HK1092054A - Novel injectable depot formulations - Google Patents

Description

Novel depot injection

Technical Field

The present invention relates to injectable depot formulations (injectable formulations) for aryl-heterocyclic compounds such as arylpiperazine-C2 and-C4 alkylene heterocyclic compounds including ziprasidone and to processes for their preparation. The novel injectable depot formulations of the invention allow controlled release of the active aryl-heterocyclic ingredients over a prolonged period of time, for example after intramuscular administration to a patient.

Background

Certain aryl-heterocycles are known to have psychotropic effects. Ziprasidone is a chloro-hydroxy-indole aryl-heterocyclic compound often used as an atypical antipsychotic for the treatment of schizophrenia. Compared with the traditional antipsychotic, the atypical antipsychotic ziprasidone has obvious advantages, small side effects (such as extrapyramidal symptoms) and obvious treatment effect on some patients who have no effect on the traditional drug treatment. Some diseases such as schizophrenia are difficult to treat with drugs due to heterogeneity, and patients respond very differently to the same treatment modality. It is more difficult that the treatment period for diseases such as schizophrenia is long and that patients may not be treated according to the treatment schedule. In fact, it is generally accepted that most schizophrenic patients are not amenable to medication, and only a small fraction of patients can be treated. The lack of co-administration can lead to relapse of psychosis, thereby offsetting prior treatment results.

Since patient compliance is an issue, long-acting pharmaceutical dosage forms are highly desirable. I.e., a dosage form that enables sustained release of the drug over an extended period of time with a single administration. Simplifying the regimen that the patient must adhere to, thereby reducing the chance of noncompliance that can occur with more rigorous regimens. Depot formulations are one of these dosage forms and can be administered by a variety of routes of administration including intramuscular injection. Depot injections allow the drug to be slowly absorbed from the site of administration, each time maintaining the patient's blood level at the same therapeutic level for several days or weeks. However, this formulation has not been used in the following several cases. For example: ziprasidone immediate release capsules are administered 1 or 2 times a day for acute or long-term treatment of schizophrenia; intramuscular administration is used to rapidly control the excitability state of schizophrenic patients.

Ziprasidone is poorly soluble. For the direct intramuscular administration mentioned above, even ziprasidone mesylate (ziprasidone mesylate), which is relatively soluble in other known ziprasidone salts, has to be solubilized to render it therapeutically with the cyclodextrin mentioned in U.S. Pat. No. 6,232,304, which is incorporated herein by reference.

Ziprasidone is poorly soluble and is suitable for use in depot formulations, which do not require good solubility of the drug to avoid simultaneous release of large amounts of drug, necessitating extended release times of the drug, and in fact, use of such formulations does not provide adequate pharmacokinetic parameters.

Thus, in the treatment of schizophrenia and the like (including mammals such as humans), ziprasidone, an aryl-heterocyclic compound, requires a depot formulation to maintain an effective therapeutic concentration of the drug over a period of time.

Summary of The Invention

The present invention is based on the surprising fact that the solubilized forms of aryl-heterocycles, which are usually associated with a rapid release (or even a level of solubilization of the active ingredient greater than a rapid release), can be formulated as depot preparations. In one aspect, therefore, the present invention is directed to an injectable depot formulation comprising a solubilized aryl-heterocyclic compound, such as ziprasidone, and a viscosity agent.

Detailed Description

The depot injections of the present invention provide significantly enhanced solubility of aryl-heterocyclic drugs in the formulation. The present invention achieves improved drug loading and release through the use of solubilizers and viscosity agents, which are typical characteristics of depot formulations, to achieve controlled release of the drug.

The invention has great utility in the treatment of psychotic disorders such as schizophrenia in mammals including humans in need of such treatment. The invention is also useful for the treatment of other disorders and conditions which are facilitated by the use of ziprasidone. Thus, the present invention may be used, for example, in U.S. patent 6,245,766; 6,245,765; 6,387,904, respectively; 5,312,925; 4,831,031 and EP 0901789 published 1999, 3.17.C., all of which are incorporated herein by reference.

The drugs which can be used in the present invention include aryl-heterocyclic compounds, and are particularly suitable for drugs having pharmacological activity such as the treatment of psychiatric disorders. The present invention is not limited to the details of the aryl-heterocyclic compounds, and the structures of the embodiments of the aryl-heterocyclic compounds embodying the present invention are as follows:

ar is benzisothiazolyl or oxides and dioxides thereof, each of which is optionally substituted by one fluorine, chlorine, trifluoromethyl, formyl, cyano or nitro group, n is 1 or 2; and

x or Y forms, together with the phenyl group to which they are attached, a benzothiazolyl group; 2-aminobenzothiazolyl; benzisothiazolyl; (ii) an indazolyl group; 3-hydroxyindazolyl; an indolyl group; optionally 1-3C₁-C₃Alkyl, or 1 chloro-, fluoro-or phenyl-substituted hydroxyindolyl (oxindolyl), said phenyl being optionally substituted with one 1 chloro or fluoro; a benzoxazolyl group; 2-aminobenzoxazolyl; a benzoxazolonyl group; 2-aminobenzozazolinyl; a benzothiazolonyl group; a benzimidazolonyl group; or a benzotriazole group. Typical examples of compounds falling within the definition can be found in U.S. patent No.4,831,031.

In one embodiment, the present invention is preferably the above compound, wherein X or Y forms a hydroxyindole with the phenyl to which it is attached; more preferably, the hydroxyindole moiety is 6-chloro-hydroxyindol-5-yl. In a preferred embodiment, Ar is benzisothiazolyl; in another preferred embodiment, n is 1. A particularly preferred aromatic-heterocyclic compound suitable for the present invention is ziprasidone, having the structure:

although the aryl-heterocycles described herein may be in the form of the free base, it is preferred that the aryl-heterocycles are in the form of pharmaceutically acceptable salts. By "salt" herein is meant an acid addition salt of an aryl-heterocyclic compound such as ziprasidone. To form the dosage forms of the present invention, the salt may be in anhydrous form or in the form of one or more solvates, such as hydrates, including mixtures thereof. Salts may also exist in different polymorphic forms. For example, the mesylate salt of the aryl-heterocyclic ziprasidone may exist in dihydrate or trihydrate forms as described in U.S. Pat. Nos. 6,110,918 and 6,245,765, both of which are incorporated herein by reference. Without limitation, preferred salts are selected from the group consisting of tosylate, tartrate, naphthalenesulfonate, benzenesulfonate, aspartate, ethanesulfonate, methanesulfonate. In a particularly preferred embodiment, the aryl-heterocyclic compound is ziprasidone mesylate, more preferably in its trihydrate form.

As used herein, ziprasidone includes, unless otherwise specified, ziprasidone free base and all pharmaceutically acceptable salts of ziprasidone including all polymorphic forms thereof.

The injectable depot formulations of the invention provide release of an effective concentration of the aryl-heterocyclic compound over a sustained period of time, i.e., over the period of action of immediate release administration, for the treatment of certain conditions, such as schizophrenia. Further, the depot injections of the invention provide effective plasma concentrations of the active ingredient for at least about 8 hours using commonly used injection volumes such as about 0.1-3ml, 1-2 ml. Preferably, using the above injection volumes, the present invention provides a sustained release time of at least 24 hours; more preferably up to about 1 week; more preferably 1-2 weeks or including up to about 8 weeks.

For example, in the case of ziprasidone, such formulations of the invention are capable of delivering from 0.5 to 350mgA of drug per ml of injection. Typically, the injection volume is about 1-2ml, thus providing about 0.5-700mgA of ziprasidone for a sustained period of time. More preferably, ziprasidone is provided in an amount of about 10-560mgA, even more preferably about 280-560mgA, over a sustained period of time. As described above, administration of a depot injection results in a sustained release of ziprasidone over a period of time. In one embodiment, the period of time is at least 8 hours, more preferably at least about 24 hours, and even more preferably at least about 1 week. In another embodiment, the injection provides a sustained release of the amount of ziprasidone for a period of at least about 2 weeks. In another embodiment, the injection provides a sustained release of the amount of ziprasidone for a period of up to about 8 weeks.

In the practice of the invention, the aryl-heterocyclic is solubilized. The term "solubilization" and related terms as used herein means that the heterocyclic compound has a solubility in water that exceeds the solubility of the heterocyclic compound in its free or salt form, such that it provides a prolonged period of time for the active agent to interact with the body while achieving the desired therapeutic level. Without limitation, the heterocyclic compound is "solubilized" using a cyclodextrin or other solubilizing agent for the purpose of increasing solubility as defined herein. Thus, the heterocyclic compound may be partially or fully solubilized. For ease of understanding, the present invention is further described with ziprasidone as an example of an aryl heterocyclic compound. It is to be understood that the following discussion is not intended to limit the scope of the present invention and that the techniques described hereinafter are suitable for the aryl-heterocyclic compounds mentioned herein. Other techniques for accomplishing this may be used, and are contemplated in the inventive practice.

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

In one embodiment, the ziprasidone concentration (including dissolved and suspended drug) in the depot formulation of the invention is at least about 0.5 to 350mg/ml, such as about 60 mgA/ml. More preferably, for ziprasidone, the depot formulation has a concentration ranging from about 70 to 280mgA/ml, including about 140-210 mg/ml; higher concentrations are also within the scope of the invention. Ziprasidone is solubilized using various techniques such as cyclodextrins or other solubilizing agents to achieve the concentration ranges described above.

A preferred solubilizer (to form the solubilized aryl-heterocyclic compound) is cyclodextrin. Cyclodextrin is a hollow cyclic oligosaccharide with hydroxyl groups on the outside. The outer surface is hydrophilic so that the cyclodextrin is soluble in water, while its inner cavity is generally hydrophobic. Cyclodextrins are capable of forming complexes with guest molecules such as ziprasidone. Cyclodextrins for use in the present invention include, but are not limited to: α, β, γ -cyclodextrin; methylated cyclodextrins; hydroxypropyl β -cyclodextrin (HPBCD); hydroxyethyl-beta-cyclodextrin (HEBCD); branched cyclodextrins in which one or 2 glucose or maltose moieties are enzymatically attached to the cyclodextrin ring, ethyl-and ethyl-carboxymethyl cyclodextrins; (ii) a dihydropropyl cyclodextrin; and sulfoether cyclodextrins, such as sulfobutyl ether-beta-cyclodextrin (SBECD). As is well known in the art, cyclodextrins may be unsubstituted or partially, fully substituted; mixtures of cyclodextrins are also commonly used. Preferred cyclodextrins for the depot formulations of the invention include gamma-cyclodextrin, HPBCD, SBECD, and mixtures thereof; SBECD is the best choice.

The complex of cyclodextrin and ziprasidone enables them to be dissolved in water as described in U.S. patent 6,232,304, incorporated by reference above. For the purposes of the present invention, the cyclodextrin can be used as a preformed (solid) complex with ziprasidone, or the cyclodextrin can be added separately to the depot formulation to increase the solubility of ziprasidone, for example, the cyclodextrin or a viscosity agent or other ingredients can be added to the depot formulation together or as a mixture.

Viscosity agents include those known in the art such as viscous water, pharmaceutically acceptable oils and oil-based materials, polymers and other non-aqueous viscous vehicles. Preferred viscosity agents include, but are not limited to: cellulose derivatives, polyvinylpyrrolidone, alginates, chitosan, dextrans, gelatin, polyethylene glycols, polyoxyethylene ethers, polyoxypropylene ethers, polylactic acid, polyglycolic acid, polycaprolactone, polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polycarbonates, polyorthocarbonates, polyphosphazenes, succinates, polycarbonates, poly (maleic acid), poly (amino acids), polyhydroxycellulose, chitin and copolymers, terpolymers, and mixtures thereof of the foregoing. Preferred cellulose derivatives include methylcellulose, sodium carboxymethylcellulose (NaCMC) and hydroxypropylmethylcellulose. Preferred polylactic acid, polyglycolic acid, and copolymers and terpolymers thereof include poly (lactic-co-glycolic acid) (PLGA). Also contemplated as viscosity agents are in situ gelling systems such as Stearic Acid (SA) and N-methylpyrrolidone (NMP) combinations, sucrose acetate isobutyrate, PLGA.

In the practice of the present invention, the viscosity agent is present in an effective amount to achieve the desired effect in the depot formulation. It is further contemplated that an effective amount of a viscosity agent is an amount necessary to provide a viscosity of the depot formulation greater than 3.2 centipoise, more preferably from 20 to 200 centipoise, and even more preferably from 30 to 165 centipoise.

In a first embodiment of the invention, ziprasidone is solubilized using a cyclodextrin such as SBECD, wherein the concentration of cyclodextrin is up to about 60% w/v, more preferably, the concentration is about 40% w/v, more preferably the concentration is about 30% w/v. In another embodiment, the depot formulation comprises a cyclodextrin such as SBECD at a concentration of about 5% to 35%, particularly 10% to 20%. In a preferred aspect, the cyclodextrin depot formulation is included in the form of an aqueous suspension in which a viscosity agent, such as NaCMC or the like, is dissolved in water, such as sterile water for injection, and is present in an amount sufficient to provide a viscosity of the depot formulation greater than 3.2 centipoise, preferably between about 20 and 200 centipoise, and more preferably between about 30 and 165 centipoise. For example, NaCMC is present in an amount of about 0.1-3% w/v, preferably about 0.5-2% w/v. Optionally, the aqueous suspension depot formulation further comprises a pharmaceutically acceptable surfactant, for example a polyethylene sorbitan ester such as polysorbate 80(tween 80). Pharmaceutically acceptable surfactants are used in amounts of, for example, up to 1% w/v; preferably 0.01 to 0.1%.

In one implementation of the first embodiment, the depot formulation may be in the form of a kit, as described in commonly owned U.S. provisional application 60/421,295 filed on 10/25 2002 and those patent applications claiming priority from U.S. patent 60/421,295, the entire contents of which are incorporated herein by reference. Illustratively, the kit includes a first component, such as ziprasidone mesylate trihydrate powder, in an amount sufficient to provide a dosage in the above range, i.e., from 0.5mgA to 350mgA/ml of the depot formulation; and separately another component comprising a viscous aqueous carrier, such as NaCMC, and sufficient water to provide a total volume for injection of about 1-3ml, preferably 1-2 ml; and SBECD or another cyclodextrin, present in an amount of about 5 to 35% w/v to solubilize the ziprasidone. Optionally, a pharmaceutically acceptable surfactant, such as, without limitation, a polyethylene sorbitan ester, such as polysorbate 80(tween 80), is included with the viscous NaCMC solution to increase the moisture content of the dry ziprasidone when the two materials are mixed together to form the injectable depot formulation of the invention. A depot formulation as formulated according to one embodiment releases from 10 to 30 mg/day of ziprasidone over at least 8 hours, preferably over at least about 24 hours, more preferably over at least about 1 week, even more preferably over at least 2 weeks.

In a second embodiment of the invention, a high concentration of cyclodextrin such as SBECD is used. In this embodiment, the cyclodextrin acts here as a solubilizer and viscosity agent. That is, high concentrations of cyclodextrin and ziprasidone form aqueous solutions with viscosities high enough to provide a depot formulation. In this regard, the concentration of cyclodextrin that solubilizes ziprasidone is greater than 50% (w/v), preferably about 50% to 60% (w/v); more preferably, the concentration of cyclodextrin is about 55% -60% (w/v), such as about 56% -57% (w/v). Thus, in one implementation of this embodiment, about 80mgA/ml of ziprasidone is solubilized with about 56% SBECD to form an aqueous solution suitable for injectable depot formulations having a viscosity of about 22.6cps or greater. In optional practice, crystallization inhibitors such as polyvinylpyrrolidones (e.g., PVP30) may be added to retard crystallization and increase the physical stability of the depot formulation.

In a third embodiment of the invention, ziprasidone and a cyclodextrin are complexed and isolated as a solid. This solubilized solid complex can then be suspended in a suitable viscous vehicle, including non-aqueous viscous agents in which ziprasidone and cyclodextrin form a complex insoluble. Without limitation, the solid complex may be obtained by lyophilizing the high concentration solution of the second embodiment above. The lyophilized complex may be suspended in a non-aqueous viscous agent, including, but not limited to, sesame seed oil, including aluminum stearate, aluminum monostearate (ALMS) gelled sesame oil; and in situ gel systems such as Stearic Acid (SA) and NMP combinations.

In a fourth embodiment of the invention, ziprasidone is solubilized using a combination of cyclodextrin and one or more co-solvents in which ziprasidone is dissolved. Without limitation, mixtures of cyclodextrin SBECD with a co-solvent or co-solvents, such as pyrrolidone or a mixture of pyrrolidones, such as 2-pyrrolidone and/or NMP, in water, can be used to form the solubilized ziprasidone of the invention. Suitable viscosity agents, such as polyethylene glycol (PEG), may be used to form the injectable depot formulations of the present invention. For example, ziprasidone mesylate solutions up to 140mgA/ml can be prepared using approximately 60% NMP/water with 40% SBECD and 10% PEG (e.g., PEG 3350); in another implementation of this embodiment, a 140mgA/ml ziprasidone solution is prepared using 60% 2-pyrrolidone/water with 40% SBECD and 30% PEG3350 as the viscosity agent. In optional practice, crystallization inhibitors such as PVP30 may be added at up to 70 mg/ml. In another aspect of embodiments of the invention, a non-aqueous depot formulation can be formulated according to the invention using the above co-solvents with non-aqueous but polar solvents such as Benzyl Benzoate (BB). For example, a 140mgA/ml ziprasidone formulation with 30% BB, 70% 2-pyrrolidone and 40% SBECD having a viscous gel state suitable for long lasting effect can be prepared.

In addition, pH adjusting agents known in the art that are acidic in nature may be used in any of the foregoing formulations.

The following examples are illustrative only and should not be construed as limiting the scope or spirit of the invention.

Example 1

This example demonstrates an embodiment of the invention wherein a depot formulation comprises ziprasidone solubilized with cyclodextrin and a cellulose derivative as a viscosity agent to make an aqueous suspension.

175mgA ziprasidone powder in the form of ziprasidone mesylate trihydrate is provided. Ziprasidone powder is mixed with a vehicle consisting of:

SBECD：30％w/v

sodium carboxymethylcellulose (NaCMC): 0.5% w/v

Polysorbate 80(Tween 80): 0.02% w/v

Enough water for injection is added to 2.5 ml.

The total volume was 3 ml. Ziprasidone powder was mixed with 2.3ml of solvent to make 2.5ml of aqueous suspension with a concentration of 70 mgA/ml. After the resulting mixture was stirred for 1 minute, it was left to wet the ziprasidone powder for 15 minutes, and then stirred for another 1 minute. A syringe of specification A21 was used to load 2ml of the above mixture to provide a 140mg dose of ziprasidone. The viscosity is 31-80 cps.

Beagle dogs were used to study the Pharmacokinetic (PK) profile of the depot formulations of the aqueous suspensions described previously obtained from the kits of the invention and compared to the following samples: control sample (1): a solubilized ziprasidone immediate release formulation that does not contain a viscosity agent; and control sample (2): an aqueous suspension comprising unsolubilized ziprasidone and a viscosity agent (SBECD). 2ml was injected intramuscularly and the plasma levels were monitored over time. The results are as follows: control sample (1) had no depot effect, i.e. no serum concentration of ziprasidone was detected after 48 hours; no sustained serum concentrations developed. Control sample (2) maintained a serum concentration of 4.6. + -. 2.4ng/ml over 12-336 hours. In another aspect, the invention shows a serum concentration of ziprasidone of 12.9 + -3.7 ng/ml, which represents an increased depot effect, about 280% over the next closest sample-control sample (2).

Of the other four ziprasidone depot suspension dosage forms, each two dosage forms had ziprasidone concentrations of 140mgA/ml and 210mgA/ml, respectively, but were formulated using different concentrations of cyclodextrin, as set forth in Table 1:

TABLE 1

Vials and various combinations of instructions were used to prepare aqueous suspensions of 140 and 210mgA/ml in a vehicle containing 10 to 20% SBECD.

Recipe number	Bottle 1: pharmaceutical powder	Solvent	Instructions for use
				1	Ziprasidone mesylate 735 mgA/bottle	1.5％NaCMC 7LF，10％SBECD，0.1％Tween 804.6ml	Administered within 15-45 min after preparation
140mgA/ml, dissolved in vehicle with 10% SBECD
				2	Ziprasidone mesylate 735 mgA/bottle	0.5％NaCMC 7H3SF，20％SBECD，0.1％Tween 804.6ml	Administered within 15-45 min after preparation
140mgA/ml, dissolved in a vehicle with 20% SBECD
	3	Ziprasidone mesylate 735 mgA/bottle	1.5％NaCMC 7LF，10％SBECD，0.1％Tween 802.9ml	Administered within 15-45 min after preparation
210mgA/ml, dissolved in a vehicle with 10% SBECD
	4				Ziprasidone mesylate 735 mgA/bottle	0.5％NaCMC 7H3SF，20％SBECD，0.1％Tween 802.9ml	Administered within 15-45 min after preparation
210mgA/ml, dissolved in a vehicle with 20% SBECD

Example 2

This example demonstrates an embodiment of the invention wherein the depot formulation is a non-aqueous suspension comprising a pre-prepared ziprasidone/cyclodextrin complex and a viscosity agent.

The ziprasidone mesylate trihydrate and SBECD complex, prepared separately and in advance, was prepared as follows:

a batch of 1095.3gm of solution was prepared in an 80 degree water bath. After SBECD was dissolved in sterile water for injection (SWFI), ziprasidone mesylate trihydrate was added thereto. Magnetic stirring was carried out throughout the process. The drug solution (82mgA/ml) was filtered through a 0.45um filter, and 2ml of the drug solution was inhaled per 20ml vial.

The liquid filled vials are lyophilized to obtain a lyophilized powder of the ziprasidone/cyclodextrin complex. The conditions for lyophilization were as follows: 1) a freeze-drying step: the temperature is-55 ℃ and the speed is 1 ℃/min; 2) primary drying: standing at-55 deg.C to-32 deg.C at 0.05 deg.C/min at-32 deg.C for 7 days with vacuum degree of 70 mTorr; 3) secondary drying: -32 ℃ to 8 ℃, 0.1 ℃/min; standing at 8 deg.C for 20 hr, and vacuum degree of 70 mTorr. The complex consisted of approximately 80mgA/ml ziprasidone and 56% SBECD.

The lyophilized composite samples were suspended in a variety of biocompatible, slow-release, non-aqueous vehicles. The mean blood ziprasidone levels at 12-336 hours for beagle dogs receiving the non-aqueous depot suspension are shown in table 2.

TABLE 2

Group of formulas	Depot long-acting dosage form formulation	Mean blood concentration (ng/ml)
			1	Suspension in 2% aluminum monostearate (ALMS) gelled sesame oil (60 mgA/ml; 2ml for injection)	Reservoir 18ng/ml
2	Suspension in 100-300mg Stearic Acid (SA) in NMP (70 mgA/ml; injection 2ml)	Reservoir 18ng/ml

Example 3

This example demonstrates an embodiment of the invention in which a reservoir dosage form comprises ziprasidone solubilized with a cyclodextrin, which also functions as a viscosity agent. This particular example uses a high concentration of SBECD to prepare an aqueous solution of ziprasidone containing about 80mgA/ml ziprasidone and 56% SBECD.

To facilitate dissolution of the drug, a pre-weighed amount of SBECD (gram weight of SBECD corresponding to ml of depot formulation to be prepared) was dissolved in water heated in a water bath at 50 ℃. Ziprasidone mesylate was added in approximately 50mg increments and the system was held at a constant temperature of 50-60 ℃. Ziprasidone mesylate, in a total amount of 572.99mg, was added to 3ml of a 100% SBECD solution to make a clear viscous solution of 140mgA/ml (191 mg/ml). The liquid was cooled at room temperature and the solution remained clear for two weeks. Due to volume swelling, the final concentration of ziprasidone was approximately 80mgA/ml with 56% cyclodextrin.

The above solutions were scaled up to prepare stock solutions and the volumes were analyzed for swelling and ziprasidone concentrations were determined by HPLC:

stock solutions were prepared as described above, but with larger volumes (20ml) the dissolution time was longer (more than 4 hours), even with micronized ziprasidone. During the mixing process, a significant volume expansion can be noted. To correct for volume swell, the specific gravity of the solution was measured to be 1.188 gm/ml. This solution was prepared using 20ml of water and the final volume of the solution was 36.6ml, weighing 43.5 mg. Thus considering the volume expansion of 83%, the corrected concentrations of drug and SBECD in this solution were 77mgA/ml and 55% w/v, respectively. High performance liquid analysis of this solution using the potency method showed a potency of 75mgA/ml (102.3mg/ml) with no degradation products detected.

The two methods described above resulted in a ziprasidone solution of 77mgA/ml with 55% SBECD, indicating a higher solubility of ziprasidone at a relatively low molar ratio of SBECD to drug (1.3: 1), higher than expected based on the linear phase solubility diagrams of ziprasidone and SBECD. The extent of solubilization was further confirmed using the same method to make 82mgA/ml ziprasidone solution with 59% SBECD. The viscosity is greater than 160 cps.

Claims (15)

1. A depot injection comprising: a solubilized aryl-heterocycle; and a tackifier.

2. The injectable depot formulation of claim 1 wherein the aryl-heterocyclic compound is ziprasidone.

3. The injectable depot formulation of claims 1 and 2 wherein the aryl-heterocyclic compound is solubilized using cyclodextrin.

4. The injectable depot formulation of claims 1,2 and 3, optionally comprising a crystallization inhibitor and wherein the concentration of cyclodextrin is greater than 50% w/v.

5. The injectable depot formulation of claims 1,2 and 3 wherein the viscosity agent comprises a cellulose derivative, polyvinylpyrrolidone alginate, chitosan, dextran, gelatin, polyethylene glycol, polyoxyethylene ether, polyoxypropylene ethers, polylactic acid, polyglycolic acid, polycaprolactone, polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polycarbonates, polyorthocarbonates, polyphosphazenes, succinates, polycarbonates, poly (maleic acid), poly (amino acids), polyhydroxycellulose, chitin and copolymers, terpolymers, sucrose acetate isobutyrate, PLGA, stearic acid/NMP or combinations thereof.

6. The injectable depot formulation of claim 5 wherein the cellulose derivative comprises methylcellulose, sodium carboxymethylcellulose or hydroxypropylmethylcellulose and the polylactic acid, polyglycolic acid and copolymers and terpolymers thereof comprise lactic acid/glycolic acid copolymers.

7. The depot injection of claims 3, 4, 5 and 6 wherein the cyclodextrin is γ -cyclodextrin, β -cyclodextrin, HPBCD, SBECD or mixtures thereof.

8. The injectable depot formulation of claim 3 wherein said solubilized aryl-heterocyclic compound comprises a preformed complex with said cyclodextrin.

9. The injectable depot formulation of claim 3, further comprising water; optionally a crystallization inhibitor; a cosolvent containing pyrrolidone or a mixture of pyrrolidones.

10. The injectable depot formulation of claim 3, further comprising a non-aqueous polar solvent.

11. The injectable depot formulation of claims 1,2, 3 wherein the formulation has a viscosity of greater than about 3.2 cps.

12. A depot formulation for intramuscular injection comprising ziprasidone mesylate solubilized by SBECD; and a tackifier.

13. The depot formulation of claim 12 wherein the SBECD is at a concentration of about 5% to about 35% w/v and wherein the viscosity agent is a solution of sodium carboxymethylcellulose in an aqueous vehicle.

14. A depot formulation for intramuscular injection comprising:

ziprasidone mesylate in an amount sufficient to release at least about 10mgA to about 30 mgA/day of ziprasidone mesylate over a period of at least 8 hours to about 2 weeks, said ziprasidone mesylate solubilized with SBECD, said SBECD at a concentration of about 5% to about 35% w/v;

sodium carboxymethylcellulose, present at a concentration of about 0.25% w/v to 2% w/v;

optionally a pharmaceutically acceptable surfactant, present in an amount up to 1%; and

and (3) water.

15. A method of treating a psychotic disorder such as schizophrenia, comprising:

administering to a patient in need of said treatment by intramuscular injection a depot formulation comprising ziprasidone wherein ziprasidone mesylate is in an amount sufficient to release at least about 10mgA to about 30 mgA/day of ziprasidone mesylate over a period of at least 8 hours to 2 weeks, said ziprasidone mesylate being solubilized with SBECD, said formulation further comprising an adhesive.