HK1084321A - Depot formulations of arylheterocyclic active agents in the form of a suspension - Google Patents

Description

Depot formulations of aryl-heterocyclic active substances in the form of suspensions

Technical Field

The present invention relates to injectable depot (depot) formulations of aryl heterocyclic compounds such as arylpiperazinyl-C₂and-C₄Alkylene heterocyclic compounds including ziprasidone; and a method of making the formulation. The injectable depot formulations of the present invention allow for controlled release of the active aryl-heterocyclic substances over a prolonged period of time after administration to a patient by, for example, Intramuscular (IM) injection. In a particular aspect, the invention relates to a pharmaceutical kit from which ziprasidone suspensions suitable for use as an injectable depot formulation can be prepared.

Background

Certain aryl heterocyclic compounds are known to have psychotropic (pscychotropic) effects. Ziprasidone, in particular, is a chlorooxindole aryl heterocycle, an atypical antipsychotic often prescribed for the treatment of schizophrenia. Atypical antipsychotics such as ziprasidone offer significant advantages over traditional antipsychotics in the range where they are associated with a lower incidence of side effects, such as extrapyramidal symptoms (EPS), and confer greater therapeutic efficacy on patients who are otherwise unresponsive to more traditional drug therapies. Certain diseases, such as schizophrenia, are particularly difficult to administer because they are considered to be heterogeneous diseases, whereby not all patients respond similarly to the same treatment regimen. Exacerbating the disease-a problem that often accompanies long-term treatment of schizophrenia; i.e., non-compliance of patients with their dosage regimen. In fact, it is generally accepted that many schizophrenic patients are not or only partially compliant with their medication. Poor compliance can cause recurrence of the psychotic condition, thereby negating any benefit obtained by the first treatment.

When patient compliance is an issue, long acting dosage forms of the drug sometimes have to be taken. That is, a dosage form in which a single administration results in a sustained release of the drug over a long period of time. This, in turn, simplifies the dosage regimen that the patient needs to adhere to, thereby reducing the chance of non-compliance as with a more rigorous regimen. Among such dosage forms are depot formulations, which may be administered in various ways including intramuscular injection. Depot dose injections are specifically formulated to provide slow drug absorption from the site of administration, typically maintaining the same therapeutic level in the patient's body for days or weeks at a time. There are situations where the use of the depot form is not applicable. For example, in current practice, ziprasidone is administered once or twice daily in the form of an Immediate Release (IR) capsule for acute and long-term treatment of schizophrenia; or in the form of an intramuscular immediate release injection for acute control of anxiety in schizophrenic patients.

Ziprasidone is poorly soluble. Indeed, for the intramuscular immediate release formulation referred to above, even ziprasidone mesylate, which is generally soluble relative to other known ziprasidone salts, must be further solubilized, currently using a cyclodextrin as described in U.S. Pat. No.6,232,304 (incorporated herein by reference) to render it effective.

In the case of ziprasidone, poor solubility has been found, which implies that depot formulations are easy to make, the drug should not be too soluble (to avoid burst dissolution), the release must be extended, and when so constituted, do not actually provide sufficient pharmacokinetic exposure.

Thus, there is a need for an injectable depot formulation of aryl heterocyclic compounds such as ziprasidone which can provide drug delivery over a sustained period of time at concentrations effective for treating schizophrenia in mammals, including humans. In particular, there is a need for a pharmaceutical kit that can be conveniently used to prepare such depot formulations.

Summary of The Invention

The present invention is premised on the following findings: it is surprising that solubilized forms of aryl heterocycles, usually associated with (or at levels even greater than) immediate release, can be prepared as depot formulations. In one aspect, the invention relates to a pharmaceutical kit comprising an aryl heterocyclic compound, such as ziprasidone; the aryl heterocyclic compound may be solubilized or unsolubilized; and a structuring liquid carrier consisting of a viscous material, with the proviso that the aryl-heterocyclic compound is unsolubilized, said aqueous liquid further comprising a solubilizer.

Detailed Description

The pharmaceutical kit of the invention conveniently provides an injectable depot formulation having significantly higher solubility of the aryl-heterocyclic drug in the formulation. The cartridge of the present invention achieves this improved drug loading and delivery by cooperatively using a solubilizing agent and a viscous substance to obtain a controlled release that is representative of depot effect.

The invention is useful in the treatment of psychiatric disorders such as schizophrenia in mammals including humans in need of such treatment. The invention is also useful in the treatment of disorders and conditions for which ziprasidone administration facilitates treatment. Thus, the present invention has application in which ziprasidone applications are shown, for example, in U.S. patent nos.6,245,766, 6,245,765, 6,387,904, 5,312,925, 4,831,031; and european EP 0901789, published on 17.3.1999, which is incorporated herein by reference in its entirety.

Pharmaceutical compounds contemplated for use in the present invention are aryl heterocycles, preferably those having pharmacological activity, e.g. for the treatment of psychotic effects.

Without limitation, aryl heterocyclic compounds that are embodiments of the present invention have the following structure:

wherein

Ar is benzisothiazolyl or an oxide or dioxide thereof, each optionally substituted with one fluoro, chloro, trifluoromethyl, methoxy, cyano or nitro group: n is 1 or 2; and

x and Y together with the phenyl to which they are attached form a benzothiazolyl group; 2-aminobenzothiazolyl; benzisothiazolyl; (ii) an indazolyl group; 3-hydroxyindazolyl; an indolyl group; optionally substituted by one to three (C)₁-C₃) An alkyl group, or a chloro-, fluoro-or phenyl-substituted oxindolyl group, said phenyl group being optionally substituted with one chloro or fluoro; a benzoxazolyl group; 2-aminobenzoxazoleA group; benzoxazolonyl (benzoxazolonyl); 2-aminobenzoxazolinyl (2-aminobenzoxazolinyl), benzothiazolonyl (benzothiazolonyl), benzimidazolonyl (benzimidazolonyl), or benzotriazolyl. Representative examples of compounds falling within the foregoing definition are found in U.S. patent No.4,831,031, which is incorporated herein by reference.

In one embodiment, the present invention preferably applies to the above compounds, wherein X and Y together with the phenyl group to which they are attached form oxindole; more preferably, the oxindole moiety is 6-chlorooxindole-5-yl. In another preferred embodiment, Ar is benzisothiazolyl; in yet another preferred implementation, n is 1. A particularly preferred aryl heterocycle to which the present invention relates is ziprasidone, 5- [2- [4- (1, 2-benzisothiazol) -3-yl) -1-piperazinyl ] ethyl ] -6-chloro-1, 3-dihydro-2H-indol-2-one, which has the following structure:

although the aryl heterocyclic compounds described herein can be configured as the free base, it is preferred that the aryl heterocyclic compound be present as a pharmaceutically acceptable salt. The term "salt" in this regard means a pharmaceutically acceptable acid addition salt of an aryl heterocyclic ring, including ziprasidone. For the purpose of preparing the kit or formulation of the invention, the salt may be anhydrous or in the form of one or more solvates, such as hydrates, including mixtures thereof. The salts may also exist in different polymorphic forms. By way of example only, the mesylate salt of an aryl heterocyclic ziprasidone, as disclosed in U.S. Pat. Nos.6,110,918 and 6,245,765, both of which are incorporated herein by reference, may exist in the dihydrate or trihydrate form. Without limitation, preferred salts are selected from the group consisting of tosylate, tartrate, napsylate, besylate, aspartate, esylate, and mesylate. In a particularly preferred embodiment, the aryl heterocycle is ziprasidone mesylate, more preferably in the form of a trihydrate for purposes of preparing the kit or formulation. The term "ziprasidone" as used herein, unless otherwise indicated, includes all such forms of ziprasidone, i.e., ziprasidone free base, as well as pharmaceutically acceptable salts of ziprasidone, including anhydrous and hydrated forms of such salts.

The pharmaceutical kit of the present invention provides an injectable depot formulation that delivers the aryl heterocyclic active agent over a sustained period of time, i.e., for a period of time that exceeds that available from an immediate release injection system, at a concentration effective to treat a disease such as schizophrenia. Thus by way of further definition, the injectable depot formulations of the invention provide effective plasma levels of the active ingredient for, e.g., at least about 8 hours using typical injection volumes, e.g., from about 0.1ml to about 3ml, usually from about 1ml to about 2 ml. Preferably, the duration provided by the present invention is at least about 24 hours using the previously described injection volumes; more preferably up to about one week; still more preferably from about 1 week to about 2 weeks or more, including up to about 8 weeks. For example, in the case of ziprasidone, the practice of the invention can deliver at least about 0.5 to about 350mgA/ml depot formulation. Thus, at an injection volume of about 1-2ml, about 1 to about 700mgA per injection can be delivered over a sustained period. In another embodiment, from about 10mgA to about 560mgA ziprasidone are delivered over a sustained period. In yet another embodiment, from about 10mgA (e.g., 5mgA/ml) to about 420mgA ziprasidone (e.g., 210mgA/ml) per injection is delivered over a sustained period. In still further embodiments, from about 10mgA (e.g., 5mgA/ml) to about 280mgA (e.g., 140mgA/ml) ziprasidone per injection is delivered over a sustained period. In another embodiment, ziprasidone is delivered at about 10mgA to about 140mgA (e.g., 70mgA/ml) per injection over a sustained period. Preferred time periods for such amounts of ziprasidone delivered by injection are as described above, i.e., at least about 8 hours, preferably at least about 24 hours, more preferably at least about 1 week up to about 2 weeks, up to about 4 weeks and preferably up to about 8 weeks.

The pharmaceutical kit of the invention consists of at least two separate components: 1) a solubilized or unsolubilized aryl-heterocyclic compound, and 2) a liquid carrier for constructing the aryl-heterocyclic compound into an injectable formulation. The liquid carrier contains a viscous material and, when the aryl-heterocyclic is unsolubilized as defined herein, it also contains a solubilizer. When the two components of the cartridge are brought into contact, the solubilizer acts to solubilize the aryl heterocycle sufficiently to obtain the depot effect expected thereby. The two components may be part of a unitary structure, e.g., a dual chamber entity or the like; or more preferably they are provided in separate packages such as bottles and the like as known in the art. Thus, for example, a first package, e.g., a bottle, containing the aryl-heterocyclic and a second package, e.g., a bottle, containing the liquid carrier with the viscous substance and the solubilizer, if desired. The package is preferably shaped to allow the contents of one component to be mixed into the other component. In a preferred implementation, the bottle is made of glass or resin and is transparent or colored, such as amber. Preferably glass and more preferably amber glass is used for the aryl heterocyclic compound. The two components that make up the cassette of the present invention will now be further described.

In the practice of the present invention cartridge, the aryl heterocyclic compound may be solubilized or unsolubilized. The term "solubilized" and related variations of that term as used herein means that the heterocycle has a solubility in water that is in excess of its free or salt form to a degree sufficient to provide an extended duration of systemic exposure of the (depot) active at therapeutic levels contemplated by the present invention. Without limitation, the heterocyclic ring can be "solubilized" using cyclodextrin or other solubilizing agents to achieve the increased solubility contemplated by the present invention. Thus, the heterocyclic ring may be partially or fully dissolved and satisfy the definition of "solubilized". Conversely, the term "unsolubilized" and related variations of that term as used herein means that the heterocyclic ring has a solubility which is insufficient in nature and/or extent to provide the previously noted depot effect as intended. Under conditions where the aryl heterocycle is unsolubilized, the liquid vehicle comprising the viscous material also contains a solubilizing agent. In such an implementation, a sufficient amount of solubilizer is present in the liquid carrier to solubilize enough of the unsolubilized heterocyclic to render it soluble, suitable for the intended depot purpose.

It will be understood that various embodiments of the present invention cassette are applicable and all are within the intended scope of the present invention. For example, in one embodiment, the aryl heterocyclic compound is sufficiently solubilized to provide the desired depot effect; in this case, the liquid carrier may, but need not, contain any additional solubilizers. The solubilized aryl heterocycle in this regard can be in the form of a preformed complex with, for example, the cyclodextrin described herein. In another embodiment, the aryl heterocyclic may be partially soluble, but not enough to achieve the desired effect, i.e., the heterocyclic is "unsolubilized" for purposes of this specification. In this case, the liquid carrier contains at least sufficient solubilizer to make up the difference to dissolve enough of the still undissolved heterocyclic to provide the desired effect. Another embodiment is where the aryl heterocyclic is essentially not at all solubilized, i.e., it is "unsolubilized" for purposes of this specification. In this case, the liquid vehicle contains sufficient solubilizer to solubilize enough (if not substantially all) of the heterocyclic to obtain the depot effect. In the practice where the aryl heterocyclic ring is unsolubilized and the liquid vehicle contains the desired type and amount of solubilizer, it is preferred that when the liquid vehicle is contacted with the aryl heterocyclic compound, the contacting occurs for a period of time sufficient to effect solubilization of the heterocyclic ring prior to injection of the resulting depot formulation. For example, the two components should be allowed to contact for at least about 15 minutes, and more preferably, from about 15 minutes to about 45 minutes should elapse to effect solubilization prior to injection. As will be appreciated by those skilled in the art, this time can be reduced to less than 15 minutes by, for example, heating and/or using sonicators, vortexers, mixers, and the like. It is further preferred to shake, e.g. vibrate, the structured suspension, preferably for about 1 minute or more, e.g. about 2 minutes, just prior to injection.

For convenience, the invention will now be further described with ziprasidone as an example of an aryl heterocyclic compound. It is to be understood that the following discussion does not limit the scope of the invention and that the techniques described hereinafter are applicable to and can be adapted to the family of aryl heterocycles as disclosed herein. Other techniques for achieving the stated objectives may also be implemented and are contemplated within the scope of the invention.

The term "mgA/ml" as used herein refers to the weight (in milligrams) of aryl-heterocyclic compound, e.g., ziprasidone, per milliliter of composition to which the term is applied. For ziprasidone free base, the molecular weight is 412.9.

In one embodiment, the ziprasidone concentration in a depot formulation of the invention is from about 0.5mgA/ml to about 350mgA/ml, for example at least about 60mgA/ml, which concentration may include the amount in solution and the amount in suspension as such. More preferably, in the case of ziprasidone, the depot is present at a concentration of between about 70mgA/ml to about 280mgA/ml, including between about 140mgA/ml to about 210 mgA/ml; higher concentrations are also within the scope of the practice of the invention. Various techniques for solubilizing ziprasidone to achieve these levels of concentration involve, without limitation, the use of cyclodextrins and other solubilizing agents.

A preferred solubilizer is cyclodextrin. Cyclodextrins are cyclic oligosaccharides with hydroxyl groups on the outer surface and a cavity in the center. The outer surface is generally hydrophilic, and thus the cyclodextrin is soluble in water. On the other hand the cavities are generally hydrophobic. Cyclodextrins have the ability to form complexes with guest molecules, such as ziprasidone. Cyclodextrins contemplated by the present invention include, but are not limited to: alpha, beta, gamma-cyclodextrin, methylated cyclodextrin, hydroxypropyl-beta-cyclodextrin (HPBCD), hydroxyethyl-beta-cyclodextrin (HEBCD), branched cyclodextrins in which one or two glucose or maltose moieties are enzymatically linked to the cyclodextrin ring, ethyl and ethyl carboxymethyl cyclodextrins, dihydropropyl cyclodextrins, and sulfoalkyl ether cyclodextrins, such as sulfobutyl ether-beta-cyclodextrin (SBECD). As is known in the art, cyclodextrins may be unsubstituted, or fully or partially substituted; mixtures of cyclodextrins may also be used. Preferred cyclodextrins for use in the depot formulations of the present invention include gamma-cyclodextrin, HPBCD, SBECD or mixtures thereof; most preferably SBECD.

The complex of ziprasidone and cyclodextrin can be rendered soluble in water as described in U.S. Pat. No.6,232,304, which is incorporated herein by reference. For the purposes of the present invention, a preformed (solid) complex of cyclodextrin and ziprasidone may be used as the first component of the kit of the invention, or the cyclodextrin may be formulated separately into the depot formulation to solubilize the ziprasidone, for example by adding the cyclodextrin to a mixture with the viscous substance or other component that is part of the second component of the kit.

Viscous materials for use in the second component of the kit include those known in the art, such as viscosified water, pharmaceutically acceptable oils and oil-based materials, polymeric materials and other non-aqueous viscous carriers. Preferred viscous materials include, but are not limited to: cellulose derivatives, polyvinylpyrrolidone, alginates, chitosan, dextran, gelatin, polyethylene glycol, polyoxyethylene ethers, polyoxypropylene ethers, polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polycarbonates, polyorthocarbonates, polyphosphazenes, succinates, polycarbonates, poly (maleic acid), poly (amino acids), polyhydroxycellulose, chitin, copolymers and terpolymers of the above, and mixtures thereof. Preferred cellulose derivatives include methylcellulose, sodium carboxymethylcellulose (NaCMC) and hydroxypropylmethylcellulose. Preferred polylactides, polyglycolides, copolymers and terpolymers thereof include poly (lactic-co-glycolic acid) (PLGA). Also contemplated as viscous materials for use in the present invention are in situ gelling systems such as Stearic Acid (SA) and N-methylpyrrolidone (NMP) combinations, sucrose acetate isobutyrate, and PLGA.

In a first solubilizing embodiment, ziprasidone is solubilized with a cyclodextrin such as SBECD, wherein the cyclodextrin is present at a concentration of up to about 60% w/v, more preferably, about 40% w/v, still more preferably, about 30% w/v. In another embodiment, the depot comprises a cyclodextrin such as SBECD at a concentration of about 5% to about 35%, particularly about 10% to about 20%. In a preferred aspect, the depot is in this regard in the form of an aqueous suspension wherein a viscous substance such as NaCMC or the like is present in the water, e.g. sterile water for injection, in an amount sufficient to provide a viscosity of the depot of greater than 3.2cps, preferably between about 20cps and about 200cps, more preferably between about 30cps and about 165 cps. For example, NaCMC may be present in an amount of about 0.1% to about 3% w/v, preferably about 0.5% w/v to about 2% w/v. Pharmaceutically acceptable surfactants may optionally be used, and the surfactant may be present in this regard in an amount of up to about 1% w/v, preferably from about 0.01 to about 0.1%; the preferred surfactant is polyoxyethylene sorbitan ester, preferably polysorbate 80 (tween 80).

In a second solubilizing embodiment, a complex of ziprasidone and a cyclodextrin is formed and isolated in solid form. This solubilized solid complex is then suspended in a suitable viscosity vehicle, including a non-aqueous viscous material in which the ziprasidone-cyclodextrin complex is insoluble. Solid-displaying complexes can be obtained by freeze-drying the highly concentrated solution of the second embodiment described above. Suspending the freeze-dried complex in a non-aqueous viscous substance including, but not limited to: sesame seed oil, including aluminum monostearate (ALMS) gelled sesame seed oil, and in situ gelling systems such as Stearic Acid (SA) and NMP in combination.

The liquid carrier (second) component of the cartridge of the present invention may be aqueous or non-aqueous, taking into account the choice of solubilization technique used. In a preferred embodiment, the liquid carrier is aqueous, such as a liquid carrier comprising water for injection containing one or more of the above-described viscous materials. In embodiments of the kit of the invention using unsolubilized ziprasidone as the first component, it is preferred that the liquid carrier is aqueous and contains a cellulose-derived viscous material, in which case it is further preferred that the liquid carrier contains cyclodextrin as the solubilizing agent. The amount of viscous substance and solubilizing agent may vary depending on the dosing parameters, although the final viscosity of the depot formulation in the cartridge must be greater than 3.2cps, preferably between about 30 to about 165 cps.

In a preferred embodiment, the kit comprises a first package containing ziprasidone in an amount sufficient to provide at least about 10mg to about 30mg of ziprasidone per day for at least about 8 hours, more preferably at least about 24 hours, even more preferably from about 1 week to about 2 weeks, for a typical injection volume of from about 1ml to about 3ml, preferably from about 1ml to about 2 ml. Preferably, the ziprasidone is ziprasidone mesylate, more preferably ziprasidone mesylate trihydrate. Generally, it is preferred that the aryl heterocyclic compound is in a substantially dry form, such as a powder form, most particularly a micronized powder form. It is further preferred that the contents of the first package be sterilized, including, but not limited to, sterilization by irradiation or electron beam (e-beam). Preferably by gamma irradiation or electron beam irradiation; most preferably, by gamma irradiation, even more preferably by gamma irradiation at a dose of up to about 40kGy, for example from about 15 to about 35kGy, preferably about 25kGy, especially for ziprasidone mesylate.

In a preferred embodiment of the invention, the second package contains an aqueous solution of cyclodextrin at a concentration of up to about 60% w/v; a cellulose derived viscosity material at a concentration of about 0.1% w/v to about 3% w/v, preferably about 0.5% w/v to about 3% w/v. The pharmaceutically acceptable surfactant may also, optionally, be present in the second package at a concentration of up to about 1% w/v. When the aryl-heterocyclic is ziprasidone, the preferred viscosity agent is NaCMC, preferably at a concentration of about 0.1% to about 3%, preferably about 0.5% w/v to about 2% w/v. The liquid carrier is aqueous, preferably sterile water for injection. The solubilizing agent is preferably SBECD, present at a concentration of about 5% w/v to about 35% w/v of said water, and optionally a surfactant, and is preferably, without limitation, a polyoxyethylene sorbitan ester such as polysorbate 80, i.e. tween 80; more preferably, the surfactant is present at a concentration of about 0.01 to about 0.1% w/v. The water for injection is preferably present in an amount to provide an injection volume of about 1 to about 3ml per injection. The second package and its contents are preferably sterilized by suitable means, such as steam (autoclaves) sterilization at 121 ℃ for about 15 minutes.

In one embodiment, the pharmaceutical kit of the invention consists of: a first vial of (unsolubilized) ziprasidone mesylate trihydrate in the form of a sterilized, micronized powder, preferably in an amount of about 239mg (equivalent to about 175mgA ziprasidone); and a second vial of an aqueous carrier comprising sterile water for injection, about 30% w/v SBECD, about 0.5% NaCMC, about 0.02% polysorbate 80 (tween 80); the total volume of aqueous carrier so contained in the second vial was about 3 ml. This practice was developed to prepare 2.5ml of a 70mgA aqueous suspension of ziprasidone.

Various embodiments of the invention are provided in table 1, wherein the kit consists of unsolubilized ziprasidone (vial 1) and a Solubilizer (SBECD) and optionally a surfactant in water for injection (tween 80), whereby an aqueous suspension of 70mgA ziprasidone, suitable for, e.g., intramuscular depot injection, is obtained. An embodiment in which the pharmaceutical kit is used to prepare an aqueous suspension for injection, e.g., intramuscular depot, comprising 140mgA/ml of ziprasidone and 210mgA/ml of ziprasidone is provided in Table 2.

TABLE 1

A vial of 70mgA/ml aqueous suspension for IM depot injection was prepared and the combination indicated:

formulation number	Bottle 1: pharmaceutical powder	Bottle 2: carrier	Indication of medication
				1	Ziprasidone mesylate	30％SBECD+0.5％NaCMC	Constructing and immediately administering the drug
2	Ground medicament	30％SBECD+0.5％NaCMC	Constructing and immediately administering the drug
				3	1: 1 ratio of drug: composite material	0.5% NaCMC and 0.1% Tween 80	Constructing and immediately administering the drug
4	Ziprasidone mesylate	30% SBECD + 0.5% NaCMC + 0.1% Tween 80	The administration is carried out after 1 hour of incubation at 50 DEG C
				5	Ziprasidone mesylate	30% SBECD + 0.1% Tween 80	Constructing and immediately administering the drug
6	Ziprasidone mesylate	40％SBECD+0.5％NaCMC	Constructing and immediately administering the drug
				7	Ziprasidone mesylate	30% SBECD + 0.5% NaCMC + 0.1% Tween 80	The administration is carried out after 1 hour of incubation at 50 DEG C
8	Ziprasidone mesylate	30% SBECD + 0.1% NaCMC + 0.02% Tween 80	The administration is carried out after 1 hour of incubation at 30 DEG C
				9	Ziprasidone mesylate	30％SBECD+0.5％NaCMC + 0.02% Tween 80	The administration is carried out after 1 hour of incubation at 30 DEG C
10	Ziprasidone mesylate	30% SBECD + 0.25% NaCMC + 0.02% Tween 80	The administration is carried out after 1 hour of incubation at 30 DEG C

TABLE 2

Instructions for the preparation of 140 and 210mgA/ml aqueous suspensions with vehicles containing 10% and 20% SBECD and different combinations of two vials:

formulation number	Bottle 1: pharmaceutical powder	Bottle 2: carrier	Indication of medication
				1	Ziprasidone mesylate 735 mgA/bottle	1.5% NaCMC7LF, 10% SBECD, 0.1% Tween 804.6ml	Constructing and administering within 15 to 45 minutes
Containing 140mgA/ml in 10% SBECD carrier
	2	Ziprasidone mesylate 735 mgA/bottle	0.5% NaCMC 7H3SF, 20% SBECD, 0.1% Tween 804.6ml	Constructing and administering within 15 to 45 minutes
Containing 140mgA/ml in 20% SBECD vector
	3				Ziprasidone mesylate 735 mgA/bottle	1.5% NaCMC7LF, 10% SBECD, 0.1% Tween 802.9ml	Constructing and administering within 15 to 45 minutes
Containing 210mgA/ml in 10% SBECD vector
	4	Ziprasidone mesylate 735 mgA/bottle	0.5% NaCMC 7H3SF, 20% SBECD, 0.1% Tween 802.9ml	Constructing and administering within 15 to 45 minutes
Containing 210mgA/ml in 20% SBECD vector

The following examples are illustrative only; they are not to be construed as limiting the scope or spirit of the invention.

Example 1

The pharmaceutical kit contemplated by the present invention of one embodiment is prepared as follows:

bottle-1: to a previously washed 10ml amber glass vial, about 239gms ziprasidone mesylate trihydrate (equivalent to about 175mgA per vial) was manually added. Stoppered glass bottle and folded (crimped)Then sterilized by gamma irradiation at a dose of 25 kGy. + -. 10%. Bottle-1, constructed in accordance with the present invention, contains 239mg of sterile ziprasidone mesylate trihydrate, equivalent to 175mgA of ziprasidone.

Bottle-2: the aqueous liquid comprising the viscous substance and the solubilizer is prepared as follows: approximately 15mg of NaCMC 7H3SF was dispersed in approximately 1600mg of water for injection at room temperature, stirred at 350RPM for more than 2 hours until completely dissolved, and hydration of NaCMC was achieved. Thereafter, approximately 900mg of SBECD was dissolved in the NaCMC solution while stirring. Polysorbate 80 was added in an amount of approximately 0.6mg and make-up water for injection was added to bring the total water for injection used to about 2441.4 mg. The resulting solution was filtered through a filter unit (train) consisting of 10. mu.l polypropylene filter and 6. mu.l polypropylene filter. The initial filtrate was discarded and the subsequent filtrate was collected. Approximately 3ml of this subsequent filtrate was added to a 10ml flint type 1 glass tube. After the vial was stoppered and sealed, it was sterilized by auto-autoclaving at about 121 ℃ for about 15 minutes. Bottle-2, constructed according to the present invention, was an aqueous vehicle (3ml) containing 30% w/v SBECD, 0.5w/v NaCMC, and 0.02% polysorbate 80 (Tween 80).

Example 2

This example demonstrates the dissolution profile of ziprasidone over time after constitution, depending on the concentration in solution. A first set of 15 drug cassettes was prepared as in example 1. Using the same procedure as in example 1 (but with the viscous substance NaCMC7LF instead of NaCMC 7H3 sf. nacmcc 7LF having a lower viscosity than NaCMC 7H3 SF), a second set of 15 drug cassettes representing another embodiment of the invention was prepared.

Each drug cassette was configured as an injectable aqueous suspension depot formulation as follows: approximately 2.3ml of the aqueous carrier from vial 2 was injected into vial 1 containing ziprasidone powder. The dissolution profile was determined using 15 cartridges for each of the above embodiments, with 5 different time points, i.e., first, 15 minutes, 30 minutes, 60 minutes and 24 hours, 3 cartridges per time point, for the experimental protocol. The suspension from 3 drug cassettes at each time point was filtered through a 0.22 μm filter to give a clear supernatant for analysis. Vials designated as "initial" time point vials were prepared and used for HPLC analysis immediately after construction, one at a time. The resulting dissolution characteristics are reported in table 3 below:

TABLE 3

Time	0.5% NaCMC7LF average concentration. + -. SD (mgA/ml)	Average concentration of 0.5% NaCMC 7H3 SF. + -. SD (mgA/ml)
			Initially (n ═ 3)	14.2±1.19	18.1±0.48
15 minutes (n is 3)	21.4±0.14	20.5±1.21
			30 minutes (n is 3)	22.2±0.17	21.5±0.05
60 minutes (n is 3)	22.0±0.36	21.6±0.46
			24 hours (n is 3)	24.7±0.48	23.8±0.12

As can be seen from Table 3, the concentration stabilized at about 21 to 22mgA/ml from 15 to 60 minutes; thereafter, the concentration of ziprasidone solution increases only slightly, regardless of the viscosity of the carrier. Thus, the high viscosity of the solution does not affect the solubility of ziprasidone. Once constructed, the suspension depot formulation can be administered from 15 to 60 minutes without significant difference in the amount of drug in solution that the patient will receive. Because ziprasidone concentration does not change significantly after 15 minutes, an equilibration period of about 15 to about 60 minutes, more preferably about 15 to about 45 minutes, following constitution of the suspension prior to administration is a preferred practice of this embodiment of the invention.

Example 3

This example demonstrates the dissolution profile of a depot formulation of injectable ziprasidone aqueous suspension containing 140mgA/ml and 210mgA/ml according to the invention.

Each kit (140mgA/ml ziprasidone and 210mgA/ml ziprasidone) was configured as an injectable aqueous suspension depot formulation as follows: a 959mg vial was filled with 4.4ml of the vehicle construct to result in a 5ml 140mgA/ml suspension, and a 1438mg vial was filled with 4.2ml of the vehicle construct to result in a 5ml 210mgA/ml suspension. After the vehicle was added using a 5cc syringe fitted with an 18G needle, each tube was shaken by hand for 2 minutes and set aside for the desired time. The sample was shaken for an additional 2 minutes (except initially) before sample collection. Samples were collected at the initial, 15 minute, 45 minute, 3 hour, 6 hour, and 24 hour time points. Each time point and formulation configuration used two drug cassettes or 2 vials. The samples were centrifuged at 5000rpm for 5 minutes at 25 ℃. The supernatant was collected and filtered through a 0.45 μm filter (vehicle containing 10% SBECD) or first through 1 μm and then through 0.45 μm (vehicle containing 20% SBECD due to high viscosity). Clear supernatants were used to prepare HPLC samples and analyzed for drug concentration in solution as solubility. As can be seen from the results below, the solution concentration of ziprasidone in the formulation is significantly higher than the solubility of ziprasidone mesylate.

TABLE 4

Dissolution characteristics after construction of a 140mgA/ml aqueous suspension for IM depot injection:

Time	carrier containing 10% SBECD	Carrier containing 20% SBECD
			Average concentration of 1.5% NaCMC7LF, 10% SBECD and 0.1% Tween 80 in Water. + -. SD (mgA/ml)	Average concentration of 0.5% NaCMC 7H3SF, 20% SBECD and 0.1% Tween 80 in water. + -. SD (mgA/ml)
	Initially (n ═ 2)	8.11±0.05			13.97±0.47
15 minutes (n is 2)			9.22±0.06	17.68±0.35
	45 minutes (n is 2)	9.24±0.20			17.73±0.18
3 hours (n is 2)			8.89±0.05	17.72±0.24
	6 hours (n is 2)	9.18±0.09			17.54±0.35
24 hours (n is 2)			9.53±0.19	17.39±0.37

NaCMC7LF and NaCMC 7H3SF are low and high viscosity grades of NaCMC

TABLE 5

Dissolution characteristics of 210mgA/ml aqueous suspension for IM depot injection after construction.

Time	Carrier containing 10% SBECD	Carrier containing 20% SBECD
			Average concentration of 1.5% NaCMC7LF, 10% SBECD and 0.1% Tween 80 in Water. + -. SD (mgA/ml)	Average concentration of 0.5% NaCMC 7H3SF, 20% SBECD and 0.1% Tween 80 in water. + -. SD (mgA/ml)
	Initially (n ═ 2)	8.52±0.22			17.40±0.14
15 minutes (n is 2)			9.17±0.14	18.07±0.49
	45 minutes (n is 2)	9.17±0.05			17.80±0.56
3 hours (n is 2)			8.94±0.27	17.29±0.40
	6 hours (n is 2)	9.23±0.08			18.18±0.17
24 hours (n is 2)			9.14±0.13	17.56±0.38

NaCMC7LF and NaCMC 7H3SF are low and high viscosity grades of NaCMC.

Example 4

This example demonstrates the pharmacokinetic profile of the depot formulation obtained using the pharmaceutical kit prepared according to example 1. The kit of example 1 was constructed by injecting approximately 2.3ml of the water-soluble carrier of vial 2 into vial 1 to give 2.5ml of a 70mgA/ml ziprasidone aqueous suspension. After construction, the vial was shaken for about 1 minute, then set aside for about 15 minutes, and then shaken for about another 1 minute. The viscosity is between about 31 and 165 cps. A22 gauge, 1-1.5 inch needle was loaded with 2ml of the depot formulation so constructed as to give a dose of about 140mg ziprasidone.

The Pharmacokinetic (PK) profile of the above-described aqueous suspension depot formulation obtained from the pharmaceutical kit of the invention was studied in beagle dogs and compared to the following samples: comparative sample (1): an immediate release formulation consisting of solubilized ziprasidone, but no viscosity agent; and comparative sample (2): an aqueous suspension consisting of a viscous material (SBECD) and unsolubilized ziprasidone. The results are as follows: comparative sample (1) showed no depot effect, i.e. the serum concentration of ziprasidone was not quantifiable after 48 hours; there was no continuous serum concentration. Comparative sample (2) showed ziprasidone serum concentrations of 4.6 ± 2.4ng/ml (average 12-336 hours). In another aspect the present invention shows a serum concentration of ziprasidone of 12.9 ± 3.7ng/ml, which represents an increase of about 280% of the depot effect relative to the next closest sample, comparative sample (2).

Example 5

Table 6 shows the pharmacokinetic profile of a depot formulation of an aqueous suspension containing 140mgA/ml ziprasidone and 210mgA/ml ziprasidone using a kit according to the invention. Each formulation also contained 0.1% tween 80 in addition to ziprasidone; the formulation containing 10% SBECD additionally contained 1.5% NaCMC7LF, and the formulation containing 20% SBECD additionally contained 0.5% NaCMC 7H3 SF. These characteristics were obtained in six groups (groups a-F) of beagle dogs injected with the indicated depot formulations in a similar manner as described in example 4. The result was ng ziprasidone/ml plasma.

TABLE 6

Time	Group A:contains 140mgA/ml in 10% SBECD carrier; injection volume of 1ml	Group B:contains 140mgA/ml in 10% SBECD carrier; injection volume of 2ml	Group C:contains 210mgA/ml in 10% SBECD carrier; injection volume of 1ml	Group D:contains 140mgA/ml in 20% SBECD carrier; injection volume of 1ml	Group E:contains 210mgA/ml in 20% SBECD carrier; injection volume of 1ml	And F group:contains 210mgA/ml in 20% SBECD carrier; injection volume of 2ml
							One week (168 hours)	25.1	26.5	23.4	30.3	36.0	46.2
Two weeks (336 hours)	40.8	75.2	23.8	22.3	33.8	58.0
							Three weeks (504 hours)	10.9	20.6	7.71	7.69	9.30	17.0

Example 6

This example demonstrates the preparation of solubilized ziprasidone solid for use in a pharmaceutical kit embodiment of the invention. The solubilized ziprasidone in this example is a preformed complex of ziprasidone and a cyclodextrin.

The isolated complex of preformed ziprasidone mesylate trihydrate and cyclodextrin SBECD is prepared as follows: ziprasidone-SBECD complex isolated in solid form can be provided as a component of a pharmaceutical kit of the invention. In one embodiment of this example, the other component of the kit contains a liquid carrier in which the complex is insoluble, thereby forming a non-aqueous suspension of solubilized ziprasidone when the pharmaceutical kit is configured as a depot formulation.

A batch of 1095.3gm of solution was prepared in a water bath at 80 ℃. SBECD was dissolved in sterile water for injection (SWFI), and ziprasidone mesylate trihydrate was added to the resulting solution. Throughout the process, the solution was magnetically stirred. The drug solution (82mgA/ml) was filtered through a 0.45 μm filter and 2ml aliquots were removed into 20ml vials.

The vial solution prepared above was lyophilized to obtain ziprasidone-SBECD complex as a lyophilized solid. A freeze-drying cycle was used with the following conditions: 1) a freezing step: the temperature is-55 ℃ and the speed is 1 ℃/min; 2) initial drying: keeping at-32 deg.C for 7 days at 0.05 deg.C/min from-55 deg.C to-32 deg.C, and vacuum at 100 mTorr; 3) and (3) secondary drying: from-32 ℃ to 8 ℃ at 0.1 ℃/min, for 20 hours at 8 ℃, under a vacuum of 70mTorr, and then from 8 ℃ to 30 ℃ at 0.1 ℃/min, for 20 hours at 30 ℃, under a vacuum of 70 mTorr. The complex consists of about 80mgA/ml ziprasidone and about 56% SBECD.

Samples of the freeze-dried complexes were suspended in different biocompatible, sustained-release non-aqueous carriers. These dosage forms, and the ziprasidone serum concentrations they achieve after administration to beagle dogs, are shown in table 7 below:

TABLE 7

Numbering	Depot formulations	12-336 mean serum concentration (ng/ml) over a short period of time
			1	Suspension (60 mgA/ml; 2ml for injection) in sesame oil gelled with 2% aluminium monostearate (ALMS)	18ng/ml
2	Suspension in 100-300mg Stearic Acid (SA) in NMP (70 mgA/ml; 2ml injection)	18.76ng/ml

Example 7

This example demonstrates various representative dosing using embodiments of the pharmaceutical kit of the invention. A pharmaceutical kit prepared according to example 1 is provided. The construction of the drug cassette used to create the injectable depot formulation was as follows:

a3 ml Luer-Lok syringe fitted with 22G1 or a 1.5 inch needle withdraws 2.5ml of the liquid carrier from vial-2. Air bubbles are removed (e.g., by tapping). The volume of liquid carrier was brought to the 2.3ml mark on the syringe. Vial 1 is shaken (e.g., tapped) to ensure that ziprasidone is at the bottom of the vial. The liquid carrier in the syringe is injected into vial-1 with vial-1 in an upright position. Vial-1 was again shaken (tapped) so that any ziprasidone did not fall into the creases around the bottom of the vial. Before removing the needle syringe from vial-1, the syringe plunger is released to reduce positive pressure blockage in the vial. The syringe with the needle is withdrawn without pressing the plunger. The resulting suspension is shaken (e.g., mixed, shaken) for 2 minutes. The bottle was then set aside for 30. + -. 15 minutes. Just prior to administration, the vial suspension so constructed is shaken (e.g., shaken) for 2 minutes. For administration, a suitable syringe fitted with a 22G, 1 or 1.5 inch needle (or a 16-21 gauge needle) is used to withdraw a suitable volume of the homogeneous suspension. The generated (trapped) air bubbles were expelled by tapping the syringe barrel. The volume of suspension in the syringe was scaled appropriately to deliver doses of 7 to 140mgA as representatively described in table 8.

TABLE 8

The dose delivered (mgA)	Type of syringe	Volume of administration (ml)	Actual dose delivered, mean. + -. SD (mgA)
				7	1ml B-D Luer-Lok syringe	0.1ml	7.13±0.21
70	1ml B-D Luer-Lok syringe	1ml	69.08±1.05
				140	3ml B-D Luer-Lok syringe	2ml	136.23±2.39

Claims (15)

1. A medication cassette comprising:

(i) a solubilized or unsolubilized aryl-heterocyclic compound; and

(ii) a liquid carrier comprising a viscous material, with the proviso that: when the aryl-heterocyclic compound is unsolubilized, the liquid carrier also contains a solubilizer.

2. The kit of claim 1, wherein said aryl-heterocyclic compound is ziprasidone.

3. The pharmaceutical kit of claim 1 or 2, wherein said solubilizing agent is a cyclodextrin.

4. The pharmaceutical kit of claim 3, wherein said cyclodextrin is γ -cyclodextrin, β -cyclodextrin, HPBCD, SBECD, or a mixture thereof.

5. The pharmaceutical kit of any of claims 1-4, wherein said viscous substance comprises a cellulose derivative, polyvinylpyrrolidone, alginate, chitosan, dextran, gelatin, polyethylene glycol, polyoxyethylene ether, polyoxypropylene ether, polylactide, polyglycolide, polycaprolactone, polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polycarbonates, polyorthocarbonates, polyphosphazenes, succinates, polycarbonates, poly (maleic acid), poly (amino acid), polyhydroxycellulose, chitin, copolymers or terpolymers of the foregoing, sucrose acetate isobutyrate, PLGA, stearic acid/NMP, and combinations thereof.

6. The pharmaceutical kit of claim 5, wherein said cellulose derivative comprises methylcellulose, sodium carboxymethylcellulose, or hydroxypropylmethylcellulose; and wherein said polylactide, polyglycolide, or copolymers and terpolymers thereof comprise polylactic acid-glycolic acid copolymers.

7. A pharmaceutical kit according to any of claims 1 to 6, wherein said liquid carrier (ii) further comprises a pharmaceutically acceptable surfactant.

8. The kit of claim 7 wherein said surfactant is polyoxyethylene sorbitan ester.

9. A pharmaceutical kit for an injectable depot formulation, the kit comprising:

(i) a first package containing ziprasidone; and

(ii) a second package containing an aqueous solution of cyclodextrin, a cellulose-derived viscous substance, and optionally a pharmaceutically acceptable surfactant.

10. A kit for an injectable depot formulation according to claim 9, wherein the ziprasidone is present in an amount sufficient to provide at least about 0.5 to about 350mg ziprasidone per ml; said cyclodextrin is present in an amount sufficient to form a concentration of up to about 60% w/v; said cellulose-derived viscosity material is present at a concentration of about 0.5 to about 3% w/v; and said surfactant is optionally present in an amount sufficient to provide a concentration of up to about 1% w/v.

11. A kit for an injectable depot formulation according to claim 10 wherein said ziprasidone is present in an amount sufficient to provide at least about 10mgA to about 210mgA of ziprasidone per ml of said depot formulation.

12. The kit of claim 10 or 11 wherein said ziprasidone is ziprasidone mesylate; the cyclodextrin is SBECD; said cellulose-derived viscous substance is NaCMC; and said optional surfactant is polyoxyethylene sorbitan ester.

13. A kit for preparing an intramuscular depot injectable formulation of ziprasidone, the kit comprising:

(i) a first package containing sterilized micronized ziprasidone mesylate; and

(ii) a second package containing the following solutions: water suitable for injection; (ii) SBECD in an amount sufficient to form a concentration of about 5% to about 35% w/v of said depot injection; NaCMC in an amount sufficient to form a concentration of about 0.1% to about 3% w/v of said depot formulation; and an amount of polyoxyethylene sorbitan ester sufficient to form said depot injection formulation up to a concentration of about 1% w/v;

wherein said solution in (ii) is present in an amount sufficient to provide an injection volume of about 1 to about 3ml for injection, and said ziprasidone in (i) is present in an amount effective to deliver about 10 to about 30mg ziprasidone per day for about 1 to about 2 weeks with said injection volume.

14. A method of preparing an injectable depot formulation, the method comprising: contacting a solubilized or unsolubilized substantially dry aryl-heterocyclic compound with an aqueous liquid containing a viscosity agent and optionally a pharmaceutically acceptable surfactant to form a suspension, with the proviso that: when said aryl-heterocyclic compound is unsolubilized: a) said aqueous liquid further comprising a solubilizing agent, and b) said contacting is for a time sufficient to effect solubilization of said aryl-heterocyclic compound by said solubilizing agent prior to injection of said depot formulation.

15. The method of claim 14, wherein said aryl-heterocyclic compound is unsolubilized ziprasidone; the solubilizer is cyclodextrin; and the viscous substance is a cellulose derivative.