WO2011085188A1

WO2011085188A1 - Pharmaceutical compositions comprising anti-psychotic drugs

Info

Publication number: WO2011085188A1
Application number: PCT/US2011/020505
Authority: WO
Inventors: Gopi M. Venkatesh; Jin-Wang Lai; Michelle Papp
Original assignee: Eurand America Inc
Current assignee: Adare Pharma Solutions Inc
Priority date: 2010-01-07
Filing date: 2011-01-07
Publication date: 2011-07-14
Anticipated expiration: 2012-07-07

Abstract

This invention relates to pharmaceutical compositions comprising one or more weakly basic antipsychotic drugs, and methods of making and using such compositions.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING ANTI-PSYCHOTIC DRUGS

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. Provisional Application No.

61/293,067 filed January 7, 2010, which is incorporated herein by reference in its entirety for all purposes.

BACKGROUND OF THE INVENTION

Schizophrenia is a chronic clinically heterogeneous, brain disabling disorder that is characterized by symptoms such as hallucinations, delusions and disordered thinking, cognitive impairment, anxiety and/or depression. This disorder has a lifetime prevalence of approximately 1 percent, affecting about 24 million people worldwide, including 2 million Americans.

Bipolar I disorder (also known as manic-depressive disorder) is the sixth leading cause of disability in the world characterized by episodes of elevated moods, extreme irritability, decreased sleep and increased energy, depression (overwhelming feelings of sadness, suicidal thoughts), or a combination of both. This disorder affects about 1 percent of adults, including 10 million Americans.

The treatment of schizophrenia is fraught with issues and serious side effects:

Olanzapine - weight gain and metabolic syndrome; Ziprasidone - cardiac effects; Risperidone - hyperprolactinemia; Quetiapine - sedation; Perphenazine - extrapyramidal symptoms (EPS)

Physicians have the complicated task of managing treatment by weighing the response to drug versus side effects versus discontinuation and noncompliance in the use of drug

• Risk perception is a significant driver in the selection and use of antipsychotics

• Use of atypical antipsychotics has largely replaced typical antipsychotics such as perphenazine and haloperidol due to a belief that atypical antipsychotics provide a lower incidence of EPS. In terms of value, atypical antipsychotics accounted for almost 95% of the total schizophrenia market in 2007.

Compliance is a significant problem during treatment, and insuring and/or increasing compliance remains an unmet need. The level of compliance is generally believed to be influenced by restrictive dosing regimen, cognitive deficits, patients' insight, and negative attitude to medication. Unfortunately, there is evidence that greater than half of schizophrenic patients have problems with regularly taking their medications. Those problems include the willful refusal to take the medications, as well as patient disorganization and cognitive issues.

Finnish researchers were quoted in recent medical report dated July 12, 2009 as saying that schizophrenia patients given a cheap older drug (clozapine, the first generation of atypical antipsychotic drug) are less likely to die prematurely than people on newer treatments, despite the older product's well-known adverse side effects. Furthermore, an analysis of 10 years of records for 67,000 Finnish patients found that, compared to treatment with the first-generation antipsychotic drug (non-atypical), perphenazine, the risk of early death for patients on clozapine was reduced by 26 percent. Similarly, the mortality risk was 41 percent higher for those on Seroquel (active: quetiapine, the current market leader); 34 percent higher with Johnson & Johnson's Risperdal (active: resperidone); and 13 percent higher with Eli Lilly's Zyprexa (active: olanzapine).

No non-inferiority study in terms of efficacy and adverse events in comparison to the new atypical antipsychotic Saphris and any typical antipsychotic drug has been performed.. Saphris (asenapine (atypical antipsychotic) sublingual tablet) has been recently approved by the FDA as a first-line treatment of schizophrenia in adults and acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults. Saphris (5 mg twice daily) demonstrated statistically significant efficacy versus a placebo, and acute bipolar I disorder studies showed that Saphris (10 mg twice daily) demonstrated a statistically significant reduction of bipolar mania symptoms versus placebo.

CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) was the largest, longest and most comprehensive independent trial ever conducted examining the treatment options for schizophrenia relative to the effectiveness of typical and atypical antipsychotics, with the exception of clozapine. Most previous studies of atypical antipsychotics were of short duration (4 to 8 weeks), focused on narrow outcomes, had strict inclusion/exclusion criteria and usually only had one comparator drug. A National Institutes of Mental Health, (NIMH)-sponsored research program overseen by clinician teams from the University of North Carolina, Yale University, Duke University and Columbia University, was conducted from January 2001 to December 2004 to evaluate the effectiveness of antipsychotic medications for schizophrenia and Alzheimer's disease in broad patient populations (1,460 participants, 18-65 years old) and "real-world" settings (concomitant medications, medical illnesses, and substance use disorders allowed and no adjunctive antipsychotic allowed after randomization). The phase I double blind, randomized study was conducted in 1460 patients with Schizophrenia (see Stroup TS et al. Schizophr Bull. 2003;29: 15-31) assigned to (1) Olanzapine (dose: 7.5 mg to 30 mg), (2) Perphenazine (dose: 8 mg to 32 mg), (3) Quetiapine (dose: 200 mg to 800 mg), (4) Risperidone (dose: 1.5 mg to 6 mg), and (5) Ziprasidone (dose: 40 mg to 160 mg). The study findings were published in New England J. Med., vol 353 (Sep 2005), titled: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia (see Table 1). Results of the trial showed that:

1. The majority of patients in each group discontinued their assigned treatment

owing to inefficacy, i.e., symptom reduction, hospitalization rate, or intolerable side effects, i.e., weight gain, extrapyramidal symptoms (EPS), prolongation of QT interval, or for other reasons.

2. Olanzapine was the most effective in terms of the rates of discontinuation, and the efficacy of the conventional antipsychotic drug while perphenazine appeared to be similar to that of quetiapine, risperidone, and ziprasidone.

3. Olanzapine was associated with greater weight gain and increases in measures of glucose and lipid metabolism.

4. Study finds little advantage in newer costlier antipsychotic drugs over older, cheaper drugs.

Table 1 : Comparison of Antipsychotic drugs

> Due to worsening of schizophrenia

Thus, the CATIE findings showed that perphenazine, a dopamine D1/D2 receptor antagonist, and a first generation typical oral antipsychotic for the management of schizophrenia, had no worse incidence of EPS as a typical antipsychotic than most atypical antipsychotics currently prescribed, and that the effectiveness of most atypical antipsychotics over perphenazine is questionable. Perphenazine, which was used in the CATIE study, was first approved by the FDA in 1957. It is a piperazme phenothiazine and is structurally similar to other weakly basic compounds such as trifluoperazine, prochlorperazine, and fluphenazine. Perphenazine is also characterized by its bitter taste (Osol, A. and J.E. Hoover, et al. (eds.), Remington's

Pharmaceutical Sciences). Furthermore, perphenazine has low aqueous solubility with a pH- dependent solubility profile, i.e., it is sparingly soluble below pH of 3.0 and practically insoluble above a pH of 6.0. The low solubility presents a huge challenge in developing a QD dosage form of perphenazine.

Perphenazine is used in the treatment of various psychoses including schizophrenia and mania as well as disturbed behavior and in the short-term, adjunctive management of severe anxiety. Perphenazine is also used for the management of postoperative or chemotherapy-induced nausea and vomiting and for the treatment of intractable hiccup (Martindale, 2008). Perphenazine is usually given as the base by mouth and sometimes by intramuscular or intravenous injection. Long-acting decanoate or enanthate esters of perphenazine, available in some countries, are given by intramuscular injection. It is currently administered b.i.d. to q.d. (twice daily to once daily), 8-64 mg daily depending on severity. The usual initial dose for the treatment of schizophrenia, mania, and other psychoses is 4 mg tliree times daily by mouth. The dose is adjusted according to response up to a typical maximum of 24 mg daily, although up to 64 mg daily has occasionally been used in hospitalized patients. Similar doses have been used for the management of severe agitated or violent behavior or in severe anxiety. Perphenazine has sometimes been used in preparations with tricyclic antidepressants such as amitriptyline in the treatment of anxiety with depression (Martindale, 2008).

The more common side effects associated with perphenazine and other anti-psychotic drugs of this chemical class include neuroleptic effect (reduced initiative, interest in the environment, and display of emotion or affect), extrapyramidal reactions, and sedation. With the piperazine group (of that perphenazine is an example), the extrapyramidal symptoms are more common, and others (e.g., sedative effects, jaundice, and blood dyscrasias) are less frequently seen (Package Insert Schering-Plough, 2002). Extrapyramidal reactions are defined as physical symptoms, including tremor, slurred speech, akathisia (feelings of inner restlessness), dystonia, anxiety, distress, paranoia, and bradyphrenia, which are primarily associated with improper dosing of or unusual reactions to neuroleptic (antipsychotic) medications (medicine.net, 2008). The frequency of adverse reactions has not been fully described or reported. A wide variety of target effects have been reported. The primary adverse effects are reported in the immediate-release (IR) tablet package insert (Schering- Plough, 2002) . The severity side effects from IR dosage form, non-availability of a QD dosage form, bitter taste of the drug, and unavailability of a convenient dosage form to avoid 'cheeking', are considered to foster a lack of compliance in the use of perphenazine.

Thus, there is an immediate unmet medical need to develop a perphenazine product without the bitter taste and a sustained-release (SR) once-daily product for improving patient convenience and compliance. It would also be useful to have an formulation of perphenazine that maintains clinically effective therapeutic serum levels of the drug below that observed for the current IR product over a 24 hour period to allow for once-a-day dosing while minimizing C_max related side effects. Furthermore, given the effectiveness and incidence of EPS for perphenazine compared to a number of atypical antipsychotics, perphenazine, could be positioned as a less expensive and equally good alternative to more expensive atypical antipsychotic drugs in an environment of changing attitudes over risk perception. It is also evident from the above studies that patients taking other atypical medications such as Geodon^® (ziprasidone IR capsules twice a day), Zyprexa (olanzapine IR tablet or ODT although indicated once a day), Saphris (asenapine sublingual tablets twice daily), and products containing other atypical/typical antipsychotic drugs may significantly benefit from controlled release dosage forms exhibiting reduced C_max but significantly extended plasma concentration profiles in terms of reductions in side effect profiles. Thus, although the primary objective of the invention disclosed hereafter is focused on the development of CR dosage forms, the technologies to be described are equally applicable for the development of CR dosage forms containing olanzapine, ziprasidone, asenapine, etc.

SUMMARY OF THE INVENTION

In certain embodiments, this invention relates to pharmaceutical compositions comprising one or more weakly basic antipsychotic drugs, and methods of making and using such compositions.

In certain embodiments, the present invention is related to a pharmaceutical composition comprising one or more antipsychotic drugs, such as perphenazine or ziprasidone, which comprises at least one population of controlled-release (CR) particles, wherein each CR particle comprises a core comprising a pharmaceutically acceptable antipsychotic drug such as perphenazine or a pharmaceutically acceptable salt, polymorph, isomer, hydrate, solvate, and/or ester thereof, and an optional polymeric binder, a first coating disposed over said drug core, comprising a water-insoluble polymer alone or a water- insoluble polymer in combination with an optional water-soluble polymer, followed by an optional second coating comprising an enteric polymer or an enteric polymer in combination with a water insoluble polymer disposed over said first coating. Upon oral administration in a patient in need of said medication, the CR particle provides an extended plasma

concentration profile of the antipsychotic drug suitable for a once-daily dosing regimen. In a particular embodiment, the pharmaceutical composition may further comprise a second population of IR particles, wherein the IR particle of the second population comprises a weakly basic antipsychotic drug, such as perphenazine, or a pharmaceutically acceptable salt, polymorph, isomer, hydrate, solvate, and/or ester thereof. Yet another embodiment of the present invention also provides for a taste-masked component in addition to one or more SR or CR bead populations in the form of an orally disintegrating tablet, an alternate mode of oral administration in patients experiencing dysphagia or to prevent/minimize potential for 'cheeking' .

In other embodiments, the present invention is directed to a pharmaceutical composition comprising controlled-release (CR) particles of one or more antipsychotic drugs, wherein each CR particle comprises a core comprising at least one pharmaceutically acceptable organic acid (e.g., a pharmaceutically acceptable organic acid crystal with a desired average particle size, a pellet comprising an organic acid, a polymeric binder, and optionally a filler, or an organic acid plus a polymeric binder layered onto an inert core), a first coating disposed over said organic acid core, comprising a water-insoluble polymer alone or a water-insoluble polymer in combination with an optional water-soluble or enteric polymer, a second coating disposed over said CR acid core, comprising a weakly basic antipsychotic drug and an optional polymeric binder, and a third coating disposed over said drug core comprising a water-insoluble polymer, followed by an optional fourth coating comprising an enteric polymer or an enteric polymer in combination with a water insoluble polymer disposed over said third coating. Upon oral administration to a patient in need of said medication, the organic acid in the acid core of the CR bead creates an acidic pH microenvironment inside the coated bead in the intestinal tract at a pH of 6.0 or higher where the weakly basic drug is practically insoluble, to solubilize the drug prior to releasing it into the hostile alkaline pH environment of the intestinal region. In a particular embodiment of the invention, the pharmaceutical composition is in the form of a hard gelatin capsule further comprising a second population of IR particles, wherein the IR particle of the second population comprises a weakly basic antipsychotic drug, such as perphenazine, or a pharmaceutically acceptable salt, polymorph, isomer, hydrate, solvate, and/or ester thereof. Certain embodiments of the present invention also provide for a taste-masked IR component as well as a dosage form in the form of an orally disintegrating tablet comprising taste- masked and multicoated particles and rapidly dispersing microgranules, which rapidly disintegrates on contact with saliva creating a smooth, easy-to-swallow suspension containing multicoated weakly basic antipsychotic drug particles.

In yet another embodiment, the present invention is related to a pharmaceutical composition comprising controlled-release (CR) beads, wherein said CR bead comprises a first coating of a solid dispersion disposed over inert cores, comprising a weakly basic drug, at least one pharmaceutically acceptable solubility-enhancing/crystallization-inhibiting polymer, and optionally an organic acid; an optional protective seal coating disposed over the solid solution layer, and a second coating comprising a water insoluble polymer alone or a water insoluble polymer in combination with a water soluble polymer, an optional third coating comprising an enteric polymer or an enteric polymer in combination with a water insoluble polymer; wherein the weakly basic drug comprises a weakly basic antipsychotic drug having a solubility of not more than 200 μg/mL at pH 6.8. Upon oral administration to humans in need of said medication, the amorphous form of the weakly basic drug in-situ formed in the solid solution coating enables, in conjunction with the optional organic acid, solubilization of the weakly basic drug within the coated bead prior to its release into the intestinal tract at a pH of 6.0 or higher, in a sustained manner over an extended period of time.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 A shows the solubility profile for perphenazine, a weakly basic, typical antipsychotic drug (Perphenazine) as a function of pH. FIG I B shows the serum concentrations of perphenazine in slow and rapid hydroylators of debrisoquin.

FIG. 2 illustrates the cross-section of a controlled-release (CR) bead, (10) in certain embodiments of the invention comprising an optional delayed-release (DR) or timed, pulsatile release (TPR) coating layer, (9), disposed over a sustained-release (SR) coating layer coating, (7), that is disposed over an optional protective seal coating layer (5), disposed over an antipsychotic drug layer, (3), disposed over a pharmaceutically acceptable inert core such as a sugar sphere or cellulosic sphere, (7). The drug layer comprises a weakly basic typical or atypical antipsychotic drug and a polymeric binder as disclosed in Example 2 and 6 or a solid solution comprising a weakly basic typical or atypical antipsychotic drug and a water soluble crystallization-inhibiting polymer at a ratio of from 4: 1 to 1 :4, as disclosed in Example 4. Optionally, an organic acid may also be included in the solid solution formulation to further modulate the release of the drug.

FIG. 3 illustrates the cross-section of a controlled-release (CR) bead, (20), in certain embodiments of the invention comprising an optional delayed-release (DR) or timed, pulsatile release (TPR) coating layer, (79), a sustained-release (SR) coating layer, (77), disposed over an optional protective seal coating layer (75), disposed over an antipsychotic drug layer, (73), disposed over a SR or TPR coating layer, (77), disposed over a

pharmaceutically acceptable solubility-enhancing organic acid core (e.g., organic acid layer, (Al), comprising an organic acid and a polymeric binder disposed on an inert core such as a sugar sphere, (A2), as disclosed in Example 4, a pellet comprising an organic acid, a polymeric binder, and optionally a filler, or simply an organic acid crystal as disclosed in Example 5.

FIG. 4 shows the simulated plasma concentration - time profiles of IR dose x tid over 24 hrs and a once-daily controlled-release (CR) multiparticulate composition (IR/CR bead population at 1 :3 with Kl = 0.4) as disclosed in Example 1.

FIG. 5 shows the deconvoluted in vitro drug release profiles of a controlled-release (CR) multiparticulate composition exhibiting target plasma concentration - time profiles in poor/slow and extreme/rapid metabolizers referred to in Example 1.

FIG. 6 shows the in vitro release profiles from SR (ethylcellulose coated) particle populations of weakly basic antipsychotic perphenazine layered on 25-30 or 60-80 mesh sugar spheres of Example 2.

FIG. 7 shows the comparative in vitro release profiles of organic acid (fumaric acid) and weakly basic antipsychotic drug (perphenazine) from an SR multiparticulate composition of Example 3.D.

FIG. 8 shows the comparative in vitro perphenazine release profiles from SR and CR multiparticulate compositions of Example 3.D/3.E.

FIG. 9 shows the comparative in vitro release profiles of said weakly basic antipsychotic drug (perphenazine) from CR multiparticulate solid solution compositions of Example 4 when dissolution tested in a pH 6.8 buffer.

DETAILED DESCRIPTION OF THE INVENTION

The following description includes information that may be useful in understanding the invention. It is not an admission that any of the information provided herein is prior art or that any publication specifically or implicitly referenced is prior art.

All documents cited herein are incorporated by reference in their entirety for all purposes to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference. As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

The term "drug", "active", "active agent", or "active pharmaceutical ingredient" as used herein includes a pharmaceutically acceptable and therapeutically effective compound, pharmaceutically acceptable salts, stereoisomers and mixtures of stereoisomers, solvates (including hydrates), polymorphs, and/or prodrugs thereof. Unless otherwise indicated, when referring to a drug in the descriptions of the various embodiments of the invention, the reference encompasses the base drug, pharmaceutically acceptable salts, stereoisomers and mixtures of stereoisomers, solvates (including hydrates), polymorphs, and/or prodrugs thereof.

The term "salts" refers to the product formed by the reaction of a suitable inorganic or organic acid with the "free base" form of the drug. Suitable acids include those having sufficient acidity to form a stable salt, for example acids with low toxicity, such as the salts approved for use in humans or animals. Non-limiting examples of acids that may be used to form salts of perphenazine include inorganic acids, e.g., HF, HC1, HBr, HI, H2SO4, H3PO4; non-limiting examples of organic acids include organic sulfonic acids, such as C₆-i6 aryl sulfonic acids, C_6-i 6 heteroaryl sulfonic acids or C M 6 alkyl sulfonic acids - e.g., phenyl, a- naphthyl, β-naphthyl, (S)-camphor, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, pentyl and hexyl sulfonic acids; non-limiting examples of organic acids includes carboxylic acids such as Cj_ i 6 alkyl, C₆-i 6 aryl carboxylic acids and C4-16 heteroaryl carboxylic acids, e.g., acetic, glycolic, lactic, pyruvic, malonic, glutaric, tartaric, citric, fumaric, succinic, malic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic and 2-phenoxybenzoic acids; non-limiting examples of organic acids include amino acids, e.g. the naturally-occurring amino acids, lysine, argimne, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine, etc. Other suitable salts can be found in, e.g., S. M. Birge et al., J. Pharm. Sci., 1977, 66, pp. 1-19 (herein incorporated by reference for all puiposes). In most embodiments, "salts" refers to salts that are biologically compatible or pharmaceutically acceptable or non-toxic, particularly for mammalian cells. The salts of drugs useful in the invention may be crystalline or amorphous, or mixtures of different crystalline forms and/or mixtures of crystalline and amorphous forms.

The term "prodrug" means a form of the compound of formula I suitable for administration to a patient without undue toxicity, irritation, allergic response, and the like, and effective for their intended use, including ketal, ester and zwitterionic forms. A prodrug is transformed in vivo to yield the compound of formula 1 , for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

The terms "orally disintegrating tablet", "orally dispersible tablet", or "ODT" refers to a tablet that disintegrates rapidly in the oral cavity of a patient after administration, without the need for chewing. The rate of disintegration can vary, but is faster than the rate of disintegration of conventional solid dosage forms (e.g., tablets or capsules) that are intended to be swallowed immediately after administration, or faster than the rate of disintegration of chewable solid dosage forms, when tested as described herein (e.g. the USP <701> test method).

The term "about" used herein in reference to a numerical quantity includes the noted numerical quantity, as well as values near the numerical quantity. For example, "about 60 second" includes 60 seconds, exactly, as well as values close to 60 seconds (e.g., 50 seconds, 55 seconds, 59 seconds, 61 seconds, 65 seconds, 70 seconds, etc.). As used herein, the term "controlled-release" coating encompasses coatings that delay release, sustain release, prevent release, and/or otherwise prolong the release of a drug from a particle coated with a controlled-release coating. The term "controlled-release" encompasses "sustained-release" and "timed, pulsatile release", thus a "controlled-release coating" encompasses a sustained release coating, timed, pulsatile release coating or "lag-time" coating.

The term "pH sensitive" as used herein refers to polymers that exhibit pH dependent solubility.

The term "enteric polymer", as used herein, refers to a pH sensitive polymer that is resistant to gastric juice (i.e., relatively insoluble at the low pH levels found in the stomach), and that dissolves at the higher pH levels found in the intestinal tract.

As used herein, the term "immediate release" (IR; in reference to a pharmaceutical composition that can be a dosage form or a component of a dosage form), refers to a pharmaceutical composition that releases greater than or equal to about 50% of the active, in another embodiment greater than about 75% of the active, in another embodiment greater than about 90% of the active, and in other embodiments greater than about 95% of the active within about 2 hours, or within about one hour following administration of the dosage form. The term can also refer to pharmaceutical compositions in that the relatively rapid release of active occurs after a "lag time" (in that little or no release of active occurs). The term "immediate release bead" or "immediate release particle" refers broadly to an antipsychotic drug-containing bead or particle that exhibits "immediate release" properties with respect to the antipsychotic drug as described herein.

The term "solid solution" or "solid dispersion" refers to a composition of a weakly basic drug and a water-soluble polymer (e.g., vinylpyrrolidone-vinylacetate copolymer commercially available from BASF as Kollidon^® VA 64) that is capable of enhancing the solubility of the weakly basic drug by inhibiting/preventing crystallization of the drug. In certain embodiments of the invention, such a solid solution can be formed by spraying a solution comprising both of the components (i.e., the weakly basic drug and water-soluble polymer) onto inert cores and maintaining the drug largely in the amorphous form during the shelf-life of the pharmaceutical multiparticulate composition. In addition, the resulting solid solution-containing particles are individually coated with hydrophobic polymers to minimize the possibility of moisture-induced crystallization of the amorphous drug.

The term "sustained release (SR) bead" or "sustained release particle" refers broadly to a bead or particle comprising an SR coating, as described herein, disposed over an antipsychotic drug-containing core coated with an SR coating as described herein.

The term "lag-time coating" or "TPR coating" refers to a controlled-release coating comprising the combination of water-insoluble and enteric polymers as used herein. A TPR coating by itself provides an immediate release pulse of the drug, or a sustained drug-release profile after a pre-determined lag time.

The term "lag-time (TPR) bead" or "lag-time particle" refers broadly to a bead or particle comprising a TPR coating, as described herein, disposed over an antipsychotic drug- containing core.

The term "delayed release (DR) bead" or "delayed release particle" refers broadly to an antipsychotic drug-containing core coated with a DR coating as described herein.

The term "controlled release (CR) bead" or "controlled release particle" refers broadly to an antipsychotic drug-containing core having an inner SR coating followed by an outer DR or TPR coating or an inner TPR coating followed by an outer DR coating, as described herein.

The term "lag-time" as used herein refers to a time period wherein less than about 10% of the active is released from a pharmaceutical composition after ingestion of the pharmaceutical composition (or a dosage form comprising the pharmaceutical composition), or after exposure of the pharmaceutical composition, or dosage form comprising the pharmaceutical composition, to simulated body fluid(s), for example evaluated with a USP apparatus using a two-stage dissolution medium (first 2 hours in 700 mL of 0. IN HCl at 37°C followed by dissolution testing at pH = 6.8 obtained by the addition of 200 mL of a pH modifier).

The term "disposed over", in reference to a coating over a substrate, refers to the relative location of the coating in reference to the substrate, but does not require that the coating be in direct contact with the substrate. For example, a first coating "disposed over" a substrate can be in direct contact with the substrate, or one or more intervening materials or coatings can be interposed between the first coating and the substrate. In other words, for example, a SR coating disposed over a drug-containing core can refer to a SR coating deposited directly over the drug-containing core or acid crystal or acid-containing core, or can refer to a SR coating deposited onto a protective seal coating deposited on the drug- containing core.

The term "sealant layer" refers to a protective membrane disposed over a drug- containing core particle or a functional polymer coating. The sealant layer protects the particle from abrasion and attrition during handling, and/or minimize static during processing.

The term "substantially disintegrates" refers to a level of disintegration amounting to disintegration of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% disintegration. The term "disintegration" is distinguished from the term "dissolution", in that "disintegration" refers to the breaking up of or loss of structural cohesion of the constituent particles comprising a tablet, whereas "dissolution" refers to the solubilization of a solid in a liquid (e.g., the solubilization of a drug in solvents or gastric fluids).

In certain embodiments of the invention, the compositions comprise a plurality of antipsychotic drug-containing particles comprising an antipsychotic drug-containing core coated with a first and second coating as described herein, wherein the first coating comprises at least one water-insoluble polymer. The first coating can be disposed directly on the antipsychotic drug-containing core, coated onto a sealant layer that is disposed over the drug- containing core, coated over the second coating, coated over a sealant layer that is disposed over the second coating, etc.

The term "water-insoluble polymer" refers to a polymer that is insoluble or very sparingly soluble in aqueous media, independent of pH, or over a broad pH range (e.g., pH 0 to pH 14). A polymer that swells but does not dissolve in aqueous media can be "water- insoluble," as used herein.

The term "water-soluble polymer" refers to a polymer that is soluble (i.e., a significant amount dissolves) in aqueous media, independent of pH. The term "enteric polymer" refers to a polymer that is soluble (i.e., a significant amount dissolves) under intestinal conditions; i.e., in aqueous media under ~ neutral to alkaline conditions and insoluble under acidic conditions (i.e., low pH).

The term "reverse enteric polymer" or "gastrosoluble polymer" refers to a polymer that is soluble under acidic conditions and insoluble under neutral (as in water) and alkaline conditions.

The terms "plasma concentration - time profile, C_max, AUC, T_max, elimination half life" have their generally accepted meanings as defined in the FDA Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations (issued March 2003).

Unless stated otherwise, the amount of the various coatings or layers described herein (the "coating weight") is expressed as the percentage weight gain of the particles or beads provided by the dried coating, relative to the initial weight of the particles or beads prior to coating. Thus, a 10% coating weight refers to a dried coating that increases the weight of a particle by 10%.

Non-adherence to dosing regimens is a major medical problem worldwide— costing billions of dollars and affecting the lifestyles of millions of people. In addition to a properly designed drug delivery system, the time of administration is equally important. However, there are several challenges to be overcome before an acceptable solution can be found. Factors known to limit the absorption via the oral route of the weakly basic typical or atypical antipsychotic drugs include poor pH dependent solubility, inadequate stability in GI fluids, poor permeability across the intestinal epithelium, enzymatic degradation / metabolism in certain segments, and complexation or high protein binding. While the orally administered pharmaceutical dosage form passes through the human digestive tract, the drug should be released from the dosage form and be available in solution form at or near the absorption site in the gastrointestinal (GI) tract for absorption to occur. The rate at which the drug goes into solution and is released from a dosage form is important for the kinetics of drug absorption. The dosage form and hence the active ingredient is subjected to varying pHs during the transit, i.e., pH varying from about 1.2 (stomach pH during fasting but may vary between 1.2 and 4.0 upon consumption of food) to about 7.4 (bile pH: 7.0-7.4 and intestinal pH: 5 to 7). Moreover, the transit time of a dosage form in individual parts of the digestive tract, especially the gastric residence time, may vary significantly depending on its size and prevailing local conditions. Furthermore, the fluid volume in individual parts of the digestive tract varies significantly [e.g., stomach: (fasted: 46 mL) and (fed: 686 mL); small intestine: (fasted: 105 mL) and (fed: 54 mL)) and colon: (fasted: 13 mL) and (fed: 1 1 mL)]. The surface area available for drug absorption also varies significantly in different parts of the GI tract. After oral administration, drugs are subjected to biochemical processes of absorption, distribution, metabolism, and elimination (ADME) differently. For example, different drugs of the same therapeutic class may be absorbed into the bloodstream at different rates and sometimes through different processes. The rate and extent of absorption for a particular drug, and among different drugs, may vary along the GI tract. For example many drugs are absorbed faster and to a greater extent in the small intestine than in the large intestine. The drug absorbed into the bloodstream may be rapidly distributed in the peripheral tissues, metabolized (e.g., oxidizing, hydrolyzed, and/or conjugated by enzymes n the liver, epithelial cells in gut wall producing sometimes active metabolites, and eventually eliminated/excreted from the body via kidney in urine or in bile acids via liver into the GI tract for hepatic recirculation or excretion in feces. Another drug characteristic (elimination half life) that affects the feasibility of developing extended release dosage form can be measured by its half-life which refers to the time required to reduce drug's plasma concentration by 50% of its time zero value.

Pharmacokinetic modeling is typically constructed by fitting the plasma concentration - time data from intravenous and immediate release (IR) peroral dosage forms of a weakly basic antipsychotic drugs of interest, and/or pharmacokinetic constants, such as absorption constant (K_a), bioavailability (F), volume of distribution (V), rate constants (Kj?, ?i ,) to and from the peripheral compartment, distribution rate constant (a per hr), elimination rate constant (β per hr), and lag time (T)_aii)) and assuming one- or two-compartmental models and first order absorption/ elimination, and linear pharmacokinetics, using a PK/PD simulation software, WinNonlin^® from Pharsight^® Corporation (Mountain View, CA) and/or

GastroPlus™ from Simulationsplus, Inc., so that the predicted plasma concentration - time profiles closely match the actual plasma concentration - time profiles reported in the literature. A set of theoretical release rates (Ki , K]₂, K₂i etc. values would then be used in the simulations of once-daily plasma concentration - time profiles to estimate C_max, T_max, AUC values for comparison with that of immediate release reference listed drug (IR RLD) dose x bid to qid. From the analysis and in view of the effective therapeutic range, the most desired plasma profile for the antipsychotic drug of interest would be selected, and based on assumed IV /IV correlations, target in vitro release profiles are deconvoluted and once-daily prototypes for the weakly basic antipsychotic drug of interest would be designed based on strategic approaches (e.g., Diffucaps^® technology based on the organic acid /or solid solution approach) for evaluation in a comparative human PK study.

It was surprisingly discovered that suitable once-daily drug delivery systems containing a weakly basic antipsychotic drug can be provided by incorporating a solubility- enhancing organic acid such as citric acid, or a crystallization-inhibiting water-soluble polymer such as pyrrolidone-vinyl acetate copolymer (commercially available from BASF as Kollidon VA 64). Without being bound by any mechanisms, it is postulated that when an organic acid is present, the acid creates an acidic pH microenvironment within the CR coated drug particle in which the drug is soluble prior to releasing it to a hostile alkaline pH environment where the weakly basic drug is practically insoluble.

In certain embodiments of the invention, a solid solution can also be used to enhance solubility. Without being bound by any particular mechanism, when the crystallization- inhibiting polymer and the antipsychotic drug are dissolved in a common solvent mixture to achieve molecular level mixing, the solid solution so produced creates and maintains the drug in the amorphous form which is significantly more soluble irrespective of the physiological pH allows prolonged drug release from CR coated beads. In particular embodiments of the invention, the type and amount of solubility- enhancing/crystallization-inhibiting polymer is selected so that the combination of active pharmaceutical ingredient and solubility-enhancing/crystallization-inhibiting polymer form a solid solution as defined herein. Some of the solubility-enhancing/crystallization-inhibiting polymers useful for preparing solid solutions/dispersions are conventionally used as binders. However, in order to provide a solid solution of the antipsychotic drug, the ratio of solubility- enhancing/crystallization-inhibiting polymer to drug is generally significantly higher than the ratio of polymeric binder to active pharmaceutical ingredient in conventional pharmaceutical formulations. (In conventional pharmaceutical formulations, the ratio of polymeric binder to drug is typically less than 1/9, for example about 1/50 to about 1/20.) In one embodiment, the ratio of solubility-enhancing/crystallization-inhibiting polymer to drug in the solid solution ranges from 9/1 to 1/6 (by weight). In another embodiment, the ratio the solubility- enhancing/crystallization-inhibiting polymer to drug in the solid solution ranges from about 3/1 to about 1/3 (by weight). In yet another embodiment, the ratio the s solubility- enhancing/crystallization-inhibiting polymer to drug in the solid solution ranges from about 2/1 to about 1/2 (by weight), or about 1/1.

When pharmaceutical compositions of the present invention are formulated into an ODT dosage form, the compositions may further comprise rapidly dispersing microgranules. The rapidly dispersing microgranules comprise at least one disintegrant in combination with at least one sugar alcohol and/or saccharide. Non-limiting examples of suitable disintegrants include crospovidone (crosslinked polyvinylpyrrolidone), starch, low-substituted

hydroxypropylcellulose, sodium starch glycolate, and crosslinked sodium carboxymethyl cellulose. Non-limiting examples of sugar alcohols include arabitol, erythritol, lactitol, maltitol, mannitol, sorbitol, and xylitol. Non-limiting examples of suitable saccharides include lactose, sucrose, and maltose. The ratio of the disintegrant to the sugar alcohol and/or saccharide in the rapidly dispersing microgranules ranges from about 1/99 to about 10/90, and in some embodiments is about 5/95 (by weight). Since ODT dosage forms disintegrate rapidly in the oral cavity of a patient, the organoleptic properties of the ODT are an important consideration. For example, the ODT should be formulated to provide good "mouthfeeF and taste characteristics. "Mouthfeel" describes how a product feels in the mouth. In order to obtain a "mouthfeel" which is not gritty, the drug containing beads, rapidly dispersing microgranules, and optional IR beads should have an average particle size of about 400 μιη or less, in some embodiments about 300 μιη or less, and in still other embodiments, about 200 μιη or less. In one embodiment, the primary particles comprising the rapidly dispersing microgranules (i.e., particles of a disintegrant and sugar alcohol and/or saccharide which are agglomerated to form the rapidly dispersing microgranules) have an average particle size of about 30 μηι or less, in other embodiments about 25 μιη or less, and in still other embodiments about 20 μηι or less.

Rapidly dispersing granules comprising a sugar alcohol and/or saccharide having an average particle size of less than about 30 μηι provide superior oral disintegration properties compared to granules comprising larger average particle sizes of sugar alcohol or saccharide. The combination of less than about 30 μιη sugar alcohol and/or saccharide particles with particular disintegrants (e.g., crospovidone, crosslinked sodium carboxymethyl cellulose, and low-substituted hydroxypropylcellulose) provides particularly good disintegration properties. Embodiments

Suitable antipsychotic drugs according to the invention include, but are not limited to, perphenazine, iloperidone, risperidone, ziprasidone, olanzapine, quetiapine, blonanserin, asenapine, lurasidone, loxapine, bifeprunox, paliperidone, fluphenazine, chlorpromazine, haloperidol, sertindole, and the like, or a pharmaceutically acceptable salt, solvate, or ester thereof; more particularly, the antipsychotic drug is perphenazine or salts, and/or solvates thereof.

Perphenazine, a piperazinyl phenothiazine, (2-[4-[3-(2-chlorophenothiazin-10- yl)propyl]piperazin-l -yl]ethanol), was first approved by the FDA in 1957 and is available as oral tablets containing 2 mg, 4 mg, 8 mg, and 16 mg of perphenazine. It is a weakly basic drug with a pKa of 7.9 and Log Poci/wa_t ⁼ 5.2 vs. predicted Log P: 4.27 (lipophilic indicating perphenazine to be well absorbed along the GI tract). Its solubility in water (24°C) is 28.3 μg/mL and at pH 6.8 (35°C) is 57.5 μg/mL. Its pH dependent solubility profile is shown in FIG. 1 A. Perphenazine is bitter, but odorless, and a typical antipsychotic drug and indicated for use in the treatment of schizophrenia and for the control of severe nausea and vomiting in adults. The dosage form is usually 24 to 32 mg dosed three times per day, and the pharmacological effect is measured after a long-time treatment. Thus, the monitored plasma concentration is usually at steady state. It has not been shown effective for the management of behavioral complications in patients with mental retardation.

Its structural formula is:

C₂₁H_2eCIN₃OS M.W. 403.97

Following oral administration of TRILAFON Tablets (immediate release perphenazine), mean peak plasma perphenazine concentrations were observed between 1 to 3 hours. The plasma elimination half-life of perphenazine was independent of dose and ranged between 9 and 12 hours. Perphenazine, like many other neuroleptic drugs that have chemical similarities to tricyclic antidepressants, is extensively metabolized in the liver, mainly by sulfoxidation, hydroxylation, dealkylation, and glucuronidation (Bolvig Hansen & Elley, Br. J. Clin. Pharmacol. 1979;7, 75-80). to a number of metabolites. The pharmacokinetics of perphenazine covary with the hydroxylation of debrisoquine that is mediated by cytochrome P450 2D6 (CYP 2D6) and thus is subject to genetic polymorphism— i.e., 7%-10% of Caucasians and a low percentage of Asians have little or no activity and are called "poor metabolizers." Poor metabolizers of CYP 2D6 will metabolize perphenazine more slowly and will experience higher concentrations compared with normal or "extensive" metabolizers. Thus, perphenazine exhibits a very large inter-subject variability in plasma concentration and extent of exposure after administration of a single dose of the drug in clinical studies (e.g., Bolvig Hansen & Larsen. Psychopharmacology 1977; 53, 127-130; Bolvig Hansen et al. Psychopharmacology 1981 ; 74, 306-309; Dahl-Puustinen et al., Clin. Pharmacol. Ther. 1989; 46, 78-81). The mean plasma concentration - time profiles observed in poor versus extreme metabolizers upon a single dose of 6 mg perphenazine IR tablet in the PK study by Dahl- Puustinen et al., (Clin. Pharmacol. Ther. 1989; 46, 78-81 ) are shown in Figure IB. An optimal therapeutic plasma concentration range of 2-3 nmol/L (0.8-1.21 μg/L) for orally treated patients (Bolvig Hansen et al. Lancet 1977; 2, 584-586) and 2-6 nmol/L for parenterally treated patients (Bolvig Hansen & Larsen Nord. Psykiatr. Tidsskr.1984; 38 (Suppl 7), 15-19).

At higher concentrations there is an increased risk of extrapyramidal side effects. From among a population of approximately 800 subjects who had been phenotyped with respect to debrisoquin hydroxylation 12 healthy volunteers (9 women and 3 men between the ages of 23 and 41 years) considered as either rapid metabolizers or slow metabolizers were recruited for the comparative single dose study (Dahl-Puustinen et al., Clin. Pharmacol. Ther. 1989; 46, 78-81 ; six in each group). It is noteworthy that the slow hydro xylators of debrisoquin had peak serum concentrations that were within or near the suggested therapeutic range after a single dose of 6 mg perphenazine. After long-term treatment with normal doses of the drug, slow metabolizers would have an increased risk of side effects. Thus, in addition to the challenges to be overcome during the development of once-daily dosage forms of weakly basic antipsychotic drags, the additional challenges of perphenazine need to be addressed.

In certain embodiments of the invention, each of the antipsychotic drug-containing particles comprises a core comprising a weakly basic antipsychotic drug and is coated with one or more functional polymer coatings that impart the desired extended release properties. In a particular embodiment, the weakly basic antipsychotic drug-containing core comprises a pharmaceutically acceptable organic acid crystal, a pellet comprising an organic acid, or an organic acid layer disposed over an inert core and coated with one or more functional polymer coatings that impart the desired extended release properties. The first coating disposed over the organic acid core comprises at least one water-insoluble polymer, and the second optional coating disposed over the first SR coating layer comprises an enteric polymer and an optional water-insoluble polymer. The first and second coatings can be applied in any order. Further, the first coating comprising a water insoluble polymer is disposed over the weakly basic antipsychotic drug layer, followed by the second coating comprising an enteric polymer optionally in combination with a water insoluble polymer. Alternatively, the first coating comprises a combination of enteric and water insoluble polymers applied over the antipsychotic drug-containing core particle followed by a second delayed release coating. Other coatings in addition to the first and second coating can also be applied (e.g., seal coatings or other extended release coatings) in any order, i.e., prior to, between, or after either of the first and second coatings. Yet another embodiment of the invention is a pharmaceutical composition comprising:

(a) a population CR particles, wherein each CR particle comprises an acid core comprising a pharmaceutically acceptable organic acid and optionally a polymeric binder;

(b) a first coating that is disposed over the acid core, comprising at least one water-insoluble polymer or water-insoluble polymer in combination with an enteric polymer to produce a SR/TPR coated acid core;

(c) a second coating that is disposed over said SR/TPR acid core, comprising a weakly basic antipsychotic drug or a pharmaceutically acceptable salt, solvate, or ester thereof such as perphenazine and a polymeric binder to produce an antipsychotic drag coated acid core;

(d) a third coating that is disposed over said antipsychotic drug coated acid core comprising a water-insoluble polymer or water-insoluble polymer in combination with an enteric polymer. This embodiment further comprises a second population of IR particles, wherein each IR particle comprises an antipsychotic drug or a pharmaceutically acceptable salt, solvate, or ester thereof.

Yet another embodiment of the invention also provides for taste-masking of a component of the composition in the form of an orally disintegrating tablet.

Another embodiment according to the invention is a pharmaceutical composition comprising:

(a) a population of CR particles, wherein each particle comprises an acid core comprising a pharmaceutically acceptable organic acid and a polymeric binder disposed over an inert core such as a sugar sphere or a cellulosic sphere;

(b) a first coating that is disposed over the acid core, comprising at least one water-insoluble polymer to produce a coated acid core;

(c) a second coating that is disposed over the coated acid core comprising a weakly basic antipsychotic drug or a pharmaceutically acceptable salt, solvate, or ester thereof and a polymeric binder to produce an antipsychotic drug core; and

(d) a third coating that is disposed over the antipsychotic drug core comprising a water insoluble polymer and optionally in combination with an enterosoluble polymer to produce a SR or TPR bead; wherein said organic acid in the acid core solubilizes the weakly basic drug by creating an acidic pH microenvironment inside the coated bead prior to releasing it into the hostile pH environment of the intestinal region where the weakly basic drug is practically insoluble.

Yet another embodiment of the invention is a pharmaceutical composition comprising:

(a) a population CR particles, wherein each CR particle comprises an acid core comprising an organic acid crystal with a desired mean particle size;

(b) a first coating that is disposed over the acid crystal comprising at least one water-insoluble polymer to produce a coated acid core;

(c) a second coating that is disposed over the coated acid core comprising an enteric polymer and optionally in combination with a water-insoluble polymer to produce a multi-coated acid core; (d) a third coating that is disposed over the multi-coated acid core comprising a weakly basic antipsychotic drug or a pharmaceutically acceptable salt, solvate, or ester thereof and a polymeric binder to produce an antipsychotic drug core;

(e) a fourth coating that is disposed over said antipsychotic drug core comprising at least one water-insoluble polymer to produce a coated antipsychotic drug core; and (f) a fifth coating disposed over the coated antipsychotic drug core comprising an enteric polymer and optionally in combination with a water-insoluble polymer to produce a multi-coated antipsychotic drug core.

Yet another embodiment according to the invention is related to a dosage form further comprising:

(g) a plurality of rapidly-dispersing microgranules each having an average particle size of not more than about 400 μπι and (1) a disintegrant and (2) a sugar alcohol and/or a saccharide, wherein said sugar alcohol and/or saccharide each have an average particle size of not more than about 30 μηι; and

(h) a drug core, which comprises an antipsychotic drug and a polymeric binder disposed over an inert core, comprising a taste-masking layer, which comprises a water insoluble polymer or a water insoluble polymer in combination with a gastrosoluble organic, inorganic or polymeric pore-former;

(i) one or more CR particle populations from step e) or f) as described above; wherein said dosage form is an orally disintegrating tablet. Yet another embodiment according to the invention is directed to a method of preparing a CR pharmaceutical composition comprising:

(a) preparing a plurality of taste-masked beads comprising an antipsychotic drug layer disposed over inert cores; (b) preparing a plurality of controlled release beads comprising a weakly basic antipsychotic drug layer disposed over said SR/TPR coated organic acid cores;

(c) preparing a plurality of rapidly-dispersing microgranules comprising a disintegrant and a sugar alcohol and/or a saccharide; and

(d) blending said taste-masked beads of step (a), said controlled release beads of step (b), and rapidly dispersing microgranules of step (c) and other pharmaceutically acceptable excipients such as a flavor, a sweetener, etc.; and

(e) forming said blend of step (d) into orally disintegrating tablets

The aforesaid process wherein the blending is carried out on a rotary tablet press equipped with an external lubricating device to lubricate die and punch surfaces prior to each compression to produce ODTs that rapidly disintegrate into a smooth, easy-to-swallow suspension containing coated beads.

Still another embodiment according to the invention is directed to a method of treating a patient subject to intestinal hypermotility or irritable bowel syndrome, comprising administering a therapeutic effective amount of the composition of the invention to the patient in need thereof.

Still another embodiment according to the invention is directed to a method of treating a patient subject to schizophrenia, or manic or mixed episodes of bipolar I disorder with or without psychotic features, comprising administering a therapeutically effective amount of the composition of the invention to the patient in need thereof.

Still another embodiment according to the invention is directed to pharmaceutical compositions comprising a plurality of CR and IR particles, wherein the CR particles each comprise an inert core coated with a weakly basic drug and a polymeric binder followed by a protective seal coating comprising a hydrophilic water soluble polymer, a first coat disposed over the seal coating comprising a pharmaceutically acceptable alkaline buffer and an optional polymeric binder, a second coating comprising an SR layer followed by a TPR or DR layer (enteric polymer coating); both the CR and the IR particles each comprise the weakly basic typical or atypical antipsychotic drug in combination with pharmaceutically suitable excipients. Still another embodiment according to the invention is directed to the CR particles comprising an inert core (e.g., a sugar sphere, cellulosic sphere etc.) sequentially coated with a pharmaceutically acceptable solid solution comprising the antipsychotic drug (e.g.

perphenazine or a pharmaceutically acceptable salt and/or solvate thereof) and a

pharmaceutically acceptable water soluble, solubility-enhancing/crystallization-inhibiting polymer (e.g., povidone, hydroxypropylcellulose, hypromellose, polyvinyl pyrrolidone-vinyl acetate commercially available as Kollidon VA 64 from BASF) and an optional organic acid; an optional protective seal coating layer (e.g. comprising a water soluble polymer such as hydroxypropyl methylcellulose); and a SR layer comprising a water insoluble polymer such as ethyl cellulose, and an optional TPR layer (e.g., comprising a water insoluble polymer such as ethyl cellulose, an enteric polymer such as hydroxypropylmethyl-cellulose phthalate, and an optional pharmaceutically acceptable plasticizer such as triethyl citrate) or an enteric polymer.

In certain other embodiments, the first coating layer disposed over the organic acid core comprises an enteric polymer in combination with an optional water-insoluble polymer, thereby providing a timed, pulsatile release (TPR) coating.

Still another embodiment according to the invention is directed to where the IR beads/particles release at least about 50% of the weakly basic antipsychotic drug (e.g., perphenazine) within about 30 minutes when dissolution tested in 0.1N HC1, or achieve C_max similar to that of the Reference Listed Drug (RLD) following administration of the dosage form. In particular embodiments, the IR particles are rapid release (RR) particles, and release at least about 80 wt.% of the antipsychotic drug in about 30 minutes when dissolution tested using United States Phannacopoeia (USP) dissolution methodology (Apparatus 2 - paddles@ 50 RPM, 0.1N HC1 at 37°C).

Still another embodiment according to the invention is directed to where the RR particles can have any suitable structure that provides the required rapid release properties. For example, the IR/RR particles can comprise the antipsychotic drug deposited directly on an inert core (e.g., 60-80 mesh sugar sphere, cellulose sphere (e.g., Celphere 102 from Asahi Kesahi or Cellets 100 or Cellets 200 from Glatt Air Technique, or a cellulose-lactose sphere with a smaller average diameter if to be incorporated into an orally disintegrating tablet (ODT); otherwise, more appropriately larger size inert cores may be used) and optionally, with a pharmaceutically acceptable binder. These IR particles can also be taste-masked by solvent coacervation or fluid bed coating with a water insoluble polymer and optionally in combination with a gastrosoluble, organic, inorganic or polymeric pore-forming agent if intended to be incorporated into an ODT in accordance with any of the disclosures of US Patent Application Ser. Nos. 10/827106, 1 1/248596, 1 1/256653, or 1 1/213266, each of which is hereby incorporated by reference for any purpose in its entirety. In other embodiments, the IR/RR particles comprise the antipsychotic drug disposed over an SR or TPR coated organic acid crystal or organic acid-containing core that is prepared by depositing an organic acid- polymeric binder layer onto inert cores.

In certain embodiments of the invention, suitable taste masking layers comprise one or more pharmaceutically acceptable water-insoluble polymers optionally combined with one or more pore forming agents. Non-limiting examples of suitable pharmaceutically acceptable water-insoluble polymers for the taste masking layer include, e.g. ethylcellulose, cellulose acetate, cellulose acetate butyrate, polyvinyl acetate, and methacrylate polymers (e.g., Eudragit RL, RS, and NE30D). Non-limiting examples of suitable pore forming agents include sodium chloride, calcium carbonate, calcium phosphate, calcium saccharide, calcium succinate, calcium tartrate, ferric acetate, ferric hydroxide, ferric phosphate, magnesium carbonate, magnesium citrate, magnesium hydroxide, magnesium phosphate, polyvinyl pyrrolidone, Eudragit El 00, Eudragit EPO, and mixtures thereof. The ratio of water- insoluble polymer to pore former in the taste masking layer ranges from about 95/5 to about 50/50, or in some embodiments about 85/15 to about 65/35. The amount of taste masking layer applied to the IR bead can range from about 5% to about 50% of the total weight of the coated IR bead, in some embodiments about 10% to about 50% of the total weight of the coated IR bead.

Another embodiment according to the invention is directed to an extended release oral dosage form useful for the treatment of schizophrenia or bipolar I disorders is an orally disintegrating tablet (ODT) wherein appropriate amounts of IR/RR particles are compressed with one or more TPR or CR bead populations, wherein the TPR/CR particles comprise inert cores sequentially coated with: an organic acid and a binder (e.g., hydroxypropyl cellulose); a sustained release (SR) layer comprising a water-insoluble polymer (e.g., ethyl cellulose) and/or a timed, pulsatile release layer comprising a water-insoluble polymer in combination with an enteric polymer (e.g., hypromellose phthalate, HP-55) and an optional plasticizer (e.g., optionally triethyl citrate); a drug layer comprising an antipsychotic drug and a binder (e.g., povidone); an optional sealing layer (e.g. hydroxypropyl methylcellulose); and a SR layer (ethyl cellulose and an optional plasticizer (e.g., triethyl citrate) and optionally, a delayed release layer (e.g., an enteric polymer coating) or a TPR layer comprising ethyl cellulose, hydroxypropylmethyl cellulose phthalate, and an optional plasticizer (e.g., optionally triethyl citrate); and the IR/RR particles comprise an antipsychotic drug and a binder disposed over inert cores or SR-coated or a seal-coated organic acid (e.g., fumaric acid) cores.

In various embodiments, the second coating or outer layer disposed over the SR coated antipsychotic drug core comprises an enteric polymer in combination with an optional water-insoluble polymer, thereby providing a timed, pulsatile release (TPR) coating. In still other embodiments, the second coating comprises an enteric polymer disposed on the antipsychotic drug-containing particle, thereby providing a delayed release (DR) coating.

In particular embodiments of the invention, the coating disposed over the

antipsychotic drug core comprises, in addition to at least one water-insoluble polymer, a water soluble polymer. Suitable water soluble polymers include, but are not limited to methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, polyvinylpyrrolidone or mixtures thereof.

Yet another embodiment according to the invention is directed to the antipsychotic drug-containing cores in the form of antipsychotic drug-layered beads, pellets (e.g., extruded and spheronized compositions containing at least one antipsychotic drug), antipsychotic drug- containing granules, or even antipsychotic drug crystals. Potentially different coating configurations resulting in different release profiles for the antipsychotic drug and organic acid under in vitro dissolution test conditions are shown in detail in FIG. 2 to 4.

Yet another embodiment according to the invention is directed to the antipsychotic drug-containing core as a drug-layered bead, which refers to an inert bead (e.g. a sugar sphere) coated with a drug layer, e.g., an antipsychotic drug layer. In other embodiments according to the invention, an inert bead can comprise microcrystalline cellulose, mannitol- microcrystalline cellulose, or silicon dioxide. The inert beads typically have particle sizes of about 20-170 mesh, for example about 20-25 mesh, about 25-30 mesh, about 45-60 mesh, or about 60-80 mesh or larger (i.e., smaller than about 250 μηι in size).

In certain embodiments of the invention, the antipsychotic drug is coated on to an acid core comprising a pharmaceutically acceptable organic acid. This acid core can be, but is not limited to, a pharmaceutically acceptable organic acid crystal with a desired average particle size, a pellet comprising an organic acid, a polymeric binder, and optionally a filler, or an organic acid plus a polymeric binder layered onto an inert core

A non-limiting list of pharmaceutically acceptable organic acids is selected from the group consisting of citric acid, lactic acid, fumaric acid, malic acid, maleic acid, tartaric acid, succinic acid, oxalic acid, aspartic acid, and glutamic acid; more particularly the

pharmaceutically acceptable organic acid is fumaric acid.

A core thus coated with a drug layer, and lacking extended release coatings has immediate release properties, and can be referred to as an "IR bead or a rapid release bead". The drug can be deposited on core by any suitable method Icnown in the art. For example, the drug can be deposited from solution directly onto the inert core or a coated organic acid core or crystal without using a binder. In various other embodiments according to the invention, the drug layer contains a binder (typically a pharmaceutically acceptable water-soluble polymer) that facilitates the binding of the antipsychotic drug to the inert sugar sphere or cellulose sphere.

Examples of suitable polymeric binders include, but are not limited to,

polyvinylpyrrolidone (PVP), polyethylene oxide, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), and polysaccharides. The binder can be present in an amount ranging from about 0.5 to about 10 weight % based on the total weight of the drug layer. In a particular embodiment, the drug layer is deposited by spraying a drug and optionally binder containing solution onto the inert cores, e.g., using a fluidized bed coating apparatus. The drug layering solution comprises a pharmaceutically acceptable solvent in that the antipsychotic drug and optional binder are dissolved. In some embodiments according to the invention, the antipsychotic drug may be present in the form of a suspension. Depending on the viscosity, the solids content of the drug-layering solution may be up to about 35 weight %, for example about 10%, about 15%, about 20%, about 25%, about 30%, etc. Pharmaceutically acceptable solvents include water, alcohols (such as ethanol), acetone, etc. Alternatively, the antipsychotic drug-containing core can be a granulate comprising the antipsychotic drug in combination with one or more pharmaceutically acceptable excipients (e.g., lactose, mannitol, microcrystalline cellulose, etc.). Such granulates can be prepared by conventional granulation methods, and may optionally include suitable binders as described herein. In the case of solid solutions, the antipsychotic drug, the crystallization-inhibiting polymer, and an organic acid (if used) are dissolved in sufficient quantities in a common solvent mixture to form the drug in the amorphous form in the solid solution layer.

The antipsychotic drug-containing core of the invention has an average particle size of not more than 2 mm in some embodiments if to be filled into a hard gelatin capsule, or not more than about 400 μιη in other embodiments, not more than about 300 μιη in some other embodiments, if intended to be incorporated into an ODT.

In one embodiment, the first coating comprising the water-insoluble polymer is coated onto the antipsychotic drug-containing core (wherein the core is optionally coated with a sealant layer), thereby providing a sustained release (SR) coating.

Non-limiting examples of suitable water-insoluble polymers include ethylcellulose, cellulose acetate, cellulose acetate butyrate, polyvinyl acetate, neutral copolymers of acrylate/methacrylate esters (e.g., Eudragit NE, which is a copolymer of ethyl acrylate and methyl methacrylate, as well as Eudragit RL or RS ), waxes, and mixtures thereof. In a particular embodiment according to the invention, the water-insoluble polymer comprises ethylcellulose. In another particular embodiment according to the invention, the water- insoluble polymer comprises ethylcellulose with a mean viscosity of 10 cps in a 5% solution in 80/20 toluene/ alcohol measured at 25°C on an Ubbelohde viscometer.

In some embodiments, suitable coating weights for the first SR coating disposed over the organic acid core, the antipsychotic drug layer, or an alkaline buffer layer comprising a water-insoluble polymer range from about 3% to about 40%, including about 3%, about 5%, about 7%, about 10%, about 12%, about 15%, about 17%, about 20%, about 22%, about 25%, about 27%, about 30%, about 35%, and about 40%, inclusive of all ranges and subranges there between.

In some embodiments, the water-insoluble polymer provides suitable properties (e.g., extended release characteristics, mechanical properties, and coating properties) without the need for a plasticizer. For example, coatings comprising polyvinyl acetate (PVA), neutral copolymers of acrylate/methacrylate esters, ethylcellulose, waxes, etc. can be applied without plasticizers. In yet another embodiment, the water-insoluble polymer may include a plasticizer. The amount of plasticizer required depends upon the plasticizer, the properties of the water- insoluble polymer, and the ultimate desired properties of the coating. Suitable levels of plasticizer range from about 1 % to about 20%, from about 3% to about 20%, about 3% to about 5%, about 7% to about 10%, about 12% to about 15%, about 17% to about 20%, or about 1%), about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%), about 15%, or about 20% by weight relative to the total weight of the coating, inclusive of all ranges and subranges there between.

Non-limiting examples of suitable plasticizers include triacetin, glycerol and esters thereof (e.g., substituted triglycerides and glycerides, monoacetylated glycerides, acetylated mono- or diglycerides (e.g., Myvacet® 9-45)), glyceryl monostearate, glyceryl triacetate, glyceryl tributyrate, phthalates (e.g., dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dioctyl phthalate), citrates (e.g., acetylcitric acid tributyl ester, acetylcitric acid triethyl ester, tributyl citrate, acetyltributyl citrate, triethyl citrate), glyceroltributyrate; sebacates (e.g., diethyl sebacate, dibutyl sebacate), adipates, azelates, benzoates, chlorobutanol, polysorbate 80, polyethylene glycols, propylene glycol, vegetable oils (e.g., castor oil, hydrogenated castor oil, rape seed oil, sesame oil, olive oil, etc.), glycerin sorbitol, fumarates, (e.g., diethyl fumarate), malates, (e.g., diethyl malate), oxalates (e.g., diethyl oxalate), succinates (e.g., dibutyl succinate), butyrates, cetyl alcohol esters, malonates (e.g., diethyl malonate), fatty acids, and mixtures thereof; more particularly triacetin, citrate esters, triethyl citrate, acetyltriethyl citrate, tributyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, dibutyl phthalate, dioctyl phthalate, methyl paraben, propyl paraben, propyl paraben, butyl paraben, dibutyl sebacate, substituted triglycerides and glycerides, monoacetylated and diacetylated glycerides (e.g., Myvacet® 9-45), glyceryl monostearate, glyceryl tributyrate, polysorbate 80, polyethylene glycol, propylene glycol, oils (e.g. castor oil, hydrogenated castor oil, rape seed oil, sesame oil, olive oil, etc.), glycerin sorbitol, diethyl oxalate, diethyl malate, diethyl fumarate, diethylmalonate, dibutyl succinate, fatty acids, and mixtures thereof.

In another embodiment, the plasticizer(s) used in the coatings on the organic acid- containing, solid solution-containing, and/or drug-containing particles are free of phthalates. In another embodiment, the first coating comprising a water- insoluble polymer and optionally a water-soluble polymer comprises a plasticizer that is free of phthalates. In another embodiment, the second coating comprising an enteric polymer and optionally a water- insoluble polymer comprises a plasticizer that is free of phthalates. In another embodiment, the first and second coatings each comprise a plasticizer that is free of phthalates. In another embodiment, all of the coatings disposed over the drug core are free of phthalates.

In certain embodiments of the invention, the plasticizer may constitute from about 3% to about 30% by weight of the polymer(s) in the controlled-release coating. In still other embodiments, the amount of plasticizer relative to the weight of the polymer(s) in the controlled-release coating is about 3%, about 5%, about 7%, about 10%, about 12%, about 15%, about 17%, about 20%, about 22%, about 25%, about 27%, and about 30%, inclusive of all ranges and subranges there between. The presence of plasticizer, or type(s) and amount(s) of plasticizer(s) can be selected based on the polymer or polymers and nature of the coating system (e.g., aqueous or solvent-based, solution or dispersion-based and the total solids).

Similar to the SR coating, in certain embodiments of the invention, DR and TPR coatings can also include one or more optional plasticizers (e.g. any of the plasticizers described herein). The amount of plasticizer required depends upon the plasticizer, the properties of the water-insoluble and/or enteric polymer(s), and the ultimate desired properties of the coating. Suitable levels of plasticizer may range from about 1 % to about 20%, from about 3% to about 20%, about 3% to about 5%, about 7% to about 10%, about 12% to about 15%, about 17% to about 20%, or about 1 %, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, or about 20% by weight relative to the total weigh of the coating, inclusive of all ranges and subranges therebetween.

Non-limiting examples of suitable enteric polymers include cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, pH-sensitive methacrylic acid/methylmethacrylate copolymers (e.g., Eudragit^® L, S and FS polymers), shellac, and mixtures thereof. In certain embodiments, non-polymeric enteric materials such as non-polymeric waxes and fatty acid compositions may be used instead of enteric polymers, provided they have the pH sensitive solubility associate with enteric polymers. These enteric polymers may be used as a solution in a solvent mixture or an aqueous dispersion. Some commercially available materials that may be used are methacrylic acid copolymers sold under the trademark Eudragit (LI 00,

SI 00, L30D) manufactured by Rohm Phanna, Cellacefate (cellulose acetate phthalate) from Eastman Chemical Co., Aquateric® (cellulose acetate phthalate aqueous dispersion) from FMC Corp., and Aqoat (hydroxypropyl methylcelluiose acetate succinate aqueous dispersion) from Shin Etsu® K.K.

In one embodiment, the hydrophilic/water-soluble, solubility-enhancing/

crystallization-inhibiting polymer is vinylpyrrolidone-vinylacetate copolymer (e.g.,

Kollidon^® VA 64 from BASF) at a ratio of weakly basic antipsychotic drug to Kollidon^® VA 64 of 1 :2. Non-limiting examples of suitable hydrophilic polymers include water-soluble hydroxypropylcellulose (e.g., Klucel^® LF), hydroxypropyl methylcelluiose or hypromellose (e.g., Opadry^® Clear or Pharmacoat™ 603), polyvinylpyrrolidone (Povidone),

methylcelluiose, and vinylpyrrolidone-vinylacetate copolymer. The crystallization-inhibiting polymer and the weakly basic antipsychotic drug at a ratio of 4: 1 to 1 :2 are dissolved in a pharmaceutically acceptable solvent mixtures. The amorphous nature of the antipsychotic drug in the composition is confirmed by powder X-ray diffraction studies.

When the first coating disposed over the organic acid core or second or outer coating disposed over the antipsychotic drug comprises a water- insoluble polymer in combination with the enteric polymer (e.g., a TPR coating), the ratio of the water-insoluble polymer to enteric polymer ranges from about 10: 1 to about 1 : 1, including the ranges of from about 9: 1 to about 3: 1 , and from about 3: 1 to about 1 : 1. In particular embodiments, the ratio of water- insoluble polymer to enteric polymer is about 1 : 1 , about 1.5: 1 , about 2: 1 , about 2.5: 1 , about 3: 1 , about 3.5: 1 , about 4: 1, about 4.5: 1 , about 5: 1 , about 5.5: 1 , about 6: 1 , about 6.5: 1 , about 7: 1 , about 7.5: 1 , about 8: 1 , about 8.5: 1 , about 9: 1 , about 9.5: 1 , or about 10: 1 , inclusive of all values, ranges, and subranges there between.

In certain embodiments of the invention, when compositions comprise a TPR coating, the TPR coating is applied at a coating weight of about 5% to about 60% by weight, including the ranges of from about 10% to about 50%, from about 20% to about 40%, and from about 25% to about 35%, or at a coating weight of about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 12%, about 14%, about 16%, about 18%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%, inclusive of all ranges and subranges there between. In a particular embodiment, the TPR coating comprises ethylcellulose (e.g., EC-10) as the water-insoluble polymer and hypromellose phthalate (e.g., HP-55) as the enteric polymer. As described herein, in various embodiments the controlled release compositions of the invention comprise a plurality of antipsychotic drug-containing particles, coated with a first coating of an SR layer (comprising a water-insoluble polymer, or a combination of a water-insoluble polymer and a water-soluble polymer) and a second coating of a DR or a TPR coating layer (comprising an enteric polymer or a combination of enteric and water- insoluble polymers).

In yet another embodiment of the invention, the extended release compositions may further comprise a sealant layer disposed on the antipsychotic drug-containing particle, e.g. between the first and second coatings, beneath the first and second coatings, and/or over both of the first and second coatings to prevent (or minimize) static and/or particle attrition during processing and handling.

In one embodiment, the sealant layer comprises a hydrophilic polymer. Non-limiting examples of suitable hydrophilic polymers include hydrophilic hydroxypropylcellulose (e.g., Klucel^® LF), hydroxypropyl methylcellulose or hypromellose (e.g., Opadry^® Clear or Pharmacoat™ 603), vinylpyrrolidone-vinylacetate copolymer (e.g., Kollidon^® VA 64 from BASF), and ethylcellulose, e.g. low- viscosity ethylcellulose. The sealant layer can be applied at a coating weight of about 1 % to about 10%, for example about 1 %, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%, inclusive of all ranges and subranges there between. In another embodiment of the invention, the compositions further comprise a compressible coating disposed over the controlled-release coating (i.e., disposed on the outermost functional coating). The compressible coating comprises a polymer, including but not limited to hydroxypropylcellulose, poly( vinyl acetate-vinyl pyrrolidone), polyvinyl acetate, ethylcellulose (e.g., plasticized low-viscosity ethylcellulose latex dispersions), etc. The compressible coating can be plasticized or unplasticized, and promotes the integrity of the controlled-release coating during compression. In one embodiment, the compressible coating comprises a plasticizer that is free of phthalates.

In another embodiment of the invention, controlled release compositions can further comprise rapidly disintegrating granules comprising a saccharide and/or a sugar alcohol in combination with a disintegrant. Suitable disintegrants include, but are not limited to for example, disintegrants selected from the group consisting of crospovidone, sodium starch glycolate, starch, crosslinked sodium carboxymethylcellulose, low-substituted hydroxypropylcellulose, gums (e.g., gellan gum) and combinations thereof. Suitable saccharides and/or sugar alcohols may be selected from the group consisting of arabitol, erythritol, glycerol, hydrogenated starch hydrolysate, isomalt, lactitol, lactose, maltitol, mannitol, sorbitol, xylitol, sucrose, maltose, and combinations thereof. The saccharide and/or sugar alcohol may also be supplemented or replaced with artificial sweeteners such as, but not limited to sucralose. In certain embodiments, the ratio of the disintegrant to the saccharide and/or sugar alcohol in the rapidly dispersing microgranules ranges from about 1 :99 to about 10:90, from about 5:95 to about 10:90 on a weight basis and inclusive of all ranges and subranges there between. In particular embodiments, the disintegrant or the saccharide and/or sugar alcohol, or both, are present in the form of particles having an average particle size of about 30 μπι or less in accordance with the specifications co-pending US Patent Application Ser. No. 10/827,106 (published as US 2005/0232988 Al) and No. 12/166,757 (published as US 2009/0092672 Al ). Each of these applications set forth herein are incorporated by reference in their entireties for all purposes. The ratio of the antipsychotic drug-containing beads to the rapidly disintegrating granules can range from about 1 :6 to about 1 :2, from about 1 :5 to about 1 :3, or about 1 :6, about 1 :5, about 1 :4, about 1 :3, or about 1 :2, inclusive of all ranges and subranges there between.

Without being bound by any particular mechanism, it is believed that the multiple controlled-release coatings of the compositions of the invention contribute to the control of dissolution at the drug interface and hence control the release of the antipsychotic drug (e.g. perphenazine or salts, and/or solvates thereof) from the particles of the controlled release compositions of the invention. The lag time, delayed release time, or sustained-release properties depend on the composition and thickness of the controlled-release coatings.

Specific factors that can affect achieving optimal once-daily dosage forms include, but are not limited to, the pKa of the antipsychotic drug and its solubility, e.g. in GI fluids.

The in vitro drug release data obtained from particles coated with the multiple controlled release coatings described herein provide release profiles for antipsychotic drugs which provide pharmacokinetic profiles suitable for a once- or twice-daily dosing regimens. In one embodiment, the sustained-release coating provides release of an antipsychotic drug that is sustained over about 12 to about 16 hours when tested in the two-stage dissolution method (700 mL of 0.1 N HC1 (hydrochloric acid) for the first 2 hours and thereafter in 900 mL at pH 6.8 obtained by adding 200 mL of a pH modifier), suitable for a once- or twice- daily dosing regimen.

The controlled release compositions of the invention can be formulated with optional pharmaceutically acceptable excipients (binders, a disintegrants, fillers, diluents, compression aids (e.g., macrocrystalline cellulose/fused silicon dioxide), lubricants, etc.) into any suitable oral dosage form, for example sachets, tablets, capsules, or orally disintegrating tablets (ODTs). In one embodiment, the dosage form is a tablet, for example a tablet with a friability of less than about 1 %. In another embodiment, the dosage form is a capsule filled with at least one population of particles comprising the controlled release composition of the invention. The capsule can be for example, a gelatin capsule, or an HPMC

(hydroxypropylmethylcellulose) capsule.

In other embodiments, the dosage form is an ODT. ODTs of the invention disintegrate in the oral cavity, and are easily swallowed without water. For example, an ODT of the invention substantially disintegrates within about 60 seconds after contact with saliva in the oral cavity or with simulated saliva fluid. In another embodiment, the ODT substantially disintegrates within about 30 seconds. Disintegration is tested according to the USP <701 > Disintegration Test (herein incorporated by reference in its entirety for all purposes). In most embodiments, the ODT substantially disintegrates in the oral cavity of a patient, forming a smooth, easy-to-swallow suspension having no gritty mouthfeel or aftertaste, and provides a target PK profile (e.g., plasma concentration vs. time plot) of the antipsychotic drug (e.g., perphenazine) suitable for a once- or twice-daily dosing regimen. For example, the ODT provides prolonged release of the antipsychotic drug over a period of about 8-18 hrs. ODT formulations of the invention are especially useful for treating geriatric patients (who often have difficulty swallowing conventional tablets and capsules) or for treating mentally ill patients (who often resist or "cheek" their medications). The

administration of ODTs to geriatric and/or mentally ill patients will reduce the frequency of dosing and ease patient non-compliance issues.

In a particular embodiment, the ODT of the invention comprises a therapeutically effective amount of perphenazine or salts and/or solvates thereof. After administration, the ODT substantially disintegrates in the oral cavity of a patient, forming a smooth, easy-to- swallow suspension having no gritty mouthfeel or aftertaste, and provides a target PK profile (i.e., plasma concentration vs. time plot) of perphenazine suitable for a once- or twice-daily dosing regimen. In addition to the controlled release composition of the invention and rapidly disintegrating granules, the ODT of the invention optionally includes

pharmaceutically acceptable excipients such as compressible diluents, fillers, coloring drugs, and optionally a lubricant. In some embodiments, the ODT weighs not more than about 2000 mg; for example, about 2000 mg or less; about 1500 mg or less; about 1000 mg or less; about 500 mg or less. In another embodiment, the ODT weighs not more than about 1600 mg. In another embodiment, the ODT weighs not more than about 800 mg. In another embodiment, the ODT weights not more than about 500 mg. The dosage forms of the invention can comprise two or more populations of antipsychotic drug-containing particles, including at least one population of controlled release particles as described herein. For example, the dosage form can comprise a population of controlled release particles as described herein, and in addition, immediate release (IR) particles, for example uncoated cores comprising an antipsychotic drug. In one embodiment, the dosage form comprising two or more populations of antipsychotic drug-containing particles is an ODT. When the dosage form is ODT, the two or more populations of antipsychotic drug-containing particles are combined with rapidly disintegrating microgranules, and the antipsychotic drug-containing particles and rapidly disintegrating microgranules have a particle size that provides a smooth, non-gritty mouth feel after disintegration of the ODT in the oral cavity. In one embodiment, an ODT of the invention comprises either of SR, DR or CR particle populations; in another embodiment, the ODT comprises a combination of IR particles and SR particles; in yet another embodiment, the ODT comprises SR particles in combination with enteric coated TPR particles, and optionally in combination with (optionally taste-masked) IR particles (in addition to rapidly disintegrating microgranules). In yet another embodiment, an ODT of the invention comprises: enteric coated SR beads with or without a compressible coating in combination with rapidly dispersing granules (e.g., mannitol-crospovidone microgranules).

In a particular embodiment of the invention, the ODT includes IR particles, which may be coated with a taste-masking coating that allows immediate release of the

antipsychotic drug but prevents release in the oral cavity, and thus any off-taste from the antipsychotic drug. In certain embodiments of the invention, a taste-masked IR particle releases not more than about 10% of the total amount of antipsychotic drug contained in the IR particle in about 3 minutes (the longest typical residence time anticipated for the ODT in the buccal cavity) when dissolution tested in simulated saliva fluid (pH ~ 6.8), while releasing not less than about 75% of the total amount antipsychotic drug in the IR particles in about 60 minutes when dissolution tested in 0.1N HC1.

In various embodiments of the invention, when the dosage form comprises IR particles in addition to the controlled release particles, the ratio of IR particles to total of CR particles (e.g., a SR particle population with an enteric or TPR coating) ranges from about 0: 100 (i.e., no IR particles) to about 50:50, for example from about 10:90 to about 20:80, from about 30:70 to about 40:60, or about 5:95, about 10:90, about 15:85, about 20:80, about 25:75, about 30:70, about 35:65, about 40:60, about 45:55, or about 50:50, inclusive of all ranges and subranges therebetween.

In a particular embodiment of the dosage forms of the invention, the dosage forms comprise perphenazine or salts, and/or solvates.

In other embodiments of the invention, the plurality of beads in a dosage form can yield different desired antipsychotic drug (e.g., perphenazine) release profiles. In one embodiment, for example, a once-daily dosage form comprising antipsychotic drug with an elimination half-life of from about 2 hours to 14 hours may contain a mixture of a population of taste masked IR particles (which provides an immediate-release pulse of the antipsychotic drug) and one or more CR particle populations, exhibits the target release profile over about 8-18 hours, and maintains clinically effective plasma concentrations of the antipsychotic drug at about 12-24 hours.

The step of preparing the core may be accomplished by any of the methods known in the art; for example, layering an organic acid onto an inert bead (e.g., sugar, microcrystalline cellulose, mannitol-microcrystalline cellulose, silicon dioxide, etc.) with a solution comprising the acid and optionally a polymeric binder (e.g., by fluid-bed or pan coating), or by controlled spheronization or powder layering, using, for example, Granurex from Vector Corporation, etc.) Alternatively, "preparing a core" can comprise obtaining or preparing organic acid particles or crystals of the desired particle size (e.g., about 100-500 μηι, including about 150-250 μπι).

In some embodiments, the method comprises preparing core particles comprising the antipsychotic drug (as described herein), then coating the core particles with an SR coating (as described herein), followed by a TPR coating (as described herein) or a DR coating (as described herein). In other embodiments, the method comprises preparing core particles comprising the antipsychotic drug, and then coating the core particles with a TPR coating, followed by a DR coating. Each of these embodiments, optional sealant layers can be applied under, over, and/or between the controlled-release layers.

In yet another embodiment, the method of the invention further comprises filling appropriate amounts of IR beads and one or more CR bead populations into hard gelatin capsules containing therapeutically effective amounts of the antipsychotic drug for oral administration in patients in need of medication thereof. Alternatively, appropriate amounts of taste -masked IR and CR bead populations and rapidly dispersing microgranules, are blended in a V blender and compressed into ODTs using a rotary tablet press equipped with an external lubrication device to lubricate die and punch surfaces prior to each compression.

In another embodiment, the method further comprises coating a compressible layer comprising a hydrophilic polymer (e.g., hydroxypropylcellulose), over the controlled-release layers to eliminate/minimize damage to the extended-release coating(s) of the CR particles during compression into an ODT.

In yet another embodiment, the method of the invention further comprises blending the controlled-release composition described herein with optional excipients (e.g., additional disintegrant, compression aid such as microcrystalline cellulose, a sweetener, a flavorant, a colorant), and compressing the blended composition into a tablet.

In a particular embodiment, the method of the invention comprises the steps of: a) preparing organic acid cores (crystals, microgranules, acid layered beads, or pellets by controlled spheronization using Granurex from Vector Corporation or the like with an desired average particle size (e.g., about 100-400 μηι or about 150-300 μηι for use in ODTs or about 300-600 μιη or about 350-500 μιη for use in CR capsules); b) applying a sustained-release (SR) coating comprising a water-insoluble polymer or timed pulsatile release (TPR) coating comprising a water-insoluble polymer in combination with an enteric polymer at a weight ratio of from about 10: 1 to 1 :4, onto the acid cores at a coating weight of from about 10% to 30%, thereby forming SR or TPR acid beads comprising an organic acid; c) optionally applying a TPR coating comprising a water-insoluble polymer in combination with an enteric polymer at a weight ratio of from about 10: 1 to 1 :4 onto the SR acid beads from step (b) at a coating weight of from about 10% to 30%, thereby forming controlled-release (CR) acid beads; d) preparing immediate release (IR) beads comprising applying an antipsychotic drug or its salt, and/or solvate onto the SR or TPR acid beads from step (b) or CR acid beads from step (c), forming drug-layered beads that are optionally provided with a protective seal- coat; e) applying a sustained-release (SR) coating comprising a water-insoluble polymer or TPR coating comprising a water-insoluble polymer in combination with an enteric polymer onto the IR beads at a coating weight of from about 5% to 30%, thereby forming SR or TPR beads comprising the antipsychotic drug; f) optionally applying a delayed-release (DR) coating comprising an enteric polymer onto the SR or TPR beads at a coating weight of from about 10% to 30%, thereby forming CR beads; or g) applying a lag-time (TPR) coating onto perphenazine SR beads comprising the combination of a water-insoluble polymer and an enteric polymer at a weight ratio of from about 10: 1 to 1 :4 onto SR beads, at a coating weight of from about 10% to 60%, thereby forming CR beads; h) filling required amounts of the SR or TPR beads from step (e) and/or CR beads from step (f) and/or (g) into hard gelatin capsules to produce CR capsules containing a therapeutically effective dose of the antipsychotic drug.

In yet another embodiment, the invention is directed to a method of preparing a controlled release composition further comprising the steps of: i) preparing a plurality of rapidly-dispersing microgranules comprising a disintegrant and a sugar alcohol and/or a saccharide in accordance with the disclosures in the co-pending US Patent Application Ser. No. 10/827,106 (published as US 2005/0232988 Al) and 12/166,757 (published as US 2009/0092672 Al); and blending required amounts of the SR or TPR beads from step (e) and/or CR beads from step (f) and or (g) and rapidly-dispersing microgranules from step (i) and compressing the blend into orally disintegrating tablets on a rotary tablet press equipped with an external lubricating devise to lubricate the die and punch surfaces prior to each compression to produce ODTs that rapidly disintegrate into a smooth, easy-to-swallow suspension containing coated beads.

In certain other embodiment, the invention is directed to a method of preparing a controlled release composition comprising the steps of: a) preparing a plurality of IR beads comprising an antipsychotic drug and a polymeric binder layer disposed over inert cores and optionally providing a protective seal coat disposed thereof; b) applying a sustained-release (SR) coating comprising a water-insoluble polymer or TPR coating comprising a water-insoluble polymer in combination with an enteric polymer onto the IR beads at a coating weight of from about 5% to 30%, thereby forming SR or TPR beads comprising the antipsychotic drug; c) optionally applying a delayed-release (DR) coating comprising an enteric polymer onto the SR or TPR beads at a coating weight of from about 5% to 30%, thereby forming controlled-release (CR) beads; d) filling required amounts of the SR or TPR beads from step (b) and/or CR beads from step (c) into hard gelatin capsules to produce CR capsules containing a therapeutically effective dose of the antipsychotic drug.

In yet certain other embodiment, the invention is directed to a method of preparing a controlled release composition comprising the steps of: a) preparing a plurality of IR beads comprising a solid solution layer disposed over inert cores comprising an antipsychotic drug, a crystallization-inhibiting polymer at a desired ratio, and an organic acid (if present) in accordance with the procedures disclosed in the co-pending US Patent Application Ser. No. 1 1/847,219 (published as US 2008/0069878 Al) and optionally providing a protective seal coat disposed thereof, thereby forming IR beads comprising a weakly basic antipsychotic drug; b) applying a sustained-release (SR) coating comprising a water-insoluble polymer optionally in combination with a water-soluble polymer or a TPR coating comprising a water-insoluble polymer in combination with an enteric disposed over the IR beads at a coating weight of from about 5% to 30%, thereby forming SR or TPR beads comprising drug; c) optionally applying a delayed-release (DR) coating comprising an enteric polymer onto the SR or TPR beads at a coating weight of from about 5% to 30%, thereby forming controlled-release (CR) beads ; d) filling required amounts of the SR or TPR beads from step (b) and/or CR beads from step (c) into hard gelatin capsules to produce CR capsules containing a therapeutically effective dose of the antipsychotic drug.

In certain other embodiment, the invention is directed to a method of preparing a controlled release composition further comprising the steps of: e) preparing a plurality of IR beads comprising an antipsychotic drug layer disposed over inert cores and optionally providing a protective seal coat disposed thereof; f) taste-masking said IR beads in accordance with the procedures disclosed in the co-pending US Patent Application Ser. No. 10/827,106 (published as US 2005/0232988 Al), 1 1/248,596 (published as US 2006/0078614 Al), 1 1/213,266 (Published as US

2006/0105038 Al), and 1 1/256,653 (Published as US 2006/0105039 Al); g) further filling the plurality of the IR beads from step (e) into hard gelatin capsules of step (d) to produce CR Capsules containing a therapeutically effective dose of the antipsychotic drug as IR and one or more CR bead populations; or h) preparing a plurality of rapidly-dispersing microgranules comprising a disintegrant and a sugar alcohol and/or a saccharide in accordance with the disclosures in the co-pending US Patent Application Ser. No. 10/827,106 (published as US 2005/0232988 Al) and 12/166,757 (published as US 2009/0092672 Al); i) blending required amounts of the SR or TPR beads from step (b) and/or CR beads from step (c), taste-masked beads of step (f), rapidly-dispersing microgranules from step (h), and other pharmaceutically acceptable excipients such as a flavor, a sweetener, etc.; and j) forming said blend into orally disintegrating tablets on a rotary tablet press equipped with an external lubricating devise to lubricate die and punch surfaces prior to each compression to produce ODTs that rapidly disintegrate into a smooth, easy-to-swallow suspension containing coated beads.

Suggested dosages for tablets for various conditions follow:

- Moderately disturbed nonhospitalized patients with schizophrenia: 4 to 8 mg tablets tid initially; reduce as soon as possible to minimum effective dosage.

- Hospitalized patients with schizophrenia: 8 to 16 mg tablets bid to qid; avoid dosages in excess of 64 mg daily.

- Severe nausea and vomiting in adults: 8 to 16 mg tablets daily in divided doses; 24 mg occasionally may be necessary; early dosage reduction is desirable.

Examples

The invention is described in greater detail in the sections below. The following examples involving perphenazine are used to illustrate the invention. It should be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application.

Example 1

Pharmacokinetic modeling was constructed by fitting the plasma concentration - time data for perphenazine immediate release (IR) tablets available from Dahl-Puustinen et al. (Clin. Pharmacol. Ther. 1989; 46, 78-81) using a PK/PD simulation software, WinNonlin^® from Pharsighf^® Corporation (Mountain View, CA) and/or GastroPlus™ from

Simulationsplus, Inc., so that the predicted plasma concentration - time profiles closely match the actual plasma concentration - time profiles reported by Dahl-Puustinen et al. Both one-compartmental and two-compartmental open models fitted well with the data using WinNonlin. The AIC (Akaike Information Criterion) and Schwarz Criterion that provide an indication of 'goodness of fit' are given by: AIC = n x log(objective value) + 2p

SC = n x log(objective value) + p x log(n)

Wherein n is the number of fitted data points, log (objective value) is the natural logarithm of the objective function value, and p is the number of optimized parameters (Akaike H. Institute of Statistical Mathematics 1969; 21 : 243-7; as reported in GastroPlus™ User Manual (see pp 316, Akaike Information Criterion and Schwarz Criterion)). The calculated values are listed in Table 1 below. Both one-compartmental and two- compartmental open models fitted well the data using WinNonlin.

Table 3. AIC and SC values for one-compartmental and two-compartmental analysis

The one compartmental model fits the plasma concentration - time data observed in the poor metabolizers while the two-compartmental model fits the plasma concentration - time data observed in the extreme metabolizers.

PK parameters for perphenazine in poor metabolizers

PK parameters for perphenazine in extreme metabolizers

parameters (hr ¹) (hr ¹) (hr ¹) (hr ¹) (hr ¹) (hr ¹) (L) (L/hr) (hr)

1.1976 0.1457 0.07931 0.15400 0.3055 0.0734 15347 2235.5 9.4

To maintain the plasma concentration within the therapeutic window, an ideal plasma concentration profile from a CR formulation should be above 1 nmol/L (0.4 μg/L) at 18 hours and the C_max should be below 3 nmol/L (1.21 μg/L). Varying the parameters estimated earlier, the desired once-a-day plasma concentration - time profiles were simulated. The simulations performed by varying the PK parameters established earlier suggest that the plasma concentration profiles were well maintained up to about 16 hrs post dosing, and drops off dramatically thereafter. However, for a drug that distributes extensively to perripheral compartments, which has a high volume of distribution, the distribution process is likely to decrease when the plasma level reaches the steady state since the peripheral compartments are saturated. FIG. 5 shows the simulated extended plasma concentration profiles that were simulated at a K of 0.4 versus IR dose x TID over a 24 hr period at steady state. The desired target in vitro profiles estimated for extreme and poor metabolizers are shown in FIG. 6.

Example 2

2.A Perphenazine IR Beads: A binder polymer (30.3 g) such as

hydroxypropylcellulose (Klucel LF) was slowly added to ethanol (USP 190 proof; 606.4 g) while stirring with a low shear mixer to prepare a clear solution. Water (USP 404.3 g) was slowly blended in, and then the weakly basic drug (30.3 g of perphenazine) was slowly added to the binder solution while mixing to dissolve. A Glatt GPCG 3 equipped with a 7" bottom spray Wurster insert x 22 mm partition height, 14 mm tubing, 100 mesh screen, 1.0 mm nozzle tip, was charged with 25-30 mesh sugar spheres (1586.1 g), which were then fluidized and sprayed with the binder/drug solution at the following processing conditions: inlet air temperature: 42°C; product temp. 30-32°C; air volume: 10-12 cfm; flow rate: 6 mL/min - 10 mL/min. Following completion of drug layering, the IR beads were then dried to drive off residual solvents (including moisture), and sieved to discard oversized particles and fines. Using an identical procedure, IR beads were produced starting with 60-80 mesh sugar spheres.

2.B Perphenazine SR Beads: The IR beads from Example 2.A above were coated in a Glatt GPCG 3 with an SR coating formulation as follows - water insoluble ethylcellulose (10 cps; 1 17.4 g) was slowly added into acetone (2231 g) to dissolve while stirring, triethylcitrate (13.0 g plasticizer) added to dissolve, then water (247.9 g) to mix well followed by the addition of hypromellose (12.4 g as a pore former) to form a clear solution. The IR beads (1500 g; 25-30 mesh) were coated with the functional polymer solution at the product temperature of 35°C and flow rate of 1 1-12 mL/min and upon completion of spraying, the SR beads were dried to drive off residual solvents (including moisture), The IR beads (60-80 mesh; 1590 g) from Ex. l .A were also coated for a weight gain of 1 1.1 % by weight. While the coating levels applied on the 25-30 mesh were too much, the small starting cores released the drug too fast.

2.C Perphenazine IR Beads (60-80 mesh): Hydroxypropylmethylcellulose (Pharmacoat 603; 20.3 g) was slowly added to ethanol (USP 190 proof; 1928.7 g) while stirring with a low shear mixer to prepare a clear solution. Water (USP 1285.8 g) was slowly blended in, and then the weakly basic drug (174.0 g of perphenazine) was slowly added to the binder solution while mixing to dissolve. A Glatt GPCG 5 equipped with a 9" bottom spray Wurster insert x 10" partition height, 16 mm tubing, 200 mesh screen, 1.0 mm nozzle tip, was charged with 60-80 mesh sugar spheres (2705.7 g), which were then fiuidized and sprayed with the binder/drug solution at the following processing conditions: inlet air temperature: 45°C; product temp. 36-38°C; air volume: 100±10 cfm; flow rate: 10 mL/min ramping up to 22 mL/min. Following completion of drug layering, the drug layered beads were provided with a seal coat of 2% by weight by spraying at a rate of 13 mL/min and product temperature of 47°C. The IR beads were then dried to drive off residual solvents (including moisture), and sieved to discard oversized particles and fines.

2.D Perphenazine SR Beads (Ethylcellulose): The IR beads manufactured as disclosed in Ex. 2.C above were coated in a Glatt GPCG 3 with an SR coating formulation consisting of ethylcellulose (178.8 g) and triethylcitrate (TEC, 19.7 g) dissolved in ethanol- water for a weight gain of 8% as disclosed in Example 2.B above. Samples were pulled at coating levels of 3.6%, 5.4%, and 7.2% for dissolution testing. FIG. 6.B demonstrates that practically no perphenazine was released in the pH 6.8 buffer from the 4% ethylcellulose coated SR beads containing the weakly basic typical antipsychotic drug was layered on 25-30 sugar spheres. Even from the SR beads containing 60-80 mesh inert cores, the release was less than 40% at 12 hr time point suggesting the need to include an organic acid or to convert the drug into highly activated amorphous state to enhance its solubility/dissolution rate. The alternate approach was to evaluate the use of a water insoluble polymer which is highly permeable to poorly soluble drugs such as Eudragit NE30D, RL, and/or RS polymers. These polymers were found to be applicable at least at low doses during in vitro dissolution testing in pH 6.8 buffer.

2.E Perphenazine SR Beads (NE30D): The IR beads manufactured as disclosed in Ex. 2.C above were coated in the Glatt GPCG 3 with an SR coating formulation. Water (150 g) was heated to 70-80°C, polysorbate 80 (26.7 g) and mono- and di-glycerides (20.7 g) were mixed at high speed for 10 min. Upon cooling to room temperature, Eudragit NE30D (654.3 g) was added slowly to disperse, The IR beads from step l .C above (1250 g) were coated with the functional SR polymer solution at the product temperature of 23±1 °C, air flow of 10 cfm, and flow rate of 4-6 mL/min and upon completion of spraying, the beads were coated with Opadry Clear, YS- 1-7006 for a 2% weight gain, and dried in the unit to drive off residual solvents including moisture. The SR beads were sieved with 40 and 70 mesh sieves to discard overs and fines.

2.F Perphenazine SR Beads (NE30D + talc): The IR beads manufactured as disclosed in Ex. 2.C above were coated in the Glatt GPCG 3 with an SR coating formulation. Water (166.6 g) was mixed with Eudragit NE30D dispersion (555.7 g) while gently stirring. Talc (166.6 g) was added and mixed at medium speed, The IR beads from step l .C above (1000 g) were coated with the functional SR polymer solution at the product temperature of 21±1 °C, air flow of 8 cfm, and flow rate of 4-10 mL/min and dried in the unit to drive off moisture. The SR beads were sieved with 40 and 70 mesh sieves to discard overs and fines.

2.G Perphenazine CR Beads (Eudragit L-55 over NE30D): The SR beads from Ex. 2.F above were coated in the Glatt GPCG 3 with an delayed release (DR) coating formulation. Water (20.3 g) was heated to 70-80°C, polysorbate 80 (37.0 g) and mono- and di-glycerides (9.2 g) were mixed at high speed for 10 min. Upon cooling to room

temperature, ethanol (190 proof; 2593.0 g) was mixed with the addition of Eudragit L-55 (189.6 g) to dissolve while gently stirring. Triethylcitrate (18.4 g) was mixed at medium speed for not less than 30 min, The SR beads from step 1.D above (1300 g) were coated with the enteric polymer solution at the product temperature of 25±1°C, air flow of 10-12 cfm, and flow rate of 5-8 mL/min and dried in the unit to drive off moisture. The SR beads were sieved with 40 and 70 mesh sieves to discard overs and fines.

2.H Perphenazine CR Beads (Eudragit L-55 over NE30D): The SR beads from Ex. 2.G above were coated in the Glatt GPCG 3 with an delayed release (DR) coating formulation. Eudragit L-55 (361.7 g) was slowly added into ethanol (190 proof; 6517.1 g) to dissolve while gently stirring. Triethylcitrate (35.0 g) was mixed followed by the addition of talc (170 g) while stirring at medium speed for not less than 30 min, The SR beads from step 1.E above (1 100 g) were coated with the enteric polymer solution at the product temperature of 29±1°C, air flow of 9 cfm, and flow rate of 6-10 mL/min and dried in the unit to drive off residual solvent. The SR beads were sieved with 35 and 60 mesh sieves to discard overs and fines. Required quantities of IR and CR multiparticulate populations at a ratio of 1 :3 (of the weakly basic drug) are filled into hard gelatin capsules containing 32 mg of perphenazine using a capsule filling machine, MG Futura is used for analytical testing and stability monitoring per the ICH (International Conference on Harmonization) guidelines.

2.1 Perphenazine TPR Beads (Eudragit L-55/NE30D): The IR beads from

Example 2.C above were coated in the Glatt GPCG 3 with an TPR coating formulation comprising Eudragit NE30D and L30D-55. Water (90 g) was heated to 70-80°C, polysorbate 80 (20.6 g) and mono- and diglycerides (23.6 g) were mixed at high speed for 10 min. Upon cooling to room temperature, Eudragit NE30D (838.0 g) was added slowly to dissolve, Eudragit L30D-55 (185.7 g) was added to dissolve. The IR beads from step 2.C above (1350 g) were coated with the functional TPR polymer solution at the product temperature of 24°C, air flow of 1 1 -12 cfm, and flow rate of 4-12 mL/min and upon completion of spraying, the beads were coated with Opadry Clear, YS-1-7006 for a 2% weight gain, and cured in the unit at 45±1 °C for one hour. The TPR beads were sieved with 50 and 70 mesh sieves to discard overs and fines.

2.J Perphenazine TPR Beads: The IR beads from Example 2.C above were coated in the Glatt GPCG 3 with an TPR coating formulation. Water insoluble ethylcellulose (10 cps; 167.5 g) was slowly added into acetone (3775.5 g) to dissolve while stirring, hypromellose phthalate (HP-55 from Shin-Etsu; 134.0 g) added to dissolve, triethylcitrate (33.5 g plasticizer) added to dissolve, then water (77.0 g) was added to form a clear solution. The IR beads (1340 g) were coated with the functional TPR polymer solution at the product temperature of 33±1°C and flow rate of 4 mL/min; jacked up to 25 mL/min and upon completion of spraying, the SR beads were dried to drive off residual solvents (including moisture). Example 3

3.A - Fumaric Acid Layered Beads: Hydroxypropylcellulose (Klucel LF; 10.2 g) was slowly added into 90/10 ethanol (190 proof; 2203.2 g)/water (244.8 g) while stirring at medium speed to dissolve, and then fumaric acid (91.8 g) was added slowly to dissolve. Sugar spheres (25-30 mesh; 1598.0 g) were charged into a Glatt GPCG 3 fluid bed coater equipped with a 7" bottom spray Wurster, 22 mm partition height, 16 mm tubing, bottom air distribution plate 'C covered with a 100 mesh product retention screen; spray nozzle opening: 1.0 mm and coated with the fumaric acid solution at the following processing conditions: - atomization air pressure: 1.5 bar; product temperature: 32±2°C), inlet air volume: 10-12 CFM; spray rate: 8 to 18 mL/min). The fumaric acid beads were sieved through 20 and 30 mesh sieves to discard oversized and fines.

3.B Fumaric Acid SR Beads: Fumaric acid cores (1450 g) from step 3. A above were charged into a Glatt GPCG 3 (e.g., equipped with a 7" bottom spray Wurster 7 13/16" column height, "C" bottom air distribution plate covered with a 200 mesh product retention screen) and coated with a solution (7% solids) of ethylcellulose (60.7 g) and triethylcitrate

(6.1 g) dissolved in ethanol (190 proof; 888.4 g) and water (380.8 g) by spraying at a rate of 6 to 1 1 mL/min. The fumaric acid cores were applied with a 2% Opadry Clear coating to minimize tackiness of SR acid beads. The SR acid beads were dried in the unit for 5 min to drive off residual solvent/moisture and sieved to discard doubles, if any. 3.C Perphenazine IR Beads: Hydroxypropylcellulose (Klucel LF; 10.6 g) was slowly added to a solvent system (e.g., 564.2 g water and ethanol (190 proof; 846.2 g) to prepare a binder solution. Perphenazine (90.7 g) was slowly added to the binder solution while mixing. The GPCG 3 was charged with SR acid beads (1410 g) from step 3.B above, which were then fluidized and sprayed with the binder/drug solution at a spray rate of 6 mL/min; nozzle tip size: 1.0 mm; atomization air pressure: 1.5 bar; inlet air volume: 11-13 cfm; product temperature: 40±2°C. Following completion of drug layering, the drug layered beads are applied with a seal coat by spraying an aqueous solution of Opadry Clear for a weight gain of 2 wt.% to produce IR Beads. The IR beads are then dried to drive off residual solvents (including moisture), and can be sieved to discard oversized particles and fines.

3.D Perphenazine SR Beads: The IR beads (1410 g) from Example 3.C above were coated in the Glatt GPCG 3 with an SR coating of a water-insoluble polymer (e.g., ethyl cellulose; 59.0 g) and plasticizer(e.g., triethylcitrate at 5.9 g) dissolved in ethanol (190 proof; 863.2 g)/water (369.9 g). The IR beads are then dried to drive off residual solvents (including moisture), and can be sieved (e.g., through 18 and 30 mesh screens) to discard oversized particles and fines. FIG. 7 demonstrates the slower in vitro release of perphenazine compared to that of fumaric acid when SR beads containing weakly basic typical antipsychotic perphenazine were dissolution tested in pH 6.8 buffer.

3.E Perphenazine CR (TPR over SR coat) Beads: The SR beads (1480 g) from Example 3.D above were coated in the Glatt GPCG 3 with a TPR coating (e.g., ethyl cellulose at 185.0 g; Hypromellose phthalate, HP-55 at 148.0 g; triethylcitrate at 37.0g) dissolved in acetone (2281.6 g)/water (2281.6 g) at a spray rate of 6 mL/min (ramped up to 19 ml/min). The TPR beads were then dried to drive off residual solvents (including moisture) and sieved (e.g., through 18 and 25 mesh screens) to discard oversized particles and fines. FIG. 8. A demonstrates the perphenazine release profiles from CR beads when dissolution tested in 0.1N HCl. FIG. 8.B demonstrates the perphenazine release profiles from SR beads as well as CR beads when dissolution tested in pH 6.8 buffer. At a TPR coating at only 5% by weight has no effect on the drug release profiles of SR beads.

3. F Perphenazine CR (DR Coating over SR Coating) Beads: The SR beads from Example 3.D above are coated in a Glatt GPCG 3 with a DR coating of an optionally plasticized (e.g., triethylcitrate at 10% w/w) enteric polymer (e.g., hypromellose phthalate, HP-55) for a weight gain of up to 15%. The CR beads are then dried to drive off residual solvents (including moisture), and can be sieved (e.g., through 14 and 30 mesh screens) to discard oversized particles and fines.

Example 4

4. A IR Beads (Solid solution approach): Povidone (K-29/30; 102.0 g) was slowly added to ethanol (USP 190 proof; 1 137.6 g) while stirring with a low shear mixer to prepare a clear solution. Water (USP 1285.8 g) was slowly blended in, and then the weakly basic drug (102.0 g of perphenazine) was slowly added to the solution while mixing to dissolve to produce a solid solution of perphenazine and povidone at a ratio of 1 : 1. The Glatt GPCG 3 equipped with a 7" bottom spray Wurster insert x 22 mm partition height, 14 mm tubing, bottom air distribution plate: 'C and 200 mesh retention screen, 1.0 mm nozzle tip, was charged with 60-80 mesh Sugar Spheres (1496.0 g), which were then fluidized and sprayed with the solid solution at the following processing conditions: inlet air temperature: 60°C; product temp. 40°C; air volume: 8-10 cfm; flowrate: 4 mL/min ramping up to 10 mL/min. Following completion of drug layering, the drug layered beads were dried to drive off residual solvents (including moisture), and sieved to discard oversized particles and fines. 4.B TPR Beads (Solid solution approach): The IR beads (1340 g) from Example

4.B above were coated in the Glatt GPCG 3 with a TPR coating (e.g., ethyl cellulose at 167.5 g; Hypromellose phthalate, HP-55 at 134.0 g; triethylcitrate at 33.5 g) dissolved in acetone (4049.6 g)/water (82.7 g) at a spray rate of 8 mL/min (ramped up to 23 ml/min) and product temperature of 32±1°C . The TPR beads were then dried to drive off residual solvents (including moisture) and sieved (e.g., through 40 and 70 mesh screens) to discard oversized particles and fines. FIG. 9 demonstrates the drug release profiles for weakly basic, antipsychotic perphenazine when dissolution tested in pH 6.8 alkaline buffer. The drug release profiles are too fast and incomplete. In order to slow down the release profile and to achieve complete release, solid solutions comprising a weakly basic antipsychotic drug and a crystallization-inhibiting polymer such as Kollidon VA 64 (vinylpyrrolidone-vinyl acetate copolymer) at a 1 :2 ratio of drug to VA 64 with and without an organic acid would be prepared.

4.C IR Beads (Solid solution approach): Kollidon VA 64 (800 g) is slowly added to 72.5/22.5/5 ethanol 95% 190 proof alcohol/ acetone/water (4930g/1530g/340g) while stirring vigorously to dissolve, and then perphenazine (400 g) is slowly added to dissolve. Glatt GPCG 3 equipped with a 7" bottom spray/8" column height Wurster insert, 20 mm partition gap, air-distribution plate ( 100 μηι screen), 1.0 mm nozzle port, atomization air pressure of 1.5 bar, is charged with 2584 g of 25-30 mesh sugar spheres. About 40 g of talc is homogenized in the solution to minimize static build-up. The drug solution, with a solids content of 15% by weight, is sprayed onto sugar spheres at a spray rate of 8-17 mL/min while maintaining the product temperature at about 37±2°C and inlet air volume of 10-12 cfm. Upon completion of spraying, the drug-layered beads are coated with a protective seal-coat of Opadry^® Clear at product temperature: 37-41°C; spray rate: 5-12 g/min) for 2% weight gain, and further dried at 40°C in the unit for about 5 min to drive off residual solvent/moisture. 4.D TPR Beads (Solid solution approach): IR beads from Ex. 4.C above are coated by spraying a solution of Eudragit RS/L/TEC/talc at a ratio of 45/40/10/5 dissolved (talc suspended in the solution in 45/55 acetone/ethanol (190 proof) at 10% solids for a weight gain of up to 20% by weight. First, Eudragit RS polymer is slowly added to the solvent mixture to achieve a clear solution while stirring. Next, Eudragit L polymer and finally the plasticizer (triethycitrate) are slowly added to dissolve in the solution. Talc is separately homogenized in the solvent mixture before suspending in the solution. Glatt GPCG 3 equipped with a 7" bottom spray Wurster insert. The solution is sprayed in the Glatt GPCG 3 at a spray rate of 6-1 1 mL/min and at a product temperature of 35-38°C. The coated beads are dried in the Glatt at 40°C for 30 minutes. The cured beads are sieved to discard any doubles if formed. Samples pulled at a coating of about 5% , 10%, and 15% by weight for testing for assay and drug release using a HPLC methodology. FIG. 9 demonstrates the drug release profiles from TPR beads coated at 5, 10, 15, and 20% by weight when dissolution tested in pH 6.8 buffer.

4. E CR Beads (DR over TPR Coating): TPR beads at 15% coating from Ex. 4.D above are provided with an optional DR coating by spraying a solution of Eudragit

L/TEC/talc at a ratio of 80/10/10 dissolved (talc suspended in the solution) in 45/55 acetone/ethanol (190 proof) at 10% solids for a weight gain of up to 20% by weight. HPMC capsules are filled with IR and CR bead populations at a ratio of 3:7 based on perphenazine content to produce CR perphenazine capsules, 16 mg & 32 mg for analytical testing.

EXAMPLE 5

5. A TPR Coated Organic Acid Crystals: Succinicic acid crystals (50-80 mesh) are coated in a Glatt GPCG 3 with a TPR coating of an optionally plasticized (e.g., triethylcitrate at 10%) w/w) water-insoluble polymer (e.g., ethyl cellulose) in combination with an enteric polymer (e.g., hypromellose phthalate, HP-55) at a weight ratio of 65/25/10 for a weight gain of up to 25%. The TPR beads are then dried to drive off residual solvents (including moisture), and can be sieved to discard oversized particles and fines 5.B IR Beads Containing Weakly Basic Antipsychotic Drug: A Glatt GPCG 3 is charged with TPR coated succinic acid crystals of Ex. 5. A above, which are then sprayed with the binder/ziprasidone solution. Following completion of drug layering, a 2 wt.% Opadry Clear protective seal coat is applied to the drug layered beads.

5.C CR Beads Containing Weakly Basic Antipsychotic Drug: The IR beads from Example 5.B above are first coated in the same fluidized bed coater with an SR coating 70/20/10 ethyl cellulose (EC- 10)/hydroxypropylcellulose/triethylcitrate for a weight gain of 10%, followed by a second TPR coating at a ratio of EC-10/HP-55/Tec of 65/25/10 at 15% w/w.

5.D Compressible Coated CR Beads: A compressible coating solution (e.g., hydroxypropylcellulose such as Klucel® LF) dissolved in a solvent is sprayed onto CR Beads of Ex. 5.C above for a weight gain of about 3%. The resulting Compressible coated CR beads are dried in the same unit to drive off residual solvents.

5.E Taste-masked IR Beads: IR beads comprising an antipsychotic drug ziprasidone) are prepared in a Glatt GPCG 3 by spraying the drug/binder solution onto microcrystalline cellulosic spheres (e.g., Cellets 100 from Glatt) as disclosed in Ex. 5.B above. The IR beads are taste-masked first by solvent coacervation with ethylcellulose (Ethocel Premium Standard 100) for a coating at 5% w/w as disclosed in the co-pending US Patent Application Ser. No. 10/827,106 (published as US 20050232988 Al) and further coated with an optionally plasticized ethylcellulose (EC- 10), a gastrosoluble polymeric pore- former (e.g., Eudragit EPO) at a ratio of about 1 : 1 for a weight gain of 20 wt.% as disclosed in the co-pending US Patent Application Ser. No. 1 1/248,596 (published as US 2006/00614 Al) and dried in the same fluidized bed coater to drive off residual solvents.

5.F Rapidly Dispersing Microgranules: The rapidly dispersing microgranules are prepared following the procedure disclosed in the co-pending US Patent Application Ser. No. 10/827,106 (published as US 2005/0232988 Al), and 12/166,757 (US 2009/0092672 Al), the contents of which are hereby incorporated by reference for all purposes. D-mannitol with an average particle size of approximately 20 μπι or less (e.g., Pearlitol 25 from Roquette, France) is blended with 8 kg of cross-linked povidone (e.g., Crospovidone XL-10 from ISP) in a high shear granulator (GMX 600 from Vector) and granulated with purified water and wet-milled using Comil from Quadro and dried in a fluid bed coater/dryer to obtain a loss on drying (LOD) of less than about 1 %. The dried granules are sieved, and oversized material is milled to produce rapidly dispersing microgranules with an average particle size in the range of approximately 175-300 μιτι.

5.G Controlled-Release ODT Containing IR and CR Beads: Rapidly dispersing microgranules from Ex. 5.F above are blended with taste-masked IR beads of Ex. 5.E, compressible coated CR beads from Ex. 5.D above, and other optional pharmaceutical acceptable ingredients, such as flavor, sweetener (e.g., sucralose), additional crospovidone, and macrocrystalline cellulose (e.g., Avicel PH101) at a ratio of rapidly dispersing microgranules to totality of coated bead populations of about 3 :2 in a twin shell V-blender for a sufficient time to obtain a homogeneously distributed blend for compression. ODTs comprising 50 mg of weakly basic antipsychotic drug are compressed using a production scale tablet press equipped with an external lubrication system at the following conditions: - tooling: 13 mm round, flat face, radius edge; compression force: 8-12 kN; mean weight: 1000 mg; mean hardness: 20-40 N; and friability: <0.50%. The resulting ODT (50 mg dose) thus produced rapidly disintegrates in the oral cavity, creating a smooth, easy-to-swallow suspension comprising coated beads and provides an expected a drug-release profile suitable for a once-daily dosing regimen.

Example 6

6.A IR Beads Comprising a Weakly Basic Antipsychotic Drug: Glatt GPCG 3 is charged with Cellets 200 (microcrystalline cellulose spheres from Glatt) and a weakly basic antipsychotic drug (olanzapine) is layered onto these inert cores by spraying the spheres with a solution comprising the drug and a binder. A protective seal coat is also applied. The IR beads are dried in the same unit to drive off residual solvents including moisture, and sieved to discard doubles and/or fines.

6.B Taste-Masked IR Beads: IR Beads from Example 6. A are taste masked by coating with EC-10 and Eudragit^® E100, TEC, and magnesium stearate at a ratio of 44/44/6/6 dissolved/dispersed in 95/5 acetone/water in a Glatt GPCG 3 for a weight gain of about 25% as disclosed in co-pending US Patent Application Ser. No. 12/370,852 (published as US 2009/0202630 Al), the entire contents of which are hereby incorporated by reference for all purposes. 6.C TPR Coated Organic Acid Crystals: A pharmaceutically acceptable acid (e.g., aspartic acid) crystals are charged into a GPCG 3 and coated with a TPR coating comprising EC-10/HP-55/Tec at a ratio of 55/35/10 dissolved in 95/5 acetone/water (7% solids) for a weight gain of 35%, and dried in the unit to drive off residual solvents including moisture.

6.D CR Beads Comprising Antipsychotic Drug: The acid TPR beads of step 6.C above are charged into a Glatt GPCG 3 and coated with olanzapine for a drug load of 10% based on the weight of IR beads including the seal coat. IR beads are coated with a TPR coating comprising EC-10/HP-55/TEC at a ratio of 55/35/10 dissolved in 95/5 acetone/water (7% solids) for a weight gain of 25%, followed by a delayed release coating with plasticized HP-55 for a weight gain of 20%. The CR beads are dried in the unit for 10 min and sieved to discard doubles and fines.

6.E Controlled-Release ODT Comprising taste-masked IR beads and CR Beads:

Two parts of rapidly dispersing microgranules from Example 2.F and one part of multicoated multiparticulate populations of CR beads and taste masked IR beads of olanzapine from Example 6.B and 6.D at a ratio of 3: 1 are blended with other optional pharmaceutical acceptable ingredients, such as flavor, sweetener (e.g., sucralose), additional crospovidone, and microcrystalline cellulose (e.g., Avicel PH101 in a twin shell V-blender for a sufficient time to obtain a homogeneously distributed blend for compression. ODTs comprising 20 mg of olanzapine as IR/CR beads are compressed using a production scale tablet press equipped with an external lubrication system: The resulting ODT (20 mg dose) rapidly disintegrates in the oral cavity, creating a smooth, easy-to-swallow suspension comprising coated beads and provides an expected a drug-release profile suitable for a once-daily dosing regimen.

The skilled artisan will recognize that the above procedures and compositions can be suitably modified to provide the appropriate dose of weakly basic antipsychotic drug.

While the invention has been described in connection with the specific embodiments herein, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to that the invention pertains and as may be applied to the essential features hereinbefore set forth and as follows in the scope of the appended claims.

All documents, patents, patent applications, and publications cited herein are incorporated by reference in their entirety for all purposes.

Claims

We claim:

1. A controlled release pharmaceutical composition comprising a plurality of controlled- release particles, each comprising:

(a) an acid core comprising a pharmaceutically acceptable organic acid;

(b) a first coating that is disposed over the acid core, comprising at least one

water-insoluble polymer to form a controlled release coated acid core;

(c) a second coating that is disposed over said controlled release coated acid core, comprising an antipsychotic drug or a pharmaceutically acceptable salt, solvate, or ester thereof, and a polymeric binder to pioduce an antipsychotic drug coated acid core; and

(d) a third coating that is disposed over the antipsychotic drug coated acid core comprising at least one water-insoluble polymer to form controlled release coated antipsychotic drug particle.

2. The controlled release pharmaceutical composition of claim 1 , wherein said acid core comprises a pharmaceutically acceptable organic acid crystal.

3. The controlled release pharmaceutical composition of claim 1 , wherein said acid core comprises an organic acid coating disposed over an inert core.

4. A controlled release pharmaceutical composition comprising a plurality of controlled- release particles, each comprising:

(a) a core comprising a solid dispersion of a pharmaceutically acceptable weakly basic antipsychotic drug in a solubility-enhancing, crystallization-inhibiting polymer disposed over an inert core ;

(b) a first coating that is disposed said solid dispersion core, comprising at least one water-insoluble polymer, thereby forming a controlled release coated antipsychotic drug particle.

5. A controlled release pharmaceutical composition comprising a plurality of controlled- release particles, each comprising: (a) a pharmaceutically acceptable weakly basic antipsychotic drug and a pharmaceutically acceptable, polymeric binder, disposed over an inert core, thereby forming an antipsychotic drug core;

(b) a first coating that is disposed over the antipsychotic drug core, comprising at least one water-insoluble polymer, thereby forming a controlled release coated antipsychotic drug particle.

6. The controlled release pharmaceutical composition of claim 1, 4, or 5 further

comprising a population of immediate release antipsychotic drug particles.

7. The controlled release pharmaceutical composition of claim 1 , 4, or 5, wherein said first coating further comprises an enteric polymer.

8. The controlled release pharmaceutical composition of claim 7, wherein the ratio of the water-insoluble polymer to the enteric polymer is about 10: 1 to about 1 :2.

9. The controlled release pharmaceutical composition of claim 1 , wherein said third coating further comprises an enteric polymer.

10. The controlled release pharmaceutical composition of claim 1, 4, or 5, wherein a protective seal coating is disposed over said antipsychotic drug core.

1 1. The controlled release pharmaceutical composition of claim 1 further comprising a fourth coating comprising at least one enteric polymer disposed over the third coating.

12. The controlled release pharmaceutical composition of claim 4 or 5 further comprising a second coating comprising at least one enteric polymer disposed over the first coating.

13. The controlled release pharmaceutical composition of claim 1 1 , wherein said fourth coating further comprises a water insoluble polymer at a ratio of the water-insoluble polymer to the enteric polymer of from about 10: 1 to about 1 :2.

14. The controlled release pharmaceutical composition of claim 12, wherein said second coating further comprises a water insoluble polymer at a ratio of the water-insoluble polymer to the enteric polymer of from about 10: 1 to about 1 :2.

15. The controlled release pharmaceutical composition of claim 1 , wherein at least one of the first, third, and fourth coatings further comprises a plasticizer.

16. The controlled release pharmaceutical composition of claim 4 or 5, wherein at least one of the first and second coatings further comprises a plasticizer.

17. The controlled release phannaceutical composition of claim 1 , wherein the second coating further comprises a polymeric binder selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone and mixtures thereof.

18. The controlled release pharmaceutical composition of claim 3, wherein the organic acid coating further comprises a polymeric binder selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpynOlidone and mixtures thereof.

19. The controlled release pharmaceutical composition of claim 3, wherein said inert core is selected from the group consisting of a sugar sphere, cellulosic sphere, cellulose- lactose, cellulose-mannitol, or fused silicon dioxide spheres.

20. The controlled release pharmaceutical composition of claim 1 , wherein said third coating further comprises at least one water soluble polymer selected from the group consisting of methylcellulose, hydroxypropyl cellulose, hydroxypropyl

methylcellulose, polyethylene glycol, polyvinylpyrrolidone and mixtures thereof.

21. The controlled release pharmaceutical composition of claim 4 or 5, wherein said first coating further comprises at least one water soluble polymer selected from the group consisting of methylcellulose, hydroxypropyl cellulose, hydroxypropyl

methylcellulose, polyethylene glycol, polyvinylpyrrolidone and mixtures thereof. The controlled release pharmaceutical composition according to claim 1, 4, or 5, wherein the water-insoluble polymer is selected from the group consisting of ethylcellulose, cellulose acetate, cellulose acetate butyrate, polyvinyl acetate, neutral methacrylic acid/methylmethacrylate copolymers such as commercially available Eudragit RL, RS, or NE30D polymer, and mixtures thereof.

The controlled release pharmaceutical composition of claim 1 , 4, or 5, wherein the enteric polymer is selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, pH-sensitive methacrylic

acid/methylmethacrylate copolymers such as commercially available Eudragit L, S, FS polymer, shellac, and mixtures thereof.

The controlled release pharmaceutical composition of claim 1 , 4, 5, wherein the water-insoluble polymer is ethylcellulose and the enteric polymer is

hydroxypropylmethylcellulose phthalate at a coating of from about 5 to about 60 wt % relative to the total weight of the controlled release coated particle.

The controlled release pharmaceutical composition of claim 4, wherein the water- insoluble, polymer is a neutral methacrylic acid/methylmethacrylate copolymer and the enteric polymer is pH-sensitive methacrylic acid/methylmethacrylate copolymer at a coating of from about 10 to about 60 wt % relative to the total weight of the controlled release coated particle.

The controlled release pharmaceutical composition of claim 1 , wherein the second coating comprises from about 5 to about 60 wt % relative to the total weight of the controlled release coated antipsychotic drug particle.

The controlled release pharmaceutical composition of claim 1, 4, or 5, wherein the antipsychotic drug is selected from the group consisting of consisting of haloperidol, perphenazine, chlorpromazine, fluphenazine, quetiapine, sertindole, ziprasidone, iloperidone, lurasidone, asenapine, loxapine, blonanserin, olanzapine and risperidone, or a pharmaceutically acceptable salt and/or solvate thereof. The controlled release pharmaceutical composition of claim 27, wherein the antipsychotic drug is perphenazine or a pharmaceutically acceptable salt and/or solvate thereof.

The controlled release pharmaceutical composition of claim 4, wherein the antipsychotic drug is ziprasidone or a pharmaceutically acceptable salt and/or solvate thereof.

The controlled release pharmaceutical composition of claim 1 , wherein the organic acid is selected from the group consisting of citric acid, fumaric acid, malic acid, maleic acid, tartaric acid, succinic acid, oxalic acid, aspartic acid, glutamic acid and mixtures thereof at a ratio of antipsychotic drug to organic acid of from about 5: 1 to about 1 :5.

The controlled release pharmaceutical composition of claim 4, wherein the hydrophilic, crystallization-inhibiting polymer is selected from the group consisting of hydroxypropylcellulose, hydroxypropyl methylcellulose, methylcellulose, hypromellose, povidone, vinylpyrrolidone-vinylacetate copolymer (e.g., Kollidon^{^} VA 64 from BASF), or a mixture thereof at a ratio of antipsychotic drug to crystallization-inhibiting polymer of from about 5: 1 to about 1 :5.

The controlled release pharmaceutical composition of claim 4, wherein said solid solution core further comprises an organic acid at a ratio of the crystallization- inhibiting polymer to organic acid of from about 3: 1 to about 1 :3.

The controlled release pharmaceutical composition of claim 6, wherein the ratio of the controlled release coated antipsychotic drug particles to the immediate release antipsychotic drug particles varies from about 80:20 to about 50:50.

The controlled release pharmaceutical composition of claim 6, wherein the immediate release particles further comprises a taste-masking coating for a weight gain of from 10% to about 40 wt.% based on the total weight of the taste-masked immediate release drug particles. The controlled release pharmaceutical composition of claim 34, wherein the taste- masking coating disposed on said immediate release antipsychotic drug particles comprises a water insoluble membrane creating taste-masked rapid release drug particles.

The controlled release pharmaceutical composition of claim 35, wherein the taste- masking coating further comprises a gastrosoluble pore-forming agent at a ratio varying from about 9: 1 to 1 : 1.

The controlled release pharmaceutical composition of claim 36, wherein said gastrosoluble pore-forming agent selected from the group consisting of calcium carbonate, sodium chloride, calcium saccharide, calcium succinate, ferric acetate magnesium carbonate, magnesium citrate, magnesium hydroxide, polyvinyl pyrrolidone, Eudragit El 00, Eudragit EPO, and mixtures thereof.

The composition of claim 1 , 4, 5, or 6 further comprising a population of rapidly- dispersing microgranules each having an average particle size of not more than about 400 μιη and comprising (1 ) a disintegrant and (2) a sugar alcohol and/or a saccharide, wherein said sugar alcohol and/or saccharide each having an average particle size of not more than about 30 um.

The composition of claim 38, wherein the ratio of rapidly-dispersing microgranules to controlled release coated antipsychotic drug particle ranges from about 6: 1 to about 1 : 1.

The composition of claim 38, wherein the rapidly-dispersing microgranules comprise a disintegrant selected from the group consisting of crosslinked polyvinylpyrrolidone, sodium starch glycolate, crosslinked carboxymethylcellulose of sodium, low- substituted hydroxypropylcellulose and mixtures thereof.

The composition of claim 38, wherein the rapidly-dispersing microgranules comprise a sugar alcohol selected from the group consisting of arabitol, erythritol, glycerol, isomalt, lactitol, maltitol, mannitol, sorbitol, xylitol, and combinations thereof.

42. A dosage form comprising the controlled release pharmaceutical composition of claim 1.

43. The dosage form of claim 44 in the form of a capsule or tablet.

44. A dosage form comprising the controlled release composition of claim 4.

45. The dosage form of claim 45 in the form of a capsule or tablet.

46. A dosage form comprising the controlled release composition of claim 5.

47. The dosage form of claim 47 in the form of a capsule or tablet.

48. The dosage form of claim 42, 44, or 46 in the form of an orally disintegrating tablet comprising rapidly-dispersing microgranules with an average particle size of not more than about 400 μπι and a disintegrant and a sugar alcohol or a saccharide or a combination thereof, each having an average particle size of not more than about 30 μηι wherein said orally disintegrating tablet exhibits the following properties:

a friability of less than 1 % by weight; and

a disintegration time of about 60 seconds or less on contact with the saliva in the oral cavity forming a smooth suspension comprising the controlled release coated antipsychotic drug particle.

49. A dosage form comprising the controlled release composition of claim 48.

50. The dosage form of claim 49 in the form of an orally disintegrating tablet comprising rapidly dispersing microgranules and sum total of said taste-masked immediate release drug particles and controlled release coated antipsychotic drug particle are at a ratio of from about 6: 1 to 1 : 1.

51. The dosage form of claim 50 in the form of an orally disintegrating tablet, wherein said organic acid core comprises:

an organic acid crystal; or an inert core coated with an organic acid and a polymeric binder; or a pellet containing the organic acid, a polymeric binder and a diluent/filler, prepared by controlled spheronization using a Vector's Granurex X-35 or equivalent, rotogranulator from Glatt or equivalent, or by granulation- extrusion-spheronization.

52. The dosage form of claim 42, 44, 46, or 50, that substantially disintegrates within about 60 seconds after administration in the oral cavity of a patient.

53. The dosage form of claim 42, 44, 46, or 50, that substantially disintegrates within about 30 seconds when tested by the <USP 701> Disintegration Test.

54. The controlled release pharmaceutical composition of claim 1, 4, 5, 42, 44, 46, 48, or 50, wherein the controlled release coated antipsychotic drug particle exhibit a drug release profile substantially corresponding to the following pattern when dissolution tested using United States Pharmacopoeia Apparatus 2 (paddles @ 50 rpm) in a 2- stage dissolution media (700 mL of 0.1N HCl for the first 2 hrs followed by testing in 900 mL buffer at pH 6.8 obtained by adding 200 mL of a pH modifier) at 37°C: after 2 hours, about 25±10% of the total perphenazine is released;

after 4 hours, about 45±15% of the total antipsychotic drug is released;

after 8 hours, about 65±15% of the total antipsychotic drug is released; and after 12 hours, about 75±10% of the total antipsychotic drug is released.

55. The dosage form of claim 38 in the form of an orally disintegrating tablet comprising rapidly-dispersing microgranules with an average particle size of not more than about 400 μ ι and a disintegrant and a sugar alcohol or a saccharide or a combination thereof, each having an average particle size of not more than about 30 μπι.

56. The dosage form of claim 55, wherein said orally disintegrating tablet substantially disintegrates within about 60 seconds after contact with saliva in the oral cavity.

57. The dosage form of claim 50, wherein said orally disintegrating tablet substantially disintegrates within about 30 seconds when tested by USP disintegration time test method.

58. A method of preparing a controlled release pharmaceutical composition of claim 1 , 7, or 8 comprising:

(a) preparing a plurality of acid cores comprising a pharmaceutically acceptable organic acid and optionally a polymeric binder;

(b) coating said cores with a water insoluble polymer, and optionally an enteric polymer to form controlled release coated acid cores;

(c) coating said controlled release coated acid cores with a second coating comprising an antipsychotic drug or a pharmaceutically acceptable salt, solvate, or ester thereof and a polymeric binder to produce an antipsychotic drug coated acid cores;

(d) coating said antipsychotic drug coated acid cores with said third coating that is disposed over the antipsychotic drug coated acid cores comprising at least one water- insoluble polymer and optionally an enteric polymer to form controlled release coated antipsychotic drug particles.

59. A method of preparing a controlled release pharmaceutical composition of claim 4, 7, or 8 comprising:

(a) preparing a plurality of weakly basic antipsychotic drug cores comprising a weakly basic antipsychotic drug, or a pharmaceutically acceptable salt, solvate, or ester thereof, and pharmaceutically acceptable crystallization-inhibiting polymer and optionally an organic acid disposed over inert cores and providing an optional protective seal coat with a hydrophilic polymer; and

(b) coating said cores with a water insoluble polymer, and optionally an enteric polymer to form a controlled release coated antipsychotic drug particles.

60. A method of preparing a controlled release pharmaceutical composition of claim 5, 7, or 8 comprising:

(a) preparing a plurality of weakly basic antipsychotic drug cores comprising a weakly basic antipsychotic drug, or a pharmaceutically acceptable salt, solvate, or ester thereof, and pharmaceutically acceptable polymeric binder and optionally an organic acid disposed over inert cores and providing an optional protective seal coat with a hydrophilic polymer; and

A method of preparing a dosage form of claim 38 or 39 comprising:

(d) granulating a sugar alcohol and/or a saccharide, each having an average particle diameter of not more than about 30 μηι, and a disintegrant, thereby producing rapidly disintegrating microgranules with an average particle size not more than about 400 μιη;

(e) blending the controlled release coated antipsychotic drug particle and optionally immediate release antipsychotic drug particles and rapidly disintegrating microgranules;

(f) compressing said blend thereby forming an orally disintegrating tablet.

The method of claim 61 , wherein the antipsychotic drug is selected from the group consisting of haloperidol, perphenazine, chlorpromazine, fluphenazine, quetiapine, sertindole, ziprasidone, iloperidone, lurasidone, asenapine, loxapine, blonanserin, olanzapine and risperidone, or a salt and/or solvate thereof.

The method of claim 62, wherein said antipsychotic drug comprises perphenazine or a salt and/or solvate thereof.

A method of treating a patient subject to psychosis in a schizophrenia, comprising administering a pharmaceutically effective amount of the controlled release pharmaceutical composition of claim 1 to a patient in need thereof.

A method of treating a patient subject to nausea and vomiting, comprising administering a pharmaceutically effective amount of the controlled release pharmaceutical composition of claim 1 to a patient in need thereof.

The pharmaceutical controlled release composition of claim 1 , 4, or 6, wherein the plasticizer is free of phthalates.