WO2005009407A2

WO2005009407A2 - Oral pharmaceutical formulations of olanzapine

Info

Publication number: WO2005009407A2
Application number: PCT/IB2004/051335
Authority: WO
Inventors: Vivek Mahendrakumar Dubey; Abhijit Mukund Deshmukh; Sanjeev Kumar Sethi; Rajiv Malik
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2003-07-29
Filing date: 2004-07-29
Publication date: 2005-02-03
Also published as: WO2005009407A3

Abstract

The present invention relates to olanzapine formulations stable to discoloration. The pharmaceutical formulations include olanzapine particles or powder, and a coating on the olanzapine particles or powder. The coating includes lactose and/or mannitol and optionally one or more pharmaceutically acceptable excipients.

Description

Description ORAL PHARMACEUTICAL FORMULATIONS OF OLANZAPINE Technical Field

[1] The present invention relates to the field of pharmaceutical sciences and describes olanzapine formulations which are stable to discoloration.

Background Art

[2] Olanzapine (2-methyl-4-(4-methyl-l-piperazinyl)-10 H-thieno [2, 3 - b] [1, 5] ben- zodiazepine) is a psychotropic agent that belongs to the thienobenzodiazepine class. It 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.

[3] Olanzapine is known to be moisture sensitive, metastable and have the tendency to undesirably discolor when contacted with certain excipients in the formulations. This discoloration, although not producing an increase in the number of total related substances, is pharmaceutically unacceptable due to aesthetic reasons. Further, the discoloration may be particularly unacceptable for psychotic patients.

[4] U.S. Patent 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 car- boxymethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrollidone, dimethy- laminoethyl methacrylate, methyl acrylate acid ester copolymer, ethyl acrylate-methyl methacrylate copolymer, methyl cellulose, and ethyl cellulose.

[5] U.S. Patent 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.

[6] We have surprisingly found that it is possible to avoid the problem of discoloration of olanzapine formulations without using the approaches followed in the prior art. Thus the present invention discloses in various embodiments of the specification coating olanzapine as such in powder or agglomerate form or coating of final dosage form that includes olanzapine. Summary of the Invention

[7] In one general aspect there is provided a pharmaceutical composition stable to discoloration. The composition includes olanzapine particles or powder, and a coating on the olanzapine particles or powder. The coating includes lactose and/or mannitol and optionally one or more pharmaceutically acceptable excipients.

[8] Embodiments of the composition may include one or more of the following features. For example, the one or more pharmaceutically acceptable excipients may be least one filler, and at least one lubricant. The binder may be selected from the group consisting of at least one cellulose polymer and at least one vinylpyrrolidone polymer. The disintegrant may be selected from the group consisting of croscarmellose sodium, crospovidone and sodium starch glycolate. The filler may be one or more of micro- crystalline cellulose, lactose and mannitol. The composition may be in the form of granules, granules filed into capsules, granules compressed into tablets, tablets, or minitablets.

[9] In another general aspect there is provided a process of making a pharmaceutical composition that is stable to discoloration. The process includes dissolving one or both of lactose and mannitol in a sufficient quantity of fluid to form a solution, spraying the solution on to olanzapine that is in the form of particles or powder, drying the sprayed olanzapine, optionally blending the dried olanzapine with one or more pharmaceutically acceptable excipients, and forming a dosage form.

[10] Embodiments of the process may include one or more of the following features or those described above. For example, the one or more pharmaceutically acceptable excipients may be selected from the group consisting of at least one binder, at least one disintegrant, at least one filler, and at least one lubricant.

[11] In another general aspect there is provided a method of treating psychotic disorders. The method includes administering a dosage form that includes olanzapine particles or powder and a coating on the olanzapine particles or powder. The coating includes lactose and/or mannitol and optionally one or more pharmaceutically acceptable excipients.

[12] Embodiments of the method of treatment may include one or more of the features described above.

[13] In another general aspect there is provided a pharmaceutical composition stable to discoloration. The composition includes olanzapine and one or more pharmaceutically acceptable excipients and a coating on the olanzapine and excipients. The coating includes at least one coating agent selected from the group consisting of carrageenan, sodium alginate, polyvinyl alcohol-polyethylene glycol graft copolymer, and titanium dioxide-talc mixture.

[14] Embodiments of the composition may include one or more of the following features or those described above. For example, the one or more pharmaceutically acceptable excipients may be selected from one or more of the group consisting of at least one binder, at least one disintegrant, at least one filler and at least one lubricant. The binder may be selected from the group consisting of cellulose polymer and vinylpyrrolidone polymers. The disintegrant may be one or more of croscarmellose sodium, crospovidone and sodium starch glycolate. The filler may be one or more of micro- crystalline cellulose, lactose and mannitol. The composition may be in the form of granules, granules filed into capsules, granules compressed into tablets, tablets, or minitablet. [15] In another general aspect there is provided a process of making a pharmaceutical composition that is stable to discoloration. The process includes mixing olanzapine and one or more pharmaceutically acceptable excipients to form a mixture, processing the mixture to make a dosage form, and coating the dosage form with at least one coating agent selected from the group consisting of carrageenan, sodium alginate, polyvinyl alcohol-polyethylene glycol graft copolymer, and titanium dioxide-talc mixture.

[16] Embodiments of the process may include one or more of the following features or those described above. For example, the one or more pharmaceutically acceptable excipients may be selected from the group consisting of at least one binder, at least one disintegrant, at least one filler, and at least one lubricant.

[17] In another general aspect there is provided a method of treating psychotic disorders. The method includes administering a composition that includes olanzapine and one or more pharmaceutically acceptable excipients and a coating on the olanzapine and excipients. The coating includes at least one coating agent selected from the group consisting of carrageenan, sodium alginate, polyvinyl alcohol-polyethylene glycol graft copolymer, and titanium dioxide-talc mixture.

[18] Embodiments of the method of treating may include one or more of the features described above.

[19] The above formulations of the invention may be obtained in dosage forms such as tablets or minitablets as coated or uncoated form. The dosage form may contain, for example, olanzapine ranging from 2.5 mg to 20 mg.

[20] The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims. Disclosure

[21] Detailed Description of the Invention

[22] The olanzapine disclosed in the various embodiments of the specification can be prepared as described in U.S. Patent No. 5,229,382, which is incorporated herein by reference. However, any other form of olanzpaine is contemplated.

[23] The term 'coated olanzapine' as used herein refers to olanzapine powder coated by at least one excipient. The coating can be achieved by spray drying, using fluid bed drier or as a result of granulation as described herein. The term powder used herein is used in general sense and also encompass agglomerates or the active ingredient in any other form as evident from various embodiments of the specification.

[24] The term 'stable to discoloration' as used herein refers to formulation of olanzapine, coated or uncoated, which do not show sign of change in color of the final dosage form for the period during the accelerated stability studies or normal shelf life of the product.

[25] The inventors have developed two general approaches to preventing discoloring of olanzapine. According to one approach, olanzapine particles are coated with lactose and/or mannitol and optionally with other suitable pharmaceutically acceptable excipients. This coated olanzapine is either formulated into granules, pellets, minitablets for filling into gelatin or non gelatin capsule, or tablets along with other pharmaceutically acceptable excipients. This dosage form does not need to be additionally coated but optionally may be coated.

[26] According to a second approach, olanzapine tablets are coated with one or more pharmaceutically acceptable excipients selected from one or more of the group consisting of carrageenan, sodium alginate, sodium carboxy methylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer and titanium dioxide - talc mixture.

[27] As described above, the coated olanzapine particles disclosed in various embodiments of the specification may be prepared using various options. In one of the options disclosed, olanzapine is dissolved in lactose and/or mannitol and the resultant dispersion spray dried. The spray-dried material is used for the formulation of the final dosage form. In another option disclosed, olanzapine is taken in fluid bed granulator and a lactose and/or mannitol dispersion in water is sprayed on to it thereby coating the olanzapine particles. The resultant coated olanzapine is further used to formulate the final dosage form of olazapine. In still another option disclosed, olanzapine is blended with a half quantity of lactose or mannitol to be used in formulation with optional excipients to obtain a blend, then granulating the blend with a dispersion made up of the remaining quantity of lactose or mannitol in water to obtain granules. The granules containing olanzapine then are used to prepare the final dosage form.

[28] Alternatively, the final formulation of olanzapine can be coated with suitable coating polymers. The coated final formulation does not require coating of olanzapine particles, however, and such a use is optional.

[29] The final olanzapine dosage form may be in the form of tablet or minitablets which are optionally coated. When the final formulation is uncoated it is necessary to use olazapine powder which is coated with lactose or mannitol or other suitable excipients. Any suitable equipment can be used for coating olanzapine particles such that the final dosage form does not require further coating.

[30] The olanzapine formulations according to various embodiments of the specification may be formulated in dosage forms with strengths of about 2.5, 5, 7.5, 10 and 15 mg which are proportionately similar to the formulations of 20 mg olanzapine disclosed in various embodiments of the present invention. The formulations are useful for the treatment of various psychotic disorders responsive to olanzapine alone or in combination with other active ingredients. The blend, granules, pellets, minitablets, or tablets according to various embodiments of the specification comprising olanzapine may be filled into gelatin or non-gelatin capsules. The formulations with coated olanzapine particles may be optionally coated with a coating solution/dispersion as disclosed in the specification.

[31] The following examples, without limiting the scope, illustrate various embodiments of the present invention without limiting to particular process or final dosage forms.

[32] EXAMPLE 1. Olanzapine Tablet 20 mg: [33]

[34] Manufacturing Process: 1. Lactose/Mannitol (80 mg) was dissolved in sufficient quantity of purified water and then olanzapine was dispersed into it. 2. The dispersion of step 1 was spray dried at a temperature of 40 - 80°C using a spray dryer. Alternately, the suspension can be sprayed into the Fluid Bed Granulator chamber at a temperature of about 40 - 80°C. 3. The material of step 2 was blended with the remaining quantity of lactose along with Microcrystalline Cellulose (Avicel PH 101) and crospovidone, and then granulated with a solution of hydroxypropyl methylcellulose/ hydroxypropyl cellulose/Plasdone S - 630 in water or isopropyl alcohol using a high shear granulation technique 4. The granules were dried at a temperature of about 40 - 80°C using a tray dryer (fluid bed dryer can also be used) until the LOD of granules was 1 - 4 % w/w.

5. The granules were sifted through suitable size mesh, blended with micro- crystalline cellulose (Avicel PH 112), crospovidone, magnesium stearate, and talc, and then compressed into tablets using punches of suitable size and shape. 6. Optionally the granules may be filled into gelatin or non-gelatin capsules. EXAMPLE 2: Olanzapine Tablet 20 mg:

[36]

[37] Mnufacturing Process: 1. Olanzapine was taken in a Fluid Bed Granulator chamber. 2. Lactose / Mannitol (80 mg) was dissolved in a sufficient quantity of purified water. 3. The solution of step 2 was sprayed onto olanzapine at a temperature of about 40-80° C. 4. The material of step 3 was blended with the remaining quantity of lactose along with microcrystalline cellulose (Avicel PH 101) and crospovidone, and then granulated with a solution of hydroxypropyl methylcellulose/hy- droxypropyl cellulose/Plasdone S - 630 in water or isopropyl alcohol using a high shear granulation technique. 5. The granules were dried at a temperature of about 40 - 80° C using a tray dryer (fluid bed dryer may also be used) until the LOD of granules was 1 - 4% w/w. 6. The granules were sifted through a suitable size mesh, blended with micro- crystalline cellulose (Avicel PH 112), crospovidone, magnesium stearate, and talc, and then compressed into tablets using punches of suitable size and shape. 7. Optionally the granules may be filled into gelatin or non-gelatin capsules.

[38] EXAMPLE 3. Olanzapine Tablet 20 mg: [39]

[40] Manufacturing Process: 1. Olanzapine was blended with Microcrystalline Cellulose (Avicel PH 101), Hydroxy Propyl Methyl Cellulose/Hydroxy Propyl Cellulose/Plasdone S - 630, Crospovidone and a half quantity of the lactose/mannitol. 2. The remaining half quantitiy of lactose / mannitol was dissolved in a sufficient quantity of purified water. 3. The solution of step 2 was added to the blend of step 1 and granulated using a high shear granulation technique. 4. The granules were dried at a temperature of about 40 - 80° C using a tray dryer (fluid bed dryer may also be used) until the LOD of granules was 1 - 4% w/w. 5. The granules were sifted through a suitable size mesh, blended with crospovidone, microcrystalline cellulose (Avicel PH 112), crospovidone, magnesium stearate, and talc, and compressed into tablets using punches of suitable size and shape. 6. Optionally the granules may be filled into gelatin or non-gelatin capsules.

[41] EXAMPLE 4. Olanzapine Tablet 20 mg: [42]

[43] Manufacturing Process: 1. Olanzapine was blended with lactose/mannitol, microcrystalline cellulose (Avicel PH 101), and crospovidone. 2. Hydroxypropyl methylcellulose/hydroxypropyl cellulose/Plasdone S - 630 was dissolved in a sufficient quantity of purified water. 3. The solution of step 2 was added to the blend of step 1 and granulated using a high shear granulation technique. 4. The granules were dried at a temperature of about 40 - 80° C using a tray dryer (fluid bed dryer may also be used) until the LOD of granules was 1 - 4% w/w. 5. The granules were sifted through a suitable size mesh, blended with micro- crystalline cellulose (Avicel PH 112), crospovidone, magnesium stearate, and talc, and compressed into tablets using punches of suitable size and shape. 6. Optionally the granules may be filled into gelatin or non-gelatin capsules. [44] Coating of tablets:

[45] The tablets made by formulations of Example 4 were coated with one or more coating compositions mentioned below. Optionally the coating solution / suspension contained a suitable colour. The coating solutions described below may be applied to formulations of Examples 1 to 3. The following are the non-limiting examples of the coating solutions/dispersions used in the formulations of the present invention where coating is needed.

[46] Option I: 1. A Lustre Clear LC 103* powdered blend was dispersed in a sufficient quantity of water to make a suspension of 5 - 10 % w/w. 2. The coating suspension of step 1 was sprayed onto tablets using conventional or perforated coating pan at a temperature of 40 - 80°C until a weight build up of 1 - 6 % w/w was achieved

[47] * Microcrystalline Cellulose - Carragenan mixture that is commercially available as 'LustreClear LC 103'. ...

[48] Option II: Sodium Alginate was dispersed in a sufficient quantity of water to make a suspension of 5 - 10 % w/w. The coating suspension of step 1 was sprayed onto tablets using conventional or perforated coating pan at a temperature of about 40 - 80°C until a weight build up of 1 - 6 % w/w was achieved.

[49] Option III: 1. Kollicoat IR* powdered blend was dispersed in a sufficient quantity of water to make a suspension of 5 - 15 % w/w. 2. The coating suspension of step 1 was sprayed onto tablets using conventional or perforated coating pan at a temperature of about 40 - 80°C until a weight build up of 1 - 6 % w/w was achieved.

[50] Polyvinyl Alcohol - Polyethylene Glycol graft copolymer available that is commercially as 'Kollicoat IR' [51] Option IV: 1. Titanium dioxide - talc mixture (80:20) was dispersed in a sufficient quantity of water to make a suspension of 5 - 15% w/w. A plasticizer, such as triethyl citrate or polyethylene glycol, was added to the suspension. 2. The coating suspension of step 1 was sprayed onto tablets using conventional or perforated coating pan at a temperature of about 40 - 80°C until a weight build up of 1 - 6 % w/w was achieved.

[52] Option V: 1. Sodium carboxymethyl cellulose was dissolved in a sufficient quantity of water to make a solution of 5 - 15 % w/w. A plasticizer, such as triethyl citrate or polyethylene glycol, was added to the solution. 2. The coating solution of step 1 was sprayed onto tablets using conventional or perforated coating pan at a temperature of about 40 - 80°C until a weight build up of 1 - 6 % w/w was achieved.

[53] EXAMPLE 5. Olanzapine Capsules 20 mg: [54]

[55] Manufacturing Process: 1. Ingredients 1 , 2, 3 and part of ingredient 4 and 5 were weighed and sifted through a 60 mesh screen. 2. The materials of step 1 were blended in suitable mixer until a suitable content uniformity was achieved. 3. The remaining part of ingredient 4 was dissolved in a sufficient quantity of purified water and then used to granulate the blend of step 2 until a wet mass of suitable consistency was formed. 4. The wet material of step 3 was dried in a Fluid Bed Dryer until the LOD of the granules was between 1 - 3 % w/w. 5. The dried granules of step 4 was sifted through a 24 mesh screen. The retentions were passed through a suitable mill and again resifted through a 24 mesh. 6. Weighed and sifted remaining part of ingredient 5 and ingredient 6 and 7 together through 40 mesh screen and blended it along with granules of step 5 in suitable blender until the desirable content uniformity was achieved. 7. Weighed and sifted magnesium stearate through a 40 mesh screen and added to the blend of step 6 and blended further for approximately 5 minutes. 8. Filled the blend of step 7 in suitable size capsule using capsule filling machine.

[56] The dosage forms made according to the examples described above were stored at ambient temperature and humidity conditions for three months and periodically checked for discoloration. Upon visual observation, there was no sign of discoloration during or after three months storage. Separately, dosage forms made according to the examples described herein were stored under accelerated aging conditions (about 80°C and 75% relative humidity) for three months. During the three months the tablets periodically were visually observed and noted for discoloration. No discoloration was noted during or at the conclusion of this three month period.

[57] 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 inventions. Accordingly, it is not intended that the inventions be limited, except as by the appended claims.

Claims

[1] A pharmaceutical composition stable to discoloration, the composition comprising: olanzapine particles or powder; and a coating on the olanzapine particles or powder, the coating comprising lactose and/or mannitol and optionally one or more pharmaceutically acceptable excipients. [2] The composition of claim 1 , wherein the one or more pharmaceutically acceptable excipients are selected from the group consisting of at least one binder, at least one disintegrant, at least one filler, and at least one lubricant. [3] The composition of claim 2, wherein the binder is selected from the group consisting of at least one cellulose polymer and at least one vinylpyrrolidone polymer. [4] The composition of claim 2, wherein the disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone and sodium starch glycolate. [5] The composition of claim 2, wherein the filler comprises one or more of micro- crystalline cellulose, lactose and mannitol. [6] The composition according to claim 1, wherein the composition is in the form of granules, granules filed into capsules, granules compressed into tablets, tablets, or minitablet. [7] A process of making a pharmaceutical composition that is stable to discoloration, the process comprising: dissolving one or both of lactose and mannitol in a sufficient quantity of fluid to form a solution; spraying the solution on to olanzapine, the olanzapine being in the form of particles or powder; drying the sprayed olanzapine; optionally blending the dried olanzapine with one or more pharmaceutically acceptable excipients; and forming a dosage form. [8] The process of claim 7, wherein the one or more pharmaceutically acceptable excipients are selected from the group consisting of at least one binder, at least one disintegrant, at least one filler, and at least one lubricant. [9] A method of treating psychotic disorders, the method comprising administering a dosage form comprising olanzapine particles or powder and a coating on the olanzapine particles or powder, the coating comprising lactose and/or mannitol and optionally one or more pharmaceutically acceptable excipients. [10] A pharmaceutical composition stable to discoloration, the composition comprising: olanzapine and one or more pharmaceutically acceptable excipients; and a coating on the olanzapine and excipients, the coating comprising at least one coating agent selected from the group consisting of carrageenan, sodium alginate, polyvinyl alcohol-polyethylene glycol graft copolymer, and titanium dioxide-talc mixture. [11] The composition of claim 10, wherein the one or more pharmaceutically acceptable excipients is selected from one or more of the group consisting of at least one binder, at lest one disintegrant, at least one filler and at least one lubricant. [12] The composition of claim 11, wherein the binder is selected from the group consisting of cellulose polymer and vinylpyrrolidone polymers. [13] The composition of claim 11 , wherein the disintegrant comprises one or more of croscarmellose sodium, crospovidone and sodium starch glycolate. [14] The composition of claim 11, wherein the filler comprises one or more of micro- crystalline cellulose, lactose and mannitol. [15] The composition according to claim 10 wherein the composition is in the form of granules, granules filed into capsules, granules compressed into tablets, tablets, or minitablet. [16] A process of making a pharmaceutical composition that is stable to discoloration, the process comprising: mixing olanzapine and one or more pharmaceutically acceptable excipients to form a mixture; processing the mixture to make a dosage form; and coating the dosage form with at least one coating agent selected from the group consisting of carrageenan, sodium alginate, polyvinyl alcohol- polyethylene glycol graft copolymer, and titanium dioxide-talc mixture. [17] The process of claim 16, wherein the one or more pharmaceutically acceptable excipients is selected from the group consisting of at least one binder, at least one disintegrant, at least one filler, and at least one lubricant. [18] A method of treating psychotic disorders, the method comprising administering a composition comprising olanzapine and one or more pharmaceutically acceptable excipients, and a coating on the olanzapine and excipients, the coating comprising at least one coating agent selected from the group consisting of carrageenan, sodium alginate, polyvinyl alcohol-polyethylene glycol graft copolymer, and titanium dioxide-talc mixture.