FORM-2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION Sec 10-Rule 13
"Coated Olanzapine Formulation."
INDOCO REMEDIES LIMITED
Indian
R-92-93, T.T.C Industrial Area, Thane Belapur Road, Rabale MIDC
NaviMumbai-400701
The following specification describes the invention.

Technical F
The present invention relates to a Coated Olanzapine Formulation. In particular, the present invention relates to a stable formulation of Olanzapine coated with Pullulan gum, starch based coating systems, vinylpyrrolidone-vinyl acetate copolymers or combinations thereof to overcome problem of degradation and discoloration.
Background & Prior Art:
Olanzapine is 2-Methyl-4-(4-methyl-l-piperazinyl)-10H-thieno (2,3-
b)(l,5) benzodiazepine and belongs to the class of drugs known as thienobenzodiazepines. It is an atypical antipsychotic approved in the treatment of schizophrenia. It is also prescribed in the acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder. It is an antagonist of dopamine at D-1 and D-2 receptors, and in addition has antimuscarinic, anti-cholinergic properties and antagonist activity at 5HT-2 receptor sites. It also has antagonist activity at noradrenergic a.-receptors.
Olanzapine is known for its metastable and moisture sensitive nature. One of the primary problems faced in the formulation of Olanzapine is the discoloration of the tablet on exposure to moisture. The intended patient population i.e. psychotic patients might get disturbed with a change in color of the medications leading to undue refusal of the medication.
Prior art does describe some solutions to the discoloration problem. European Patent No. EP733367 describes use of hydroxypropyl methylcellulose as an interim seal coat to provide moisture barrier to the Olanzapine core. The seal coat is further coated with white color mixture coating containing HPMC, PEG, Polysorbate 80 and titanium dioxide. The inventors specifically provide for a coating which does not contain PEG

in direct contact with the drug product. The other polymers which can be used instead of HPMC are hydroxyethyl cellulose, methyl hydroxyethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, dimethylaminoethyl methacrylate, methyl acrylate acid ester copolymer, ethyl acrylate-methyl methacrylate copolymer, methyl cellulose, and ethyl cellulose.
Indian patent application no 559/DELNP/2006 discloses use of carrageenan, sodium alginate, polyvinyl alcohol- polyethylene glycol graft copolymer, and titanium dioxide-talc mixture to coat the Olanzapine core to prevent discoloration.
EP1965773 describes a solution wherein the Olanzapine core is coated with polyvinyl alcohol (PVA). The PVA barrier unlike the HPMC barrier does not retard the dissolution as compared to the use of HPMC.
2880/DEL/2005 shows the actual use of Hydroxy Methyl cellulose phthalate, polyvinyl acetate phthalate as a coating material to coat the Olanzapine core. The patent application also merely describes other polymers which can be used in the invention, these are hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl alcohol, vinyl acetate copolymer, pullulan gum or zein or a combination thereof.
Olanzapine and its various polymorphic forms are sensitive to moisture and oxidation resulting into discoloration of formulation.
The current invention provides a novel solution to the aforementioned prior art problems.

Surprisingly, it has been found that when Olanzapine tablets are coated with Pullulan there is significant reduction in the rate of degradation of Olanzapine because Pulluan gum has an excellent oxygen barrier property (low permeability to oxygen and humidity) which in turn protects the Olanzapine from degradation. Pullulan coating also helps to improve appearance of the tablets. Further it has been found that coating Olanzapine formulation with a Pullulan gum, starch based coating systems or combinations of Pullulan gum with vinylpyrrolidone-vinyl acetate copolymers or combinations of vinylpyrrolidone-vinyl acetate copolymers with Pullulan gum and starch based coating systems confers better stability to Olanzapine thus circumventing the problem of degradation and discoloration.
Object of the Invention:
The main object of the present invention is to provide a stable pharmaceutical formulation comprising Olanzapine without any undesired degradation and discoloration.
Another object of the present invention is to provide a stable pharmaceutical formulation comprising Olanzapine or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients wherein the formulation is coated with coating solution comprising Pullulan gum to overcome problem of degradation and discoloration.
Another object of the present invention is to provide a stable pharmaceutical formulation comprising Olanzapine or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients wherein the formulation is coated with coating solution comprising Pullulan gum, starch based coating systems, vinylpyrrolidone-vinyl acetate copolymers or combinations thereof to overcome problem of degradation and discoloration.

Another object of the present invention is to provide a process to prepare a stable pharmaceutical formulation comprising Olanzapine or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients wherein the formulation is coated with coating solution comprising Pullulan gum to overcome problem of degradation and discoloration.
Further object of the present invention is to provide a process to prepare stable pharmaceutical formulation comprising Olanzapine or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients wherein the formulation is coated with coating solution comprising Pullulan gum, starch based coating systems, vinylpyrrolidone-vinyl acetate copolymers or combinations thereof to overcome problem of degradation and discoloration.
Summary of the Invention:
The present invention relates to a stable formulation of Olanzapine tablets coated with Pullulan gum, starch based coating systems, vinylpyrrolidone-vinyl acetate copolymers or combinations thereof to overcome problem of degradation and discoloration.
Description:
The present invention provides a stable formulation comprising Olanzapine or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients, wherein the formulation is coated with coating comprising Pullulan gum, starch based coating systems, vinylpyrrolidone-vinyl acetate copolymers or combinations thereof to overcome problem of degradation and discoloration.
According to one embodiment, the present invention relates to a stable formulation comprising Olanzapine or pharmaceutically acceptable salt thereof and

pharmaceutically acceptable excipients, wherein the formulation is coated with coating comprising Pullulan gum.
According to one embodiment, the present invention relates to a stable formulation comprising Olanzapine or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the formulation is coated with coating solution comprising starch based coating in combination with Pullulan gum.
According to one embodiment, the present invention relates to a stable formulation comprising Olanzapine or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the formulation is coated with coating solution comprising starch based coating in combination with vinylpyrrolidone-vinyl acetate copolymers.
According to one embodiment, the present invention relates to a stable formulation comprising Olanzapine or a pharmaceutically acceptable salt thereof and its pharmaceutically acceptable excipients, wherein the formulation is coated with coating solution comprising Pullulan gum in combination with vinylpyrrolidone-vinyl acetate copolymers.
The advantage of using starch based coatings is to improve the organoleptic characteristics of formulation along with the reduced time for coating operation and an effective barrier against discoloration on exposure to moisture.
Pullulan is natural water-soluble polysaccharide, produced from starch by fermentation. It is an excellent film former and displays good oxygen barrier. Vinylpyrrolidone-vinyl acetate copolymers is also an excellent film forming agent and is less hygroscopic, thus a combination of these two polymers provides an excellent moisture barrier, helping solve the problem of discoloration of Olanzapine formulations.

Polyethylene glycol, a commonly used plasticizer is one of the contributors to the discoloration problem; the current invention avoids the use of PEG thus avoiding discoloration. The current invention also avoids the use of a seal coat, as described to be used in EP733367 thus simplifying the manufacturing process and reducing cost too while achieving the same results through a novel approach.
Olanzapine formulation of the current invention contains Olanzapine Form I disclosed in Pat No. EP454436, alternatively other forms of Olanzapine may also be substituted in the invention. The forms of Olanzapine that can be used alternatively are Form II disclosed in EP733634. Other known polymorphs of Olanzapine can also be used in the current invention.
In accordance with the present invention a stable formulation comprising Olanzapine and one or more of disintegrants, binders, bulking agents, and lubricants.
Suitable disintegrants that can be used in the invention are crospovidone, sodium starch glycolate, carboxymethylcellulose sodium, microcrystalline cellulose, colloidal silicon dioxide, sodium alginate, maize starch, pregelatinised starch. Preferred disintegrant is a crospovidone.
Suitable binders which can be used in the invention are starch, cellulose, hydroxypropyl cellulose, hydroethyl cellulose, guar gum, gelatin, dextrin, synthetic gums like acacia, alginic acid. Maize starch, pregelatinised starch, sodium alginate, extract of fish moss, veegum or mixtures thereof. Preferred binder is hydroxypropyl cellulose.
Bulking agent which are suitable to be used in the invention are calcium sulfate, dibasic calcium phosphate, starch, calcium carbonate, microcrystalline cellulose, lactose, sucrose, mannitol and sorbitol, maize starch, pregelatinised starch, powdered cellulose. Preferred bulking agents are microcrystalline cellulose and lactose.

Lubricants which can be used in the invention are magnesium stearate, calcium stearate, zinc stearate, stearic acid, preferred being magnesium stearate.
According to the present invention the pharmaceutical formulation contains in parts by weight from about 2% to 6% Olanzapine, from about 75% to 85% diluent, from about 0.5 3% to 6% binder, from about 5% to 10% disintegrant and from about 1% to 3% lubricant.
Pullulan gum can be used in the range of 0.5%to to 5% and the starch based coating systems can be employed in the range of 2% to 6% based on the tablet weight. Vinylpyrrolidone-vinyl acetate copolymers can be used in the range of 0.5 to 2%.
The formulation of the present invention can be prepared by employing different processes. It can be prepared by wet granulation, direct compression or by dry granulation.
According to one embodiment, the present invention relates to a process of preparing a stable pharmaceutical formulation comprising Olanzapine or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients wherein the formulation is coated with coating solution comprising Pullulan gum to overcome problem of degradation and discoloration.
According to one embodiment, the present invention relates to a process of preparing a stable pharmaceutical formulation comprising Olanzapine or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients wherein the formulation is coated with coating solution comprising Pullulan gum, starch based coating systems, vinylpyrrolidone-vinyl acetate copolymers or combinations thereof to overcome problem of degradation and discoloration.

Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to person skilled in the art upon reference to the description. It is therefore contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined.
The invention is further exemplified with following example and is not intended to limit the scope of the invention.
Example 1

Sr. No. Ingredients mg / tablet
Core Tablet
1 Olanzapine 5.00
2 Lactose Monohydrate 172.00
3 Microcrystalline Cellulose 11.00
4 Hydroxy propyl Cellulose 7.00
5 Crospovidone 4.00
6 Magnesium Stearate 1.00
200.00 mg
Coated Tablet
1 Pullulan 1.75
2 Vinylpyrrolidone-vinyl acetate copolymers 1.75
3 Lactose monohydrate 1.00
4 Triacetin 1.00
5 Purified Talc 3.462
6 Titanium Dioxide 1.038
210.00

Manufacturing Process:
Step 1: Olanzapine, Lactose monohydrate, Microcrystalline cellulose, Hydroxypropyl
cellulose & Crospovidone were sifted together and blended well. Step 2: Magnesium stearate was added to the blend of Step 1 and mixed for 3 to 5
minutes. Step 3: The blend of Step 2 was compressed to form tablets. Step 4. Tablets of Step of 3 were coated with a mixture of Pullulan gum and
vinylpyrrolidine-vinyl acetate copolymers.

Example 2.
Sr. No. Ingredients mg / tablet
Core Tablet
1 Olanzapine 10.00
2 Lactose Monohydrate 344.00
3 Microcrystalline Cellulose 22.00
4 Hydroxy propyl Cellulose 14.00
5 Crospovidone 8.00
6 Magnesium Stearate 2.00
400.00 mg
Coated Tablet
1 Pullulan 7.00
2 Titanium Dioxide 2.08
3 Lactose monohydrate 2.00
4 Triacetin 2.00
5 Purified Talc 6.92
420.00

Manufacturing Process:
Step 1: Olanzapine, Lactose monohydrate, Microcrystalline cellulose, Hydroxypropyl
cellulose & Crospovidone were sifted together and blended well. Step 2: Magnesium stearate was added to the blend of Step 1 and mixed for 3 to 5
minutes. Step 3: The blend of Step 2 was compressed to form tablets. Step 4. Tablets of Step of 3 were coated with Pullulan gum.

Example 3.
Sr. No. Ingredients mg / tablet
Core Tablet
1 Olanzapine 10.00
2 Lactose Monohydrate 344.00
3 Microcrystalline Cellulose 22.00
4 Hydroxy propyl Cellulose 14.00
5 Crospovidone 8.00
6 Magnesium Stearate 2.00
400.00 mg
Coated Tablet
1 Pullulan 3.50
2 Vinylpyrrolidone-vinyl acetate copolymers 3.50
3 Lactose monohydrate 2.00
4 Triacetin 2.00
5 Purified Talc 6.923
6 Titanium Dioxide 2.075
420.00

Manufacturing Process:
Step 1: Olanzapine, Lactose monohydrate, Microcrystalline cellulose, Hydroxypropyl
cellulose & Crospovidone were sifted together and blended well. Step 2: Magnesium stearate was added to the blend of Step 1 and mixed for 3 to 5
minutes. Step 3: The blend of Step 2 was compressed to form tablets. Step 4. Tablets of Step of 3 were coated with a mixture of Pullulan gum and
vinylpyrrolidine-vinyl acetate copolymers.

Example 4.
Sr. No. Ingredients mg / tablet
Core Tablet
1 Olanzapine 15.00
2 Lactose Monohydrate 339.00
3 Microcrystalline Cellulose 22.00
4 Hydroxy propyl Cellulose 14.00
5 Crospovidone 8.00
6 Magnesium Stearate 2.00
400.00 mg
Coated Tablet
1 Pullulan 3.475
2 Vinylpyrrolidone-vinyl acetate copolymers 3.475
3 Lactose monohydrate 2.005
4 Triacetin 2.000
5 Purified Talc 6.920
6 Titanium Dioxide 2.075
7 FD&C Blue No.2,aluminium lake 0.050
420.00

Manufacturing Process:
Step 1: Olanzapine, Lactose monohydrate, Microcrystalline cellulose, Hydroxypropyl
cellulose & Crospovidone were sifted together and blended well. Step 2: Magnesium stearate was added to the blend of Step 1 and mixed for 3 to 5
minutes. Step 3: The blend of Step 2 was compressed to form tablets. Step 4. Tablets of Step of 3 were coated with a mixture of Pullulan gum and
vinylpyrrolidine-vinyl acetate copolymers.

Example 5.
Sr. No. Ingredients mg / tablet
Core Tablet
1 Olanzapine 20.00
2 Lactose Monohydrate 334.00
3 Microcrystalline Cellulose 22.00
4 Hydroxy propyl Cellulose 14.00
5 Crospovidone 8.00
6 Magnesium Stearate 2.00
400.00 mg
Coated Tablet
1 Pullulan 3.462
2 vinylpyrrolidone-vinyl acetate copolymers 3.462
3 Lactose monohydrate 2.006
4 Triacetin 2.000
5 Purified Talc 6.920
6 Titanium Dioxide 2.075
7 Red Oxide of iron 0.075
420.00

Manufacturing Process:
Step 1: Olanzapine, Lactose monohydrate, Microcrystalline cellulose, Hydroxypropyl
cellulose & Crospovidone were sifted together and blended well. Step 2: Magnesium stearate was added to the blend of Step 1 and mixed for 3 to 5
minutes. Step 3: The blend of Step 2 was compressed to form tablets. Step 4. Tablets of Step of 3 were coated with a mixture of Pullulan gum and
vinylpyrrolidine-vinyl acetate copolymers.

The formulation prepared in example 1 and 2 was subjected to stability testing. Stability Data: Table 1.
Name of product: Olanzapine Tablet.
Strength : 5 mg
Batch No : OLZ/R/5/26 PU + VA64.

Tests Specification Olanzapine Tablet.
Initial 3 Months
25° C/60%
RH 3 Months
40° C/75%
RH
Description White coloured, round biconvex film coated tablet plain on both side. Complies Complies Complies
Assay NLT than 90 to 110% of labeled claim. 103.2 107.0 105.1
Related Substance
Impurity B NMT 0.5% 0.01 0.04 0.16
Impurity C NMT 0.5% 0.03 0.08 0.14
Impurity Lactum NMT 0.5% 0.02 0.03 0.03
Impurity Thiolactum NMT 0.5% 0.01 0.01 0.01
TBD FI 0.02 0.02 0.01
Any known impurity (Max) NA 0.03 0.08 0.16
Any unknown impurity (Max) NMT 0.2% 0.03 0.03 0.04
Total Impurities. NMT 1.5% 0.17 0.28 0.52
Remark: Thus, it can be seen that Impurity B and Unknown Impurity formed due to oxidation is controlled after coating Olanzapine tablets with Pullulan gum and vinylpyrrolidine-vinyl acetate copolymers.

Table 2.
Name of product: Olanzapine Tablet.
Strength : 10 mg
Batch No : OLZ/R/10/20PU

Tests Specification Olanzapine Tablet.
Initial 3 Months 25° C/60% RH 3 Months
40° C/75% RH
Description White coloured, round biconvex film coated tablet plain on both side. Complies Complies Complies
Assay NLTthan 90 to 110% of labeled claim. 103.2 99.0 99.9
Related Substance
Impurity B NMT 0.5% 0.01 0.03 0.06
Impurity C NMT 0.5% 0.03 0.04 0.07
Impurity Lactum NMT 0.5% 0.01 0.01 0.01
Impurity Thiolactum NMT 0.5% 0.01 0.01 0.02
TBD FI ND 0.02 0.01
Any known impurity (Max) NA 0.03 0.04 0.07
Any unknown impurity (Max) NMT 0.2% 0.03 0.05 0.05
Total Impurities. NMT 1.5% 0.16 0.30 0.42
Remark: Thus, it can be seen that Impurity B and Unknown Impurity formed due to oxidation is controlled after coating Olanzapine tablets with Pullulan gum.

We Claim:
1. A stable pharmaceutical formulation comprising Olanzapine or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients wherein the formulation is coated with coating solution comprising Pullulan gum, starch based coating systems, vinylpyrrolidone-vinyl acetate copolymers or combinations thereof to overcome problem of discoloration and degradation.
2. A stable pharmaceutical formulation comprising Olanzapine or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients wherein the formulation is coated with coating solution comprising Pullulan gum.
3. A stable pharmaceutical formulation of Olanzapine as claimed in claim 1, wherein the wherein the formulation is coated with coating solution comprising starch based coating in combination with Pullulan gum.
4. A stable pharmaceutical formulation of Olanzapine as claimed in claim 1, wherein the formulation is coated with coating solution comprising starch based coating in combination with vinylpyrrolidone-vinyl acetate copolymers.
5. A stable pharmaceutical formulation of Olanzapine as claimed in claim 1, wherein the formulation is coated with coating solution comprising Pullulan gum in combination with vinylpyrrolidone-vinyl acetate copolymers.
6. A stable pharmaceutical formulation of Olanzapine as claimed in claim 1, wherein the Pullulan gum is used in amounts ranging from about 0.5 % to about 5 %.

7. A stable pharmaceutical formulation of Olanzapine as claimed in claim 1, wherein the vinylpyrrolidone-vinyl acetate copolymer is used in amounts ranging from about 0.5 % to about 2%.
8. A stable pharmaceutical formulation of Olanzapine as claimed in claim 1, wherein the starch is used in amounts ranging from about 2 % to about 6 %.
9. A process to prepare a stable pharmaceutical formulation as claimed in claim 1, comprising Olanzapine or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients wherein the formulation is coated with coating solution comprising Pullulan gum to overcome problem of degradation and discoloration.
10. A process to prepare a stable pharmaceutical formulation as claimed in claim 1,
comprising Olanzapine or its pharmaceutically acceptable salt and pharmaceutically
acceptable excipients wherein the formulation is coated with coating solution
comprising Pullulan gum, starch based coating systems, vinylpyrrolidone-vinyl acetate
copolymers or combinations thereof to overcome problem of degradation and
discoloration.