STABLE COATED PHARMACEUTICAL FORMULATION OF OLANZAPINE AND PROCESS FOR PREPARING THE SAME

FIELD OF THE INVENTION This invention, in general relates to the pharmaceutical formulation of olanzapine and process for preparing the same. More particularly, the present invention provides solid oral formulations of olanzapine having longer shelf life and color stability.

BACKGROUND OF INVENTION This invention provides an improved and stabilized pharmaceutically elegant solid oral coated formulation of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3- b][l,5]benzodiazepine, hereinafter referred to as olanzapine, and the process for the preparation thereof. Olanzapine is indicated for the management of the manifestations of psychotic disorders and for the short-term treatment of acute manic episodes associated with Bipolar I disorder.

Olanzapine tends to be metastable, exhibits a pharmaceutically unacceptable change in color over time, when contacted with certain excipients including powder blends, and demands care to assure homogeneity of the finished solid formulation. Further this change in color is exacerbated by ambient air conditions, at elevated temperatures, and by moist environments. Such a pharmaceutical, which changes color over a period of time, could be particularly troublesome for psychotic patients if a dosage form, such as a tablet were to be chosen, where color changes are apparent.

U.S. Pat. No. 5,919,485 discloses a solid oral formulation that includes olanzapine. The formulation is coated with a polymer selected from hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrollidone, dimethylaminoethyl methacrylate, methyl acrylate acid ester copolymer, ethyl acrylate-methyl methacrylate copolymer, methyl cellulose, and ethyl cellulose. However, it is preferred that the

formulation contain the most stable anhydrous form of Olanzapine, Form II. It also discloses high shear aqueous wet granulation with fluid bed drying as the most effective method for preparing pharmaceutically elegant, stable, oral olanzapine formulations. Thus it can be seen that this prior art advocates usage of several coating components among which some or most lack practical application and common usage amongst practitioners of the art of coating tablets designed to provide immediate release of drug into the stomach region. The use of hydroxypropyl methyl cellulose is exemplified in the commercially available Zyprexa® tablets sold by Eli Lilly.

U.S. Pat. No. 6,190,698 discloses a solid oral formulation of olanzapine. The formulation is coated with hydroxypropyl methyl cellulose. The hydroxypropyl methyl cellulose is further coated with an aqueous dispersion film coat and the oral formulation is imprinted using an edible ink, thus incorporating further steps into the formulation and making the entire process expensive.

WO 2004/035027 discloses a pharmaceutical formulation comprising a homogenous mixture of (a) olanzapine or a pharmaceutically acceptable salt thereof as an active ingredient, (b) a monosaccharide and/or oligosaccharide, and (c) a polysaccharide. However, they have avoided the use of solvents and high compaction pressures used for wet granulation and dry granulation techniques respectively, thus limiting their process to direct compression only.

WO 2005/009407 discloses coating olanzapine as such in powder or agglomerate form, wherein the coating includes lactose and/or mannitol and optionally one or more excipients, thus leading to the incorporation of several steps in the preparation of a stable olanzapine formulation.

Thus, the oral formulations disclosed in the prior art demand further improvements in light of the moisture sensitive and metastable nature of olanzapine.

Also, improved stable oral formulations were yet desired to overcome the tendency of olanzapine to undesirably exhibit color changes in tablet formulations along with the above-mentioned limitations.

The present invention provides a stabilized formulation of olanzapine, possessing marked improvement in color change over shelf life employing a selective polymer for coating, which overcomes the drawbacks of processes recited in prior arts.

SUMMARY OF THE INVENTION

In accordance with the principal aspect of the present invention, there is provided a pharmaceutical formulation of olanzapine having longer shelf-life and color stability, wherein said formulation is coated employing selective polymer system.

In accordance with another aspect of the invention, there is provided a stable pharmaceutical formulation of olanzapine, wherein, said formulation comprising effective amount of olanzapine as an active ingredient intimately mixed with pharmaceutically acceptable excipients selected from bulking agent, binder, disintegrant, or a lubricant.

In accordance with yet another aspect of the present invention, there is provided stable pharmaceutical formulation of olanzapine, wherein, said formulation is further stabilized by a coating comprising of one or more polymers selected from the group consisting of hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl alcohol, polyvinyl pyrrolidone / vinyl acetate copolymer, pullulan gum or zein or in selective combination thereof.

In accordance with yet another aspect of the invention, there is provided a stable pharmaceutical formulation of olanzapine, wherein, said formulation comprising effective amount of olanzapine as an active ingredient intimately mixed with pharmaceutically acceptable excipients selected from bulking agent, binder, disintegrant, or a lubricant and wherein said formulation further stabilized by a coating

employing a polymer selected from polyvinyl alcohol or hydroxypropyl methyl cellulose phthalate or in combination thereof.

In accordance with yet another aspect of the invention, there is provided a stable pharmaceutical formulation of olanzapine, wherein, said formulation is used herein may be any suitable form such as granules, granules filled in capsules, granules compressed into tablets, tablets, or minitablets.

In accordance with yet another aspect of the invention, there is provided a stable pharmaceutical formulation of olanzapine, wherein, said formulation is used herein comprising about 1 to 10% w/w olanzapine, about 0 to 88 % w/w lactose, about 0 to 10 % hydroxypropyl cellulose, about 0.5 to 6 % w/w crospovidone, about 0 to 88% w/w microcrystalline cellulose, or about 0 to 2% magnesium stearate.

In accordance with yet another aspect of the invention, there is provided a stable pharmaceutical formulation of olanzapine, wherein, said polymer alone or in combination thereof used herein in an amount within the range from about 10 to about 80% by weight, preferably from about 20 to about 60% by weight and more preferably from about 30 to about 50% by weight of the total weight of the coating composition.

In accordance with another aspect of the present invention there is provided a process of making a pharmaceutical formulation having longer shelf-life and color stability. The process comprises mixing olanzapine and at least one or more pharmaceutically acceptable excipients to form a mixture, processing the mixture to make a dosage form, and coating the dosage form with a coating composition comprising of at least one coating agent selected from the group consisting of hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl alcohol, polyvinyl pyrrolidone/vinyl acetate copolymer, pullulan gum and zein.

In accordance with another aspect of the present invention there is provided a method of treating psychotic disorders employing said formulation. The method comprises of administering a dosage form comprising olanzapine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient; wherein the formulation is coated with a polymer selected from hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl alcohol, polyvinyl pyrrolidone/vinyl acetate copolymer, pullulan gum and zein or mixtures thereof.

DESCRIPTION OF INVENTION

Olanzapine, a potent compound having desired nervous system activity has a tendency to undergo undesired polymorphic transformation, pharmaceutically undesired degradation or color changes, and stipulates concern on the homogeneity of the finished solid formulation.

Applicants have surprisingly discovered that coating the solid oral formulations comprising olanzapine, with one or more polymers selected from the group consisting of hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl alcohol, polyvinyl pyrrolidone / vinyl acetate copolymer, pullulan gum and zein, provides uniformity, physical stability, and effectively prevents the above-mentioned drawbacks in the prior art formulations comprising olanzapine.

Most preferred polymer coats comprise of hydroxypropyl methyl cellulose phthalate, polyvinyl alcohol and polyvinyl pyrrolidone / vinyl acetate copolymer or mixtures thereof.

The polymers may be used in an amount with in the range from about 10 to about 80 % by weight, preferably from about 20 to about 60 % by weight and more preferably about 30 to about 50 % by weight of the coating composition.

The present coating is able to provide sufficient physical and chemical stability to olanzapine and its foπnulations and remarkably overcomes the discoloration tendency of the dosage forms as available commercially or disclosed in the prior art.

The term "treating" as used herein includes prophylaxis of the named condition or amelioration or elimination of the condition once it has been established.

The composition may be in the form of compressed tablets, moulded tablets, products prepared by extrusion and the likes. The formulation is most preferably in a tablet form; however, granule formulation and the likes are desired as well.

The composition of the present invention is in the form of tablets prepared by either direct compression, dry granulation (slugging/roller compaction) or by wet granulation (aqueous / non-aqueous).

The foπnulations of the present invention contain olanzapine, its anhydrous forms, its analogues, polymorphs, solvates, hydrates and salts. Olanzapine as used herein may be in the form of particles or powder. The median particle size of olanzapine used in the formulation is within the range of approximately 5 microns to 150 microns, preferably less than 100 microns.

The solid oral formulation comprising olanzapine or a pharmaceutically acceptable salt thereof may further include one or more pharmaceutically acceptable excipients selected from a group consisting of diluent, binder, disintegrant, lubricant.

A diluent or bulking agent should be selected to provide an increase in tablet size. The artisan can utilize known methods to select a bulking agent, which provides hardness, friability, and disintegration time that is satisfactory for pharmaceutical usage. The bulking agent should be selected to provide a tablet that has characteristics desired by the patient as well as comply with applicable regulatory guidelines. One especially preferred diluent or bulking agent is lactose. Various forms of lactose are appropriate for such formulations including anhydrous, hydrous, and spray dried forms. The most

desired form of lactose can be selected based on desired dissolution, content uniformity, hardness, friability, and disintegration time. The skilled artisan is aware of the regulatory requirements for hardness, friability, and disintegration time and can adjust the diluent or bulking agents using known techniques to achieve the desired physical characteristics.

The desired formulation includes a disintegrant to facilitate the disintegration process.

There are a variety of grades available, and the grade may be selected based on the acceptable batch variability. A particularly preferred disintegrant is crospovidone. A fine grade of crospovidone provides particularly desirable consistency between batches.

The artisan may choose appropriate dry binders using known methods. Such binders should be selected to assure that satisfactory friability is attained. Most preferably, dry binder is microcrystalline cellulose; however, other appropriate dry binders may be selected. Such microcrystalline cellulose may be in a granular form.

The artisan can choose an appropriate lubricant to prevent sticking and picking of the tablets to the compression tooling. One preferred lubricant is magnesium stearate.

The formulation of the present invention may comprise from about 1 to about 10 % w/w olanzapine; from about 0 to about 88 % w/w lactose; from about 0 to about 10 % w/w hydroxypropyl cellulose; from about 0.5 to about 6 % w/w crospovidone; from about 0 to about 88% w/w microcrystalline cellulose; and from about 0 to 2 % magnesium stearate.

The artisan can readily choose other appropriate film coats. The film-coating composition may comprise of polymer/s, plasticizer/s, channeling agent/s, surfactant/s and/or pigments. The film coat can be prepared by dispersing/dissolving the polymer alone or in combination, in water/organic solvents. A preferred embodiment of a typical coating composition comprises of polyvinyl alcohol, lactose, triacetin, talc, and titanium dioxide.

A preferred formulation of the invention is a solid oral formulation comprising from about 1 to about 20 mg olanzapine as an active ingredient, wherein such solid oral formulation is coated with polyvinyl alcohol.

Most preferably, the solid oral formulation is contained in packaging materials, which protect the formulation from moisture and light. For example, suitable packaging materials include amber colored high-density polyethylene bottles, amber colored glass bottles, and other containers made of a material, which inhibits the passage of light. Most preferably, the packaging will include a desiccant pack. The container may be sealed with an aluminum foil blister to provide the desired protection and maintain product stability.

The materials for the present invention can be purchased or prepared by a variety of procedures well known to those of ordinary skill in the art. Olanzapine can be prepared as described by Chakrabarti in U.S. Pat. No. 5,229,382; herein incoiporated by reference in its entirety.

Olanzapine is effective over a wide dosage range, the actual dose administered being dependent on the condition being treated. For example, in the treatment of adult humans, dosages of from about 0.25 to 50 mg, preferably from 1 to 30 mg, and most preferably 1 to 20 mg per day may be used. A once a day dosage is normally sufficient, although divided doses may be administered. For treatment of central nervous system disorders, a dose range from 1 to 30 mg, preferably 1 to 20 mg per day is suitable.

The preferred weight of the tablets is 50 to lOOOmg, most preferably 100 to 500 mg.

The examples given below are provided for the purpose of illustration and are not construed as limiting the scope of the invention.

Examples Example 1

Pre weighed olanzapine, lactose, hydroxypropyl cellulose low substituted, crospovidone and microcrystalline cellulose were sifted and mixed in low shear mixer. The blend was lubricated using presifted magnesium stearate. The final blend was compressed using 10.0 mm round shape punches into tablets.

Stability results at test conditions:

(1 month, 4O ⁰ C/ 75% RH, open air): increase in total related compound from 0.16% to

2.63%.

Example 2

The core tablets of Example 1 were coated using the following composition

Stability results at test conditions:

(1 month, 40°C/ 75% RH, open air): increase in total related compound from 0.16% to

0.56%.

Example 3

The core tablets of Example 1 were also coated using the following composition

Stability results at test conditions:

(1 month, 40°C/ 75% RH, open air): increase in total related compound from 0.16% to

0.64%.

Example 4

Pre weighed olanzapine, lactose; part of crospovidone and part of microcrystalline cellulose were sifted and mixed in high shear mixer like RMG. It was than granulated using aqueous solution of Hydroxypropyl cellulose. Granules were dried/sifted and mixed with remaining part of crospovidone and microcrystalline cellulose and finally lubricated with magnesium stearate. The final blend was compressed using 10.0 mm round shape punches into tablets.

Tablets of example 4 were coated with the coating composition of example 3.

Stability results at test conditions:

(1 month, 40°C/ 75% RH, open air): increase in total related compound from 0.14% to 0.64 %.

It was surprisingly observed that olanzapine tablets coated with polyvinyl alcohol and / or hydroxypropyl methyl cellulose phthalate showed very good stability as compared to the uncoated tablets.

Separately, the dosage forms made according to the examples as described above were also visually observed for discoloration under test conditions (4O ⁰ C/ 75% RH, open air for 2 weeks). The commercially available Zyprexa® tablets were also studied and the observations made are tabulated as below.

The tablets of the present invention surprisingly showed remarkable improvement in color stability even over the commercially available Zyprexa® tablets which are coated with the polymers as disclosed in prior art.

While several particular forms of the inventions have been described, it will be apparent that various modifications and combinations of the inventions detailed in the text can be made without departing from the spirit and scope of the invention.