JP2008546781A - Nanoparticulate and controlled release compositions comprising aryl-heterocyclic compounds - Google Patents

Abstract

  The present invention provides a composition comprising ziprasidone useful for the treatment and prevention of psychiatric disorders similar to schizophrenia. In one embodiment, the composition comprises nanoparticulate particles comprising ziprasidone and at least one surface stabilizer. The nanoparticulate particles have an effective average particle size of less than about 2000 nm. In another embodiment, the composition comprises a modified release composition that delivers ziprasidone in a bimodal, multimodal or continuous mode upon administration to a patient. The invention also relates to dosage forms containing such compositions and methods for the treatment and prevention of psychiatric disorders similar to schizophrenia.

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention relates to compositions that are useful for the prevention and treatment of psychiatric disorders similar to schizophrenia. In particular, the present invention relates to compositions comprising aryl-heterocyclic pharmaceutical compounds such as ziprasidone. In one aspect of the invention, the composition is in nanoparticulate form and also includes at least one surface stabilizer. In another aspect, the invention also relates to novel dosage forms for the controlled delivery of aryl-heterocyclic pharmaceutical compounds, such as ziprasidone, and methods for the prevention and treatment of psychiatric disorders similar to schizophrenia.

BACKGROUND ART Chemically, 5- [2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] ethyl] -6-chloro-1,3-dihydro-2H-indole-2 -Ziprasidone, known as ON, is an antipsychotic to treat psychiatric conditions such as schizophrenia, hallucinations, delusions, hostility, and other bipolar disorders without increased lipids and other blood fats It is a benzothiazolyl piperazine derivative used as an agent. Ziprasidone has a general formula of C ₂₁ H ₂₁ ClN ₄ OS and a molecular weight of 412.94 (free base).

  The chemical structure of ziprasidone is shown below:

Ziprasidone may be administered as part of a dosage form provided under the trade name Geodon® registered by Pfizer, Inc. in the United States. Ziprasidone is a ziprasidone hydrochloride, 5- (2- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) ethyl) -6-chloro-, in Geodon® capsules. It exists in the form of 1,3-dihydro-2H-indol-2-one monohydrochloride monohydrate. This salt is a white to slightly pink powder, has a melting point of 300 ° C., a general formula of C ₂₁ H ₂₁ ClN ₄ OS · HCl · H ₂ O, and a molecular weight of 467.42. Geodon® capsules are available for oral administration in 20 mg, 40 mg, 60 mg, and 80 mg capsules. Inactive ingredients in Geodon® capsules include lactose, gelatinized starch, and magnesium stearate. Common medications for patients include oral dosage forms (capsules) for the treatment of adult schizophrenia and are dosed at 20 milligrams (mg) twice daily with meals. Higher doses may include 80 mg twice daily.

Ziprasidone is a trade name for Geodon® injection and is available for intramuscular injection in the form of ziprasidone mesylate. Geodon® for injection is ziprasidone mesylate trihydrate (5- (2- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) ethyl) -6-chloro- 1,3-dihydro -2H- indol-2-one, methanesulfonate, trihydrate (general _{formula: C 21 H 21 ClN 4 OS} · CH 3 SO 3 H · 3H 2 O; molecular weight: 563.09) of Contains the lyophilized form.Geodon® injection is available in single dose vials as ziprasidone mesylate containing 20 mg ziprasidone / mL, which is provided by the US Food and Drug Administration (FDA). Approved for the treatment of schizophrenia, the intramuscular form of ziprasidone has been approved for acute onset in schizophrenic patients.

  The elimination half-life of ziprasidone is about 7 hours. Within 1-3 days, steady state plasma concentrations are reached. The bioavailability of ziprasidone is about 60% when taken with meals. Of the 20 patients who increased to high doses of Geodon® (360 mg per day), about one was reported to show a significant improvement in cognition.

  Ziprasidone compounds are described in US Pat. Nos. 4,831,031; 6,110,918; 6,245,765; 6,150,366; 6,232,304; 6,399,777; and 6,245,766. It is described in. US Patent Publication Nos. 2004/0138237 and 2004/0146562 disclose injectable depot formulations of ziprasidone in which an active ziprasidone compound is solubilized with a cyclodextrin to form a suspension.

  Ziprasidone is extremely effective in the therapeutic treatment of patients suffering from psychiatric disorders similar to schizophrenia. However, due to the need to take ziprasidone twice daily and the further need to take ziprasidone after meals, strict patient compliance is required in the treatment of psychiatric disorders similar to schizophrenia. It has become an essential factor in the efficacy of ziprasidone. Furthermore, such frequent administration often requires the attention of medical workers and contributes to the high costs associated with treatments involving ziprasidone. Thus, current techniques for ziprasidone compositions need to overcome such problems associated with their use in the treatment of psychosis similar to schizophrenia.

In addition, ziprasidone is almost insoluble in water. This poor water solubility results in reduced bioavailability.
SUMMARY OF THE INVENTION One aspect of the present invention includes a nanoparticulate composition comprising (A) ziprasidone and (B) at least one surface stabilizer. The surface stabilizer may be adsorbed on the surface of the nanoparticulate particles or may be bound thereto. The nanoparticulate particles have an effective average particle size of less than about 2000 nm. The nanoparticulate composition may comprise one or more additional active ingredients useful for the prevention and treatment of psychiatric disorders similar to schizophrenia, and / or one or more pharmaceutically acceptable excipients. . In such embodiments, administration of the nanoparticulate composition to a subject is bioequivalent even in the fed or fasted state and can demonstrate similar pharmacokinetics.

  The invention also relates to a modified release composition having at least a first component comprising a first population of active ingredient-containing particles and a second component comprising a second population of active ingredient-containing particles, wherein each component Have different rates and / or durations of release, wherein at least one of the components comprises ziprasidone. The at least second component particles are provided in a modified release (MR) form, eg, coated with a modified release coating agent, 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 a modified release composition may comprise a nanoparticulate form of ziprasidone and at least one surface stabilizer, one or more additional effective for the prevention and treatment of psychiatric disorders similar to schizophrenia. Ingredients and / or one or more pharmaceutically acceptable excipients may be included.

  The first component of the modified release composition is released immediately but after a time delay (delayed release), wherein substantially all of the active ingredient contained in the first component is released immediately after administration of the dosage form. ), Or various release profiles may be specified, including profiles that are 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 the patient. As used herein, “rapidly released” includes a release profile in which at least about 80% of the active ingredient of the dosage form component is released within about 1 hour after administration. “Delayed release” includes a release profile in which the active ingredient of the dosage form component is released (rapidly or slowly) after a certain time delay, and the terms “controlled release” and “extended release” include A release profile is included in which at least about 80% of the active ingredient contained in the dosage form component is slowly released.

  The second component of the modified release composition may also manifest 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 demonstrates a delayed release profile in which the active ingredient of the component is released after a time delay. In another embodiment, the second component demonstrates 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 a two component embodiment where the components exhibit different release profiles, the release profile from the active ingredient composition is bimodal. In embodiments where the first component demonstrates an immediate release profile and the second component exhibits a delayed release profile, there is a lag time between the release of the active ingredient from the first component and the release of the active ingredient from the second component. Exists. The duration of the lag time can be varied by modifying the amount and / or composition of the modified release coating agent or by modifying the amount and / or composition of the modified release matrix material utilized to achieve the desired release profile. You may let me. In this way, the duration of the lag time can be designed to mimic the desired plasma profile.

  In embodiments where the first component demonstrates an immediate release profile and the second component exhibits a controlled release profile, the active ingredients in the first and second components are released over different time periods. In such embodiments, the immediate release component helps to accelerate the onset of action by minimizing the time from administration to a therapeutically effective plasma concentration level, and one or more subsequent components can be plasma throughout the dosing interval. It helps to minimize fluctuations in concentration levels and / or maintain a therapeutically effective plasma concentration. In one such embodiment, the active ingredient of the first component is released quickly and the active ingredient of the second component is released within a period of about 12 hours after administration. In another such embodiment, the active ingredient of the first component is released quickly and the active ingredient of the second component is released within a period of about 24 hours after administration. In yet another such embodiment, the active ingredient of the first component is released rapidly and the active ingredient of the second component is released over a period of about 12 hours after administration. In yet another such embodiment, the active ingredient of the first component is released rapidly and the active ingredient of the second component is released over a period of about 24 hours after administration. In yet another such embodiment, the active ingredient of the first component is released rapidly and the active ingredient of the second component is released over a period of at least about 12 hours after administration. In yet another such embodiment, the active ingredient of the first component is released rapidly and the active ingredient of the second component is released over a period of at least about 24 hours after administration.

  The plasma profile resulting from the administration of the dosage form of the present invention comprising an immediate release component and at least one modified release component is different from the plasma profile resulting from the administration of two or more IR dosage forms given sequentially or separately. It may be substantially similar to the plasma profile produced by administration of IR and MR dosage forms. The modified release composition of the present invention is particularly useful for administering ziprasidone, which is usually administered twice a day. In one embodiment of the invention, the composition delivers ziprasidone in a bimodal manner. Upon administration, such compositions provide a plasma profile that substantially mimics the plasma profile obtained by sequential administration of two IR doses of ziprasidone according to a typical treatment regime.

  According to another aspect of the present invention, the composition is designed to provide a plasma profile that minimizes or eliminates fluctuations in plasma concentration levels associated with administration of two or more IR dosage forms given sequentially. be able to. In such embodiments, the composition comprises an immediate release component to accelerate onset of action by minimizing the time from administration to a therapeutically effective plasma concentration level, and a therapeutically effective plasma concentration throughout the dosing interval. It may be provided with at least one modified release component for maintenance. Ziprasidone may be included in nanoparticulate particles that also include at least one surface stabilizer.

Modified release compositions similar to the compositions disclosed herein are disclosed and claimed in US Pat. Nos. 6,228,398 and 6,730,325 to Devane et al.
The invention also relates to dosage forms made from the compositions of the invention. In one embodiment, the dosage form is a solid oral dosage form comprising the modified release composition of the present invention. Oral dosage forms may utilize, for example, erodable formulations, diffusion controlled formulations, and osmotic controlled formulations. In such embodiments, the entire dose contained in the dosage form may be released in a pulsatile or continuous manner. In one such embodiment, a portion of the total dose is released immediately to allow for rapid onset of effect, with the remainder of the total dose remaining after the lag time or for a period of time up to about 24 hours. Released over.

  In another embodiment, the dosage form is an injectable depot formulation comprising a nanoparticulate composition comprising ziprasidone. The depot formulation dissolves slowly and releases the drug into the patient's circulation. A single injection of this formulation can provide an effective therapeutic plasma concentration of ziprasidone over 3 months.

  The present invention is also directed to a method of making a nanoparticulate composition comprising ziprasidone. Such a method comprises subjecting nanoparticulate particles comprising ziprasidone to a period of time and conditions sufficient to provide a stable nanoparticulate composition comprising at least one surface stabilizer and ziprasidone. A step of contacting with.

  The invention further relates to methods of treatment including, but not limited to, prevention and treatment of psychiatric disorders similar to schizophrenia. Such methods include the step of administering to a subject a therapeutically effective amount of a composition comprising ziprasidone, eg, a nanoparticulate composition.

  The compositions and dosage forms of the present invention reduce the required frequency of administration, thereby increasing patient convenience and patient compliance, and thus, but not limited to prevention of psychiatric disorders similar to schizophrenia and Useful to improve treatment outcomes to all treatments that require ziprasidone, including treatment. This approach can replace conventional ziprasidone dosage forms that are administered frequently daily.

  Both the foregoing general description and the following detailed description are exemplary descriptions and are intended to provide further description of the claimed invention. Other objects, advantages, and novel 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 will now be described using several definitions given below and throughout this application.
As used herein, “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. If there is a use of this term that is not clear to the skilled person in the context in which it is used, “about” means up to plus (+) or minus (−) 10% of the special term.

  As used herein, “ziprasidone” includes ziprasidone, a pharmaceutically acceptable salt, acid, ester, metabolite, complex, or other derivative thereof and the respective stereoisomers thereof. And mixtures of two or more such stereoisomers, racemates, and the like.

  As used herein, “therapeutically effective amount of ziprasidone” means a dose that produces a unique pharmacological response when ziprasidone is administered to a significant number of subjects in need of associated treatment. To do. Even if such a dose is deemed to be a therapeutically effective amount by one of ordinary skill in the art, a therapeutically effective amount of ziprasidone administered to a particular subject in a particular case will treat the condition described herein. Note that it is not always effective.

As used herein, “granular” means a state of matter characterized by the presence of discrete particles, pellets, beads, or granules, regardless of their size, shape, or form.
As used herein, “multiparticulate” means a plurality of discrete or agglomerated particles, pellets, beads, granules, or mixtures thereof, regardless of their size, shape, or form. A composition comprising a multiparticulate material is referred to herein as a “multiparticulate composition”.

  As used herein, “nanoparticulate” means a multiparticulate material in which the effective average particle size of the particles is less than about 2000 nm (2 microns) in diameter. A composition comprising nanoparticulates is referred to herein as a “nanoparticulate composition”.

  As used herein, “effective average particle size” for describing multiparticulates (eg, nanoparticulates) means that at least 50% of the particles are of a particular size. . Thus, “effective average particle size less than about 2000 nm in diameter” means that at least 50% of the particles therein are less than about 2000 nm in diameter.

  As used herein, “D50” means a particle size at which 50% of the particles in a multiparticulate are less than that. Similarly, “D90” means a particle size at which 90% of the particles in the multiparticulate material are less than that.

  As used herein in relation to stable particles, “stable” means, but is not limited to, one or more of the following variables: (1) The particles are Does not appreciably fluff or agglomerate, or otherwise increases particle size; (2) The physical structure of the particles is over time, such as by conversion from an amorphous phase to a crystalline phase. (3) the particles are chemically stable; and / or (4) when the active ingredient is not subjected to a heating step above the melting point of the particles during the production of the nanoparticles of the present invention.

  As used herein, “a drug that is hardly soluble in water” is 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. means.

As used herein, “modified release” includes non-immediate release and includes controlled release, extended release, sustained release, and delayed release.
As used herein, “time delay” refers to the period of time between administration of a dosage form comprising the composition of the invention and release of the active ingredient from that particular ingredient.

As used herein, “lag time” means the time between the release of an active ingredient from one component of the composition and the release of the active ingredient from another component of the composition.
As used herein, “erodible” refers to a formulation that can be worn, lost, or deteriorated by the action of substances within the formulation body.

As used herein, “diffusion control” refers to a formulation that may spread from a higher concentration to a lower concentration region, for example, as a result of its spontaneous movement.
As used herein, “osmotic control” can spread to a higher concentration solution as a result of its movement through a semipermeable membrane, attempting to make the concentration of the formulation equal on both sides of the membrane Related to formulation.

I. The Nanoparticulate Composition Comprising Ziprasidone The present invention provides a nanoparticulate composition comprising (A) particles comprising ziprasidone, or a salt or derivative thereof; and (B) at least one surface stabilizer. The nanoparticulate composition was first described in US Pat. No. 5,145,684. Nanoparticulate active agent compositions include, for example, US Pat. Nos. 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; 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; 582, 285; 6,592,903; 6,656,504; 6,742,734; 6,745,962; 6,811,767; 6,908,626; 6,969,529; 6,97 , 647; and 6,991,191 and U.S. Patent Publication Nos. 20020012675; 2005027774; 20050238725; 20040141925; 20040115134; 2004010589; 20040105778; 2004011566; 20040057905; 20040033267; 20040033202; 20040 20040015134; 20030232796; 200301521596; 20030185869; 2003011411; 20030137067; 20030108616; 20030095928; 20030087308; 20030023203; 20020175958; Non-crystalline small particle compositions are described in US Pat. Nos. 4,783,484; 4,826,689; 4,997,454; 5,741,522; 5,776,496.

  As noted above, the effective average particle size of the particles in the nanoparticulate composition of the present invention is less than about 2000 nm (ie, 2 microns) in diameter. In embodiments of the present invention, the effective average particle size is, for example, less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm when measured by light scattering, microscopy, or other suitable methods. Less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, about It may be less than 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.

Nanoparticulate particles may be present in a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, or a mixture thereof.
In addition to allowing for smaller solid dosage form sizes, the nanoparticulate compositions of the present invention demonstrate increased bioavailability compared to previous conventional non-nanoparticulate compositions comprising ziprasidone. Need smaller doses of ziprasidone. In one embodiment of the invention, the nanoparticulate composition of the invention has a bioavailability about 50% greater than ziprasidone administered in a conventional dosage form. In other embodiments, the nanoparticulate composition of the present invention has a bioavailability of about 40% greater, about 30% greater, about 20% or about 10% greater than ziprasidone administered in conventional dosage forms.

The nanoparticulate composition may also have a desirable pharmacokinetic profile when measured following its initial administration to a mammalian subject. The desirable pharmacokinetic profile of the composition includes, but is not limited to (1) the C _{max of the} same ziprasidone delivered at the same dose by the non-nanoparticulate composition when assayed in the plasma of a mammalian subject after administration Preferably higher C _{max of} ziprasidone; and / or (2) more preferably than the same ziprasidone AUC delivered at the same dosage by the non-nanoparticulate composition when assayed in the plasma of a mammalian subject after administration Large, AUC of ziprasidone; and / or (3) preferably less than the T _{max of the} same ziprasidone delivered at the same dosage by the non-nanoparticulate composition when assayed in the plasma of a mammalian subject after administration, The T _{max of} ziprasidone is included.

In an embodiment of the invention, the nanoparticulate composition of the invention comprises, for example, about 90% or less of the T _max of the same ziprasidone delivered at the same dosage by the non-nanoparticulate composition. T _max is specified. In other embodiments of the invention, the nanoparticulate composition of the invention is, for example, about 80% or less, about 70% or less, about 60% of the T _max of the same ziprasidone delivered at the same dosage by the non-nanoparticulate composition. % Or less, about 50% or less, about 30% or less, about 25% or less, about 20% or less, about 15% or less, about 10% or less, or about 5% or less, the T _{max of} ziprasidone contained therein Can be specified. In one embodiment of the invention, the T _max of ziprasidone when assayed in the plasma of a mammalian subject is less than about 6 to about 8 hours after administration. In other aspects of the invention, the T _max of ziprasidone is less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour, or about 30 minutes after administration. Is less than.

In an embodiment of the invention, the nanoparticulate composition of the invention comprises, for example, at least about 50% of the C _max of the same ziprasidone delivered at the same dosage by the non-nanoparticulate composition of ziprasidone contained therein C _max is specified. In other embodiments of the invention, the nanoparticulate composition of the invention is, for example, at least about 100%, at least about 200%, at least about at least about the C _{max of the} same ziprasidone delivered at the same dosage by the non-nanoparticulate composition. 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%, at least about 1100%, at least about 1200%, at least about 1300%, at least about 1400%, at least about 1500%, at least about 1600%, at least about 1700%, at least about 1800%, or at least about 1900% higher, the C _max of ziprasidone contained therein can be specified .

  In embodiments of the invention, the nanoparticulate composition of the invention comprises, for example, an AUC of ziprasidone contained therein that is at least about 25% greater than the AUC of the same ziprasidone delivered at the same dosage by the non-nanoparticulate composition. Make it explicit. In other embodiments of the invention, the nanoparticulate composition of the invention is, for example, at least about 50%, at least about 75%, at least about 100 than the AUC of the same ziprasidone delivered at the same dosage by the non-nanoparticulate composition. %, 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 1000%, at least about 1050%, at least about 1100%, at least about 1150%, or at least about 1200% greater, it is possible to express the AUC of ziprasidone contained therein.

  The present invention includes nanoparticulate compositions in which the pharmacokinetic profile after administration of ziprasidone is not substantially affected by the fed or fasted state of a subject taking the composition. This means that there is no substantial difference in the amount of ziprasidone absorbed or the rate of absorption when the nanoparticulate composition is administered in a fed state versus a fasted state. In conventional ziprasidone formulations, i.e., Geodon®, the absorption of ziprasidone increases when administered with a meal. This difference in absorption observed with conventional ziprasidone formulations is undesirable. The composition of the present invention overcomes this problem.

  The benefits of a dosage form that substantially eliminates the effects of meals do not require that the patient take a dose with or without a meal, thus improving patient convenience and improving patient compliance. Includes improving. This is important because at low patient compliance, an increase in the medical condition for which ziprasidone is prescribed can be observed.

The present invention also includes a nanoparticulate composition comprising ziprasidone, wherein administration of the composition to a fasted subject is bioequivalent to administration of the composition to a fed subject. included.
When administered in the fed state relative to the fasted state, the difference in absorption of the composition of the present invention is preferably less than about 100%, less than about 95%, less than about 90%, less than about 85%, about 80%. Less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, 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 aspect of the invention, the invention includes a composition comprising ziprasidone, wherein administration of the composition to a fasted subject is particularly compatible with the US Food and Drug Administration. It is bioequivalent to administration of the composition to a subject in a fed state, as defined by the C _max and AUC guidelines set forth by the European Regulatory Authority (EMEA). Under US FDA guidelines, two products or methods are bioequivalent (T _max measurement) if the 90% confidence interval (CI) between AUC and C _max is between 0.80 and 1.25. The value is not related to bioequivalence for regulatory purposes). To show bioequivalence between two compounds or dosage conditions that comply with European EMEA guidelines, 90% CI for AUC is between 0.80 and 1.25, 90% CI for C _max is 0 Must be between 70 and 1.43.

  The nanoparticulate composition of the present invention is proposed to have an unexpectedly dramatic dissolution profile. Rapid dissolution of ziprasidone is preferred, and generally faster dissolution results in faster onset of action and greater bioavailability. To improve the dissolution profile and bioavailability of ziprasidone, it would be useful to increase it so that the dissolution of the drug can reach levels close to 100%.

  The compositions of the present invention preferably have a dissolution profile that dissolves at least about 20% ziprasidone within about 5 minutes. In other embodiments of the invention, at least about 30% or at least about 40% ziprasidone dissolves within about 5 minutes. In still other aspects 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 dissolves within about 10 minutes. Finally, in another aspect of the invention, preferably at least about 70%, at least about 80%, at least about 90%, or at least about 100% of ziprasidone dissolves within about 20 minutes.

  Dissolution is preferably measured in a well-characterized medium. Such a dissolution medium results in two very different dissolution curves for two products with very different dissolution profiles in gastric juice, i.e. the dissolution medium predicts in vivo dissolution of the composition. An exemplary dissolution medium is an aqueous medium containing the surfactant sodium lauryl sulfate at 0.025M.

Quantification of the dissolved amount can be performed spectrophotometrically. Dissolution may be measured using the rotating blade method (European Pharmacopoeia).
An additional feature of the nanoparticulate composition of the present invention is that it is redispersed so that the particles have an effective average particle size of less than about 2000 nm in diameter. This is important because if the particles do not redisperse so as to have an effective average particle size of less than about 2000 nm in diameter, the composition provides the benefits obtained by formulating ziprasidone therein into a nanoparticulate form. Because there is a possibility of losing. This is because nanoparticulate compositions benefit from the small size of particles comprising ziprasidone. If the particles do not redisperse to a small particle size upon administration, they are “bulky” or agglomerated by the very high surface free energy of the nanoparticulate system and the thermodynamic driving forces that attempt to reduce the overall free energy Particles are generated. Due to the formation of such agglomerated particles, the bioavailability of the dosage form may be much lower than that observed in the liquid dispersion form of the nanoparticulate composition.

  In other embodiments of the present invention, the redispersed particles of the present invention (redispersed in water, biologically relevant media, or other suitable liquid media) may be subjected to light scattering, microscopy, or other suitable When measured by the method, the diameter is less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, Less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, or about Has an effective average particle size of less than 50 nm. Such methods suitable for measuring the effective average particle size are known to those skilled in the art.

  Redispersibility may be checked using any suitable method known in the art. For example, “Solid Dose Nanoparticulate Compositions Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate” See the Examples section of US Pat. No. 6,375,986 to.

  The nanoparticulate composition of the present invention is human-like as demonstrated by reconstitution / redispersion in biologically relevant aqueous media such that the effective average particle size of the redispersed particles is less than about 2000 nm. Demonstrates dramatic redispersion of particles upon administration to a non-human mammal or animal. Such a biologically relevant aqueous medium can be any aqueous medium that demonstrates the desired ionic strength and pH that underlie the biological relevance of the medium. The desired pH and ionic strength are representative of physiological conditions found in the human body. Such a biologically relevant aqueous medium may be, for example, an aqueous solution of electrolyte, or an aqueous solution of any salt, acid, or base, or a combination thereof that specifies the desired pH and ionic strength.

  Biologically relevant pH is well known in the art. For example, in the stomach, the pH ranges slightly from less than 2 (but typically greater than 1) to 4 or 5. In the small intestine the pH ranges from 4-6 and in the colon it can range from 6-8. Biologically relevant ionic strength is also well known in the art. Fasted state gastric fluid has an ionic strength of about 0.1M, whereas fasted state intestinal fluid has an ionic strength of about 0.14. For example, Lindahl et al., “Characterization of Fluids from the Stomach and Proximal Jejunum in Men and Women” Pharm. Res., 14 (4): 497-502 (1997). It is believed that the pH and ionic strength of the test solution is more critical than the content of a particular chemical. Thus, suitable pH and ionic strength values are: strong acids, strong bases, salts, one or more conjugated acid-base pairs (ie, weak acids and their corresponding salts), monoprotic and polyprotic electrolytes. , Etc. can be obtained by countless combinations.

  Exemplary electrolyte solutions can include, but are not limited to, HCl solutions ranging from about 0.001 to about 0.1 N, NaCl solutions ranging from about 0.001 to about 0.1 M, and combinations thereof. . For example, the electrolyte solution includes, but is not limited to, about 0.1 N or less HCl, about 0.01 N or less HCl, about 0.001 N or less HCl, about 0.1 M or less NaCl, about 0.01 M or less NaCl, Up to about 0.001M NaCl, and combinations thereof. Among these electrolyte solutions, 0.01M HCl and / or 0.1M NaCl are most representative of fasting human physiological conditions, depending on the pH and ionic strength conditions of the proximal gastrointestinal tract.

  The electrolyte concentrations of 0.001N HCl, 0.01N HCl, and 0.1N HCl correspond to pH 3, pH 2, and pH 1, respectively. Thus, 0.01N HCl solution mimics the typical acidic conditions found in the stomach. A solution of 0.1M NaCl provides a reasonable approximation of ionic strength conditions found throughout the body, including gastrointestinal fluid, but higher than 0.1M to mimic feeding conditions in the human GI tract Concentration may be used.

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

  As stated above, the composition also includes at least one surface stabilizer. The surface stabilizer may be adsorbed on the surface of the ziprasidone-containing particles or may be bound thereto. Preferably, the surface stabilizer attaches to or binds to the surface of the particle but does not chemically react with the particle or other surface stabilizer molecules. Individually adsorbed surface stabilizer molecules have little cross-linking between the molecules.

  The relative amounts of ziprasidone and surface stabilizer present in the composition of the present invention may vary widely. The optimum amount of the individual components may depend, inter alia, on the particular drug selected, the hydrophilic lipophilic balance (HLB) of the stabilizer, the melting point, and the surface tension of the aqueous solution. The concentration of ziprasidone is about 99.5% to about 0.001%, about 95% to about 0, based on the total weight of ziprasidone plus the surface stabilizer (s), excluding other excipients. .1%, or may vary from about 90% to about 0.5% weight. The concentration of the surface stabilizer (s) is about 0.5% based on the total dry weight of ziprasidone, or a salt or derivative thereof, and the surface stabilizer (s) without other excipients. May vary in weight from about 99.999%, from about 5.0% to about 99.9%, or from about 10% to about 99.5%.

  The choice of surface stabilizers for ziprasidone is not trivial and requires detailed experimentation to achieve the desired formulation. Thus, the present invention is directed to the surprising discovery that nanoparticulate compositions comprising ziprasidone can be made.

  In the present invention, more than one combination of surface stabilizers can be used. Useful surface stabilizers that can be utilized in the present 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 hydroxypropylmethylcellulose (known today as hypromellose), hydroxypropylcellulose, polyvinylpyrrolidone, sodium lauryl sulfate, dioctylsulfosuccinate, gelatin, casein, lecithin (phosphatide), dextran, acacia Rubber, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsified wax, sorbitan ester, polyoxyethylene alkyl ether (eg, cetomacrogol 1000 Macrogol ether), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (eg, Twe, for example) n 20® and Tween 80® (commercially available Tween® such as ICI Specialty Chemicals); polyethylene glycols (eg, Carbowax 3550® and 934® (Union Carbide) )), Polyoxyethylene stearate, colloidal silicon dioxide, phosphate ester, carboxymethylcellulose calcium, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, amorphous cellulose, magnesium magnesium silicate, triethanolamine 4- (1,1,3,3-tetramethylbuty with polyvinyl alcohol (PVA), ethylene oxide and formaldehyde ) -Phenolic polymers (also known as tyloxapol, superion, and triton), poloxamers (eg, Pluronics F68® and F108®, which are block copolymers of ethylene oxide and propylene oxide); Tetranic 908®, also known as Poloxamine 908®, which is a tetrafunctional block copolymer resulting from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, NJ) Tetronic 1508® (T-1508) (BASF Wyandotte Corporation), alkylaryl polyether Tritons X-200® (Rohm and Haas), a sulfonate; Crodestas F-110 (Croda), a mixture of sucrose stearate and sucrose distearate; Olin-lOG® or Surfactant P-isononylphenoxypoly- (glycidol), also known as 10-G® (Olin Chemicals, Stanford, Conn.); Crodestas SL-40® (Croda); and C ₁₈ H ₃₇ CH _{2 (CON (CH 3) -CH 2} (CHOH) 4 (CH 2 OH) 2 in which SA9OHCO (Eastman Kodak Co.); Dekanoniru -N- methyl glucamide; n-decyl beta-D-glucopyranoside; n-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-β-D-glucopyranoside; n-heptyl β- D-thioglucoside; n-hexyl β-D-glucopyranoside; nonanyl-N-methylglucamide; n-noyl β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside; β-D-thioglucopyranoside; PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivatives, PEG-vitamin A, PEG-vitamin E, lysozyme, vinylpyrrolidone and vinyl acetate random copolymers, and the like.

  Examples of useful cationic surface stabilizers include, but are not limited to, polymers, biopolymers, polysaccharides, cellulosics, alginate, phospholipids, and non-polymeric compounds (such as zwitterionic stabilizers). ), Poly-n-methylpyridinium, anthryul pyridinium chloride, cationic phospholipid, chitosan, polylysine, polyvinylimidazole, polybrene, polymethylmethacrylate / trimethylammonium bromide / bromide (PMMTMABr), hexadecyltrimethylammonium bromide (HDMACB) ), And polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate.

Other useful cationic stabilizers include, but are not limited to, cationic lipids, sulfonium, phosphonium, and stearyltrimethylammonium chloride, benzyl-di (2-chloroethyl) ethylammonium bromide, coco trimethylammonium chloride or bromide. Coco methyl dihydroxyethylammonium chloride or bromide, decyltriethylammonium chloride, decyldimethylhydroxyethylammonium chloride or bromide, C _12-15 dimethylhydroxyethylammonium chloride or bromide, coco dimethylhydroxyethylammonium chloride or bromide, myristyltrimethylammonium Methyl sulfate, lauryl dimethyl benzyl ammonium Nium chloride or bromide, lauryl dimethyl (ethenoxy) ₄ ammonium chloride or bromide, N-alkyl (C _12-18 ) dimethylbenzylammonium chloride, N-alkyl (C _14-18 ) dimethyl-benzylammonium chloride, N-tetradecyldimethyl Benzylammonium chloride monohydrate, dimethyldidecylammonium chloride, N-alkyl and (C _12-14 ) dimethyl 1-naphthylmethylammonium chloride, halogenated trimethylammonium, alkyl-trimethylammonium and dialkyl-dimethylammonium salts, lauryl Trimethylammonium chloride, ethoxylated alkylamidoalkyldialkylammonium salt and / or ethoxylated trialkylammonium Umum salt, dialkylbenzene dialkylammonium chloride, N-didecyldimethylammonium chloride, N-tetradecyldimethylbenzylammonium, chloride monohydrate, N-alkyl ( _C12-14 ) dimethyl 1-naphthylmethylammonium chloride and dodecyldimethyl benzyl ammonium chloride, dialkyl benzene alkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium _{bromide, C 12, C 15, C} 17 trimethyl ammonium bromide, dodecyl benzyl triethyl ammonium chloride, poly - diallyldimethylammonium Chloride (DADMAC), dimethylammonium chloride, al Killdimethylammonium halides, tricetylmethylammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyltrioctylammonium chloride (ALIQUAT 336 ^™ ), POLYQUAT 10 ^™ , tetrabutylammonium bromide , Quaternary ammonium compounds such as benzyltrimethylammonium bromide, choline esters (such as choline esters of fatty acids), benzalkonium chloride, stearalkonium chloride compounds (such as stearyltrimonium chloride and distearyldimonium chloride) , Cetylpyridinium bromide or chloride, halogenated salt of quaternized polyoxyethylalkylamine, IRAPOL ^TM, and ALKAQUAT ^TM (Alkaril Chemical Company), alkyl pyridinium salts, alkyl amines, dialkylamines, alkanolamines, polyethylenepolyamines, N, N-dialkylaminoalkyl acrylates, and amines such as vinyl pyridine, lauryl amine acetate, stearyl Amines such as amine acetates, alkylpyridinium salts, and alkylimidoazolinium salts, and amine oxides; imidoazolinium salts; protonated quaternary acrylamides, methylated quaternary polymers (poly [diallyldimethylammonium chloride] and Poly- [N-methylvinylpyridinium chloride]); and cationic guar gum.

  Such exemplary cationic surface stabilizers and other useful cationic surface stabilizers are described by J. Cross and E. Singer, “Cationic Surfactants: Analytical and Biological Evaluation) (Marcel Decker, 1994)); P. And D. Rubingh (supervised), “Cationic Surfactants: Physical Chemistry (Marcel Decker, 1991); Richmond, “Cationic Surfactants: Organic Chemistry” (Marcel Decker, 1990).

Non-polymer surface stabilizers include benzalkonium chloride, carbonium compounds, phosphonium compounds, oxonium compounds, halonium compounds, cationic organometallic compounds, quaternary phosphorus compounds, pyridinium compounds, anilinium compounds, ammonium compounds, hydroxylammonium compounds, primary Any non-polymeric compound can be used, such as an ammonium compound, a secondary ammonium compound, a tertiary ammonium compound, and a quaternary ammonium compound of the formula: NR ₁ R ₂ R ₃ R ₄ ⁽⁺⁾ . For compounds of formula: NR ₁ R ₂ R ₃ R ₄ ⁽⁺⁾ :
(I) none of R _{1 to} R ₄ is CH ₃ ;
(Ii) _{one of} R _{1 to} R ₄ is CH ₃ ;
(Iii) three of R _{1 to} R ₄ are CH ₃ ;
(Iv) all of R _{1 to} R ₄ are CH ₃ ;
(V) two of R _{1 to} R ₄ are CH ₃ , one of R _{1 to} R ₄ is C ₆ H ₅ CH ₂ , and _{one of} R _{1 to} R ₄ is an alkyl chain of 7 or less carbon atoms Is
_(Vi) two of R 1 to R ₄ is a CH _3, one of R 1 to R ₄ is a _C 6 _H 5 CH _2, and the alkyl chain of one of 19 or more carbon atoms of _R 1 to R ₄ Is
(Vii) two of R _{1 to} R ₄ are CH ₃ and one of R _{1 to} R ₄ is C ₆ H ₅ (CH ₂ ) _n (where n>1);
_(Viii) two of R 1 to R ₄ is a CH _3, one of R 1 to R ₄ is a _C 6 _H 5 CH _2, and one of _R 1 to R ₄ contains at least one heteroatom;
(Ix) two of R ₁ -R ₄ are CH ₃ , one of R ₁ -R ₄ is C ₆ H ₅ CH ₂ , and _{one of} R ₁ -R ₄ contains at least one halogen;
(X) two of R ₁ -R ₄ are CH ₃ , one of R ₁ -R ₄ is C ₆ H ₅ CH ₂ , and _{one of} R ₁ -R ₄ contains at least one cyclic fragment ;
(Xi) two of R _{1 to} R ₄ are CH ₃ and one of R _{1 to} R ₄ is a phenyl ring; or (xii) two of R _{1 to} R ₄ are CH ₃ and R _{1 to} R ₄ two is a purely aliphatic fragments.

  Such compounds include, but are not limited to, behenalkonium chloride, benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride, lauralkonium chloride, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cetylamine hydrofluoride , Chloralylmethenamine chloride (Quaternium-15), distearyldimonium chloride (Quaternium-5), dodecyldimethylethylbenzylammonium chloride (Quaternium-14), Quaternium-22, Quaternium-26, Quaterium-18 hectit (ector hector) , Dimethylaminoethyl chloride hydrochloride, cysteine hydrochloride, diethanolammonium POE (10) oleyl ether phosphate, dieta Allyl ammonium POE (3) oleyl phosphate, tallow arconium chloride, dimethyldioctadecyl ammonium bentonite, stearalkonium chloride, domifene bromide, denatonium benzoate, myristalkonium chloride, lautrimonium chloride, ethylenediamine dihydrochloride, Guanidine hydrochloride, pyridoxine HCl, iophetamine hydrochloride, meglumine hydrochloride, methylbenzethonium chloride, miltrimonium bromide, oleyltrimonium chloride, polyquaternium-1, procaine hydrochloride, cocobetaine, stearalkonium bentonite, stearalkonium hectonite , Stearyltrihydroxyethylpropylenediamine dihydrofluoride, tallownium tallow chloride, and hexadecyltrimethylammonium bromide It is.

  Surface stabilizers are commercially available and / or can be produced by techniques known in the art. Most of these surface stabilizers are known pharmaceutical excipients and have been published jointly by the American Pharmaceutical Industry Association and the British Pharmaceutical Association in the “Handbook of Pharmaceutical Excipients” (The Pharmaceutical Press, 2000).

  In addition to ziprasidone, the compositions of the present invention may include one or more compounds useful for treating schizophrenia or similar psychiatric disorders and related conditions. The composition may be administered with such compounds. These other active compounds preferably include those useful for the treatment of physical conditions such as headache, fever, pain, and other similar conditions caused by psychiatric disorders generally similar to schizophrenia. included. Such active compounds should be present in a manner that does not interfere with the therapeutic effect of ziprasidone, as determined by one skilled in the art.

  The composition of the present invention comprises one or more binders, fillers, diluents, lubricants, emulsifying and suspending agents, sweeteners, fragrances, preservatives, buffering agents, wetting agents, disintegrating agents, foaming agents, Fragrances and other excipients may also be included. Such excipients are known in the art. Furthermore, the addition of various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, etc. can ensure prevention of microbial growth. For use in injectable formulations, the composition comprises isotonic agents such as sugars, sodium chloride, and the like and agents used to delay absorption of injectable formulations, such as aluminum monostearate and gelatin. May also be included.

Examples of fillers are lactose monohydrate, lactose anhydride, and various starches; examples of binders are various cellulose and cross-linked polyvinylpyrrolidone, Avicel® PH101 and Avicel®. Microcrystalline cellulose, such as PH102, microcrystalline cellulose, and silicified microcrystalline cellulose (ProSolv SMCC ^™ ).

  Suitable lubricants, including agents that affect the flowability of the powder being compressed, are colloidal silicon dioxide such as Aerosil® 200, talc, stearic acid, magnesium stearate, calcium stearate, and silica gel. It is.

  Examples of sweeteners are any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acesulfame. Examples of fragrances are Magnasweet® (trademark of MAFCO), bubble gum flavors, fruit flavors, and the like.

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

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

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

  Examples of blowing agents are effervescent pairs such as organic acids and carbonates or bicarbonates. Suitable organic acids include, for example, citric, tartaric, malic, fumaric, adipic, succinic, and alginic acids and anhydrides and acid salts. Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate. Alternatively, only a foamable pair of sodium bicarbonate components may be present.

The compositions of the present invention may also include a carrier, adjuvant, or vehicle (hereinafter collectively “carrier”).
Nanoparticulate compositions can be made using, for example, grinding, homogenization, precipitation, freezing, or template emulsion techniques. Exemplary methods of making nanoparticulate compositions are described in the '684 patent. Methods for making nanoparticulate compositions are described in US Pat. Nos. 5,518,187; 5,718,388; 5,862,999; 5,665,331; 5,662,883; 5,560,932; 5. , 543, 133; 5,534,270; 5,510,118; and 5,470,583.

  In one method, particles comprising ziprasidone are dispersed in a liquid dispersion medium in which ziprasidone is hardly soluble. Mechanical means are then used in the presence of the grinding media to reduce the particle size to the desired effective average particle size. The dispersion medium can be, for example, water, sunflower oil, ethanol, t-butanol, glycerin, polyethylene glycol (PEG), hexane, or glycol. A preferred dispersion medium is water. The particles can be reduced in size in the presence of at least one surface stabilizer. The particles comprising ziprasidone can be contacted with one or more surface stabilizers after attrition. Other compounds, such as diluents, may be added to the composition during this size reduction process. The dispersion may be manufactured continuously or in a batch mode. One skilled in the art will appreciate that after milling, not all particles may be reduced to the desired size. In such cases, particles of the desired size may be separated and used in the practice of the present invention.

  Another method of producing the desired nanoparticulate composition is by microprecipitation. This is a method for preparing a stable dispersion of ziprasidone that is hardly soluble in the presence of a surface stabilizer and one or more colloidal stability enhancing surfactants that do not contain trace amounts of toxic solvents or solubilized heavy metal impurities. It is. Such methods include, for example: (1) dissolving ziprasidone in a suitable solvent; (2) adding the formulation from step (1) to a solution comprising at least one surface stabilizer; 3) Precipitating the formulation from step (2) using a suitable non-solvent. Following this process, any salt that is produced, if present, can be removed by dialysis or diafiltration and concentration of the dispersion by conventional means.

  Nanoparticulate compositions may be produced by homogenization. An exemplary homogenization method is described in US Pat. No. 5,510,118 for “Process of Preparing Therapeutic Compositions Containing Nanoparticles”. Such a method involves dispersing particles comprising ziprasidone in a liquid dispersion medium followed by subjecting the dispersion to homogenization to reduce the particle size to a desired effective average particle size. The particles can be reduced in size in the presence of at least one surface stabilizer. The particles may be contacted with one or more surface stabilizers either before or after grinding. Other compounds, such as a diluent, may be added to the composition before, during, or after this size reduction process. The dispersion may be manufactured continuously or in a batch mode.

  Another method of producing the desired nanoparticulate composition is by spray freezing (SFL) into a liquid. This technique involves injecting an organic or organic aqueous solution of ziprasidone and a surface stabilizer into a cryogenic liquid such as liquid nitrogen. Drug-containing solution droplets freeze at a rate sufficient to minimize crystallization and particle growth, thereby formulating the nanostructured particles. Depending on the choice of solvent system and processing conditions, the particles can have a variety of particle morphology. In the isolation step, nitrogen and solvent are removed under conditions that avoid particle agglomeration or ripening.

  As a complementary technology to SFL, ultrafast freezing (URF) may also be used to create equivalent nanostructured particles with greatly increased surface area. URF involves taking a water miscible, anhydrous, organic, or organic aqueous solution of ziprasidone and a surface stabilizer and applying it onto a cryogenic substrate. The solvent is then removed by means such as freeze drying or air freeze-drying, leaving the resulting nanostructured particles.

  Another method of producing the desired nanoparticulate composition is by template emulsion. Template emulsions create nanostructured particles with controlled particle size distribution and rapid dissolution capability. This method involves preparing an oil-in-water emulsion and then swelling it with a non-aqueous solution comprising ziprasidone and a surface stabilizer. The particle size distribution is a direct result of the size of the emulsion droplets prior to loading the emulsion with drug. In this way, the particle size can be controlled and optimized. Furthermore, emulsion stability is achieved with no or suppressed Ostwald growth by selective use of solvents and stabilizers. Subsequently, the solvent and water are removed to recover the stabilized nanostructured particles. Various particle morphologies can be achieved with proper control of processing conditions.

The present invention also provides a method comprising administering an effective amount of a nanoparticulate composition comprising ziprasidone.
The compositions of the present invention may be parenteral (eg, intravenous, intramuscular, or subcutaneous), oral (eg, in solid, liquid, or aerosol form), vaginal, nasal, rectal, ocular, topical (eg, powder) , In the form of ointments or droplets), buccal, intracisternal, intraperitoneal, or topical administration.

  Nanoparticulate compositions are liquid dispersions, gels, aerosols, ointments, depots, creams, controlled release formulations, fast melting formulations, lyophilized formulations, tablets, capsules, delayed release formulations, extended release formulations, It can be utilized in solid or liquid dosage formulations such as pulsed release formulations, mixed immediate release and controlled release formulations.

  Compositions suitable for parenteral injection include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions and reconstitution into sterile injectable solutions or dispersions. Aseptic powder may be included. Examples of suitable aqueous or non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene-glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (olive oil And injectable organic esters such as ethyl oleate. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.

  Solid dosage forms for oral administration include, but are not limited to, tablets, capsules, sachets, troches, powders, pills, or granules, for example, fast-melt dosage forms, controlled It can be a release dosage form, a lyophilized dosage form, a delayed release dosage form, an extended release dosage form, a pulsed release dosage form, a mixed 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 mixed 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 starch, lactose, sucrose, glucose, mannitol, and silicic acid; (c) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (d) Diluents such as glycerol; (e) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (f) dissolution retardants such as paraffin; g) absorption enhancers such as quaternary ammonium compounds; (h) such as cetyl alcohol and glycerol monostearate Adsorbents such as (i) kaolin and bentonite; wetting agents and (j) talc, calcium stearate, magnesium stearate, solid polyethylene glycols, lubricating agents such as sodium lauryl sulfate, or mixtures thereof. For capsules, tablets, and pills, the dosage forms may also contain buffering agents.

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

  One skilled in the art will appreciate that a therapeutically effective amount of ziprasidone can be determined empirically. The actual dosage level of ziprasidone in the nanoparticulate compositions of the present invention may be varied to obtain an amount of drug that is effective to obtain the desired therapeutic response for the particular composition and method of administration. Thus, the dosage level selected will depend on the desired therapeutic effect, the route of administration, the efficacy of the administered ziprasidone, the desired duration of treatment, and other factors.

  Dosage unit compositions may contain an amount of ziprasidone or a submultiple thereof that can be used to make up the daily dose. However, dose levels specific to any particular patient can vary depending on a variety of factors (type and extent of cellular or physiological response to be achieved; activity of the particular drug or composition utilized; patient age, weight, health General, gender, and diet; time of administration of ziprasidone, route of administration, and rate of elimination; active compounds used in combination with or simultaneously with ziprasidone; and similar factors well known in the medical arts) It will be understood that it depends.

II. Controlled release compositions comprising ziprasidone The effectiveness of a compound in the prevention and treatment of disease states depends on a variety of factors, including the rate and duration of delivery of the compound from the dosage form to the patient. The combination of the rate and duration of delivery manifested in a patient by a given dosage form can be described as its in vivo release profile, depending on the pharmaceutical compound being administered, the concentration of the pharmaceutical compound in the plasma And associated with duration (called plasma profile). Since pharmaceutical compounds differ in pharmacokinetic properties such as bioavailability and the rate of absorption and dissipation, the release profile and the resulting plasma profile are important factors to consider when designing an effective therapy.

  The release profile of the dosage form may specify different release rates and durations and may be continuous or pulsed. A continuous release profile includes a release profile in which an amount of one or more pharmaceutical compounds is continuously withdrawn throughout a dosing interval, either at a constant or variable rate. A pulsed release profile includes a release profile in which at least two separate amounts of one or more pharmaceutical compounds are released at different rates and / or different time frames. For any given pharmaceutical compound or combination of such compounds, the release profile of a given dosage form results in an associated plasma profile in the patient. When two or more components of a dosage form have different release profiles, the release profile as a whole dosage form is a combination of the individual release profiles and may be generally described as “multimodal”. The release profile of a two component dosage form where each component has a different release profile may be described as “bimodal”, and the release profile of a three component dosage form where each component has a different release profile is referred to as “trimodal”. May be described.

  Similar to the variables applicable to the release profile, the bound plasma profile in the patient may indicate a constant or variable plasma concentration level of the pharmaceutical compound over the duration of action and may be continuous or pulsed. A continuous plasma profile includes plasma profiles of all rates and durations that manifest a single maximum plasma concentration. A pulsed plasma profile includes a plasma profile in which at least two higher plasma concentration levels of a pharmaceutical compound can be separated by a lower plasma concentration level and generally described as “multimodal”. A pulsed plasma profile that manifests two peaks may be described as “bimodal” and a plasma profile that exhibits three peaks may be described as “trimodal”. Depending on the release profile of the individual components of the dosage form, as well as at least in part on the pharmacokinetics of the pharmaceutical compound contained in the dosage form, the multimodal release profile can be continuous or pulsed upon administration to a patient. Any plasma profile may be generated.

  In one aspect, the present invention provides a multiparticulate modified release composition that delivers ziprasidone or nanoparticles containing ziprasidone in a pulsatile manner. The nanoparticles are of the type described above and also include at least one surface stabilizer.

  In yet another aspect, the present invention provides a multiparticulate modified release composition that delivers ziprasidone or nanoparticles containing ziprasidone in a continuous fashion. The nanoparticles are of the type described above and also include at least one surface stabilizer.

  In yet another aspect, the invention provides that the first portion of ziprasidone or a nanoparticulate containing ziprasidone is released immediately upon administration and the one or more subsequent portions of the ziprasidone or ziprasidone containing nanoparticle are removed after an initial time delay. A multiparticulate modified release composition is provided for release.

In yet another aspect, the present invention provides a solid oral dosage form for once daily or twice daily administration comprising the multiparticulate modified release composition of the present invention.
In yet another aspect, the present invention provides a method for the prevention and / or treatment of psychiatric disorders similar to schizophrenia comprising the administration of the composition of the present invention.

  In certain embodiments, the present invention provides multiparticulate modified release compositions wherein the particles forming the multiparticulates are nanoparticulate particles of the type described above. The nanoparticulate particles may contain a modified release coating agent and / or a modified release matrix material as desired.

  According to one aspect of the present invention, there is provided a pharmaceutical composition having a first component comprising active ingredient-containing particles and at least one subsequent component comprising active ingredient-containing particles, each subsequent component comprising: It has a different release rate and / or duration than the first component, wherein at least one of said components comprises particles containing ziprasidone. In certain embodiments of the present invention, the ziprasidone-containing particles forming the multiparticulates may contain nanoparticulate particles of the type described above that themselves also comprise ziprasidone and at least one surface stabilizer. In another aspect of the invention, nanoparticulate particles of the type described above that also comprise ziprasidone and at least one surface stabilizer are themselves multiparticulate drug-containing particles. The drug-containing particles may be coated with a modified release coating. Alternatively or additionally, the drug-containing particles may include a modified release matrix material. Following oral delivery, the composition delivers ziprasidone or nanoparticles containing ziprasidone in a pulsatile manner. In one embodiment, the first component provides immediate release of ziprasidone or nanoparticles containing ziprasidone and one or more subsequent components provide ziprasidone or modified release of nanoparticles containing ziprasidone. In such embodiments, the immediate release component helps to accelerate the onset of action by minimizing the time from administration to a therapeutically effective plasma concentration level, and one or more subsequent components can be plasma throughout the dosing interval. It helps to minimize fluctuations in concentration levels and / or maintain a therapeutically effective plasma concentration.

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

  The modified release composition of the present invention administers ziprasidone because the plasma profile provided upon administration by the modified release composition is substantially similar to the plasma profile provided by sequential administration of two or more IR dosage forms. Is particularly useful.

  According to another aspect of the invention, the composition is designed to provide a plasma profile that minimizes or eliminates fluctuations in plasma concentration levels associated with administration of two or more IR dosage forms given sequentially. can do. In such embodiments, the composition comprises an immediate release component to accelerate onset of action by minimizing the time from administration to a therapeutically effective plasma concentration level, and a therapeutically effective plasma concentration throughout the dosing interval. It may be provided with at least one modified release component for maintenance.

  The active ingredient in each component may be the same or different. For example, the composition may comprise a component comprising as active ingredient only ziprasidone or nanoparticles containing ziprasidone. Alternatively, the composition comprises at least one active ingredient other than ziprasidone or ziprasidone-containing nanoparticles, suitable for co-administration with ziprasidone or ziprasidone-containing nanoparticles, and ziprasidone. One subsequent component; or a first component containing an active ingredient other than ziprasidone or nanoparticles containing ziprasidone and at least one subsequent component comprising ziprasidone or nanoparticles containing ziprasidone.

  Indeed, two or more active ingredients may be incorporated into the same ingredient, where the active ingredients are compatible with each other. An active ingredient present in one component of the composition may be accompanied by, for example, an enhancer compound or a sensitizing compound in another component of the composition to improve its bioavailability or therapeutic effect.

  As used herein, the term “enhancer” is a compound that can enhance the absorption and / or bioavailability of an active ingredient by promoting net transport through GIT in animals such as humans. Means. Enhancers include, but are not limited to, glycerides and triglycerides; medium chain fatty acids; salts, esters, ethers, and derivatives thereof; by reacting ethylene oxide with fatty acids, fatty alcohols, alkylphenols, or sorbitan or glycerol fatty acid esters. Nonionic surfactants as can be produced; cytochrome P450 inhibitors, P-glycoprotein inhibitors, etc .; and mixtures of two or more of these agents.

  In embodiments where more than one drug-containing component is present, the proportion of ziprasidone contained in each component may be the same or different depending on the desired dosage regimen. The ziprasidone present in the first component and subsequent components may be in an amount, such as sufficient to provide a therapeutically effective plasma concentration level. Ziprasidone, when applicable, may be in the form of one substantially optically pure stereoisomer or may exist as a (racemic or other) mixture of two or more stereoisomers . In one embodiment, ziprasidone is present in the composition in an amount of about 0.1 to about 500 mg. In another embodiment, ziprasidone is present in the composition in an amount of about 1 to about 100 mg. In yet another embodiment, ziprasidone is present in the first component in an amount of about 0.5 to about 60 mg. In yet another embodiment, ziprasidone is present in the first component in an amount of about 2.5 to about 30 mg. In the subsequent component, ziprasidone is present in an amount within a range similar to that described for the first component.

  The time release characteristics of the delivery of ziprasidone from each of the components may be altered by changing the composition of each component, including changing any excipients and / or coating agents that may be present. In particular, the release of ziprasidone may be controlled by varying the composition and / or amount of such coating agent on the particles, if a modified release coating agent is present. If more than one modified release component is present, the modified release coating to each of the above components may be the same or different. Similarly, when promoting modified release by inclusion of a modified release matrix material, the release of the active ingredient may be controlled by the choice and amount of modified release matrix material utilized. The modified release coating may be present in each component in any amount that is sufficient to produce the desired lag time for each particular component. The modified release coating may be present in each component in any amount that is sufficient to produce the desired time lag between the components.

  The lag time and / or time delay for the release of ziprasidone from each component can be varied by changing the composition of each component, including changing any excipients and / or coatings that may be present. May be. For example, the first component may be an immediate release component where ziprasidone is released immediately upon administration. Alternatively, the first component may be, for example, a time-delayed immediate release component in which ziprasidone releases substantially its entirety immediately after the time delay. The second and subsequent components may be, for example, time-delayed immediate release components as described above, or a time-delayed sustained release where ziprasidone is released in a controlled manner over an extended period of time or It may be an extended release component.

  As will be appreciated by those skilled in the art, the accuracy of the plasma concentration curve is influenced by the combination of all the above-mentioned factors described immediately above. In particular, the lag time during delivery of ziprasidone in each component containing ziprasidone (and thus also the onset of action) can be controlled by changing the composition of each component and the coating agent (if present). Good. Thus, a number of release and plasma profiles can be obtained due to variations in the composition of each component (including the amount and nature of the active ingredient) and variations in lag time. Depending on the duration of the lag time between the release of each component of ziprasidone and the nature of the release from each component of ziprasidone (ie, immediate release, sustained release, etc.), the plasma profile is continuous (ie, Have a single maximum), or peaks in the plasma profile are well separated and clearly defined (eg, when the lag time is long) or overlap to some extent (eg, the lag time is Can be pulsed (when short).

  The plasma profile resulting from the administration of a single dosage unit comprising the composition of the present invention is desirable to deliver two or more pulses of the active ingredient without requiring administration of two or more dosage units. It is advantageous when

  Any coating material that modifies the release of ziprasidone in the desired manner may be used. In particular, coating materials suitable for use in the practice of the present invention include, but are not limited to, cellulose acetate phthalate, cellulose acetate trimaleate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, Eudragit® RS and RL. Ammonio methacrylate copolymers such as those sold under the trade name, polyacrylic acid and polyacrylate and methacrylate copolymers such as those sold under the trademarks Eudragit® S and L, polyvinyl acetal diethylaminoacetate, Polymer coating materials such as hydroxypropylmethylcellulose acetate succinate, shellac; carboxyvinyl polymer, sodium alginate, carmellose sodium , Carmellose calcium, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, gelatin, starch, and cellulose-based cross-linked polymers (where the degree of cross-linking promotes water adsorption and polymer matrix expansion) Hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, cross-linked starch, microcrystalline cellulose, chitin, aminoacryl-methacrylate copolymer (Eudragit® RS-PM, Rohm & Haas), pullulan, Collagen, casein, agar, gum arabic, sodium carboxymethylcellulose, (swellable hydrophilic polymer) poly (hydroxyalkyl methacrylate) Rate) (molecular weight: about 5k to 5,000k), polyvinylpyrrolidone (molecular weight: about 10k to 360k), anionic and cationic hydrogels, polyvinyl alcohol with low acetate residue, agar and carboxymethylcellulose swellable mixture, Copolymers of maleic anhydride and styrene, ethylene, propylene, or isobutylene, pectin (molecular weight: about 30 k to 300 k), polysaccharides such as agar, acacia, karaya, tragacanth, algin, and guar, polyacrylamide, polyox ( (Registered trademark) polyethylene oxide (molecular weight: about 100 k to 5,000 k), AquaKeep (registered trademark) acrylate polymer, diester of polyglucan, cross-linked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, Hydrogels and gel-forming materials such as thorium starch glucolate (eg, Explotab®; Edward Mandell C); polysaccharides, methylcellulose, sodium or calcium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, nitro Cellulose, carboxymethyl cellulose, cellulose ether, oxidized polyethylene (eg, Polyox®, Union Carbide), methyl ethyl cellulose, ethyl hydroxyethyl cellulose, cellulose acetate, cellulose butyrate, cellulose propionate, gelatin, collagen, starch, maltodextrin , Pullulan, polyvinylpyrrolidone, Polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid ester, polyacrylamide, polyacrylic acid, methacrylic acid or a copolymer of methacrylic acid (eg, Eudragit®, Rohm and Haas), other acrylic acid derivatives, sorbitan esters, natural Gum, lecithin, pectin, alginate, alginate, sodium alginate, calcium, potassium, propylene glycol alginate, agar, gum of Arabia, Karaya, carob, tragacanth, carrageenan, guar, xanthan, scleroglucan and mixtures thereof And hydrophilic polymers such as blends. As will be appreciated by those skilled in the art, excipients such as plasticizers, lubricants, solvents, etc. may be added to the coating agent. Suitable plasticizers include, for example, acetylated monoglycerides; butyl phthalyl butyl glycolate; dibutyl tartrate; diethyl phthalate; dimethyl phthalate; ethyl phthalyl ethyl glycolate; glycerin; propylene glycol; triacetin; Diacetin; dibutyl phthalate; acetyl monoglyceride; polyethylene glycol; castor oil; triethyl citrate; polyhydroxyl alcohol, glycerol, acetate ester, glycerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, Butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate, epoxidized talate, triisooctyl trimellitate , Diethylhexyl phthalate, di-n-octyl phthalate, di-i-octyl phthalate, di-i-decyl phthalate, di-n-undecyl phthalate, di-n-tridecyl phthalate, tri-2-ethylhexyl trimellitate Di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl sebacate.

  When the modified release component comprises a modified release matrix material, any suitable modified release matrix material and any suitable combination of modified release matrix materials may be used. Such materials are known to those skilled in the art. As used herein, the term “modified release matrix material” includes a hydrophilic polymer, a hydrophobic, capable of modifying the in vitro or in vivo release of ziprasidone or a salt or derivative thereof dispersed therein. Polymers and mixtures thereof are included. Modified release matrix materials suitable for the practice of the present invention include, but are not limited to, microcrystalline cellulose, sodium carboxymethylcellulose, hydroxyalkylcelluloses such as hydroxypropylmethylcellulose and hydroxypropylcellulose, oxidized polyethylene, methylcellulose and ethylcellulose. Alkyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, polyalkyl methacrylate, polyvinyl acetate, and mixtures thereof.

  The modified release composition according to the present invention may be incorporated into any suitable dosage form that facilitates the pulsatile release of the active ingredient. In one embodiment, the dosage form comprises an admixture of different populations of active ingredient-containing particles that constitute immediate release and modified release components, the admixture into a suitable capsule such as a hard or soft gelatin capsule. Filled. Alternatively, different individual populations of active ingredient-containing particles may be compressed into mini-tablets (optionally with additional excipients) and subsequently filled into capsules at the proper ratio. Another suitable dosage form is that of a multilayer tablet. In this example, the first component of the modified release composition may be compressed into one layer followed by the second component as the second layer of the multilayer tablet. The population of particles making up the composition of the present invention may be further included in a fast dissolving dosage form such as a foaming dosage form or a fast melting dosage form.

  In one embodiment, the composition comprises at least two components containing ziprasidone: a first component and one or more subsequent components. In such embodiments, the first component of the composition is released rapidly but after a time delay, with substantially all ziprasidone contained in the first component being rapidly released upon administration of the dosage form. Release), or various release profiles may be specified, including profiles that are released slowly over time. In one such embodiment, the ziprasidone contained in the first component is released rapidly upon administration to the patient. As used herein, “rapidly released” includes a release profile in which at least about 80% of the active ingredient is released within about 1 hour after administration, the term “delayed release”. Includes a release profile in which the active ingredient of the ingredient is released after a time delay (rapidly or slowly), and the terms “controlled release” and “extended release” include at least about 80% of the ingredient A release profile in which the active ingredient is released slowly is included.

  The second component of such embodiments may also demonstrate a variety of release profiles including immediate release profiles, delayed release profiles, or controlled release profiles. In one such embodiment, the second component demonstrates a delayed release profile in which ziprasidone is released after a time delay.

  Plasma profile resulting from administration of a dosage form of the invention comprising an immediate release component comprising ziprasidone or ziprasidone-containing nanoparticles and at least one modified release component comprising ziprasidone or ziprasidone-containing nanoparticles Can be substantially similar to the plasma profile resulting from the sequential administration of two or more IR dosage forms, or from the administration of separate IR and modified release dosage forms. Thus, the dosage forms of the present invention may be particularly useful for administering ziprasidone when maintenance of pharmacokinetic variables may be desired while that is a problem.

  In one embodiment, the composition and the solid oral dosage form containing the composition are such that substantially all ziprasidone contained in the first component is released prior to the release of ziprasidone from at least one subsequent component. Release ziprasidone. For example, when the first component includes an IR component, the release of ziprasidone from at least one subsequent component is preferably delayed until substantially all ziprasidone in the IR component has been released. The release of ziprasidone from the at least one subsequent component may be delayed as detailed above by use of a modified release coating agent and / or a modified release matrix material.

  If it is desired to minimize patient tolerance by providing a mode of administration that facilitates washout of the first dose of ziprasidone from the patient system, the release of ziprasidone from the subsequent component is a substance contained in the first component. Thus, it may be delayed until all ziprasidone has been released, and further delayed until at least a portion of the ziprasidone released from the first component has been cleared from the patient's system. In one embodiment, the release of ziprasidone from subsequent components of the composition is substantially delayed if not complete for a period of at least about 2 hours after administration of the composition. In another embodiment, the release of ziprasidone from subsequent components of the composition is substantially delayed if not complete for a period of at least about 4 hours after administration of the composition.

  As described below, the present invention also includes various types of modified release systems that can deliver ziprasidone in either a pulsed or continuous manner. These systems include, but are not limited to: films with ziprasidone or ziprasidone-containing nanoparticles in a polymer matrix (monolithic devices); ziprasidone or ziprasidone-containing nanoparticles in a polymer (reservoir device); Polymer colloidal particles or microencapsulates (microparticles, microspheres, or nanoparticles) in the form of reservoirs and matrix devices; ziprasidone or nanoparticles containing ziprasidone are hydrophilic and / or leachable additions A system (both reservoir and matrix) that is included in a polymer containing an agent (eg, second polymer, surfactant, or plasticizer, etc.) to provide a porous device, or a device in which ziprasidone release can be controlled osmotically Device); enteric coating Agents (ionizable, melts at a suitable pH); (shared) device with a bound incidental ziprasidone molecules (soluble) polymers, and the release rate is controlled dynamically (e.g., osmotic pumps) are included.

  The delivery mechanism of the present invention can control the rate of release of ziprasidone. While there is a mechanism for releasing ziprasidone at a constant rate, others vary as a function of time depending on factors such as changes in concentration gradients and additional leaching that results in porosity.

  The polymers used in sustained release coatings are necessarily biocompatible and ideally biodegradable. Natural, such as Aquacoat® (FMC Corporation, Food & Pharmaceutical Products Division, Philadelphia, USA) (spheronized ethylcellulose, water-based pseudolatex dispersion) to submicron size Examples of polymers present in the art and synthetic polymers such as Eudragit® (Rohm Pharma, Weiterstadt, a wide range of poly (acrylate, methacrylate) copolymers) are known in the art.

Reservoir Device A typical approach to modified release is to encapsulate or contain the drug entirely within a polymer film or coat (ie, a microcapsule or spray / pan coated core) (eg, as a core). It is to be.

  Reservoir devices can easily account for a variety of factors that can affect the dispersion process (eg, additive effects, polymer functionality (ie, sink solution pH), porosity, film formation conditions, etc.) Since it can be applied, the choice of polymer must be an important consideration in the development of reservoir devices. Thus, designing the release characteristics of reservoir devices (and monolithic devices) by ziprasidone transport via a dissolution-dispersion mechanism is typically Fick's second law (unsteady state; concentration to relevant boundary conditions) Dependency outflow). When the device contains dissolved active agent, the rate of release decreases exponentially with time (ie, first order) as the concentration (activity) of the agent inside the device (ie, the driving force of release) decreases. release). However, if the active agent is in a saturated suspension, the driving force for release remains constant until the device is no longer saturated. Alternatively, the release rate kinetics may be desorption controlled and may be a function of the square root of time.

  The transport properties of a coated tablet may be enhanced by the blockiness of the tablet core (penetrant), which may allow internal accumulation of osmotic pressure compared to free polymer membranes, which then removes the penetrant from the tablet. Acts to force out.

  The effect of deionized water on salt-containing tablets coated with poly (ethylene glycol) (PEG) -containing silicone elastomers and the effect of water on free films were also examined. The release of salt from the tablet was found to be a mixture of dispersion through the water-filled pores formed by hydration of the coating agent and osmotic pumping. KCl transport through membranes containing only 10% PEG is negligible despite the large amount of swelling observed in similar free films, and porosity is required for KCl transport (Thus it was caused by through-hole diffusion). It has been found that disc-shaped coated salt tablets swell in deionized water and change shape to oblate spheroids as a result of the accumulation of internal hydrostatic pressure. This shape change provides a means for measuring the force generated. As expected, the penetrating power decreased with increasing levels of PEG content. The lower the PEG level, the more water is absorbed through the hydrated polymer, whereas the porosity generated by the coating agent that dissolves at higher levels of PEG content (20-40%) causes the flow of KCl. As a result, the osmotic pressure was relaxed.

  By monitoring (independently) the release of two different salts (eg, KCl and NaCl), a relative size calculation is made where both osmotic pumping and through-hole diffusion contribute to salt release from the tablet. Developed methods and equations to enable. At low PEG levels, the osmotic flow increased to a greater extent than through-hole diffusion due to the generation of only a low pore number density. On the other hand, at 20% loading, both mechanisms contributed almost equally to this release. However, the accumulation of hydrostatic pressure reduced osmotic inflow and osmotic pumping. At higher PEG loading, the hydrated membrane became more porous and less resistant to salt efflux. Thus, osmotic pumping was increased (compared to low loading), but through-hole diffusion was the dominant release mechanism. For microcapsules containing a water-soluble core, an osmotic release mechanism has also been reported.

Monolithic device (matrix device)
A monolithic (matrix) device may be used to control the release of the drug. This is probably because they are relatively easy to fabricate compared to reservoir devices, and there is no accidental high dose risk that can result from rupture of the reservoir device membrane. In such devices, the active agents are present as a dispersion within the polymer matrix, and they are typically formed by compression of the polymer / drug mixture or by dissolution or melting. The dose release characteristics of a monolithic device may depend on the solubility of the drug in the polymer matrix, or in the case of a porous matrix, the solubility in the sink solution in the pore network of particles, and also the network maze The degree (to a degree greater than the permeability of the membrane) depends on whether the drug is dispersed in the polymer or dissolved in the polymer. At low drug loading (0-5% W / V), the drug is released by a dissolution-diffusion mechanism (in the absence of vacancies). At higher loadings (5-10% W / V), the release mechanism becomes complicated as the drug disappears due to the presence of cavities formed near the surface of the device. Such cavities increase the release rate of the drug when filled with fluid from the environment.

  It is common to add plasticizers (eg, poly (ethylene glycol), surfactants, or adjuvants (ie, components that increase effectiveness) as a means of increasing permeability to matrix devices (and reservoir devices). Some (but in contrast, plasticizers are temporary and may simply help to form a film, which reduces permeability, which is usually more desirable in polymer coated coatings. PEG leaching increases the permeability of the (ethylcellulose) membrane linearly as a function of PEG loading by increasing the porosity, but the membrane retains its barrier properties and transports the electrolyte. It was observed that the increased permeability was a result of an effective reduction in thickness caused by PEG leaching. This is a plot of the cumulative permeate flow per unit area as a function of time and the reciprocal of film thickness at 50% W / W PEG loading, ie (Fick's) dissolution-diffusion transport in a homogeneous film. This is supported by a plot showing the linear relationship between the permeation rate and the reciprocal of the film thickness as predicted by the mechanism: extrapolating the linear region of the graph to the time axis gives a positive intercept on the time axis. As a result, the magnitude decreased to zero as the film thickness decreased, and these changing lag times resulted in two diffusion flows (drug flow and PEG flow) during the initial phase of the experiment. And the more normal lag time during the accumulation of the membrane permeant concentration, which showed a negative lag time when caffeine was used as a permeant. Was not explained, It was noted that caffeine manifests a low partition coefficient in this system and that this is also a feature of aniline permeation through polyethylene membranes that exhibits a similar negative time lag.

  The effect of the added surfactant on the (hydrophobic) matrix device was investigated. Surfactants were thought to potentially increase drug release rates by three possible mechanisms: (i) increased solubilization, (ii) “wetability” of dissolution media Improvement, and (iii) pore formation as a result of surfactant leaching. In the tested systems (Eudragit® RL 100 and RS 100, plasticized with sorbitol, flurbiprofen as drug, various surfactants), only slight drug release improvement with improved tablet wetting Only, suggesting that this release is controlled by diffusion rather than dissolution [but the effect is greater with Eudragit® RS than with Eudragit® RL], It was concluded that the greatest effect on release was due to the surfactant becoming more soluble, allowing access to the dissolution medium into the matrix by the formation of degradation products in the matrix. This is clearly important for the study of latex films that may be suitable for pharmaceutical coatings. This is because polymer latex is easier to produce with a surfactant as opposed to no surfactant. Differences were found between the two polymers, and only Eudragit® RS showed an interaction between anionic / cationic surfactant and drug. This was due to different levels of quaternary ammonium ions on the polymer.

  There are also composite devices consisting of a polymer / drug matrix coated in a drug-free polymer. Such a device was constructed from an aqueous Eudragit® lattice and was found to provide continuous release by diffusion of the drug from the core to the shell. Similarly, a drug-containing polymer core was prepared and coated with a shell eroded by gastric juice. The rate of drug release was found to be relatively linear (a function of the rate limiting diffusion process through the shell) and inversely proportional to the shell thickness. On the other hand, it was found that the release from the wick alone decreased with time.

Microspheres A method for producing hollow microspheres is described. Hollow microspheres were formed by preparing an ethanol / dichloromethane solution containing drug and polymer. As soon as it is poured into water, a coacervate-type process forms an emulsion containing dispersed polymer / drug / solvent particles, from which ethanol diffuses rapidly, precipitating the polymer on the surface of the droplets, and into dichloromethane Hard shell particles encapsulating the dissolved drug were obtained. It was then observed that a gas phase of dichloromethane was generated within the particles, forming bubbles on the surface of the aqueous phase after being dispersed through the shell. The hollow spheres were then depressurized and filled with water (which can be removed by drying for a period of time). No drug was found in this water. Very porous matrix microspheres are also described. Matrix microspheres were prepared by dissolving the drug and polymer in ethanol. When added to water, ethanol diffused from the emulsion droplets, leaving very porous particles. The suggested use of microspheres has been to float drug delivery devices for use in the stomach.

Pendent Devices Means of attaching various drugs such as analgesics and antidepressants have been developed by means of ester linking to poly (acrylate) ester latex particles prepared by aqueous emulsion polymerization. These lattices were able to autocatalyze the release of the drug by hydrolysis of the ester linkage when passing through the ion exchange resin to convert the polymer end group to its strong acid form.

  The drug was attached to the polymer and the monomer was synthesized with the accompanying drug attached. Dosage forms have been produced in which the drug is bound to the biocompatible polymer by a brittle chemical bond. For example, using polyanhydrides made from substituted anhydrides (produced by reacting the drug: methacryloyl chloride and sodium salt of methoxybenzoic acid with acid chlorides) A matrix with a second polymer (Eudragit® RL) was generated that released the drug upon hydrolysis. The use of polymeric Schiff bases suitable for use as pharmaceutical amine carriers is also described.

Enteric film The enteric coating agent consists of a pH sensitive polymer. Typically, the polymer is carboxylated and hardly interacts with water at low pH, but at high pH the polymer ionizes, causing the polymer to swell or dissolve. Thus, the coating remains intact in the acidic environment of the stomach and can be designed to protect the drug from this environment or the stomach from the drug, but dissolve in the more alkaline environment of the intestine.

Osmotic pressure control device An osmotic pump is similar to a reservoir device, but contains an osmotic agent (eg, a salt-type active agent) that acts to draw water from the surrounding medium through the semipermeable membrane. Such a device has been described, referred to as a basic osmotic pump. Inside this device, pressure is generated to expel the active agent out of the device through pores sized to minimize solute diffusion, while reducing osmotic pressure and changing device dimensions. The accumulation of hydrostatic heads which may have the effect of While the internal volume of the device remains constant and there is excess solid or saturated solution in the device, the release rate remains constant and delivers a volume equal to the volume of solvent uptake.

Electrically stimulated release devices For example, monolithic devices using polyelectrolyte gels have been manufactured that swell when an external electrical stimulus is applied to cause a change in pH. This emission may be modulated to produce a constant or pulsed emission profile by changing the applied current.

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

III. Method of using a modified release composition comprising ziprasidone According to another aspect of the present invention, a schizophrenia or similar comprising comprising administering a therapeutically effective amount of a composition of the present invention in a solid oral dosage form. Methods are provided for treating a patient suffering from a psychiatric disorder. The advantages of the method of the present invention are required by conventional frequent IR dosing regimes while still maintaining the benefits derived from pulsed plasma profiles or eliminating or minimizing fluctuations in plasma concentration levels Includes reduced dosing frequency. This reduction in dosing frequency is advantageous with respect to patient compliance, and the reduction in dosing frequency made possible by the method of the present invention reduces the cost of medical care by reducing the amount of time a healthcare worker spends on administering ziprasidone. It will contribute to restraint.

  In the following examples, all percentages are by weight unless otherwise stated. The term “purified water” as used throughout the examples refers to water that has been purified by passing through a water filtration system. It should be understood that the examples are for illustrative purposes only and should not be construed as limiting the spirit and breadth of the present invention as defined by the claims that follow.

Examples Examples 1-4 provide exemplary ziprasidone tablet formulations. These examples are not intended to limit the claims in any way, but rather provide exemplary ziprasidone tablet formulations that can be utilized in the methods of the present invention. Such exemplary tablets may include a coating agent.

  Example 1

  Example 2

  Example 3

  Example 4

Example 5
Multiparticulate modified 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 shown in Table 1. The methylphenidate solution is then coated onto nonpareil seeds at a level of approximately 16.9% solids weight gain using, for example, a Glatt GPCG3 (Glatt, Protech, Leicester, UK) fluid bed coater. Thus, IR particles of an immediate release component are generated.

(B) Modified Release Component The ziprasidone-containing delayed release particles are produced by coating the immediate release particles produced according to Example 5 (a) above with the modified release coating solution detailed in Table 2. Immediate release particles are coated to various levels up to approximately 30% using, for example, a fluid bed apparatus.

(C) Encapsulation of immediate and delayed release particles Immediate release particles produced according to Example 5 (a) above and delayed release particles produced according to 5 (b), for example, using a Bosch GKF 4000S encapsulation device Then, it is encapsulated in a size 2 hard gelatin capsule to a total strength of 20 mg. The dosing intensity of the total 20 mg ziprasidone consisted of 10 mg from the immediate release component and 10 mg from the modified release component.

Example 6
Multiparticulate modified release composition containing ziprasidone A multiparticulate modified release ziprasidone composition according to the present invention having an immediate release component and a modified release component having a modified release matrix material is shown in Tables 3 (a) and (b). Manufactured according to

Example 7
The purpose of this example is to describe a method of making a nanoparticulate ziprasidone composition.

  Combine a 5% (w / w) aqueous dispersion of ziprasidone with one or more surface stabilizers such as hydroxypropylcellulose (HPC-SL) and dioctylsulfosuccinate (DOSS) in a 10 ml chamber of NanoMill®. Trademark) 0.01 (NanoMill Systems, King of Prussia, PA; see US Pat. No. 6,431,478) with 500 micron PolyMill® grinding media (Dow Chemical Co.) (eg , 89% media load). In an exemplary method, the mixture may be ground for 60 minutes at a speed of 2500 rpm.

  Following milling, the particle size of the milled ziprasidone particles can be measured in deionized distilled water using a Horiba LA 910 particle size analyzer. In a successful composition, the initial average and / or D50 particle size of ground ziprasidone is expected to be less than 2000 nm.

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

Claims (91)

  (A) particles comprising ziprasidone and having an effective average particle size of less than about 2000 nm in diameter; and (B) a stable nanoparticulate composition comprising at least one surface stabilizer.   The composition of claim 1, wherein the particles are in a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, or a mixture thereof.   The particles have an effective average particle size of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, Less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm The composition of claim 1 selected from the group. The composition of claim 1 comprising:
(A) For administration selected from the group consisting of parenteral, oral, vaginal, nasal, rectal, transaural, ocular, local, buccal, intracisternal, intraperitoneal, or topical;
(B) into a dosage form selected from the group consisting of tablets, capsules, sachets, solutions, dispersions, gels, aerosols, ointments, creams, and mixtures thereof;
(C) To a formulation selected from the group consisting of a controlled release formulation, a fast melting formulation, a lyophilized formulation, a delayed release formulation, an extended release formulation, a pulse release formulation, and a combined immediate release and controlled release formulation; or (D ) Said composition formulated into any combination of (A), (B), or (C).   2. The composition of claim 1, further comprising one or more pharmaceutically acceptable excipients, carriers, or combinations thereof. The composition of claim 1 comprising:
(A) The ziprasidone is about 99.5% to about 0.001%, about 95% to about 95% of the total dry weight of the composition plus ziprasidone and the surface stabilizer, excluding other excipients. Present in the composition in an amount selected from the group consisting of 0.1%, or a weight of about 90% to about 0.5%;
(B) The surface stabilizer or surface stabilizer (s) is about 0. 0 based on the total dry weight of the composition plus ziprasidone and the surface stabilizer, excluding other excipients. Present in a total amount of 5% to about 99.999%, about 5.0% to about 99.9%, or about 10% to about 99.5%; or (C) (A) and (B The composition is a combination of   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 an ionic surface stabilizer. The composition of claim 1. Surface stabilizers include pyridinium cetyl chloride, gelatin, casein, phosphatide, dextran, glycerol, acacia gum, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacro Gol emulsified wax, sorbitan ester, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyethylene glycol, dodecyltrimethylammonium bromide, polyoxyethylene stearate, colloidal silicon dioxide, phosphate ester, Sodium dodecyl sulfate, carboxymethyl cellulose calcium, hydroxypropyl cellulose, hypromello 4- (1,1, with sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, ethylene oxide and formaldehyde 3,3-tetramethylbutyl) -phenol polymer, poloxamer; poloxamine, charged phospholipid, dioctyl sulfosuccinate, dialkyl ester of sodium sulfosuccinate, sodium lauryl sulfate, alkylaryl polyether sulfonate, sucrose stearate and sucrose di A mixture of stearates, p-isononylphenoxypoly- (glycidol), decanonyl-N-methylglucamide; n N-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-β-D- Glucopyranoside; n-heptyl β-D-thioglucoside; n-hexyl β-D-glucopyranoside; nonanonyl-N-methylglucamide; n-noyl β-D-glucopyranoside; octanoyl-N-methylglucamide; β-D-glucopyranoside; octyl β-D-thioglucopyranoside; lysozyme, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, lysozyme, vinyl acetate and vinylpyrrolidone Polymer, cationic poly -Cationic biopolymer, Cationic polysaccharide, Cationic cellulose, Cationic alginate, Cationic non-polymer compound, Cationic phospholipid, Cationic lipid, Polymethylmethacrylate trimethylammonium bromide, Sulphonium compound, Polyvinylpyrrolidone-2- Dimethylaminoethyl methacrylate dimethyl sulfate, hexadecyltrimethylammonium bromide, phosphonium compound, quaternary ammonium compound, benzyl-di (2-chloroethyl) ethylammonium bromide, coco trimethyl ammonium chloride, coco trimethyl ammonium bromide, coco methyl dihydroxy Ethylammonium chloride, coco methyl dihydroxyethylammonium bromide, Sill triethylammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride bromide, C _12-15 dimethyl hydroxyethyl ammonium chloride, C _12-15 dimethyl hydroxyethyl ammonium chloride bromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut dimethyl hydroxyethyl ammonium bromide, myristyl trimethyl ammonium methyl sulfate, lauryl dimethyl benzyl ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl (ethenoxy) ₄ ammonium chloride, lauryl dimethyl (ethenoxy) ₄ ammonium bromide, N- alkyl (C _{12 -18} ) Dimethylbenzylammonium chloride, N-alkyl ( _C14-18 ) dimethyl-benzylammonium chloride, N-tetradecyldimethylbenzylammonium chloride monohydrate, dimethyldidecylammonium chloride, N-alkyl and ( _C12-14 ) Dimethyl 1-naphthylmethylammonium chloride, halogenated trimethylammonium, alkyl-trimethylammonium salt, dialkyl-dimethylammonium salt, lauryltrimethylammonium chloride, ethoxylated alkylamidoalkyldialkylammonium salt, ethoxylated trialkylammonium salt, dialkylbenzenedialkylammonium salt Chloride, N-didecyldimethylammonium chloride, N-tetradecyldimethylbenzyl ammonium Nium, chloride monohydrate, N-alkyl (C _12-14 ) dimethyl 1-naphthylmethylammonium chloride, dodecyldimethylbenzylammonium chloride, dialkylbenzenealkylammonium chloride, lauryltrimethylammonium chloride, alkylbenzylmethylammonium chloride, alkylbenzyl dimethyl ammonium bromide, C ₁₂ trimethyl ammonium bromide, C ₁₅ trimethyl ammonium bromide, C ₁₇ trimethyl ammonium bromide, dodecyl benzyl triethyl ammonium chloride, poly - diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chloride, alkyl dimethyl ammonium halides (halogenides) , Tricetylmethylammonium chloride Decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyltrioctylammonium chloride, POLYQUAT10 ^™ , tetrabutylammonium bromide, benzyltrimethylammonium bromide, choline ester, benzalkonium chloride, stearalkonium chloride Compound, cetylpyridinium bromide, cetylpyridinium chloride, halogenated salt of quaternized polyoxyethylalkylamine, MIRAPOL ^™ , ALKAQUAT ^™ , alkylpyridinium salt; amine, amine salt, amine oxide, imidoazolinium salt, protonated quaternary salt 6. The method selected from the group consisting of acrylamide, methylated quaternary polymer, and cationic guar gum. Of the composition.   2. The composition of claim 1, wherein when administered under fed conditions, the composition does not result in significantly different absorption levels compared to fasted conditions.   2. The composition of claim 1, wherein its administration to a fasted subject is bioequivalent to its administration to a fed subject.   2. The composition of claim 1, wherein the pharmacokinetic profile is not significantly affected by the eating or fasting status of the subject taking it.   2. The composition of claim 1, wherein upon administration to a mammal, the therapeutic result is achieved at a dosage less than that of a non-nanoparticulate dosage form of ziprasidone. (A) the C _{max of} ziprasidone higher than the C _max of the same ziprasidone when administered at the same dose using a non-nanoparticulate formulation when assayed in the plasma of a mammalian subject after administration;
(B) A ziprasidone AUC greater than the same ziprasidone AUC when administered at the same dose using a non-nanoparticulate formulation when assayed in the plasma of a mammalian subject after administration;
(C) When assayed in the plasma of a mammalian subject after administration, the T _{max of} ziprasidone less than the T _max of the same ziprasidone when administered at the same dose using a non-nanoparticulate formulation; or (d) The composition of claim 1 having any combination of (a), (b), and (c).   The composition of claim 1 additionally comprising one or more active compounds useful for the prevention or treatment of psychiatric disorders similar to schizophrenia.   15. The composition of claim 14, wherein the one or more active compounds are selected from the group consisting of compounds useful for the treatment of a condition selected from the group consisting of headache, soreness, fever, and combinations thereof.   The particles contain a reservoir containing ziprasidone, which is surrounded by a semipermeable membrane that allows water to be absorbed into the particles, thereby creating a pressure that pushes the ziprasidone out of the particles. The composition of claim 1.   The composition of claim 1, wherein the reservoir also comprises a penetrant.   At least one surface stabilization of the particles comprising ziprasidone for a time and under conditions sufficient to provide a nanoparticulate composition comprising ziprasidone having an effective average particle size of less than about 2000 nm in diameter. A process for producing the composition of claim 1, comprising contacting with an agent.   19. The method of claim 18, wherein the contacting comprises a technique of grinding, wet grinding, homogenization, precipitation, template emulsion, or supercritical fluid particle production.   The effective average particle size of the nanoparticulate particles is less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1000 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 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 100 nm, less than about 75 nm, and less than about 50 nm 19. The method of claim 18, wherein the method is selected from the group consisting of:   A method for preventing and / or treating schizophrenia or similar psychiatric disorders comprising administering the composition of claim 1.   The effective average particle size of the particles is less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1000 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, about A group consisting of less than 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 100 nm, less than about 75 nm, and less than about 50 nm 22. The method of claim 21, wherein the method is more selected.   A pharmaceutical composition comprising a first component of an active ingredient-containing particle and at least one subsequent component of the active ingredient-containing particle, wherein at least one of said components comprises ziprasidone, and at least one of said components One further includes a modified release coating agent, a modified release matrix material, or both so that the active ingredient can be bimodal or multimodal following oral delivery to the subject. Said composition to be delivered in a mode.   24. The composition of claim 23, wherein each component comprises ziprasidone-containing particles.   24. The composition of claim 23, comprising a first component of ziprasidone-containing particles and one subsequent component of ziprasidone-containing particles.   26. The composition of claim 25, wherein the first component comprises an immediate release component and the second component comprises a modified release component.   24. The composition of claim 23, wherein the active ingredient-containing particles are erodable.   24. The composition of claim 23, wherein at least one of the components further comprises a modified release coating.   24. The composition of claim 23, wherein at least one of said components further comprises a modified release matrix material.   30. The composition of claim 29, wherein the modified release matrix material is selected from the group consisting of hydrophilic polymers, hydrophobic polymers, natural polymers, synthetic polymers, and mixtures thereof.   32. The composition of claim 30, wherein the ziprasidone is released to the surrounding environment by erosion.   32. The composition of claim 31, further comprising an enhancer.   32. The composition of claim 30, comprising from about 0.1 mg to about 1 g ziprasidone.   A pharmaceutical composition comprising a first component of an active ingredient-containing particle and at least one subsequent component of the active ingredient-containing particle, wherein at least one of said components comprises ziprasidone, and at least one of said components The composition further comprises a modified release coating agent, a modified release matrix material, or both to deliver the active ingredient in a continuous mode following oral delivery to the subject.   35. The composition of claim 34, wherein each component comprises ziprasidone-containing particles.   35. The composition of claim 34, comprising a first component of ziprasidone-containing particles and one subsequent component of ziprasidone-containing particles.   38. The composition of claim 36, wherein the first component comprises an immediate release component and the second component comprises a modified release component.   35. The composition of claim 34, wherein the active ingredient-containing particles are erodible.   35. The composition of claim 34, wherein at least one of said components further comprises a modified release coating.   35. The composition of claim 34, wherein at least one of the components further comprises a modified release matrix material.   41. The composition of claim 40, wherein the modified release matrix material is selected from the group consisting of hydrophilic polymers, hydrophobic polymers, natural polymers, synthetic polymers, and mixtures thereof.   42. The composition of claim 41, wherein ziprasidone is released to the surrounding environment by erosion.   43. The composition of claim 42, further comprising an enhancer.   42. The composition of claim 41, comprising about 0.1 mg to about 1 g ziprasidone.   24. A dosage form comprising the composition of claim 23.   46. The dosage form of claim 45, comprising an admixture of active ingredient-containing particles contained within a hard gelatin or soft gelatin capsule.   47. The dosage form of claim 46, wherein the active ingredient-containing particles are in the form of minitablets and the capsule contains a mixture of the minitablets.   48. The dosage form of claim 47, which is in the form of a tablet.   49. The dosage form of claim 48, wherein the ziprasidone-containing particles are provided in a rapidly dissolving dosage form.   49. The dosage form of claim 48, wherein the tablet is a fast melting tablet.   35. A dosage form comprising the composition of claim 34.   52. The dosage form of claim 51, comprising an admixture of active ingredient-containing particles contained within a hard gelatin or soft gelatin capsule.   53. The dosage form of claim 52, wherein the active ingredient-containing particles are in the form of mini-tablets and the capsule contains a mixture of said mini-tablets.   54. The dosage form of claim 53, which is in the form of a tablet.   55. The dosage form of claim 54, wherein the ziprasidone-containing particles are provided in a fast dissolving dosage form.   55. The dosage form of claim 54, wherein the tablet is a fast melting tablet.   24. A method for preventing and / or treating schizophrenia or similar psychiatric disorders comprising administering a therapeutically effective amount of the composition of claim 23.   35. A method for preventing and / or treating schizophrenia or similar psychiatric disorders comprising administering a therapeutically effective amount of the composition of claim 34.   30. The composition of claim 28, wherein the modified release coating releases a pulse of active ingredient in the patient after a time delay of about 6 to about 12 hours after administration of the composition to the patient. Said composition comprising a pH-dependent polymer coating for.   60. The composition of claim 59, wherein the polymer coating agent comprises a methacrylate copolymer.   60. The composition of claim 59, wherein the polymer coating comprises a mixture of methacrylate and ammonio methacrylate copolymer in a ratio sufficient to achieve a pulse of active ingredient after a time delay of at least about 6 hours.   62. The composition of claim 61, wherein the ratio of methacrylate to ammonio methacrylate copolymer is approximately 1: 1.   40. The composition of claim 39, wherein the modified release coating releases a pulse of active ingredient in the patient after a time delay of about 6 to about 12 hours after administration of the composition to the patient. Said composition comprising a pH-dependent polymer coating for.   64. The composition of claim 63, wherein the polymer coating agent comprises a methacrylate copolymer.   65. The composition of claim 64, wherein the polymer coating comprises a mixture of methacrylate and ammonio methacrylate copolymer in a ratio sufficient to achieve a pulse of active ingredient after a time delay of at least about 6 hours.   66. The composition of claim 65, wherein the ratio of methacrylate to ammonio methacrylate copolymer is approximately 1: 1.   A controlled release composition comprising (A) ziprasidone; and (B) a modified release coating agent, or alternatively or additionally, a population of nanoparticulate particles comprising a modified release matrix material, comprising: The composition wherein ziprasidone is delivered in a pulsed or continuous manner following oral delivery.   68. The composition of claim 67, wherein when administered under fed conditions, the composition does not result in significantly different absorption levels compared to fasted conditions.   68. The composition of claim 67, wherein the pharmacokinetic profile is not significantly affected by the eating or fasting status of the subject taking it.   68. The composition of claim 67, wherein its administration to a fasted subject is bioequivalent to its administration to a fed subject.   68. The composition of claim 67, wherein the population comprises modified release particles.   68. The composition of claim 67, wherein the population is an erodible composition.   68. The composition of claim 67, wherein each of the particles is in the form of an osmotic device.   72. The composition of claim 71, wherein the modified release particles comprise a modified release coating.   72. The composition of claim 71, wherein the modified release particles comprise a modified release matrix material.   72. The composition of claim 71, wherein the modified release particles are combined in a formulation that releases the ziprasidone to the surrounding environment by erosion.   72. The composition of claim 71, further comprising an enhancer.   72. The composition of claim 71, wherein the amount of active ingredient contained therein is from about 0.1 mg to about 1 g.   68. A dosage form comprising the composition of claim 67.   80. The dosage form of claim 79, comprising an admixture of active ingredient-containing particles contained within a hard gelatin or soft gelatin capsule.   81. The dosage form of claim 80, wherein the active ingredient-containing particles are in the form of mini-tablets and the capsule contains a mixture of said mini-tablets.   82. The dosage form of claim 81, which is in the form of a tablet.   83. The dosage form of claim 82, wherein the ziprasidone-containing particles are provided in a rapidly dissolving dosage form.   83. The dosage form of claim 82, wherein the tablet is a fast melting tablet.   68. A method for the prevention and / or treatment of schizophrenia or similar psychiatric disorders comprising administering a therapeutically effective amount of the composition of claim 67.   72. The composition of claim 71, wherein the modified release particles comprise a pH dependent polymer coating that is effective to release a pulsed release of the active ingredient after a 6-12 hour time delay.   90. The composition of claim 86, wherein the polymer coating agent comprises a methacrylate copolymer.   90. The composition of claim 86, wherein the polymer coating comprises a mixture of methacrylate and ammonio methacrylate copolymer in a ratio sufficient to achieve a pulse of active ingredient after a time delay.   90. The composition of claim 88, wherein the ratio of methacrylate to ammonio methacrylate copolymer is approximately 1: 1.   68. The composition of claim 67, wherein each of the particles is in the form of an osmotic device.   2. The composition of claim 1 formulated as a depot dosage form.