 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 1,000%, at least about 1,100%, at least about 1,200%, at least about 1,300%, at least about 1,400%, at least about 1,500%, at least about 1,600%, at least about 1,700%, at least about 1,800%, or at least about 1,900% higher than Cmax for the same ziprasidone distributed at the same dosage by a non-nanoparticulate composition.

In one embodiment of the present invention, a non-particulate composition of the present invention has, for example, a paraziprasidone AUC contained therein which is at least about 25% greater than AUC for the same ziprasidone distributed at the same dosage by a non-nanoparticulate composition. In other embodiments of the present invention, the nanoparticulate composition of the present invention may have, for example, a ziprasidone AUC 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 1,000%, at least about 1,050%, at least about 1,100%, at least about 1150%, or at least about 1,200% higher than AUC for the same ziprasidone distributed at the same dosage over a non-nanoparticulate composition.

The invention encompasses a nanoparticulate composition wherein the pharmacokinetic profile of ziprasidone following administration is not substantially affected by an individual's fed or fasted state ingesting the composition. This means that there is no substantial difference in the quality of absorbed ziprasidone or the rate of absorption when nanoparticulate composition is administered in the fasted fed state. In conventional ziprasidone formulations, ie Geodon®, ziprasidone absorption is increased when administered with food.

This difference in absorption observed with conventional ziprasidon formulations is undesirable. The composition of the invention overcomes this problem.

The benefits of a dosage form that substantially eliminates the effect of food include increased convenience for the individual, thereby increasing the individual's compliance, as the individual need not ensure that they are taking a dose as much as without food. This is significant since, with poor patient compliance, an increase in the medical condition for which aziprasidone is prescribed may be observed.

The invention also encompasses a nanoparticulate composition comprising ziprasidone wherein administration of the composition to an individual in the fasted state is bioequivalent to administration of the composition to an individual in the fed state.

The difference in absorption of the composition of the invention when administered in the fed versus fast state is preferably less than about 100%, less than about 95%, less than about 90%, less than about 85%, less than about 100%. 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 (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%.

In one embodiment of the invention, the invention encompasses a composition comprising ziprasidone wherein the administration of the composition to a fasted subject is bioequivalent to the administration of the composition to an individual in the fed state, particularly as defined by Foode's Cmax and AUC baselines. United States Drug Administration and the corresponding European Regulatory Agency (EMEA). Under US FDA baselines, two products or methods are bioequivalent if the 90% confidence intervals (CI) for AUC and Cmax are between 0.80 to 1.25 (Tmax measurements are not relevant for bioequivalence for regulatory purposes). ) .To show the bioequivalence between two compounds or administration conditions that persist to the European EMEA baselines, the 90% CI for AUC should be between 0.80 to 1.25 and the 90% CI for Cmax should be between 0 , 70 to 1.43.

It is proposed that the nanoparticulate composition of the invention has an unexpected dramatic dissolution profile. Rapid dissolution of daziprasidone is preferable since faster dissolution generally leads to faster onset of action and increased bioavailability. To improve the dissolution profile and bioavailability of ziprasidone, it would be useful to increase the dissolution of the drug so that it could reach a level close to 100%.

The compositions of the invention preferably have a dissolution profile wherein in about 5 minutes at least about 20% daziprasidone is dissolved. In other embodiments of the invention, at least about 30% or at least about 40% of ziprasidone is dissolved within 5 minutes. In still other embodiments of the invention, preferably at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% of ziprasidone is dissolved in about 10%. minutes Finally, in another embodiment of the invention, preferably at least about 70%, at least about 80%, at least about 90%, or at least about 100% of ziprasidone is dissolved in about 20 minutes.

Dissolution is preferably measured in a medium that is selective. Such a dissolution medium will produce two very different dissolution curves for two products with very different dissolution profiles in the gastric juice; that is, the dissolution medium is predictive of in vivo dissolution of a composition. An exemplary dissolution medium is an aqueous medium containing 0.025% sodium lauryl sulfate surfactant. Determination of the dissolved amount can be performed by spectrophotometry. The rotary slide method (European Pharmacopoeia) can be used to measure dissolution.

A further feature of the nanoparticulate composition of the invention is that particles of it redisperse such that the particles have an effective average particle size of less than about 2,000 nm in diameter. This is significant because, if the particles do not disperse such that they have an effective average particle size of less than about 2,000 nm in diameter, the composition may lose the benefits provided by formulating ziprasidone thereof in a nanoparticulate form. This is because the benefit of small particle size nanoparticulate compositions comprises aziprasidone. If the particles do not redisperse into small particle sizes upon administration, then "aggregates" or agglomerated particles are formed due to the extremely high surface free energy of the nanoparticulate system and the thermodynamic thrust force to achieve an overall reduction in free energy. With the formation of such agglomerated particles, the bioavailability of the dosage form may fall well below that observed with the liquid dispersion form of the non-particulate composition.

In other embodiments of the invention, the redispersed particles of the invention (redispersed in water, a biorelevant, or any other suitable liquid medium) have an effective average particle size of less than about 1,900 nm, less than about 1,800 nm, less than about 1 nm. .700 nm, less than about 1,600 nm, less than about 1,500 nm, less than about 1,400 nm, less than about 1,300 nm, less than 1,200 nm, less than about 1,100 nm, less than about 1,000 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 diameter, as measured by scattering methods. light, microscopy, or other appropriate methods. Such methods suitable for measuring the effective average particle size are known by a skilled technology.

Redispersibility may be tested using any of the appropriate means known in the art. See, for example, sections of U.S. Patent Example No. 6,375,986 for "Solid Dose NanoparticulateCompositions Understanding a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctil Sodium Sulfosuccinate."

The nanoparticulate composition of the present invention will exhibit dramatic dispersion of the particles upon administration to a mammal, such as a human or animal, demonstrated by reconstitution / redispersion in a biorelevant aqueous medium such that the effective particle size of the redispersed particles is less than about 2,000 nm. Such a biorelevant aqueous medium can be any aqueous medium which has the desired ionic strength and pH, which form the basis for the biorelevance of the domain. The desired pH and ionic strength are those that are representative of the physiological conditions found in the human body. Such an aqueous-relevant medium may be, for example, aqueous electrolyte solutions or aqueous solutions of any salt, acid or base or a combination thereof, which have the desired pH and ionic strength.

Biorelevant pH is well known in technology. For example, in the stomach the pH ranges from slightly less than 2 (but typically more than 1) to 4 or 5. In the small intestine the pH may range from 4 to 6, and in the colon it may range from 6 to 8. Biorelevant ionic strength It is also well known in technology. Fasted state gastric fluid has an ionic strength of about 0.1 M whereas fasted state intestinal fluid has an ionic strength of about 0.14. See, for example, Lindahl et al., "Characterization of Fluids from the Stomach and Proximal Fasting in Men and Men," Pharm. Res., 14 (4): 497-502 (1997). The pH and strength of the test solution are believed to be more critical than the specific chemical content. In this way, appropriate pH and ionic strength values can be obtained by numerous combinations of strong acids, strong bases, salts, single or multiple conjugated acid-base pairs (ie corresponding acidic and weak acidic acids), monoprotic electrolytes, polyprotics. , etc.

Representative electrolyte solutions may be, but are not limited to, HCl solutions, ranging in concentration from about 0.001 to about 0.1 N, and NaCl solutions, ranging in concentration from about 0.001 to about 0.1 M, and mixtures of these. For example, electrolyte solutions may be, but are not limited to, about 0.1 N HCl or less, about 0.01 N HCl or less, about 0.001 N HCl or less, about 0.1 MNaCl or less. about 0.01 M NaCl or less, about 0.001 M NaCl or less, and mixtures thereof. Of these electrolyte solutions, 0.01 M HCl and / or 0.1 M NaCl are more representative of fasting human physiological conditions due to the pH and ionic strength conditions of the proximal gastrointestinal tract.

Electrolyte concentrations of 0.001 N HCl, 0.01 N HCl, and 0.1 N HCl correspond to pH 3, pH 2, and pH 1, respectively. Thus, a 0.01 N HCl solution simulates typical acid conditions found in the stomach. A 0.1 M NaCl solution provides a reasonable approximation of ionic strength conditions found throughout the body, including gastrointestinal fluids, although concentrations greater than 0.1 M may be employed to simulate food conditions in the human GI tract.

Exemplary solutions of salts, acids, bases or combinations thereof having the desired pH and ionic strength include, but are not limited to, phosphoric acid / phosphate salts + sodium, potassium and calcium chloride salts, acetic acid / acetate salts + sodium salts , potassium and calcium chloride, carbonic acid / bicarbonate salts + sodium, potassium and calcium chloride salts, and citric acid / citrate salts + sodium, potassium and calcium chloride salts.

As previously stated, the composition also comprises at least one surface stabilizer. Surface stabilizer may be absorbed or associated with the surface of ziprasidone-containing particles. Preferably, the surface stabilizer adheres to or associates with the surface of the particles, but does not react chemically with the particles or other surface stabilizing molecules. Individually absorbed molecules of the surface stabilizer are essentially without intermolecular crosslinking.

The relative amount of ziprasidone and surface stabilizer present in the composition of the present invention may vary widely. The ideal amount of the individual components may depend, among other things, on the particular drug selected, the hydrophilic-lipophilic balance (HLB), melting point, and the surface tension of the stabilizer's aqueous solutions. The concentration of ziprasidone may range from about 99.5% to about 0.001%, from about 95% to about 0.1%, or about 90% to about 0.5% by weight, based on weight. combined total daziprasidone and surface stabilizer (s) without including other excipients. The concentration of surface stabilizer (s) may range from about 0.5% to about 99.999%, from about 5.0% to about 99.9%, or from about 10% to about 99.5% by weight. weight, based on the total combined dry weight of daziprasidone, or a salt or derivative thereof, and surface stabilizer (s), not including other excipients.

The choice of aziprasidone surface stabilizer (s) is non-trivial and required extensive experimentation to achieve a desirable formulation. Accordingly, the present invention is directed to the surprising discovery that nanoparticulate compositions comprising ziprasidone may be prepared.

Combinations of more than one surface stabilizer may be used in the invention. Useful surface stabilizers that may be employed in the invention include, but are not limited to, known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Surface stabilizers include nonionic, anionic, cationic, ionic and zwitterionic surfactants.

Representative examples of surface stabilizers include hydroxypropyl methylcellulose (now known as hypromellose), hydroxypropylcellulose, polyvinylpyrrolidone, sodium lauryl sulfate, dioctylsulfosuccinate, gelatin, casein, lecithin (phosphatides), dextran, gumacacia, cholesterol, tragacanthium, benzoic acid calcium stearate, glyceryl monostearate, cetostearyl alcohol, cetomacrogol wax emulsifier, sorbitan esters, polyoxyethylene alkyl ethers (eg macrogol ethers such as cetomacrogol 1,000), polyoxyethylene castorene fatty acid esters (polyoxyethylene sorbitan esters) commercially available Tweens®, such as, for example, Tween 20® and Tween 80® (ICI Specialty Chemicals)), polyethylene glycols (e.g. Carbowaxs 3550 and 934 (Union Carbide)), polyoxyethylene stearates, silicon dioxide colloidal, phosphates, calcium carboxylcellulose, carboxymethylcellu lose sodium, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, non-crystalline cellulose, aluminum magnesium silicate, triethanolamine, polyvinyl alcohol (PVA), 4- (1,1,3,3-tetramethylbutyl) -phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol, superione, and triton); poloxamers (for example, Pluronics F68® and F108®, which are ethylene oxide and propylene oxide block copolymers); poloxamines (e.g. Tetronic 908®, also known as Poloxamine 908®, which is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide diamine (BASF Wyandotte Corporation, Parsippany, N.J.)); Tetronic1508® (T-1508) (BASF Wyandotte Corporation), Tritons X-200®, which is an alkyl aryl polyether sulfonate (Rohm and Haas); Crodestas F-110®, which is a mixture of sucrose stearate and sucrose distearate (Croda Inc.); P-isononylphenoxypoly- (glycidol), also known as Olin-10G® or 10-G® Surfactant (Olin Chemicals, Stamford, CT); Crodestas SL-40® (Croda, Inc.); and SA90HCO, which is C18 H37 CH2 (CC) N (CH3) -Ch2 (CHOH) 4 (CH2OH) 2 (Eastman Kodak Co.); decanoyl-N-methylglucamide; n-decyl (3-D-glycopyranoside; n-decyl (3-D-maltopyranoside; n-dodecyl (3-D-glycopyranoside; n-dodecyl (3-D-maltoside; heptanoyl-N- methylglucamide; n-heptyl (3-D-glycopyranoside; n-heptyl RD-thioglycoside; n-hexyl PD-glycopyranide; nonanoyl-N-methylglucamide; n-noyl 3-D-glycopyranide; octanoyl-N-methylglucamide; octyl-PD-glycopyranoside; octyl (3-D-thioglycopyranoside; PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, lysozyme, random vinyl pyrrolidone and vinyl acetate copolymers, and similar.

Examples of useful cationic surface stabilizers include, but are not limited to, compounds of polymers, biopolymers, polysaccharides, cellulosics, alginates, phospholipids, and nonpolymerics, such as zwitterionic stabilizers, poly-n-methylpyridinium chloride, cationic phospholipids, polyisine, chitosan, chitosan , polyvinylimidazole, polybrene, polymethyl trimethylammonium methacrylate bromide (PMMTMABr), hexyldisyltrimethylammonium bromide (HDMAB), and polyvinylpyrrolidone-2-dimethylaminoethyl dimethyl methacrylate sulfate.

Other useful cationic stabilizers include, but are not limited to, cationic lipid compounds, sulfonium, phosphonium and quaternary ammonium, such as stearyltrimethylammonium chloride, benzyl di (2-chloroethyl) ethylammonium bromide, trimethyl ammonium coconut chloride or bromide, chloride or methyl coconut bromide dihydroxyethyl ammonium, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride or bromide, dimethyl hydroxyethyl C12-15 ammonium chloride or bromide, dimethyl hydroxyethyl ammonium chloride or bromide, myristyl trimethyl ammonium methyl sulfate, lauryl dimethyl benz chloride or bromide lauryl dimethyl (ethenoxy) 4 ammonium chloride or bromide, N-alkyl dimethylbenzyl (C1-18) ammonium chloride, N-alkyl dimethyl (C1-4) -benzyl ammonium chloride, monohydrate N-tetradecylidomethylbenzylammonium chloride, dimethyl didecyl ammonium, N-alkyl and dimethyl (C 2-4) 1-naphthylmethyl ammonium chloride, trimethylammonium halide, alkyl trimethyl salts ammonium and dialkyl dimethyl ammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkylamidoalkylalkyl ammonium salt and / or an ethoxylated detralkyl ammonium salt, dialkyl ammonium chloride, N-didecyl dimethyl ammonium chloride (N-tetradecyl dimethylbenzyl ammonium chloride) 14) 1-Naphthylmethyl ammonium dodecyldimethylbenzyl ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methylammonium chloride, alkyl benzyl dimethyl ammonium bromide, C12, C15, Cl7 ammonium trimethyl ammonium dibenzyl chloride poly-diallyl dimethyl ammonium chloride (DADMAC), dimethyl ammonium chloride, dealkyl dimethyl ammonium halides, tricetyl methyl ammonium chloride, dedecyltrimethyl ammonium bromide, dodecyl trimethyl ammonium bromide, methyl triethyl ammonium chloride (ALI) Tetrahydroamide (ALI) bromet benzyltrimethylammonium, choline esters (such as fatty acid choline esters), benzalkonium chloride, stearalconium chloride compounds (such as stearyltrimonium chloride and Di-stearyldimonium chloride), bromide or chloride of cetyl pyridinium chloride, polyoxyethylated alkylamines halide salts, MIRAPOL ™ and ALKAQUAT ™ (Alkaril Chemical Company), alkyl pyridinium salts; amines such as alkylamines, dialkylamines, alkanolamines, polyethylene polyamines, N, N-dialkylaminoalkyl acrylates, and vinyl pyridine, amine salts such as lauryl amine acetate, alkyl stearyl acetate and alkylimidazolium salt and deamine oxides, and ; imide azolinium salts; protonated quaternary acrylamides; methylated quaternary polymers such as poly [diallyl dimethylammonium chloride] and poly [N-methyl vinyl pyridinium chloride]; and cationic guar.

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 (MareeiDekker, 1994); P. and D. Rubingh (Editor), Cationic Surfactants: Physical Chemistry (Mareei Dekker, 1991); and J. Richmond, Cationic Surfactants: Organic Chemistry, (Mareei Dekker, 1990).

Nonpolymeric surface stabilizers are any nonpolymeric compound such as benzalkonium chloride, a carbonate compound, a phosphonium compound, an oxonium compound, a halon compound, a cationic organometallic compound, a phosphorous quaternary compound, a pyridinium compound, a compound of anilinium, an ammonium compound, a hydroxylammonium compound, a primary ammonium compound, a secondary ammonium compound, a tertiary ammonium compound, and quaternary ammonium compounds of the formula NRiR2R3R4 ^. For compounds of the formula NR1R2R3R4 ^:

(i) none of R1-R4 are CH3;

(ii) one of R1-R4 is CH3;

(iii) three of R 1 R 4 are CH 3;

(iv) all of RrR4 are CH3;

(v) two of R1-R4 are CH3, one of R1-R4 is C6H5CH2, and one of R1-R4 is an alkyl chain of seven carbon atoms or less, (vi) two of R1-R4 are CH3, one of R1-R4 is C6H5CH2, and one of R1-R4 is an alkyl chain of nineteen carbon atoms or more;

(vii) two of R1-R4 are CH3 and one of R1-R4 is the group C6H5 (CH2) n, where η> 1;

(viii) two of R1-R4 are CH3, one of R1-R4 is C6H5CH2, and one of R1-R4 comprises at least one heteroatom;

(ix) two of R1-R4 are CH3, one of R1-R4 is C6H5CH2, and one of R1-R4 comprises at least one halogen;

(x) two of R1-R4 are CH3, one of RpR4 is C6H5CH2, and one of R1-R4 comprises at least one cyclic fragment;

(xi) two of RpR4 are CH3 and one of R1-R4 is a phenyl ring; or

(xii) two of R1-R4 are CH3 and two of RrR4 are fragmentally aliphatic.

Such compounds include, but are not limited to, debeenalkonium chloride, benzethonium chloride, cetylpyridinium chloride, debentrimonium chloride, lauralconium chloride, ketalconium chloride, decetrimonium chloride, cetrimonium chloride, decloralylmethanamine chloride (Quaternium-15), distearyldimonium chloride (Quaternium-5), dodecyl dimethyl ethylbenzyl ammonium chloride (Quatemium-14), Quaternium-22, Quaternium-26, Quaternium-18 hectorite, dimethylaminoethyl chloride, cysteine hydrochloride, eterdiethanolammonium phosphate POE (10) , diethanolammonium ether phosphate POE (3) oletyl, alkali wax chloride, dimethyl dioctadecylammonium bentonite, stearalconium chloride, domiphene bromide, denatonium benzoate, demirystalconium chloride, laurtrimine dihydrochloride hydrochloride hydrochloride hydrochloride hydrochloride of iofetamine, meglumine hydrochloride, methylbenzetonium chloride, miti bromide mmonium, oleyl trimmonium chloride, polyquaternium-1, procaine hydrochloride, cocobetaine, stearalconium bentonite, stearalconiumectonite, trihydroxyethylpropylenediamine steari dihydrofluoride, trimonium wax chloride and hexadecyltrimethylammonium bromide.

Surface stabilizers are commercially available and / or may be prepared by techniques known in the art. Most of these surface stabilizers are known pharmaceutical excipients and are described in detail in the Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain (The Pharmaceutical Press, 2000).

The compositions of the invention may comprise, in addition toziprasidone, one or more compounds used in the treatment of schizophrenia or similar mental disorders and related conditions. The composition may also be administered together with a compound such as this. These other active compounds preferably include those used to treat body conditions such as headaches, fevers, bruises, and other similar conditions that are generally caused by schizophrenia and similar psychiatric disorders. Such active compounds should be present in a manner, as determined by a skilled artisan, such that they do not interfere with the therapeutic effect of daziprasidone.

The composition of the present invention may also comprise one or more binding agents, fillers, diluents, lubricating agents, emulsifying and suspending agents, sweetening agents, flavoring agents, preservatives, buffers, wetting agents, disintegrants, effervescing agents, perfuming agents, and other excipients. . Such excipients are known in the art. Moreover, the prevention of microorganism growth can be guaranteed by the addition of various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. For use in injectable formulations, the composition may also comprise isotonic agents such as sugars, sodium chloride and the like and agents for use in delaying absorption of the injectable pharmaceutical form such as aluminum monostearate and gelatin.

Examples of fillers are lactose monohydrate, anhydrous lactose, and various starches; Examples of binding agents are various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose such as Avicel® PH10O and Avicel® PH102, microcrystalline cellulose, and salified cellulosemicrocrystalline (ProSolv SMCC ™).

Suitable lubricants, including agents that act on the dustability of the powder to be compressed, are colloidal silicon dioxide, such as Aerosil® 200, talc, stearic acid, magnesium stearate, decalcium stearate, and silica gel.

Examples of sweeteners are any natural or artificial sweetener, such as sucrose, xylitol, saccharin sodium, cyclamate, aspartame, eacessulfame. Examples of flavoring agents are Magnasweet® (MAFCO trade name), chewing gum flavor, and its flavors, and the like.

Examples of preservatives are potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other parahydroxybenzoic acid esters such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as chloride of benzalkonium.

Suitable diluents include inert pharmaceutically acceptable fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and / or mixtures of any of the foregoing. Examples of diluents include microcrystalline cellulose such as Avicel® PH101 and Avicel® PH102; lactose, such as lactose monohydrate, anhydrous lactose, and Pharmatose® DCL21; dibasic calcium phosphate, such as Emcompress®; mannitol; starch; sorbitol; sucrose; and glucose.

Suitable disintegrants include lightly cross-linked pyrrolidone polyvinyl, corn starch, potato starch, corn starch, modified starches, croscarmellose sodium, cross-linked povidone, sodium starch glycolate and mixtures thereof.

Examples of effervescent agents are effervescent pairs, 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 acid anhydrides and 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. Alternatively, only the bicarbonate sodium component of the effervescent pair may be present.

The composition of the present invention may also comprise a carrier, adjuvant, or a vehicle (hereinafter collectively referred to as "carriers").

Nanoparticulate compositions may be prepared using, for example, milling, homogenization, precipitation, freezing, or template emulsion techniques. Exemplary methods of preparing nanoparticulate compositions are described in '684 patent. Methods of preparing nanoparticulate compositions are also described in U.S. patents. We. 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.

In one method, particles comprising ziprasidone are dispersed in a liquid dispersion medium wherein ziprasidone is poorly soluble. Mechanical means are then used in the presence of grinding media to reduce particle size to the desired effective average particle size. The dispersion medium may be, for example, water, safflower oil, ethanol, t-butanol, glycerine, polyethylene glycol (PEG), hexane, or glycol. A preferred dispersion medium is water. The particles may be reduced in size and in the presence of at least one surface stabilizer. Particles comprising ziprasidone may be placed in common or more surface stabilizing contact after friction. Other compounds, such as a diluent, may be added to the composition during the size reduction process. Dispersions can be produced continuously or in a batch mode. One of skill in the art will appreciate that it may be the case that, after grinding, not all particles can be reduced to the desired size. In such an event, particles of the desired size may be separated and used in the practice of the present invention.

Another method of forming the desired nanoparticulate composition is by microprecipitation. This is a method of preparing stable dispersions of poorly soluble ziprasidone in the presence of surface stabilizer (s) and one or more surface active agents that improve colloidal stability without any trace of toxic solvent or solubilized heavy metal impurities. A method such as this comprises, for example: (1) dissolving ziprasidone in a suitable solvent; (2) adding the formulation of step (1) to a solution comprising at least one surface stabilizer; and (3) precipitating the formulation from step (2) using an appropriate non-solvent. The method may be followed by removal of any salt formed, if present, by dialysis or diafiltration and concentration of the dispersion by conventional means.

A nanoparticulate composition can also be formed by homogenization. Exemplary homogenization methods are described in U.S. Patent No. 5,510,118, for "Process of Preparing Therapeutic Compositions Containing Nanoparticles." A method such as this comprises dispersing particles comprising ziprasidone in a liquid dispersing medium after subjecting the dispersion to homogenization to reduce the particle size to the desired effective average particle size. The particles may be reduced in size in the presence of at least one surface stabilizer. The particles may be placed in common or more surface stabilizing contact both before and after friction. Other compounds, such as a diluent, may be added to the composition before, during or after the size reduction process. Dispersions may be produced continuously or in a batch mode.

Another method of forming the desired nanoparticulate composition is by liquid spray freeze (SFL). This technology comprises injecting an organic or organo-aqueous solution of surface stabilizing ziprasidone (s) into a cryogenic liquid, such as nitrogenous liquid. The solution droplets containing the drug freeze at a rate sufficient to minimize particle crystallization and growth, thereby formulating nanostructured particles. Depending on the choice of solvent system and processing conditions, the particles may vary particle thermorphology. In the isolation step, the dissolving nitrogen is removed under conditions that prevent agglomeration or maturation of the particles.

As a complementary technology to SFL, fast freezing (URF) can also be used to create equivalent nanostructured particles with much better surface area. URF comprises taking a water-miscible, anhydrous, organic or aqueous solution of ziprasidone and surface stabilizer (s) and applying it to a cryogenic substrate. The solvent is then removed by such freeze drying or atmospheric freeze drying with the remaining nanostructured particles.

Another method of forming the desired nanoparticulate composition is by emulsion template. Jig emulsion creates nanostructured particles with controlled particle size distribution and fast dissolving performance. The method comprises preparing an oil-in-water emulsion and then digesting it with a non-aqueous solution comprising ziprasidone and surface stabilizer (s). Particle size distribution is a direct result of the emulsion droplet size prior to loading the emulsion with the medicament. Particle size can be controlled and designed in this process. In addition, through the selected use of solvents and stabilizers, emulsion stability is achieved without any Ostwald maturation or suppression thereof. Subsequently, the solvent and water are removed, and the stabilized nanostructured particles are recovered. Various particle morphologies can be achieved by proper control of the processing conditions.

The invention also provides a method comprising administering an effective amount of a nanoparticulate composition comprising ziprasidone.

The composition of the present invention may be formulated for parenteral (e.g. intravenous, intramuscular, or subcutaneous), oral (e.g. solid, liquid or aerosol, vaginal), nasal, rectal, ocular, local (e.g. powder, ointment or gout), buccal, intracisternal, intraperitoneal or topically and the like.

The nanoparticulate composition may be used in solid or liquid dosage formulations such as liquid dispersions, gels, aerosols, ointments, deposits, creams, controlled release formulations, fast melt formulations, lyophilized formulations, tablets, capsules, delayed release formulations, formulations. extended deliberation, pulsed release formulations, mixing immediate release and controlled release formulations, etc.

Compositions suitable for parenteral injection may comprise physiologically acceptable aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous or non-aqueous carriers, diluents, solvents or vehicles including water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable esters such as ethyl oleate. Proper flowability may be maintained, for example, by the use of a coating such as lecithin, maintaining the required particle size in the case of dispersions, and using surfactants.

Solid dosage forms for oral administration include, but are not limited to, tablets, capsules, sachets, lozenges, powders, pills, or granules, and the solid dosage form may be, for example, a fast melt finger form, dosage form of controlled release, lyophilized dosage form, delayed release dosage form, extended release finger form, pulsed release dosage form, mixture of immediate release and controlled release dosage form, or a combination thereof. A solid dose tablet formulation is preferred. In such solid dosage forms, 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 silylic acids; (c) binders such as carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (d) humectants, such as glycerol; (e) disintegrating agents such as agar, calcium carbonate, starch debatata or tapioca, alginic acid, certain complex silicates and sodium carbonate; (f) solution retardants, such as paraffin; (g) adsorption accelerators such as quaternary ammonium compounds; (h) wetting agents, such as cetyl alcohol and glyceryl monostearate; (i) adsorbents such as kaolin and bentonite; and (j) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. For capsules, tablets, and pills, dosage forms may also comprise buffering agents.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to ziprasidone, liquid dosage forms may comprise inert diluents commonly used in technology, such as water or other solvents, solubilizing agents, and emulsifiers. Exemplary emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoyl benzoate. benzyl, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols , sorbitan fatty acid esters, or mixtures of substances, and the like.

One of skill in the art will appreciate that a therapeutically effective amount of ziprasidone may be determined empirically. Actual dosage levels of ziprasidone in the inventive nanoparticulate compositions may be varied to obtain an amount of the medicament that is effective in obtaining a therapeutic response to a particular composition and method of administration. The dosage level selected in this way depends on the desired therapeutic effect, the route of administration, the ziprasidone potency administered, the desired duration of treatment and other factors.

Dosage unit compositions contain such amounts of ziprasidone or such submultiples thereof as they may be used to prepare the daily dosage. It is understood, however, that the specific dosage level for any particular patient will depend upon a variety of factors: the type and degree of cellular or physiological response to be achieved, specific agent activity or composition employed; the specific agents or compositions employed; the age, body weight, general health, gender and diet of the patient; time of administration, route of administration, ziprasidone excretion rate; the duration of treatment; activated compound in combination or coincidence with ziprasidone; and similar factors well known in medical technology.

II. Controlled Release Compositions Comprising Ziprasidone

The effectiveness of pharmaceutical compounds in preventing and treating disease states depends on a variety of factors including the rate and duration of compound distribution from the finger form to the patient. The combination of the rate and duration of distribution presented by a given dosage form in a patient can be described as its in vivo release profile and, depending on the pharmaceutical compound administered, will be associated with a concentration and duration of the blood plasma pharmaceutical compound referred to as a plasma profile. . Since pharmaceutical compounds vary in their pharmacokinetic properties such bioavailability, absorption and elimination rates, the release profile and the resulting plasma profile become important elements to be considered in the design of effective therapies.

Dosage form release profiles may have different release rates and durations and may be continuous or pulsating. Continuous release profiles include release profiles in which a quantity of one or more pharmaceutical compounds is continuously released over the entire dosage range at a rate. both quantovariate constant. Pulsing release profiles include release profiles in which at least two discrete amounts of one or more pharmaceutical compounds are released at different rates and / or different time frames. For any given pharmaceutical compound or combination thereof, release operaf for a given dosage form leads to an associated plasma profile in a patient. When two or more components of a dosage form have different release profiles, the deliberate dosage form profile 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 be described as "bimodal," and the release profile of a three-component dosage form wherein each component has a different release profile may be described as "trimodal."

Similar to the variables applicable to the release profile, the associated plasma profile in a patient may have constant blood plasma concentration levels or variables of the action-swelling pharmaceutical compounds and may be continuous or pulsating. Continuous plasma profiles include plasma profiles of all rates and duration that exhibit a single maximum plasma concentration. Pulsating plasma profiles include plasma profiles in which at least two higher blood plasma concentration levels of the pharmaceutical compound are separated by a lower plasma blood concentration level and may generally be described as "multimodal." Pulsing plasma profiles showing two peaks can be described as "bimodal" and plasma profiles showing three peaks can be described as "trimodal." Depending, at least in part, on the pharmacokinetics of the pharmaceutical compounds included in the dosage form as well as on the release profiles of the individual dosage form components, a multi-mode release profile may result in both a continuous and pulsating plasma profile upon administration to a patient.

In one embodiment, the present invention provides a multiparticulate modified release composition that distributesiprasidone, or ziprasidone-containing nanoparticles, of a mannapulant. Nanoparticles are of the type described above and also comprise at least one surface stabilizer.

In yet another embodiment, the present invention provides a multiparticulate modified release composition that distributesiprasidone, or ziprasidone-containing nanoparticles, in a continuous manner. Nanoparticles are of the type described above and also comprise at least one surface stabilizer.

In yet another embodiment, the present invention provides a multiparticulate modified release composition wherein a first portion of ziprasidone, or nanoparticles containing zprasidone, is released immediately upon administration, and one or more subsequent portions of ziprasidone, or nanoparticles containing zprasidone, are released after administration. an initial delay in time.

In yet another embodiment, 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.

In yet another embodiment, the present invention provides a method for preventing and / or treating schizophrenia and similar psychiatric disorders comprising administering a composition of the present invention.

In one embodiment, the present invention provides a multiparticulate modified release composition wherein the particles forming the multiparticulate are nanoparticulate particles of the above-described type. The nanoparticulate particles may as desired contain a modified release coating and / or a modified release matrix material.

According to one aspect of the present invention, there is provided a first component pharmaceutical composition comprising the active ingredient containing particles, and at least one subsequent component comprising the active ingredient containing particles, with a subsequent component with a different rate and / or duration of release than the first component in particular. that at least one of said components comprises ziprasidone-containing particles. In one embodiment of the invention, multiparticulate-containing ziprasidone-containing particles may themselves contain nanoparticulate particles of the type described above comprising ziprasidone and also at least one surface stabilizer. In another embodiment of the invention, nanoparticulate particles of the type described above which comprise zasprasidone and also at least one surface stabilizer itself are multiparticulate medicament-containing particles. The particles containing the medicine may be coated with a modified release coating. Alternatively or additionally, the particles containing the medicament may comprise a modified release matrix material. After oral delivery, the composition delivers ziprasidone, or ziprasidone-containing nanoparticles, in a pulsating manner. In one embodiment, the first component provides an immediate release of zaprasidone, or ziprasidone-containing nanoparticles, and one or more subsequent components provide a modified release of daziprasidone, or ziprasidone-containing nanoparticles. In such embodiments, the immediate release component serves to accelerate the onset of action by minimizing administration time to a therapeutically effective plasma concentration level, and one or more subsequent components serve to minimize variation in plasma concentration levels and / or maintain plasma concentration. therapeutically effective throughout the dosage range.

The modified release coating and / or modified release matrix material causes a time delay between the release of the active ingredient from a first active ingredient-containing particle population and the release of the active ingredient from subsequent populations of active ingredient-containing particles. Where more than one active ingredient containing particle population provides a modified release, the modified release coating and / or modified release matrix material causes a time lag between the active ingredient release of the different active ingredient containing particle populations. The duration of these delay times may be varied by altering the composition and / or the amount of the modified release liner and / or changing the composition and / or amount of modified release matrix material used. Thus, the duration of the delay time can be designed to mimic a desired plasma profile.

Because the plasma profile produced by the modified release composition upon administration is substantially similar to the plasma profile produced by the administration of two or more sequentially given IR fingerprints, the modified release composition of the present invention is particularly used for administration of ziprasidone.

According to a further aspect of the present invention, the composition may be designed to produce a plasma profile that minimizes or eliminates variations in plasma concentration levels associated with administration of two or more IR dosage forms thereafter. In such embodiments, the composition may be provided as an immediate release component to accelerate the onset of action by minimizing administration time to a therapeutically effective plasma concentration level, and at least modified release component to maintain a therapeutically effective plasma concentration level throughout the interval. Dosing

The active ingredients in each component may be the same or different. For example, the composition may comprise components comprising only ziprasidone, or nanoparticles containing ziprasidone, as the active ingredient. Alternatively, the composition may comprise a first component comprising zprasidone, or ziprasidone-containing nanoparticles, and at least one subsequent component comprising an active ingredient other than aziprasidone, or ziprasidone-containing nanoparticles, suitable for co-administration with ziprasidone, or a first component containing an ingredient. active other than ziprasidone, or ziprasidone-containing nanoparticles, and at least one subsequent component comprising zprasidone, or ziprasidone-containing nanoparticles. In fact, two or more active ingredients can be incorporated into the same component when the active ingredients are compatible with each other. An active ingredient present in one component of the composition may be attached, for example, to a enhancing compound or a sensitized compound in another component of the composition, in order to modify its bioavailability or therapeutic effect.

As used herein, the term "enhancer" refers to a compound that is capable of enhancing absorption and / or bioavailability and an active ingredient by promoting network transport along the GIT in an animal, such as a human. Enhancers include, but are not limited to, medium chain fatty acids; salts, esters, ethers and derivatives thereof, including glycerides and triglycerides; nonionic surfactants, such as those which may be prepared by reacting ethylene oxide with a fatty acid, a fatty alcohol, an alkylphenol or a desorbitan fatty acid ester or glycerol; cytochrome P450 inhibitors, P-glycoprotein inhibitors and the like; and mixtures of two or more of these agents.

In embodiments where more than one component containing drug is present, the proportion of ziprasidone contained in each component may be the same or different depending on the desired fingering regimen. Ziprasidone present in the first component and subsequent components can be any amount sufficient to produce a therapeutically effective plasma concentration level. Aziprasidone, where applicable, may be present either as a substantially optically pure stereoisomer or as a mixture, racemic or otherwise, of two or more stereoisomers. In one embodiment, ziprasidone is present in the composition in an amount from about 0.1 to about 500 mg. In another embodiment, aziprasidone is present in the composition in an amount of from about 1 to about 100 mg. In yet another embodiment, ziprasidone is present in the first component in an amount of about 0.5 about 60 mg. In yet another embodiment, ziprasidone is present in the first component in an amount of from about 2.5 to about 30mg. If in subsequent components, ziprasidone is present in amounts in ranges similar to those described for the first component.

The release characteristics over time for ziprasidone distribution from each of the components may be varied by modifying the composition of each component, including modifying any of the excipients and / or coatings that may be present. In particular, the release of ziprasidone may be controlled by altering the composition and / or the amount of the modified release coating on the particles, if such a coating is present. If more than one modified release component is present, the modified deliberation coating for each of these components may be the same or different. Similarly, when modified release is facilitated by the inclusion of a modified release matrix material, active release can be controlled by the choice and amount of the modified release matrix material used. The modified release liner may be present in each component in any amount that is sufficient to produce the desired delay time for each particular component. The modified release coating may be present in each component in any amount to produce the desired time delay between components.

The time delay and / or time delay for the release of deziprasidone from each component may also be varied by modifying the composition of each component, including modifying any of the excipients and coatings that may be present. For example, the first component may be an immediate release component wherein zasprasidone is released immediately upon administration.

Alternatively, the first component may be, for example, a time delay immediate release component in which ziprasidone is released substantially in its entirety immediately after a time delay. The second and subsequent components may be, for example, an immediate time delay release component as described above or, alternatively, a sustained release or extended time delay release component in which ziprasidone is released in a controlled manner over a period of time. extended time.

As those skilled in the art understand, the exact nature of the plasma concentration curve will be influenced by the combination of all these factors described above. In particular, the time lag between the distribution (and thus also the onset of action) of ziprasidone in a ziprasidone-containing component can be controlled by varying the composition and coating (if present) of each of the components. Thus, by varying the composition of each component (including the amount and nature of the active ingredient (s)) and by varying the delay time, numerous releases and plasma profiles can be obtained. Depending on the time delay between the release of ziprasidone from each component and the nature of ziprasidone release from each component (ie immediate release, sustained release etc.), the plasma profile may be continuous (ie with a single maximum) or where the plasma profile peaks can be well separated and clearly defined (eg when the delay time is long) or overlapped to a degree (eg when the delay time is short).

The plasma profile produced from administration of a single dosage unit comprising the composition of the present invention is advantageous when it is desired to dispense two or more active ingredient pulses without the need for administration of two or more dosage units.

Any coating material that modifies deziprasidone release in the desired manner may be used. In particular, coating materials 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 trimaleate, hydroxypropyl methylcellulose phthalate, vinyl polyacetate phthalate, ammonium methacrylate copolymers, such as those sold under the tradename Eudragit® RS and RL, polyacrylic acid and polyacrylate and methacrylate copolymers, such as those sold under the trade name of Eudragit® SeL, polyvinyl acetaldiethylamino acetate, hydroxypropyl methylcellulose succinate acetate, shellac; hydrogels and gel-forming materials such as carboxyvinyl polymers, sodium alginate, sodium carmelose, calcium carmelose, carboxymethyl sodium starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, gelatin, starch, and cellulose-based cross-linking polymers. cross-linking is low in order to facilitate water adsorption and polymer matrix expansion, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, amidoriculate, microcrystalline cellulose, chitin, aminoacryl methacrylate copolymer (Eudragit® RS-30 PM, Rohm & Haas), pullul , collagen, casein, agar, gum arabic, sodium carboxymethyl cellulose, (intumescent polymer hydrophilic) poly (hydroxyalkyl methacrylate) (mol. weight ~ 5k-5,000k), polyvinylpyrrolidone (mol.wt. ~ 10k-360k), hydrogelionic and cationic, low residual acetate polyvinyl alcohol, an intumescent mixture of agar and carboxymethyl cellulose, copolymers styrene maleic anhydride, ethylene, propylene or isobutylene, pectin (mol.- weight 30k-300k), polysaccharides such as agar, acacia, caraia, tragacanth, algines and guar, polyacrylamides, Polyox® ethylene polyoxide (mol. ~ 100k-5,000k), AquaKeep® acrylate polymers, depoliglucan diesters, cross-linked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, sodium starch glycolate (eg Explotab®; Edward Mandell C. Ltd.); hydrophilic polymers, such as polysaccharides, methylcellulose, sodium or calcium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, nitrocellulose, carboxymethylcellulose, decellulose ethers, ethylene polyoxides (e.g. Poliox®, Union Carbide), methylethylcellulose, ethylhydroxyethylcellulose , cellulose acetate, cellulose butyrate, cellulose propionate, gelatin, collagen, starch, maltodextrin, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, vinyl polyacetate, glycerol acid acid esters, polyacrylamide, polyacrylic acid methacrylic acid copolymers (e.g. Eudragit®, Rohm and Haas), other acrylic acid derivatives, sorbitan esters, natural gums urals, lecithins, pectin, alginates, ammonium alginate, sodium alginates, calcium, potassium, propylene glycol alginate, agar, and gums such as arabica, caraia, locust bean, tragacanth, carrageenans, guar, xanthan, scleroglycine and mixtures and combinations thereof. As skilled in the art, excipients such as plasticizers, lubricants, and similar solvents may be added to the coating. Suitable plasticizers include, for example, acetylated monoglycerides; phthalylbutyl butyl glycolate; dibutyl tartrate; diethyl phthalate; dimethyl phthalate; deethyl phthalyl ethyl glycolate; glycerin; propylene glycol; triacetin; citrate; tripropiolin; diacetin; dibutyl phthalate; acetyl monoglyceride; polyethylene glycols; Castor oil; triethyl citrate; polyhydric alcohols, glycerol, acetate esters, glycerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dediexyl phthalate, butyl octyl phthalate, butyl octhalate phthalate, dioctyl azate, trimethylate triacetate di-n-octyl phthalate, di-n-octyl phthalate, di-octyl phthalate, di-n-decyl phthalate, di-n-undecyl phthalate, di-n-tridecyl phthalate, tri-2-ethylexyl trimellate di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl sebacate.

Where the modified release component comprises a modified release matrix material, any suitable modified deliberation matrix material or combinations of suitable modified deliberation matrix material may be used. Such materials are known to those skilled in technology. The term "modified deliberation matrix material" as used herein includes hydrophilic polymers, hydrophobic polymers and mixtures thereof that are capable of modifying ziprasidone release, or a salt or derivative thereof, dispersed therein in vitro or in vivo. Suitable modified release matrix materials for the practice of the present invention include, but are not limited to, cellulosemicrocrystalline, sodium carboxymethylcellulose, hydroxyalkylcelluloses such as hydroxypropyl methylcellulose and hydroxypropylcellulose, ethylene polyoxide, alkylcellulose such as methylcellulose and ethylcellulose, polyethylene glycol, polyvinylpyrrolidone, polyvinyl acetate, , cellulose butyrate acetate, cellulose acetate phthalate, cellulose acetate trimelitate, polyvinyl deacetate phthalate, polyalkyl methacrylates, vinyl polyacetate and mixtures thereof.

A modified release composition according to the present invention may be incorporated into any suitable dosage form which facilitates the release of the active ingredient from a mannapulant. In one embodiment, the dosage form comprises a combination of different populations of active ingredient-containing particles which constitute immediate release and modified release components, the combination being loaded into suitable capsules, such as hard or soft gelatin capsules. Alternatively, different individual populations of active ingredient-containing particles may be compressed (optionally with additional excipients) into mini-tablets which may subsequently be loaded into capsules in appropriate proportions. Another suitable dosage form is that of a multilayer tablet. In this case, the first component of the modified release composition may be compressed into one layer, with the second component subsequently added as a second layer of the multilayer tablet. Particle populations constituting the composition of the invention may further be included in fast dissolving dosage forms, such as an effervescent dosage form or a rapid melt dosage form.

In one embodiment, the composition comprises at least two ziprasidone-containing components: a first component and one or more subsequent components. In such an embodiment, the first component of the composition may have a variety of release profiles including profiles in which substantially all of the ziprasidone contained in the first component is released rapidly upon administration of the dosage form, released rapidly, but after a delay time (delayed release), or released slowly over time. In such a mode, the ziprasidone contained in the first component is rapidly released upon administration to a patient. As used herein, "rapidly released" includes release profiles in which at least about 80% of the active ingredient in a component is released within about an hour after administration, the term "delayed release" includes release profiles in which the active ingredient in a component is released. a component is released (quickened or slowly) after a delay time, and the terms controlled release "and" extended release "include release profiles in which at least about 80% of the active ingredient contained in a component is released slowly.

The second component of such an embodiment may also present a variety of release profiles including an immediate deliberation profile, a delayed release profile or a controlled release profile. In such an embodiment, the second component has a delayed release profile in which ziprasidone is released after a delay time.

The plasma profile produced by the administration of finger forms of the present invention comprising an immediate deliberation component comprising ziprasidone, or zprasidone-containing nanoparticles, and at least modified release component comprising ziprasidone, or ziprasidone-containing nanoparticles, may be substantially similar to the plasma profile produced by the administration of ziprasidone. two or more sequentially given IR dosage forms, or the plasma profile produced by administration of separate IR and modified release dosage forms. Accordingly, the dosage forms of the present invention may be particularly used for deziprasidone administration where maintenance of pharmacokinetic parameters may be desired, but is problematic.

In one embodiment, the composition and solid oral dosage forms containing the ziprasidone release composition such that substantially all of the ziprasidone contained in the first component is released prior to the release of ziprasidone from at least one subsequent component. When the first component comprises an IR component, for example, it is preferred that the release of ziprasidone from at least one subsequent component is delayed until substantially all aziprasidone in the IR component has been released. Release of ziprasidon at least one subsequent component may be delayed as previously detailed by use of a modified release coating and / or a modified release matrix material.

When it is desired to minimize patient tolerance by providing a dosage regimen that facilitates the undermining of a ziprasidone first dose from a patient system, release of daziprasidone from subsequent components may be delayed until substantially all of the ziprasidone contained in the first component has been achieved. released, and further delayed until at least a portion of the liberated daziprasidone of the first component has been removed from the patient system. In one embodiment, release of ziprasidone from subsequent components of the composition is substantially, if not completely, delayed by a period of at least about two hours after administration of the composition. In another embodiment, ziprasidone release from subsequent components of the composition is substantially, if not completely, delayed by a period of at least four hours after administration of the composition.

As described hereinafter, the present invention also encompasses various types of modified release systems by which aziprasidone may be delivered in both a pulsed and continuous manner. These systems include, but are not limited to: comziprasidone films, or ziprasidone-containing nanoparticles, in a depolymer matrix (monolithic devices); systems in which ziprasidone, or ziprasidone-containing particles, is contained by a polymer (reservoir devices); polymeric or microencapsulated colloidal particles (microparticles, microspheres or nanoparticles) in the form of reservoir and matrix devices; systems wherein ziprasidone, or ziprasidone-containing nanoparticles, is contained by a polymer that contains a hydrophilic and / or leachable additive, for example a second polymer, surfactant or plasticizer, etc. to give a porous device, or a device in which the release of ziprasidone can be osmotically controlled (both reservoir and matrix devices); enteric coatings (ionizable and dissolved at a suitable pH); (soluble) polymers with pendant (covalently) attached ziprasidone molecules and devices where the release rate is dynamically controlled: for example, the osmotic pump.

The delivery mechanism of the present invention can control the release rate of ziprasidone. Although some mechanisms release ziprasidone at a constant rate, others vary as a function of time depending on factors such as change in concentration gradients or leaching additive leading to porosity, etc.

Polymers used in sustained release coatings are necessarily biocompatible, and ideally biodegradable. Examples of naturally occurring polymers, such as Aquacoat® (FMCCorporation, Food & Pharmaceutical Products Division, Philadelphia, USA) (sub-micron size dispersions of mechanically spheronized, water-based, pseudo-latex), as well as synthetic polymers such as Eudragit® (Rohm Pharma, Weiterstadt.) which range from copolymerospoli (acrylate, methacrylate) are known in the technology. Reservoir Devices

A typical approach for modified release is to encapsulate or contain the drug entirely (for example, as a core), in a film or polymer coating (ie, microcapsules or jet-coated cores).

The various factors that may affect the diffusion process can readily be applied to reservoir devices (e.g., the effects of additives, polymer functionality porosity (and thus cavity solution pH), film casting conditions, etc.). ), and therefore the choice of polymer should be an important consideration in the development of reservoir devices. Modeling the release characteristics of reservoir devices (and monolytic devices) in which ziprasidone transport is by a solution diffusion mechanism in this way typically involves a solution to Fick's second law (unstable state conditions; concentration dependent flow) for the conditions relevant limit. When the device contains dissolved active agent, the release rate decreases exponentially with time as the concentration (activity) of the agent (ie, the force driving the release) in the device decreases (ie, first order release). If, however, the active agent is in a saturated suspension, then the force driving the release is kept constant until the device is no longer saturated. Alternatively the deliberation rate kinetics may be controlled desorption, and a function of the square root dotempo.

The conveying properties of coated tablets may be improved compared to polymer-free films due to the closed nature of the (permeable) tablet core which may allow the internal construction of an osmotic pressure which will then act to force the tablet out.

The effect of deionized water on salt-containing tablets containing poly (ethylene glycol) (PEG) containing silicone elastomer, and also the effects of water on free films were investigated. The salt release of the tablets was observed to be a diffusion mixture through water-loaded pores formed by hydration of the coating and osmotic pumping. KCl transport through films containing only 10% PEG was negligible, despite the extensive swelling observed in similar free films, indicating that porosity was required for KCl release which then occurred by transporus diffusion. It has been observed that coated salt-shaped, salt-shaped tablets swell in deionized water and change the shape to a spheroidoblate as a result of the internal hydrostatic pressure construction: the change in shape providing a means for measuring the force generated. As expected, osmotic force decreased with increasing levels of PEG content.

The lower PEG levels allowed water to be soaked through the hydrated polymer, while the porosity resulting from the dissolution of the coating at higher levels of PEG content (20 to 40%) allowed the pressure to be replaced by the KCl flow.

Methods and equations were developed that by monitoring (independently) the release of two different salts (eg, KCl and NaCl) allowed the calculation of the relative magnitudes that both osmotic pumping and transporus diffusion contributed to tablet salt release. At low PEG levels, osmotic flow was increased to a greater extent than trans-pore diffusion due to the generation of only a low pore number density: at 20% loading, both mechanisms contributed approximately equally to release. Hydrostatic pressure construction, however, decreased osmotic influx and osmotic pumping. In larger PEG loading, the hydrated film was more porous and less resistant to salt overflow. Thus, although osmotic pumping increased (compared to smaller loading), trans-pore diffusion was the dominant release mechanism. An osmotic release mechanism has also been reported for microcapsules containing a water-soluble nucleus.

Monolithic Devices (Array Devices)

Monolithic devices (matrix) can be used to control the release of a drug. This is possible because they are relatively easy to manufacture compared to the reservoir devices, and the danger of a high accidental dosage that may result in membrane rupture of a reservoir device is not present. In such a device, the active agent is present in the form of a polymer matrix dispersion, and they are typically formed by compressing a polymer / drug mixture or by dissolving or melting. The dosage release properties of monolithic devices may be dependent upon the solubility of the drug in the polymer matrix or, in the case of porous matrices, the solubility in the cavity solution in the particle pore network, and also the tortuosity of the network (to a greater extent than permeability). depending on whether the drug is dispersed in the polymer or dissolved in the polymer. For low drug loads (0 to 5% w / v), the drug will be released by a solution-diffusion mechanism (in the absence of pores). At larger loads (5 to 10% w / v), the release mechanism will be complicated by the presence of cavities formed near the surface of the device once the drug is lost: such cavities fill with ambient fluid increasing the drug release rate.

It is common to add a plasticizer (e.g., a poly (ethylene glycol)), a surfactant, or an adjuvant (ie, an effectiveness enhancing ingredient) to the matrix devices (reservoir devices) as a means to improve permeability ( while, on the contrary, plasticizers may be fugitive, and simply serve to aid film formation and thereby decrease permeability - a property usually more desirable in polymer ink coatings). PEG leaching increased the permeability of (ethyl cellulose) films linearly as a PEG loading function increasing porosity, however, the films retained their barrier properties, not allowing electrolyte transport. It was deduced that the improvement of its permeability was as a result of the effective decrease in thickness caused by PEG leaching. This was evidenced from cumulative permeation flow charts by area unit as a function of time and reciprocal film thickness in a loading of 50% w / w PEG: Graphs showing a linear relationship between the permeation rate and reciprocal film thickness as expected by a solution-diffusion (Fickian) transport mechanism on a homogeneous membrane. Extrapolation of the linear regions of the graphs to the time axis gave positive intersections on the time axis: whose magnitude decreased to zero with decrease in film thickness.

These delay time changes were attributed to the occurrence of two diffusional streams during the early stages of the experiment (the domedication flow and also the PEG flow), and also to the usual delay time at which the permeant concentration in the film is constructed. Caffeine, when used as a permeant, showed negative delay times.

No explanation of this was forthcoming, but it was observed that caffeine had a low partition coefficient in the system, and that this was also an aniline permeation characteristic through polyethylene films which had a similar negative delay time.

The effects of surfactants added on (hydrophobic) matrix devices were investigated. It has been believed that surfactant can increase the release rate of a drug by three possible mechanisms: (i) increased solubilization, (ii) better wettability to the dissolution medium, and (iii) pore formation as a result of surfactant bleaching. For the system studied (Eudragit® RL 100 sorbitol RS 100 plasticizer, flurbiprofen as the drug, and a range of surfactants) it was concluded that better compressed wettability led to only a partial improvement in drug release (indicating that release was diffusion, rather than controlled dissolution), although the effect was greater for Eudragit® RS than Eudragit®RL, while the greatest influence on release was by the more soluble surfactants due to the formation of disruptions in the matrix allowing the dissolution medium to access matrix. This is of obvious relevance to a study of latex films which should be suitable for pharmaceutical coatings, because of the ease with which a polymer latex can be prepared with surfactant as opposed to surfactant semagingly. Differences were found between the two polymersoments with Eudragit® RS showing interactions between cationic / surfactant agent and drug. This was attributed to levels that differ from quaternary ammonium ions in the polymer.

Composite devices consisting of a polymer / drug matrix coated on a polymer containing no drugs also exist. Such a device was constructed of watery Eudragit® slats, and has been found to provide continuous diffusion release of the core through the shell. Similarly, a polymer core containing the drug was produced and coated with a shell that was eroded by the gastric fluid. The release rate of the drug was observed to be relatively linear (a function of the diffusion process that limits the rate through the shell) and inversely proportional to the thickness of the shell, while the release of the nucleus alone decreased over time.

Microspheres

Methods for the preparation of concave microspheres have been described. Concave microspheres were formed by preparing a ethanol / dichloromethane solution containing the drug and polymer. Pouring into a water, an emulsion is formed containing the dispersed polymer / drug / solvent particles, by a coacervation-like process from which ethanol rapidly diffused the precipitation polymer onto the droplet surface to give a hard shell particle that closes the dissolved drug nodichloromethane. . A phase of dichloromethane gas then generated in the particle, after diffusing through the shell, was observed to bubble to the surface of the aqueous phase. The concave sphere, under reduced pressure, then charged with water that would be removed for a drying period. No medicines were found in the water. Highly porous matrix type microspheres have also been described. The matrix type microspheres were prepared by dissolving the drug and polymer in ethanol. Upon addition of water, ethanol diffused from the emulsion droplets to leave a highly porous particle. One suggested use of the microspheres was a floating drug delivery device for use in the stomach.

Pending Devices

A means of attaching a range of medicaments, such as analgesics and antidepressants, etc., by an ester bond to the polyacrylate ester latex particles prepared by aqueous emulsion polymerization has been developed. These cross-links, when passed through an ion exchange resin so that the polymer end groups are converted to their strong acid forms, could self-catalyze drug release by ester bond hydrolysis.

Medicaments have been attached to the polymers, and also monomers have been sintered with a pending attached drug. Dosage forms have been prepared wherein the medicament is bound to a biocompatible polymer by a labile chemical bond, for example polyanhydrides prepared from a substituted anhydride (itself producing a chloride). Acid with the drug: methacryloyl chloride and sodium benzoic methoxide sodium osal) were used to form a matrix with a second polymer (Eudragit® RL) which released the drug into hydrolysis in the gastric fluid. The use of polymeric Schiff bases suitable for use as pharmaceutical amine carriers has also been described.

Enteric coatings consist of aopH sensitive polymers. Typically the polymers are carboxylated and interact very little with water at low pH, while at high pH the polymers ionize causing polymer swelling or dissolution. Coatings may thus be designed to remain intact in the acidic environment of the stomach, protecting both the drug from this environment and the stomach from drug, but to dissolve in the more alkaline environment of the intestine.

Osmotically Controlled Devices

The osmotic pump is similar to a reservoir device, but contains an osmotic agent (for example, the active agent in the desal form) that acts to absorb water from the surrounding medium through a semipermeable membrane. Such a device, called an elementary osmotic pump, has been described. Pressure is generated in the device that forces the reactive agent out of the device through a hole in a projected size to minimize solute diffusion, while preventing the construction of a hydrostatic pressure head that can have the effect of decreasing the pressure. osmotic and change the dimensions of the device.

While the internal volume of the device remains constant, and there is an excess of solid or saturated solution in the device, then the release rate remains constant distributing a volume equal to the volume of absorbed solvent.

Electrically Stimulated Release Devices

Monolithic devices have been prepared using polyelectrolyte gels that swell when, for example, an external electrical stimulus is applied causing a change in pH. Release can be modulated by changes in applied current to produce a constant or pulsating deliberation profile.

In addition to their use in drug matrices, hydrogels find use in numerous biomedical applications, such as, for example, soft contact lenses, and various soft implants, and the like.

III. Methods of Using Modified Release Compositions Understanding Ziprasidone

According to another aspect of the present invention, there is provided a method for treating a patient suffering from schizophrenia or a similar psychiatric disorder comprising the step of administering a therapeutically effective amount of the composition of the present invention in a solid oral dosage form. Advantages of the method of the present invention include a reduction in dosing frequency required by conventional multiple IR dosing regimens while maintaining the benefits derived from a thrusting plasma profile or by eliminating or minimizing variations in plasma concentration levels. This reduced dosage frequency is advantageous in patient compliance terms and the reduction in dosage frequency made possible by the method of the present invention would contribute to controlling health care costs by reducing the amount of time spent by health care workers in administering ziprasidone.

In the following examples, all percentages are weight by weight unless otherwise stated. The term "purified water" as used in all examples refers to water that has been purified by passing it through a water filtration system. It is understood that the examples are for illustrative purposes only and should not be construed as restricting the spirit and scope of the invention as defined for the purposes of the following claims.

Examples

Examples 1 to 4 provide exemplary deziprasidone tablet formulations. These examples should not limit the claims in any respect, but instead provide exemplary ziprasidone tablet formulations that may be used in the methods of the invention. Such exemplary tablets may also comprise a coating agent.

Example 1

<table> table see original document page 60 </column> </row> <table>

Example 2

<table> table see original document page 60 </column> </row> <table>

Example 3

<table> table see original document page 60 </column> </row> <table> Example 4

<table> table see original document page 61 </column> </row> <table>

Example 5

Modified Multiparticulate Release Composition Containing Ziprasidone

A multiparticulate modified release composition according to the present invention comprising an immediate release component and a modified release component containing ziprasidone is prepared as follows.

(a) Immediate Release (IR) Component.

A solution of ziprasidone is prepared according to any of the formulations given in table 1. The methylphenidate solution is then coated on nonpareil seeds to a level of approximately 16.9% solids weight gain using, for example, fluid delight equipment. Glatt GPCG3 (Glatt, Protech Ltd., Leicester, UK) to form the IR particles of the immediate release component.

TABLE 1

Immediate Release Component Solutions

<table> table see original document page 61 </column> </row> <table>

(b) Modified Release Component

Delayed release particles containing Ziprasidone are prepared by coating immediate release particles prepared according to Example 5 (a) above with a modified release coating solution detailed in Table 2. The immediate release particles are coated and varied up to approximately 30% gain. weighing, for example, a fluid bed apparatus.

<table> table see original document page 62 </column> </row> <table>

Talc is simultaneously applied during coating for formulations in column (i), (iv) and (vi)

(c) Encapsulation of Immediate and Delayed Release Particles.

The immediate and delayed release particles prepared according to example 5 (a) and (b) above are encapsulated in size 2 hard degelatin capsules at a general dosage strength of 20 mg using, for example, a Bosch GKF 4000S encapsulation apparatus. The overall dosage intensity of 20 mg ziprasidone was 10 mg immediate release component and 10 mg modified deliberation component.Example 6

15 Multiparticulate Modified Release Composition Containing Ziprasidone

Multiparticulate modified release ziprasidone compositions according to the present invention with an immediate deliberation component and a modified release component with a modified release matrix material are prepared according to the formulations shown in Table 3 (a) and (b).

TABLE 3 (a)

100 mg of the IR component is encapsulated with 100 mg of the modified deliberation (MR) component to give a 20 mg dosage intensity product <table> table see original document page 63 </column> </row> <table>

TABLE 3 (b)

50 mg MR component is encapsulated with 50 mg modified release component (MR) to give a 20 mg dosage product.% (W / w)

<table> table see original document page 63 </column> </row> <table>

Example 7

The purpose of this example is to describe now a particulate ziprasidone composition can 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) can be ground in a 10 mL chamber of a 0.01 NanoMill® ( NanoMill Systems, King of Prussia, PA; see, for example, US Patent No. 6,431,478), together with 500 micron PolyMill® friction medium (Dow Chemical Co.) (for example, at an average load of 89%). . In the exemplary process, the mixture may be milled at a speed of 2,500 rpm for 60 minutes.

After milling, the particle size of the milled deziprasidone particles could be measured in deionized distilled water using a Horiba LA 910 particle size analyzer. For a successful composition, it is expected that the initial mean teniprasidone particle size and / or ground D50 is less than 2,000 nm.

It is apparent to those skilled in the art that various modifications and variations may be made to the methods and compositions of the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention cover the modifications and variations of the invention, provided that they fall within the scope of the appended claims and their equivalents.

Claims (91)

Stable nanoparticulate composition, characterized in that it comprises (A) particles comprising ziprasidone, said particles having an effective average particle size of less than about-2,000 nm in diameter; and (B) at least one surface stabilizer. Composition according to Claim 1, characterized in that said particles are in a crystalline phase, a phaseamorph, a semicrystalline phase, a semi-amorphous phase, or a mixture thereof. Composition according to Claim 1, characterized in that the effective average particle size of said particles is selected from the group consisting of less than about 1,900 nm, less than about 1,800 nm, less than about 1,700 nm, less that about-1,600 nm, less than about 1,500 nm, less than about 1,400 nm, less than about 1,300 nm, less than about 1,200 nm, less than 1,100 nm, less than about 1,000 nm, less than about 900nm, less than about 800 nm, less than about 700 nm, less than 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm nm, less than about -200 nm, less than about 100 nm, less than about 75 nm and less than 50 nm in diameter. Composition according to Claim 1, characterized in that the composition is formulated: (A) for selected administration from the group consisting of parenterally, orally, vaginally, nasally, rectally, optically, locally, buccally, intracisternally, intraperitoneally (B) in a dosage form selected from the group consisting of tablets, capsules, sachets, solutions, dispersions, gels, aerosols, ointments, creams and mixtures thereof; (C) in a formulation selected from the group consisting of controlled release, rapid melt formulations, lyophilized formulations, delayed release formulations, extended deliberation formulations, pulsed release formulations, and a mixture of immediate release and controlled release formulations; or (D) any combination of (A), (B) or (C). Composition according to Claim 1, characterized in that it further comprises one or more pharmaceutically acceptable excipients, carriers, or a combination thereof. Composition according to Claim 1, characterized in that: (A) said ziprasidone is present in said composition in an amount selected from the group consisting of about 99.5% to about 0.001%, about 95%. % to about 0.1%, or about 90% about 0.5% by weight of dry ziprasidone stabilizer and total surface combined in the composition, without including other excipients; (B) said surface stabilizer or Surface stabilizers are present in a total amount of from about 0.5% to about 99.999%, from about 5.0% to about 99.9%, or from about 10% to about 99.5% by weight, based on ziprasidone dry weight and total combined surface stabilizer in the composition without including other excipients; or (C) a combination of (A) and (B). Composition according to Claim 1, characterized in that the surface stabilizer is selected from the group consisting of a nonionic surface stabilizer, an anionic surface stabilizer, a cationic surface stabilizer, a zwitterionic surface stabilizer, and a stabilizer. of ionic surface. Composition according to Claim 1, characterized in that the surface stabilizer is selected from the group consisting of cetyl pyridinium chloride, gelatin, casein, phosphatides, dextran, glycerol, acacia, cholesterol, tragacanth, stearic acid, chloride. debenzalkonium, calcium stearate, glyceryl monostearate, ketoestearyl alcohol, ketomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl esters, polyoxyethylene castor oil fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol, trimethylene polyethylene glycol trimethylene glycol esters silicon dioxide, phosphates, sodium dodecyl sulfate, calcium carboxylcellulose, hydroxypropyl cellulose, hypromellose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, non-crystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinyl alcohol olidone, 4- (1,1,3-tetramethylbutyl) -phenol polymer with deethylene oxide and formaldehyde, poloxamers; poloxamines, a charged phospholipid, dioctylsulfosuccinate, sodium dialkyl esters of sulfosuccinic acid, sodium lauryl sulfate, alkyl aryl polyether sulfonate, mixtures of sucrose stearate and sucrose distearate, p-isononylphenoxypoly (glycidol) N-decanylamide; ndecyl (3-D-glycopyranoside; n-decyl PD-maltopyranoside; n-dodecyl R-glycopyranoside; n-dodecyl PD-maltoside; heptanoyl-N-methylglucamide; n-heptyl (3-D-glycopyranoside; n-heptyl ( 3-D-thioglycoside; n-hexyl (3-D-glycopyranoside; nonanoyl-N-methylglucamide; n-noyl (3-D-glycopyranoside; octanoyl-N-methylglucamide; n-octyl- (3-D-glycopyranoside; octyl (3-D-thioglycopyranoside; lysozyme, PEG-phospholipid, PEG-cholesterol, derivative PEG-cholesterol, PEG-vitamin A, PEG-vitaminE, lysozyme, random vinyl acetate and vinyl pyrrolidone copolymers, a cationic polymer, a cationic biopolymer, a cationic polysaccharide, a cationic cellulose, a cationic alginate, a non-cationic polymeric compound, a cationic phospholipid, cationic lipids, trimethylammonium depolymethyl methacrylate bromide, sulfonium compounds, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethylammonium dimethylammonium dimethylammonium compound, quaternary ammonium ostos, benzyl-di (2-chloroethyl) ethylammonium bromide, coconut trimethylammonium chloride, trimethyl ammonium coconut bromide, methyldihydroxyethyl ammonium coconut chloride, methyl dihydroxyethyl ammonium coconut bromide, dediethyl triethyl ammonium chloride, decyl dimethyl chloride hydroxyethyl ammonium, decyl dimethyl hydroxyethyl ammonium chloretobromide, Cn-isdimethylhydroxyethyl ammonium chloride, C12-15 dimethyl hydroxyethyl ammonium bromide chloride, dimethyl hydroxyethyl ammonium coconut chloride, dimethylhydroxyethyl ammonium coconut bromide, methyl myristyl trimethyl ammonium sulfate lauryl dimethyl benzyl ammonium, lauryl dimethyl benzyl ammonium bromide, delauryl dimethyl (ethoxy) 4 ammonium chloride, lauryl dimethyl (ethenoxy) 4 ammonium bromide, N-C1-18 dimethylbenzyl ammonium chloride, N-C14 alkyl chloride 18) dimethyl benzyl ammonium, N-tetradecylidomethylbenzyl ammonium hydrochloride, dimethyl didecyl ammonium chloride, N-alkyl and dimethyl chloride 1 (C12-14) 1-naphthylmethyl ammonium, trimethylammonium halide, alkyl trimethylammonium salts, dialkyl dimethylammonium salts, ethoxylated lauryl trimethylammonium salts, an ethoxylated dialkyl ammonium alkylamidoalkylammonium chloride, dialkylene chloride -didecyldimethyl ammonium, N -tetradecyldimethylbenzyl ammonium chloride hydrochloride, N-C12-14-dimethyl 1-naphthylmethyl ammonium chloride, dodecyl dimethylbenzyl ammonium chloride, dialkyl benzenealkylammonium chloride, lauryl trimethyl ammonium chloride, alkylammonium chloride benzyl dimethyl ammonium bromides, C12 trimethylammonium bromides, C15 trimethyl ammonium bromides, Cl7 trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium chloride (DADMAC), dimethyl ammonium chloride, dimethyl ammonium chloride triethyl ammonium chloride, ammonium, decyltrimethylammonium bromide, dodecyltriethylammonium bromide o, detetradecyltrimethylammonium bromide, methyl trioctylammonium chloride, POLIQUAT 10 ™, tetrabutylammonium bromide, benzyl trimethylammonium bromide, decoline esters, benzalconium chloride, stearalconium chloride compounds, cetyl pyridinium bromide, cetyl halide pyridinium chloride, quaternized, MIRAPOL, ALKAQUAT, dealkyl pyridinium salts; amines, amine salts, amine oxides, imidaazolium salts, protonated quaternary acrylamides, methylated quaternary polymers, and cationic guar. Composition according to Claim 1, characterized in that the composition does not produce significantly different absorption levels when administered under feeding compared with fasting conditions. Composition according to Claim 1, characterized in that the administration of the composition to a fasting individual is bioequivalent to the administration of the composition to an individual in the fed state. Composition according to Claim 1, characterized in that the pharmacokinetic profile of the composition is not significantly affected by the fed or fasted state of an individual ingesting said composition. Composition according to Claim 1, characterized in that, upon administration of said composition to a mammal, the composition produces therapeutic results at a dosage which is less than that of a non-nanoparticulate dosage form deziprasidone. Composition according to Claim 1, characterized in that it has: (a) a Cmax for ziprasidone when tested in a mammalian plasma after administration which is greater than Cmax for the same ziprasidone when administered at the same dose using a formulation. (b) an AUC for ziprasidone when tested on plasma from a mammalian subject after administration that is greater than AUC for the same ziprasidone when administered at the same dose using a non-nanoparticulate formulation; (c) a Tmax for ziprasidone when tested on plasma a mammalian subject after administration, which is lower than Tmax for the same ziprasidone when administered at the same dose using a non-nanoparticulate formulation; or (d) any combination of (a), (b), and (c). Composition according to Claim 1, characterized in that it further comprises one or more active compounds used for the prevention and treatment of schizophrenia and similar psychiatric disorders. Composition according to Claim 14, characterized in that the one or more active compounds are selected from the group consisting of compounds used in the treatment of a condition selected from the group consisting of headaches, bruising, fever, and combinations thereof. . Composition according to Claim 1, characterized in that said particles contain a reservoir containing ziprasidone, said reservoir being enclosed by a semipermeable membrane that allows water not to reach said particles, thereby generating pressure that forces said ziprasidone to flow into the water. out of said particles. Composition according to Claim 1, characterized in that said reservoir also comprises an osmotic agent. Method for preparing the composition as defined in claim 1, characterized in that it comprises placing particles comprising said ziprasidone in contact with at least one surface stabilizer for a period of time and under conditions sufficient to provide a nanoparticulate composition comprising zasprone with a particle size. effective average of less than about 2,000 nm in diameter. A method according to claim 18, characterized in that contacting comprises grinding, wet grinding, homogenizing, precipitating, emulsifying the template, or supercritical fluid department generation techniques. The method according to claim 18, characterized in that the effective average particle size of the particulate nanoparticles is selected from the group consisting of less than about -1900 nm, less than about 1,800 nm, less than about 1,700 nm. , less than about 1600 nm, less than about 1,500 nm, less than about 1,000 nm, less than about 1,400 nm, less than about 1,300 nm, less than about 1,200 nm, less than about 1,100 mu, less 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 200 nm, less than about 100 nm, less than about 75 nm, less than about 50 nm in diameter. Use of a composition as defined in claim 1, characterized in that it is in the preparation of a medicament for preventing and / or treating schizophrenia or similar psychiatric disorders. Use according to claim 21, characterized in that the effective average particle size of the particles is selected from the group consisting of less than about 1,900 nm, less than about-1,800 nm, less than about 1,700 nm, less than about 1,600 nm, less than about 1,500 nm, less than about 1,000 nm, less than about 1,400 nm, less than about 1,300 nm, less than about 1,200 nm, less than about 1,100 mu, less that about 900 nm, less than 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 100 nm, less than about 75 nm, and less than about 50 nm of diameter. 23. Pharmaceutical composition, characterized in that it comprises a first active ingredient-containing particle component and at least one subsequent active ingredient-containing particle component, wherein at least one of said components compriseseziprasidone and at least one of said components including a modified release coating. , a modified release matrix material, or both, such that the composition, after oral distribution to an individual, distributes the active ingredient in a bimodal or multimodal manner. Composition according to Claim 23, characterized in that each component comprises particles containing ziprasidone. Composition according to Claim 23, characterized in that the composition comprises a first component of ziprasidone-containing particles and a subsequent component of ziprasidone-containing particles. Composition according to Claim 25, characterized in that the first component comprises an immediate release component and the second component comprises a modified release component. Composition according to Claim 23, characterized in that the particles containing the active ingredient are erodible. Composition according to Claim 23, characterized in that at least one of said components further comprises a modified release coating. Composition according to Claim 23, characterized in that at least one of said components further comprises a modified release matrix material. Composition according to Claim 29, characterized in that said modified release matrix material is selected from the group consisting of hydrophilic polymers, hydrophobic polymers, natural polymers, synthetic polymers and mixtures thereof. Composition according to Claim 30, characterized in that ziprasidone is released into the environment by erosion. Composition according to Claim 31, characterized in that said composition further comprises an enhancer. Composition according to Claim 30, characterized in that it comprises from about 0.1 mg to about 1 gda ziprasidone. 34. Pharmaceutical composition, characterized in that it comprises a first active ingredient-containing particle component and at least one subsequent active ingredient-containing particle component, wherein at least one of said components comprisesiprasidone and at least one of said components including a modified release coating. , a modified release matrix material, or both, such that the composition, after oral distribution to an individual, distributes the active ingredient in a continuous manner. Composition according to Claim 34, characterized in that each component comprises particles containing ziprasidone. Composition according to Claim 34, characterized in that the composition comprises a first component of ziprasidone-containing particles and a subsequent component of ziprasidone-containing particles. Composition according to Claim 36, characterized in that the first component comprises an immediate release component and the second component comprises a modified release component. Composition according to Claim 34, characterized in that the particles containing the active ingredient are erodible. Composition according to Claim 34, characterized in that at least one of said components further comprises a modified release coating. Composition according to Claim 34, characterized in that at least one of said components further comprises a modified release matrix material. Composition according to Claim 40, characterized in that said modified release matrix material is selected from the group consisting of hydrophilic polymers, hydrophobic polymers, natural polymers, synthetic polymers and mixtures thereof. Composition according to Claim 41, characterized in that ziprasidone is released into the environment by erosion. Composition according to Claim 42, characterized in that said composition further comprises an enhancer. Composition according to Claim 41, characterized in that it comprises from about 0.1 mg to about 1 gda ziprasidone. Dosage form, characterized in that it comprises the composition as defined in claim 23. Dosage form according to claim 45, characterized in that a mixture of active ingredient-containing particles contained in a hard gelatin or soft gelatin capsule. Dosage form according to claim 46, characterized in that the active ingredient-containing particles are in the form of mini tablets and the capsule contains a mixture of said mini tablets. Dosage form according to claim 47, characterized in that it is in tablet form. Dosage form according to claim 48, characterized in that the ziprasidone-containing particles are supplied in a rapidly dissolving dosage form. Dosage form according to claim 48, characterized in that the tablet is a rapid melt tablet. Dosage form, characterized in that it comprises the composition as defined in claim 34. Dosage form according to claim 51, characterized in that it comprises a mixture of particles containing active ingredient contained in a hard gelatin or soft gelatin capsule. Dosage form according to claim 52, characterized in that the active ingredient-containing particles are in the form of mini tablets, and the capsule contains a mixture of said mini tablets. Dosage form according to claim 53, characterized in that it is in tablet form. A dosage form according to claim 54, characterized in that the ziprasidone-containing particles are supplied in a rapidly dissolving dosage form. Dosage form according to claim 54, characterized in that the tablet is a rapid melt tablet. Use of a composition as defined in claim 23, characterized in that it is in the preparation of a medicament for preventing and / or treating schizophrenia or similar psychiatric disorders. Use of a composition as defined in claim 34, characterized in that it is in the preparation of a medicament for preventing and / or treating schizophrenia or similar psychiatric disorders. Composition according to Claim 28, characterized in that the modified release coating comprises a pH-dependent polymer coating to release a pulp of the active ingredient in said patient after a time delay of about 6 to about 12 hours thereafter. of administering said composition to the dithopatient. Composition according to Claim 59, characterized in that said polymer coating comprises methacrylate polymers. Composition according to Claim 59, characterized in that the polymer coating comprises a mixture of methacrylate and ammonium methacrylate copolymers in a ratio sufficient to achieve a pulse of the active ingredient after a time delay of at least about 6 hours. . Composition according to Claim 61, characterized in that the ratio of ammonium methacrylate paramethacrylate copolymers is approximately 1: 1. Composition according to Claim 39, characterized in that the modified release coating comprises a pH-dependent polymer coating to release a pulse of the active ingredient in said patient after a time delay of about 6 to about 12 hours thereafter. of administering said composition to the dithopatient. A composition according to claim 63, characterized in that said polymer coating comprises methacrylate polymers. Composition according to Claim 64, characterized in that the polymer coating comprises a mixture of methacrylate and ammonium methacrylate copolymers at a rate sufficient to achieve a pulse of the active ingredient after a time delay of at least about 6 hours. . Composition according to Claim 65, characterized in that the ratio of ammonium methacrylate paramethacrylate copolymers is approximately 1: 1. 67. Controlled release composition, characterized in that it comprises a population of nanoparticulate particles comprising: (A) ziprasidone; and (B) a modified release coating or, alternatively, or additionally, a modified deliberation matrix material; such that the composition after oral delivery an individual distributes ziprasidone in a pulsating or continuous manner. Composition according to Claim 67, characterized in that said composition does not produce significantly different levels of absorption when administered under food compared with fasting conditions. Composition according to Claim 67, characterized in that the pharmacokinetic profile of said composition is not significantly affected by the fed or fasted state of an individual ingesting said composition. Composition according to Claim 67, characterized in that the administration of said composition to an individual in the fasting state is bioequivalent for administration of said composition to an individual in the fed state. Composition according to Claim 67, characterized in that the population comprises modified release particles. Composition according to Claim 67, characterized in that the population is an erodible formulation. Composition according to Claim 67, characterized in that said particles are each in the form of an osmotic device. Composition according to Claim 71, characterized in that the modified release particles comprise a modified release coating. Composition according to Claim 71, characterized in that the modified release particles comprise a modified release matrix material. Composition according to Claim 71, characterized in that said modified release particles are combined in a formulation which releases said ziprasidone by erosion into the surrounding environment. Composition according to Claim 71, characterized in that it further comprises a enhancer. Composition according to Claim 71, characterized in that the amount of active ingredient contained therein is from about 0.1 mg to about 1 g. Dosage form, characterized in that it is a composition as defined in claim 67. Dosage form according to claim 79, characterized in that it comprises a mixture of particles containing active ingredient contained in a hard gelatin or soft gelatin capsule. Dosage form according to claim 80, characterized in that the active ingredient-containing particles are in the form of mini tablets, and the capsule contains a mixture of said mini tablets. Dosage form according to claim 81, characterized in that it is in tablet form. A dosage form according to claim 82, characterized in that the ziprasidone-containing particles are supplied in a rapidly dissolving dosage form. Dosage form according to claim 82, characterized in that the tablet is a rapid melt tablet. Use of a composition as defined in claim 67, characterized in that it is in the preparation of a medicament for preventing and / or treating schizophrenia or similar psychiatric disorder. Composition according to Claim 71, characterized in that the modified release particles comprise a pH-dependent polymer coating which is effective in pulse release of the active ingredient after a time delay of six hours. Composition according to Claim 86, characterized in that the polymer coating comprises methacrylate polymers. Composition according to Claim 86, characterized in that the polymer coating comprises a mixture of methacrylate and ammonium methacrylate copolymers in a ratio sufficient to achieve a pulsed release of the active ingredient after a time delay. Composition according to Claim 88, characterized in that the ratio of ammonium methacrylate paramethacrylate copolymers is approximately 1: 1. Composition according to Claim 67, characterized in that said particles are each in the form of an osmotic device. Composition according to Claim 1, characterized in that the composition is formulated as a deposit finger form.