FIELD OF INVENTION

The invention relates to a novel process for preparing pharmaceutical composition comprising antipsychotic agent or its pharmaceutically acceptable salts thereof. More particularly, the invention relates to a novel process for preparing ziprasidone pharmaceutical compositions.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ART

Ziprasidone is an antipsychotic agent and used for the treatment of schizophrenia and also for the treatment of bipolar disorder. Chemically it is known as (5-[2-[4-(l, 2-benzisothiazol-3-yl)-l-piperazinyl] ethyl]-6-chloro-l, 3-dihydro-2H-indol-2-one mono hydrochloride, monohydrate and is disclosed in US 4,831,031 and US 5,312,925.

Ziprasidone is marketed under the trade name Geodon in the form of capsule in the US and Europe, which contains ziprasidone hydrochloride, lactose, pregelatinized starch and magnesium stearate.

Ziprasidone is typically administered as the hydrochloride acid addition salt. The hydrochloride salt is advantageous in having high permeability however; it has very poor aqueous solubility. In addition to this, ziprasidone is difficult to wet which is problematic when formulating its dosage form. Further, when it comes in contact with an aqueous liquid, ziprasidone tends to form agglomerates, which would also slow down the dissolution of ziprasidone when in contact with GI fluids. The relatively poor aqueous solubility ultimately unfavorably affects the bioavailability.

US 6,150,366 disclose ziprasidone formulations, wherein said formulation comprises crystalline ziprasidone free base or crystalline ziprasidone hydrochloride particles having a mean particle size equal to or less than about 85 micrometers and are shown to exhibit good dissolution properties at physiological pH. This patent suggests micronisation of ziprasidone to improve bioavailability. However, the formulation prepared using above approach has a very limited solubility in term of solubilisation as the particle size modification will results only the rate of solubilisation and not the overall solubility of ziprasidone HC1.

US 8,026,286 and US 8,202,912 discloses a composition comprising: (a) a drug in a pharmaceutically acceptable solubility-improved form that is a crystalline highly soluble salt form other than the crystalline hydrochloride salt; and (b) a concentration-enhancing polymer selected from the group consisting of cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose phthalate, and hydroxypropyl methyl cellulose acetate succinate wherein said drug alone has an aqueous solubility of up to about 1 to 2 mg/mL; and said composition is not a dispersion and said drug and said polymer are present as particles in a dry physical mixture.

US 7,939,104 and US 7,727,556 discloses a composition having improved solubility comprising a hydrophobic drug or pharmaceutically acceptable salt thereof including ziprasidone and a compound having at least one carboxylic acid moiety, wherein the molar ratio of the compound having at least one carboxylic acid moiety to the hydrophobic drug or pharmaceutically acceptable salt thereof is from about 0.1:1 to about 25:1.

US 7,887,840 discloses a ziprasidone composition comprising: (a) a drug in a solubility-improved form and (b) a concentration-enhancing polymer selected from the group consisting of hydroxypropyl methyl cellulose acetate succinate, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, and cellulose acetate trimellitate.

US 2011/0002989 disclose a ziprasidone dosage form comprising a solid mixture of ziprasidone and a polymer, at least a portion of which ziprasidone in the solid mixture is in a semi-ordered state.

US 2009/0142404 disclose a dosage form comprising particles of ziprasidone wherein the surface of said particles is at least partially coated with a precipitation-inhibiting polymer.

US 2008/286373 discloses ziprasidone formulation containing at least (a) one ziprasidone compound and at least an excipient component (b) that includes at least one of (i) one or more of a mono-, di-, or tri-ester of C12-24 fatty acids and glycerol, in which each fatty acid group is chosen independently of the others, or mixtures thereof; and/or (ii) one or more mono- or di-esters of Q2-24 fatty acids and polyC2-3alkyleglycol, in which each fatty acid group is chosen independently of the others, or mixtures thereof; and/or (iii) a vitamin E TPGS (Vitamin E tocopherol-succinic acid-polyethyleneglycol); and where this component (b) may optionally include (iv) optionally free poly C2-3 alkyl glycol; (v) optionally free glycerol; and (vi) optionally free fatty acids having 12-24 carbon atoms; and (vii) mixtures thereof; the formulation further comprising (c) at least one surfactant selected from anionic and non-ionionic surfactants and still further comprising (d) at least one hydroxyalkyl alkyl cellulose in which each alkyl group and each hydroxyalkyl group independently has from 1 to 4 carbon atoms.

US 2005/0163858 disclose a composition comprising ziprasidone or a pharmaceutically acceptable salt thereof, having a mean particle size greater than 85 micrometers; along with pharmaceutically acceptable carrier.

WO 2011/080706 discloses a composition comprising ziprasidone or pharmaceutically acceptable salt thereof having a mean particle size greater than 85 micrometers and a pharmaceutically acceptable carrier or pharmaceutically acceptable carriers characterized in that said pharmaceutical composition is prepared by a method that includes at least both internal phase and an external phase.

WO 2007/126322 discloses a composition comprising ziprasidone or a pharmaceutically acceptable salt thereof, to improve solubility and thus bioavailability of the drug, characterized in that the active agent is slugged together with one or more pharmaceutically acceptable excipients. More particularly, this patent publication discloses the use of hydrophilic excipients for increasing the solubility of ziprasidone or a pharmaceutically acceptable salt thereof.

Though several compositions/ process comprising ziprasidone with enhanced dissolution and bioavailability are known in the prior art, but most of them are either restricted to the use of micronisation technology or by the use of a particular types of polymers.

Further, the commercially available ziprasidone HC1 capsules is prepared according to the method disclosed in US 6,150,366, which exhibits marked food effect with an approximate two fold increase in bioavailability, observed in presence of food. Further, the Geodon® capsules gives incomplete dissolution upon alternation in either pH of dissolution media or surfactant concentration indicating there is limited improvement of solubility by particle size reduction. This might be one of the reasons for food effect associated with absorption of ziprasidone from Geodon capsules. Hence, there is always a need to develop an improved composition (s) / process which is simple, cost effective and less time consuming having no or minimal food effect.
The inventors of the present invention successfully developed ziprasidone pharmaceutical compositions which are prepared by a novel process, mainly by solid dispersion using Hot-Melt extrusion process which obviates the need of micronisation to improve the solubility, which overcomes the drawback of having very limited solubility in terms of increase in rate of solubilisation and not the overall solubility of API in case of micronisation and maintains a desired solubility irrespective of change in particle size or dissolution media or surfactant concentration. Moreover in case of Hot-Melt extrusion process, due to entrapment of drug in polymer matrix, it also provides good stability against moisture uptake and polymorphic conversion.

SUMMARY AND OBJECTIVE OF THE INVENTION

The invention relates to a novel process for preparing ziprasidone pharmaceutical compositions.

More particularly, the invention relates to a process for preparing ziprasidone pharmaceutical compositions by Hot-Melt extrusion process.

The invention further relates to solid oral pharmaceutical compositions comprising ziprasidone or its pharmaceutically acceptable salts thereof, at least one polymer and optionally one or more pharmaceutically acceptable excipient(s), wherein the composition is prepared by Hot-Melt extrusion process.

The invention also relates to solid oral pharmaceutical compositions of ziprasidone prepared by Hot-Melt extrusion process, wherein said composition in the form of capsule has comparable in-vitro dissolution profile as well as in-vivo pharmacokinetic parameter when compared with the commercially available Geodon capsule.

Yet in another aspects, the present invention relates to solid oral pharmaceutical compositions of ziprasidone prepared by Hot-Melt extrusion process, wherein said composition has either no or minimal food effect.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

The invention relates to a novel process for preparing ziprasidone pharmaceutical compositions. More particularly, the invention relates to a process for preparing ziprasidone pharmaceutical compositions by Hot-Melt extrusion process.

The invention further relates to solid oral pharmaceutical compositions comprising ziprasidone or its pharmaceutically acceptable salts thereof, at least one polymer and optionally one or more pharmaceutically acceptable excipient(s), wherein the composition is prepared by Hot-Melt extrusion process.

Different methods used for enhancing solubility and bioavailability of poorly soluble drugs like, the use of surfactant, size reduction, complexation and solid dispersions etc. Amongst all the above methods solid dispersion is widely used which involves a dispersion of one or more active ingredients in an inner carrier or matrix in solid state prepared by either Hot-Melt extrusion, Hot-Melt granulation, dissolution in solvent or melting solvent method. Amongst all the above, Hot-Melt extrusion process has several advantages over traditional pharmaceutical processing techniques such as enhanced bioavailability of poorly soluble compounds in the absence of solvents and water, economical process with reduced production time, fewer processing steps, and also being a continuous operation.

In the context of the invention, it is believed that solid dispersion / solid solution is being formed in-situ during said Hot-Melt extrusion process.

Hot-Melt extrusion is the process of transferring a powder blend of drug and carrier/ polymer (s) by a rotating screw through the heated barrel of an extruder and pressing the melt through a die into a product of uniform shape. Hot-Melt extrusion represents a fast, continuous manufacturing process without the requirement of further drying or discontinuous process steps. The high flexibility of the process features enables the production of single and multi-particulates. The short thermal exposure of the drug allows the processing of heat sensitive actives as well.

In context of the invention, terms like "active" or "active ingredient" or "drug" or "drug substance" or "pharmacologically active agent" or "active substance" may be used interchangeably and synonymously for ziprasidone or its pharmaceutically acceptable salt thereof and the pharmaceutical compositions comprising ziprasidone or its salt, at least one polymer and optionally one or more pharmaceutically acceptable excipient(s).

The term "solid oral pharmaceutical compositions" according to the invention relates to dosage form for oral administration which is in the form of tablets, capsules, pills, powders, granules, particles, pellets, beads, or mini-tablets.

"Pharmaceutically acceptable salts", as used herein, include those salts in which the anion does not contribute significantly to the toxicity or pharmacological activity of the salt, and, as such, they are the pharmacological equivalents of the bases of the ziprasidone. Preferable examples include but are not limited to hydrochloric, hydrobromic, hydroiodic, citric, acetic, benzoic, mandelic, phosphoric, nitric, mucic, isethionic, palmitic, and the like.

The polymer(s) according to present invention can be any of the hydrophilic or hydrophobic one, which can be processed with ziprasidone or its salts thereof using Hot-Melt extruder to get the desired extrudes. Non-limiting examples of such hydrophilic polymer(s) includes but not limited to povidone, copovidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyethylene oxide and the like or combinations thereof. Hydrophobic polymer(s) includes ethyl cellulose, cellulose acetate, polymethacrylic acid esters copolymer such as Eudragit NE30D and Eudragit NE40D, copolymers of polyvinyl alcohol and high molecular weight polyvinyl alcohols, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate and glyceryl distearate or combination thereof. More preferably, the present invention used hydrophilic polymer i.e. copovidone.

In other aspects, the pharmaceutical compositions of ziprasidone prepared by Hot-Melt extrusion process as per the present invention produces a constant drug release profile irrespective of types of dissolution media or concentration of surfactant.

Yet in further aspects, the pharmaceutical compositions of ziprasidone prepared by Hot-Melt extrusion process as per the present invention has either no or minimal food effect.

The term "no or minimal food effect" according to present invention relates to the dissolution profile or bioavailability of ziprasidone or its salt which is remain unaffected / unaltered with respect to presence or absence of food in gastrointestinal tract.

Yet in another aspect, the dissolution profile of ziprasidone pharmaceutical composition prepared according to present invention is almost complete in all the physiological media with a release of more than about 85% of drug in 60 min in all type of dissolution studies including various media.

The term "physiological media" as used herein refers to various dissolution media comprising buffer(s) of different pH in combination with various surfactant either in the same or different concentration. Examples of such media are the combination of 0.1N HCl+2% Sodium lauryl sulfate (SLS), pH 4.5 acetate buffer+2% SLS, pH 4.5 acetate buffer+2% SLS, pH 7.5 phosphate buffer+2% SLS etc.

The pharmaceutical compositions according to the present invention in addition to the polymer may further comprise one or more pharmaceutically acceptable excipient(s) which include, but are not limited to diluents, binders, disintegrants, lubricants and the like or combinations thereof.

Diluents according to the invention, are selected from a group comprising lactose, cellulose, mannitol, microcrystalline cellulose, dextrose, calcium phosphate, fructose, maltose and the like or combinations thereof.

Binders according to the invention, are selected from a group comprising povidone, copovidone, hyroxypropyl methylcellulose, hyroxypropyl cellulose, polyvinyl alcohol, sodium alginate, sodium carboxymethyl cellulose, polydextrose, methacrylic acid copolymers, hydroxypropyl methylcellulose phthalate, polyvinyl alcohol phthalate, cellulose acetate phthalate and the like or combinations thereof.

Disintegrants according to the invention, are selected from a group comprising starch, sodium starch glycolate, calcium carboxymethlycellulose, croscarmellose sodium, polacrillin potassium, alginic acid, crospovidone, low-substituted hydroxypropyl cellulose and the like or combinations thereof.

Lubricants according to the invention are selected from a group comprising magnesium stearate, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and the like or combinations thereof.

The Hot-Melt extrusion process according to the invention can be carried out in a twin screw extruder with a new micro-plunger feeder, which simulates the continuous extrusion process. More preferably, the Hot-Melt process according to the present invention is carried out in Leistritz (Model Type Nano 16) twin screw extruder wherein the blended mass of ziprasidone and at least one polymer are passed into it followed by optimizing all the process parameters.

Various processing parameters of the Hot-Melt extruder, such as barrel temperature, screw speed, feed rate, torque and melt pressure are controlled and maintained in order to get the desired extrudes.

According to an embodiment of the invention, the pharmaceutical compositions comprising ziprasidone or its pharmaceutically acceptable salts thereof, at least one polymer and optionally one or more pharmaceutically acceptable excipient(s), prepared by Hot-Melt extrusion process, comprise the following steps:

i. Blending ziprasidone or its pharmaceutical acceptable salts thereof with at least one polymer and optionally one or more pharmaceutically acceptable excipients using a suitable blender;

ii. Passing the blend of step (i) through Hot-Melt extruder followed by milling;

iii. Mixing the milled extrudes of step (ii) with one or more additional pharmaceutically acceptable excipient(s) to form uniform blend;

iv. Lubricating the blend of step (iii) and

v. Finally encapsulating the blend obtained in step (iv) into a capsule shell.

The processing parameters of Hot-Melt Extruder used in the process for the preparation of ziprasidone pharmaceutical compositions were set at following values:
Further, it has been found that the ziprasidone capsules prepared according to the invention are bioequivalent to the commercially available Geodon capsule.

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.

Example 1

Unit Composition:

Brief Manufacturing Process:

1. Ziprasidone and copovidone were blended together.

2. The blend of step (1) was passed through hot melt extruder using suitable parameters to get extrudes.

Barrel Temp: 110°C-170°C

Screw speed: 200 rpm

Torque: 12-13 Nm/cm3

3. The extrudes of step (2) were milled using Quadro® co-mil® fitted with 40G screen followed by sifting through #25 ASTM to get the desired granules.

4. The extragranular lactose anhydrous and polacrillin potassium were sifted through #30 ASTM and magnesium stearate was sifted through #60 ASTM.

5. The granules of step (3) were blended with the extragranular materials of step (4) to get the desired blend.

6. The blend of step (5) was lubricated using magnesium sterate of step (4) and

7. The blend of step (6) was filled into a capsule shells.

The capsule shell used according to an embodiment the invention has the following parameters, i.e.

Dissolution Study:

The composition as disclosed in Example 1 was studied for In-vitro drug release in different media using USP dissolution apparatus II (paddle) having media volume of 900ml with the paddle speed set at 75 rpm. The results are presented in Table 1 as compared with commercially available Geodon® capsule:

Table 1

As per the Table-1 given above, it is concluded that the present invention shows a comparable/ increase in solubility and also produces almost complete solubility, i.e. more than 85% drug release in 60 mins in all the physiological media as compared to Geodon* capsule.

Further, the composition as disclosed in Example 1 was studied in pH 4.5 acetate buffer with different surfactant concentration (0.5% SLS and 2% SLS) and the results are (Si presented in Table-2, comparing the same with commercially available Geodon capsule:

Table 2

As per the Table-2 given above, it is concluded that the present invention shows an increase in solubility and also produces almost complete solubility, i.e. more than 85% drug release in 60 mins irrespective of increase in surfactant concentration as compared to Geodon capsule.

Example 2

Unit Composition:

Example 3

Unit Composition:

The compositions given in examples 2 and 3 were prepared by using similar procedure as described in example 1.

Dissolution Study:

The composition as disclosed in Example 2 and 3 were studied for drug release in pH 4.5 acetate buffer and 0.5% SLS media using USP dissolution apparatus II (paddle) having media volume of 900ml with the paddle speed set at 75 rpm. The results are presented in Table 3 as compared with commercially available Geodon capsule:

Table 3

Bio Study:

Ziprasidone capsule prepared according to Example 2 and 3 (test products) and Geodon® 20 mg capsule (reference products) were evaluated for the in-vivo bioequivalence study in healthy human volunteers under fed condition and the resultant data is compiled in Table 4.

Table 4

T/R ratio-refers to test to reference ratio AUC (oiol) - refers to area under the plasma concentration curve from hour 0 to the last detectable concentration at time t, calculated by the trapezoidal rule. AUC (o |0 jnf) - refers to area under the concentration-time curve extrapolated to infinity, calculated as the sum of AUCt and the area extrapolated to infinity Cm>1 - refers to a maximum plasma concentration obtained

Tm„- refers to time of maximum measured plasma concentration obtained

Thus from the above in-vivo bioequivalence data it is found that the ziprasidone capsules prepared by Hot-Melt extrusion process showed comparative in-vivo bioequivalence profile with that of marketed Geodon 20 mg capsule. It is further concluded that increase in rate of release results in increase in the rate and extend of ziprasidone absorption as indicated by T/R ratio of Cmax and AUC.

Stability Study:

The capsule prepared according to Example 3 of the invention was subjected to stability studies at accelerated conditions [40°C/75% RH] in blister pack for 12 weeks and parameters such as assay, drug dissolution, related substance and water by KF were analyzed. The results are summarized in Table 5.

WE CLAIM:

1. A Hot-Melt extrusion process for preparing pharmaceutical compositions comprising ziprasidone or its pharmaceutically acceptable salts thereof, at least one polymer and optionally one or more pharmaceutically acceptable excipient(s).

2. A solid oral pharmaceutical compositions comprising ziprasidone or its pharmaceutically acceptable salts thereof, at least one polymer and optionally one or more pharmaceutically acceptable excipient(s), wherein the said composition is prepared by Hot-Melt extrusion process.

3. A Hot-Melt extrusion process for preparing pharmaceutical compositions comprising ziprasidone or its pharmaceutically acceptable salts thereof, at least one polymer and optionally one or more pharmaceutically acceptable excipient(s), wherein said process involves the following steps:

vi. Blending ziprasidone or its pharmaceutical acceptable salts thereof with at least one polymer and optionally one or more pharmaceutically acceptable excipients using a suitable blender;

vii. Passing the blend of step (i) through Hot-Melt extruder followed by milling;

viii. Mixing the milled extrudes of step (ii) with one or more additional pharmaceutically acceptable excipient(s) to form uniform blend;

ix. Lubricating the blend of step (iii) and

x. Finally encapsulating the blend obtained in step (iv) into a capsule shell.

4. The process or composition according to any of the preceding claim(s), wherein said polymer is selected from a group comprising povidone, copovidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyethylene oxide, ethyl cellulose, cellulose acetate, eudragit, copolymers of polyvinyl alcohol and high molecular weight polyvinyl alcohols, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate and glyceryl distearate or combination(s) thereof.

5. The process or composition according to any of the preceding claim(s), wherein the said excipient(s) are selected from a group consisting of diluent(s), binder(s), disintegrant(s) and /or lubricant(s).

6. A solid oral pharmaceutical compositions in the form of capsule comprising ziprasidone having following unit composition:

Wherein said capsule is prepared by Hot-Melt extrusion process.

7. A solid oral pharmaceutical compositions in the form of capsule comprising ziprasidone having following unit composition:

Wherein said capsule is prepared by Hot-Melt extrusion process.

8. The process or composition according any of the preceding claim(s), wherein the release of ziprasidone is more than about 85% in 60 min in all type of physiological media.