FIELD OF INVENTION

The present invention relates to oral pharmaceutical compositions comprising ziprasidone or its pharmaceutically acceptable salts, and mixtures thereof.

More particularly, the present invention is related to oral pharmaceutical compositions comprising ziprasidone, wherein said composition comprises ziprasidone-ion-exchange complex in combination with pharmaceutically acceptable excipients.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ART

Ziprasidone is a psychotropic agent, having a neuroleptic action and is used for the treatment of schizophrenia.

Chemically it is 5-{2-[4-(l,2- benzisothiazol-3-yl)-l-piperazinyl]ethyl}-6- chloro-l,3-dihydro-2H-indol-2-one, having the structure presented below; formula (I), known generically as ziprasidone and is commonly used in the pharmaceutically accepted forms: crystalline ziprasidone itself, ziprasidone hydrochloride, ziprasidone hydrochloride monohydrate, ziprasidone mesylate. (chemistry bond)

It is commercially available in the United States and other countries as capsules [Geodon™; Zeldox™ (Ziprasidone HCl)] and IM injections [Geodon™ (Ziprasidone Mesylate)]

Ziprasidone is described in U.S. Patent Nos. 4,831,031 and 5,312,925.

Ziprasidone is a hydrophobic drug, having poor solubility and dissolution in aqueous solution and hence presents considerable challenge in formulating bioavailable dosage forms. Increasing the solubility and bioavailability of low- solubility drugs has been the subject of much research.

Typical approaches for the above research usually involve: (1) using particular excipients, which increase solubility, for example surfactants; (2) formulating the drug in a small particle size, thereby increasing the surface area of the drug to facilitate more rapid dissolution; (3) inclusion complexes with water- soluble carriers such as cyclodextrins; (4) solid dispersions with water-soluble carriers such as polymers and the like.

U.S. Patent No. 4,344,934 discloses the use of combination of drug and polymer for increasing drug solubilization, wherein poorly soluble drugs are mixed with polymers such as hydroxypropyl methylcellulose (HPMC) and added an aqueous surfactant solution to the drug-polymer mixture. While this results in improved dissolution, there is only slight enhancement of drug concentration in plasma, relative to the equilibrium concentration.

U.S. Patent No. 5,955,459 discloses the covalent conjugates of a fatty acid with certain antipsychotic agents, giving the unexpected property of extended therapeutic effectiveness.

U.S. Patent No. 6,150,366 describes compositions comprising crystalline ziprasidone free base or crystalline ziprasidone hydrochloride particles having a mean particle size equal to or less than 85 µm and a pharmaceutically acceptable carrier, as being substantially bioequivalent and useful to treat psychoses such as schizophrenia. However, the patent states that the reduced particle size approach to enhance the bioavailability of a drug can present difficult and expensive formulation and quality control challenges.

The present inventors have surprisingly found that ziprasidone in molecular complex with ion-exchange resin alleviates the inherent drawbacks of poor solubility and dissolution and produces oral solid pharmaceutical compositions which has comparable dissolution profile with that of the marketed dosage form Geodon™.

SUMMARY AND OBJECTIVES OF THE INVENTION

The present invention relates to oral pharmaceutical compositions comprising ziprasidone or its pharmaceutically acceptable salts, and mixtures thereof.

More particularly, the present invention is related to oral pharmaceutical compositions comprising ziprasidone, wherein said composition comprises ziprasidone-ion-exchange complex in combination with pharmaceutically acceptable excipients.

In one embodiment, the present invention provides a molecular complex of ziprasidone with ion-exchange resins in combination with optionally one or more pharmaceutically acceptable auxiliary ingredients.

In an another embodiment, the present invention provides a process for preparing a complex of ziprasidone with ion-exchange resins in combination with optionally one or more pharmaceutically acceptable auxiliary ingredients.

In another embodiment, the present invention provides oral pharmaceutical compositions comprising ziprasidone ion-exchange complex and one or more pharmaceutically acceptable excipients.

In yet another embodiment, the present invention provides a process for preparing oral pharmaceutical composition comprising ziprasidone ion-exchange complex and one or more pharmaceutically acceptable excipients.

U.S. Patent No. 6,399,777 discloses the method of increasing the solubility of ziprasidone hydrochloride salts by preparing inclusion complexes of ziprasidone hydrochloride with cyclodextrin. However, cyclodextrin preparations have several disadvantages, as the drug loading is low and this method only works with drugs which fit into the cavity of the cyclodextrin and which have a high complex-forming constant.

U.S. Patent Application Nos. U.S. 2003/0228358, U.S. 2003/0224043 and U.S. 2003/0219489 disclose solid amorphous dispersions of drugs with polymers to increase drug bioavailability. However the solid dispersion technique also is associated with several drawbacks, such as change in the polymorphic form of the drug used; use of high temperature; use of organic solvents; and further the process is time-consuming and being expensive.

Other means of attempting to improve ziprasidone solubility and dissolution characteristics include providing ziprasidone as monohydrate, hemi- hydrate, and anhydrate as disclosed in U.S. Patent No. 5,312,925; preparing prodrugs as disclosed in U.S. Patent No. 5,935,960; and preparing ziprasidone mesylate hydrates as in U.S. Patent No. 6,110,918 and U.S. Patent No. 6,245,765.

All of the above techniques used to make a formulation of ziprasidone hydrochloride are time-consuming and involves numerous complexities as a part of the process and not all the process are economical. Hence, there is a need for a process to formulate ziprasidone hydrochloride wherein the solubility and dissolution characteristics are independent of the above discussed drawbacks and produce the requisite bioavailability and pharmacological actions.

It has been unexpectly found that the above problem can be addressed by incorporating ziprasidone in molecular complex with ion-exchange resins and formulating the said complex in to suitable dosage form in combination with pharmaceutically acceptable excipients.

Further embodiment of the present invention provides for oral pharmaceutical compositions of ziprasidone wherein the in vitro dissolution release profile matches with the commercially available formulations of ziprasidone.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1: DSC thermogram of Ziprasidone Hydrochloride monohydrate.

Fig. 2: DSC thermogram of Ion-exchange resin: Amberlite™ IRP 88.

Fig. 3: DSC thermogram of Ziprasidone Hydrochloride monohydrate-Amberlite™ IRP 88 complex.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to oral pharmaceutical compositions comprising ziprasidone or its pharmaceutically acceptable salts, and mixtures thereof.

More particularly, the present invention is related to oral pharmaceutical compositions comprising ziprasidone, wherein said composition comprises ziprasidone-ion-exchange complex in combination with pharmaceutically acceptable excipients.

An embodiment of the invention provides for a molecular complex of ziprasidone with ion-exchange resin in combination with optionally one or more pharmaceutically acceptable auxiliary ingredients.

In the context of the present invention, the terms "active" or "active ingredient" or "drug" or "drug substance" or "pharmacologically active agent" or "active substance" may be used interchangeably and synonymously for ziprasidone.

The tenn "ziprasidone" as used herein includes both the free base of ziprasidone and all pharmaceutically acceptable salts and hydrates of this compound. The preferred ziprasidone salts are ziprasidone mono hydrochloride, ziprasidone mono hydrochloride monohydrate, ziprasidone dihydrochloride, ziprasidone dihydrochloride dihydrate and ziprasidone mesylate.

The term "molecular complex" as used herein refers to the ziprasidone product which is the result of a reversible process of exchange of ions between the drug particles and the ion-exchange resins.

Ion-exchange materials are used to exchange ions between a solution and an insoluble solid. Ion exchange resins may be of both inorganic and organic origin. Organic ion exchangers consist of hydrocarbon polymers in which ionizable exchange groups have been introduced i.e. fixed anionic (cationic exchangers) or cationic groups (anionic exchangers) which have mobile cations and anions, respectively, associated with them.

A wide range of cationic ion-exchange resins is potentially available to form drug-resin complexes for use in the present invention. Suitable pharmaceutically acceptable cationic ion-exchange resins are commercially available and include a range of synthetic cationic ion-exchange resins with different polymeric matrices which may be cross-linked. A synthetic cationic ion- exchange resin may for example be a polymer of styrene, or acrylic or methacrylic acid, and the resin may derive its exchange activity from either weakly or strongly acidic groups such as carboxylic acid or sulphonic acid groups.

Ion-exchange resins, particularly suitable for use in compositions of the invention, include strongly cationic resins having sulphonic acid groups on a polystyrene polymer matrix, which resins are suitably cross-linked, preferably by a divinyl or polyvinyl compoimd such as divinylbenzene. Suitable resins are those commercially available under the trade names Amberlite™ and Duolite™ from Rohm and Haas Co. and Dowex™ from the Dow Chemical Co. The resin may be in either acid form or in the form of a salt with an alkali metal such as sodium or potassium.

Examples of drug-resin complexes for use in the present invention are those formed between ziprasidone and the sodium form of a sulphonated styrene- divinylbenzene resin, for example Amberlite™ IRP-69, or the potassium form of a methacrylic acid-divinylbenzene resin, for example Amberlite™ IRP-88, A further example is that formed between ziprasidone and a methacrylic acid- divinylbenzene resin in the free acid form, for example Amberlite™ IRP-64.

The scope of invention is not limited to any particular ratio of the drug to ion-exchange resin. It has however been found that optimal adsorption and release of drug is achieved when the drug content of the drug-resin complex is at least 40% by weight, suitably between 45% and 70% by weight and preferably between 50% and 65% by weight.

The drug ion-exchange resin complex can be prepared by any of the methods known in the art. The typical method, known to those skilled in the art, for loading ionizable substances onto an ion exchange resin to form the drug-ion exchange resin complex is to dissolve an acidic or basic, ionizable substance in water, and then mix it with a suitable ion exchange resin. See, for example, U.S. Patent No. 2,990,332.

The drug ion-exchange resin complex of the present invention can be prepared by admixing the drug and ion-exchange resin in deionized water with stirring, washing thoroughly with deionized water, filtering it under vacuirai in a Buchner fimnel, and then dried in a suitable drier to yield a drug-resin complex.

The drug ion-exchange resin complex is characterized using different techniques. Preferable technique according to the present invention is Differential Scanning Calorimetry (DSC), which is performed, according to standard methods, for example those described in Hoehne, G.W.H. et al (1996), Differential Scanning Calorimetry, Springer, Beriin. All DSC thermograms according to the present invention were recorded on a Mettler-Toledo SR instrument.

The DSC thermograms of ziprasidone hydrochloride monohydrate, ion- exchange resin Amberiite™ IRP-88, and the ziprasidone hydrochloride monohydrate-Amberiite™ IRP-88 complex are illustrated in Fig. 1, Fig. 2 and Fig. 3 respectively. The DSC thermograms are characterized by sharp endothermic peak at their respective melting points. Ziprasidone hydrochloride monohydrate has a melting point in the range of 290°C-310°C, and a corresponding endothermic peak can be seen in Fig. 1. Similar observations are also observed in case of DSC thermogram of Amberiite™ IRP-88 as shown in Fig. 2. However, the DSC thermogram of ziprasidone hydrochloride monohydrate-Amberlite™ IRP-88 complex as illustrated in Fig. 3 shows the absence of the characteristic endothermic peak observed in Fig. 1 and the presence of a new endothermic peak at around 152°C and 230°C, thus showing the formation and presence of ion- exchange complex with the drug; as a result of which the typical physical properties of ziprasidone are altered.

An embodiment of the invention provides for a molecular complex of ziprasidone with ion-exchange resin in combination with optionally one or more pharmaceutically acceptable auxiliary ingredients.

Suitable pharmaceutically acceptable auxiliary ingredients which can be used in combination with ziprasidone ion-exchange complex include, but are not limited to hydrophilic carriers like polymers of N-vinyl pyrrolidone commonly known as polyvinylpyrrolidone (PVP), gums, cellulose derivatives, cyclodextrins, gelatins, hypromellose, hypromellose phthalate, sugars, polyhydric alcohols, polyethylene glycol, polyethylene oxides, polyoxyalkylene derivatives, methacrylic acid copolymers, polyvinyl alcohol, propylene glycol derivatives and the like.

Any pharmaceutically acceptable auxiliary ingredient is acceptable as long as it allows the formation of the molecular complex of ziprasidone ion-exchange complex as described herein is compatible with ziprasidone and is acceptable for pharmaceutical use. The choice of such an auxiliary ingredient is within the scope of understanding of a person skilled in the art and is not limited by the above listed examples.

The present invention provides for oral pharmaceutical compositions comprising ziprasidone ion-exchange resin complex and one or more pharmaceutically acceptable excipient and a process to prepare the same.

The drug ion-exchange complex of the present invention can be formulated as solid compositions for oral administration in the form of tablets, capsules, pills, powders, granules, particles, pellets, beads, or mini-tablets. Preferably the composition in the form of tablets, mini-tablets, capsules or granules are preferred. In these compositions, the drug ion-exchange resin complex is mixed with one or more pharmaceutically acceptable excipients.

Pharmaceutically acceptable excipients which can be used in the preparation of the composition according to the invention may include, but are not limited to diluents such as microcrystalline cellulose (MCC), silicified MCC, lactose, starch, pregelatinized starch, mannitol, sorbitol, dextrates, dextrin, calcium carbonate, calciimi sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesiimi carbonate, magnesium oxide and the like; binders such as PVP, cellulose derivatives such as hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, carboxy methyl cellulose sodium, starch and the likes; disintegrants such as cros-povidone, sodium starch glycolate, starch and its derivatives, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose and the like; glidant and lubricants such as colloidal silicon dioxide, talc, stearic acid and its salts and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film former, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

The compositions according to this invention are prepared by forming a homogenous mixture in which the active ingredient in the form of drug ion- exchange complex is combined with other pharmaceutically acceptable excipients and are either filled into the capsule shell or compressed into tablets.

Processing techniques employed prior to filling into the capsule shell or compressing into a tablet involve granulation techniques such as dry granulation or wet granulation. In dry granulation, the ingredients are blended in dry form, made denser by slugging or compaction and reduced to granules by grinding or milling, using suitable eqmpments. The groimd particles or granules are then either filled into empty capsule shells or compressed into tablet form in conventional manner using lubricants, glidants, etc., which can take any of the conventional shapes, e.g., roimd, elongated, oval, etc. A tablet press fitted with suitably sized punches and dies is used to form the tablet core.

The wet granulation technique can also be used. According to this procedure, the dry active ingredient in the form of complex with ion-exchange resins, and other diluents are blended, for example, in a planetary mixer or a rapid mixer granulator. The powders are wetted with a granulating liquid like water, isopropyl alcohol or acetone or dichloromethane and other hydro-alcoholic solvents such as isopropyl alcohol-water mixture. Binders may be included in the granulating liquid. The moist mass is granulated, e.g., by forcing through a screen of suitable mesh size, dried, and, if desired, the particles further reduced in size. Granulates are then either filled into empty capsule shells or compressed into tablets in conventional manner, using lubricants, glidants, etc., as required.

The tablet core can optionally be coated with a film coat, which provides an aesthetic appeal or can also provide some functional role such as moisture protection, taste masking etc. The film coat may comprise polymers such as cellulose derivatives such as one which is commercially available as Opadry®.

Conventional coating machines, for example, pan coaters, rotary drum- type coaters, Wurster-type fluidizing coaters and fluidizing coaters may be employed in the method of the invention.

Further embodiment of the invention provides for oral pharmaceutical compositions of ziprasidone wherein the in vitro dissolution release profile matches with the commercially available formulations of ziprasidone.

The compositions according of the present invention can be used for the treatment of schizophrenia, bipolar mania, agitation in schizophrenic patients and other neuro-psychotic conditions.

The following examples illustrate specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.

A. Ziprasidone Ion-exchange complex

Example: 1

Brief manufacturing procedure:

1. Ziprasidone hydrochloride monohydrate is added in water followed by Amberlite™ IRP 88 and stirred for 24 hours.

2. This suspension is filtered under vacuum and solid mass is dried at 50°C.

3. Dried material is sifted through 30 mesh and filled in hard gelatin capsule.

The above complex of ziprasidone was studied for drug release to evaluate the effect of the ion-exchange resin complex with ziprasidone on drug release and dissolution. The drug release was studied in pH 7.5 Phosphate Buffer with 2% SLS, 900 ml, USP II [Paddle] dissolution apparatus at 75 rpm. The results are enumerated in Table 1.

Table 1:

B. Compositions comprising Ziprasidone Ion-exchange Complex.

Example 2:

Brief manufacturing procedure:

1. Ziprasidone Hydrochloride complex with Amberlite™ 88, Lactose monohydrate, pregelatinized starch are sifted through #40 mesh and mixed for 10 minutes in a blender.

2. This blend is compacted in roller compacter and further compacted flakes are milled to get granules.

3. Above granules are lubricated using magnesium stearate (previously sifted through #60 mesh) and filled in hard gelatin capsule.

Example 3:

Brief manufacturing procedure:

1. Sift Ziprasidone HCl monohydrate and Amberlite IRP 88 separately with mechanical sifter fitted with appropriate sieve/Quadro Comill fitted with an appropriate screen.

2. Stir Ziprasidone HCl monohydrate, Amberiite IRP 88 in sufficient quantity of water for sufficient time.

3. Pass step 2 in colloidal mill for sufficient time.

4. Dissolve Povidone in sufficient quantity of purified water under stirring.

5. Add step 4 ingredients to step 3 materials under stirring and stir for sufficient time.

6. Sift Lactose with mechanical sifter fitted with appropriate sieve/Quadro Comil fitted with an appropriate screen.

7. Granulate Lactose of step 6 with solution of step 5 in a Fluidized Bed Processor.

8. Dry the granules of step 7 till the desired loss on drying is achieved.

9. Pass the dried granules of step 8 through mechanical sifter fitted with appropriate sieve/Quadro Comil fitted with an appropriate screen.

10. Sift magnesium stearate with mechanical sifter fitted with appropriate sieve/Quadro Comil fitted with an appropriate screen.

11. Lubricate step 9 ingredients with step 10 materials in bin blender for suitable time and filled the resultant blend in hard gelatin capsules.

The composition according to Example 2 and Example 3 was tested for in- vitro drug release profile in pH 7.5 Phosphate Buffer with 2% SLS, 900 ml, USP II [Paddle] dissolution apparatus at 75 rpm and compared with the marketed product Geodon™ Capsules also tested under the same conditions. The results are enumerated in Table 2.

Table 2:

From above dissolution data it is seen that formulations of Ziprasidone HCl capsules 20 mg using Ziprasidone HCl resinate shows drug release of more than 60% in 60 minutes and is comparable with the marketed product Geodon™ Capsules 20 mg.

WE CLAIM

1. Ziprasidone ion-exchange complex comprising ziprasidone or its pharmaceutically acceptable salt thereof and an ion-exchange resin.

2. The ion-exchange resin according to claim 1, selected from a group consisting of polymers or co-polymers of styrene, acrylic and methacrylic acids.

3. The ziprasidone ion-exchange complex according to claim 1, further comprises one or more pharmaceutically acceptable auxiliary ingredients.

4. The auxiliary ingredients according to claim 3, are selected from the group comprising N-vinyl pyrrolidone, gums, cellulose derivatives, cyclodextrins, gelatins, hypromellose, hypromellose phthalate, sugars, polyhydric alcohols, polyethylene glycol, polyethylene oxides, polyoxyalkylene derivatives, methacrylic acid copolymers, polyvinyl alcohol, propylene glycol derivatives and mixtures thereof.

5. A process for preparing a ziprasidone ion-exchange complex according to claim 1, wherein said process comprises:

a) admixing ziprasidone or its pharmaceutically acceptable salts and ion-exchange resin in de-ionized water with stirring to form a suspension/ dispersion;

b) washing the above suspension/ dispersion thoroughly with de- ionized water and filtering it under vacuum; and

c) drying the filtrate obtained in b) to form ziprasidone ion-exchange complex.

6. An oral pharmaceutical composition comprising ziprasidone or its pharmaceutically acceptable salts thereof, wherein said composition comprises ziprasidone-ion-exchange complex in combination with atleast one pharmaceutically acceptable excipient.

7. The composition according to claim 6, wherein said pharmaceutically acceptable excipient is selected from the group consisting of diluents, binders, glidants, lubricants, film former, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and mixtures thereof.

8. The composition according to claim 6, wherein said composition is in the form of tablets, capsules, pills, powders, granules, particles, pellets, beads, mini-tablet or combinations thereof.

9. An oral pharmaceutical composition comprising ziprasidone or its pharmaceutically acceptable salts thereof, wherein said composition comprises about 20-40% by weight of ziprasidone hydrochloride; about 10-25% by weight of Amberlite™ IRP 88; about 1-7% by weight of polyvinyl pyrrolidone; about 40-60% by weight of lactose monohydrate, and about 0.3 - 1.5% by weight of magnesium stearate.

10. A process for preparing an oral pharmaceutical composition comprising ziprasidone or its pharmaceutically acceptable salts thereof, wherein said process comprises:

a) admixing ziprasidone or its pharmaceutically acceptable salts and ion-exchange resin in de-ionized water with stirring to form a suspension/ dispersion;

b) washing the above suspension/ dispersion thoroughly with de- ionized water and filtering it under vacuum; and

c) drying the filtrate obtained in b) to form ziprasidone ion-exchange complex.

d) admixing ziprasidone ion-exchange complex with a binder solution;

e) granulating lactose and optionally other pharmaceutically acceptable excipient with said binder solution containing ziprasidone ion-exchange to get granules;

f) drying and optionally milling said granules;

g) lubricating said granules with suitable lubricants and glidants and optionally other pharmaceutically acceptable excipient; and

h) filling said lubricated granules in a suitable capsule shell.