FORM 2 THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATIONS
(SECTION 10)
"PHARMACEUTICALLY STABLE COMPOSITION OF
ZOLMITRIPTAN"


REGISTERED UNDER THE INDIAN COMPANIES ACT, 1956, HAVING ITS REGISTERED OFFICE LOCATED AT UNICHEM
UNICHEM LABORATORIES LIMITED, A COMPANY
BHAVAN, PRABHAT ESTATE, OFF S. V. ROAD, JOGESHWARI
(WEST), MUMBAI - 400102,
MAHARASTRA, INDIA

The following specification particularly describes the invention and the manner in which it is to be performed.


"PHARMACEUTICALLY STABLE COMPOSITION OF ZOLMTTRTPTAN"
FIELD OF INVENTION
[0001] The present invention relates to the preparation of stable, dose proportional, easily disintegrating and dissolving pharmaceutical composition comprising zolmitriptan or its pharmaceutical^ acceptable salt, enantiomers or mixtures thereof. In particular, the present invention is related to pharmaceutical technology, which discloses the stable composition for zolmitriptan orodispersible tablets.
BACKGROUND OF THE INVENTION
[0002] The development of solid formulations that disintegrate quickly in the mouth, without the requirement of water, are very interesting due to the advantages that these pharmaceutical formulations suits for pediatric or aged patients, having difficulty swallowing conventional tablets or capsules, or for individuals who may not have difficulty swallowing, but may have an aversion to swallowing conventional tablets or capsules. Orally disintegrating tablets also are convenient under circumstances in which taking an oral dosage form with water may be inconvenient (e.g., while working or traveling) since this dosage form makes it possible for the drug to be administered without the need of water. Moreover, this formulation disintegrates in the mouth, making the drug available for absorption in the oral, pharyngeal and gastrointestinal regions. The pre-gastric drug absorption avoids hepatic first-pass metabolism.
[0003] Quicker onset of action of drug is also required in the treatment of acute conditions. So, drugs used in the management of such conditions can be developed into an immediate release or orodispersible tablets for their better therapeutic effectiveness. In particular, acute conditions need minimum effective concentration of the drug in the circulating blood within a very short time.
[0004] Many of the drugs used in the management of various acute conditions like, pain reducing agents (naproxen, ibuprofen, acetaminophen etc.), anti-depressants (tranylcypromine, buproprion etc.) decongestants (phenylephrine, pseudoephedrine etc), anti-convulsants (tiagabine etc.),, anti-platelet agents (ticlopidine, clopidogrel etc.), anti-histamines (cetirizine, montelukast sodium etc.), anti-hypertensives (diltiazem HC1, Verapamil HC1 etc.) anti-tussives (dextromethorphan hydrobromide etc.), proton pump inhibitor (esomeprazole etc.), anti-platelet agents (ticlopidine,
;■■■.. 2

clopidogrel etc.) are prone to degradation in the presence of oxygen. Stability of any active pharmaceutical ingredient alone or in combination with any of the excipient used in the preparation of pharmaceutical composition is desired throughout its shelf life, i.e., at least for a period of two years.
[0005] Active pharmaceutical ingredients that are unstable and degrade in the presence of oxygen, can be stabilized by several different methods. The drug product and the API may be processed under inert atmospheres, e.g., under argon or nitrogen gas blankets, which requires special manufacturing conditions and adds to the cost of the product. Antioxidants such as, bisulfites and ascorbic acid may be utilized to help stabilize oxygen sensitive API's, however there are some safety issues associated with their usage.
[0006] Zolmitriptan is a selective 5-HT1 receptor agonist of subtypes IB/ID. It is a triptan, used in the acute treatment of migraine attacks with or without aura and cluster headaches. The 5HT1-receptor mediates vasoconstriction and thus modifies blood flow to the carotid vascular bed. 5HT1 -receptor agonists are beneficial in the treatment (including prophylaxis) of disease conditions, wherein vasoconstriction in the carotid vascular bed is indicated, for example migraine, cluster headache and headache associated with vascular disorders, hereinafter referred to collectively as 'migraine'. Zolmitriptan has been developed for the acute treatment of migraine in the form of either 2.5 mg or 5 mg tablet, it can be taken up to a maximum dose of 15 mg per day. It has excellent absorption characteristics following oral administration. It has the chemical name of (S)-4-{{3-[2-(dimethylaminoethyl]-lH-indol-5-yl] methyl]-2-oxazolidinone. It has a molecular formula of C16H21N3O2with a molecular weight of 287.357.
[0007] Orodispersible tablets of zolmitriptan are currently marketed by AstraZeneca under the brand name of Zomig-ZMT in two different strengths i.e., 2.5mg and 5mg in the USA which were approved by the USFDA. In Europe, it is marketed under the trade name of Zomig Rapimelt. The products, Zomig ZMT and Zomig Rapimelt have very less hardness requiring special peelable Alu-alu blister and have to be handled very carefully.
[0008] Immediate release tablets of zolmitriptan are marketed by AstraZeneca under the brand names of Zomig (in USA); Zomig, Zomigon (in Greece & Argentina). AscoTop (in Germany) and Zomigoro (in France).

[0009] U.S. Patent. No. 5,466,699 (Robertson Alan D. et al, 1994) discloses a class of chemical compounds for the treatment and prophylaxis of migraine. It also discloses that this class of compounds may be formulated for oral, sublingual, buccal, parenteral (for example subcutaneous, intramuscular or intraveneous), rectal, topical and intranasal administration and examples of such possible formulations, including an example of an intranasal formulation.
[00010] US Patent US6024981 (Rajendra K. Khankari et al., April 09, 1998)
describes a hard, rapidly dissolving dosage form comprising active ingredient as coated particle along with other non-compressible filler, lubricant and further describes said dosage form is prepared by direct compression. Even though the disclosed final composition can be manufactured by direct compression, coated particles comprising active ingredient needs to be manufactured before final compression. This is additional step of manufacturing, which is costly and cumbersome.
[00011] US Patent 2007/0259040 (S. Rao Cherukuri., November 08, 2007)
describes novel, rapidly disintegrating oral formulations of triptans comprising taste masked active pharmaceutical ingredient (prepared by mixing with a resin), other pharmaceutically acceptable excipients and taste making agent in the form of coating. Preparation of taste masked active pharmaceutical ingredient and taste masking agent in the form of coating adds additional steps to the manufacturing process and therefore increases the cost of the manufacturing process.
[00012] WO 2007/113856 A2 (Pilgaonkar Pratibha, S., October 11, 2007)
describes the process of preparing orally disintegrating tablets. The process comprises preparation of directly compressible composite, containing a water soluble carbohydrate and water soluble polyhydric alcohol or its salt, is prepared by spray drying. Composition of formulations in this invention also contains surfactants, salivating agents and utilizes crospovidone as one of the preferred disintegrant, making the composition more complex and making it less stable for oxygen sensitive active pharmaceutical ingredient like zolmitriptan. Preparation of directly compressible composite increases the unit operations in the manufacturing process and thereby increases the cost.
[00013] US Patent 2005/0232988 (Gopi M. Venkatesh., October 20, 2005)
describes the methods of manufacture of orally disintegrating tablets made up of rapidly dispersible microgranules (containing a sugar alcohol or a saccharide or mixture), taste masked microcapsule (containing active pharmaceutical ingredient, a
4

polymeric binder) and additional pharmaceutical ingredients. Manufacturing process
involved in this invention is cumbersome i.e., unlike direct compression it includes
additional unit operations like wet granulation and microencapsulation, increasing the
cost of manufacturing. In addition, the composition contains, sumatriptan as
preferable active ingredient and crospovidone as preferred disintegrant. Sumatriptan is
prone to oxidative degradation. Presence of peroxide residues in crospovidone, makes
the pharmaceutical compositions of oxidation prone drugs less stable.
[00014] Even though different compositions are disclosed for the manufacture of
Zolmitriptan orodispersable tablets, there is a need for simple and cost effective pharmaceutical composition and process for preparing the same, which could eliminate all these disadvantages.
OBJECT OF THE INVENTION
[00015] The object of the present invention is to provide a stable, dose
proportional, simple and cost effective pharmaceutical composition of zolmitriptan
using zolmitriptan or its pharmaceutically acceptable salt, enantiomers or mixtures, and
process for the preparation thereof.
[00016] Another object of the present invention is to provide a composition of
dosage forms which can be handled easily without the requirement of any special
packaging.
[00017] Still another object of the present invention is to provide a composition
with good stability with respect to impurity profile.
[00018] Further object of the present invention is to provide a stable composition
even at accelerated storage conditions.
SUMMARY OF THE INVENTION
[00019] The present invention relates to an orodispersible pharmaceutical
composition comprising zolmitriptan or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof, in a pharmaceutically effective amount, croscarmellose sodium in a stabilizing effective amount along with other pharmaceutically acceptable excipients.

[00020] Further, embodiment of the present invention also provides a method of
manufacturing a stable zolmitriptan orodispersible tablets including the steps of mixing of a dry blend of said zolmitriptan in a pharmaceutical effective amount with other pharmaceutically acceptable excipients, which essentially contains croscarmellose sodium as a stabilizer. The method may further include the step of compressing the mixture to form a directly compressed tablet.
[00021] Further more, the present invention provides a method of stabilizing
pharmaceutical compositions containing oxidation prone drugs by utilizing peroxide scavenging property of croscarmellose sodium .
BRIEF DESCRIPTION OF THE DRAWINGS
[00022] Figure 1: Comparative dissolution profiles of Example 1 and Zomig
Rapimelt® inO.lNHCl
[00023] Figure 2: Comparative dissolution profiles of Example 1 in 0.1 N HC1
stored at accelerated storage conditions
[00024] Figure 3: Comparative dissolution profiles of Example 2 and Zomig
Rapimelt® inO.lNHCl
[00025] Figure 4: Comparative dissolution profiles of Example 2 in 0.1 N HC1
stored at accelerated storage conditions DETAILED DESCRIPTION OF THE INVENTION
[00026] The present invention provides a highly stable pharmaceutical composition
comprising, zolmitriptan or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof. The present invention also provides a simple and cost effective manufacturing process, by direct compression technique.
[00027] In particular, the present invention is an orodispersible pharmaceutical
composition comprising, zolmitriptan or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof, and one or more of pharmaceutically acceptable excipients.
[00028] The composition of the present invention may include the active
ingredient in the range of about 1 mg to about 15 mg. Preferably formulation may contain 2.5 mg or 5 mg of the active ingredient. The term 'active ingredient' refers zolmitriptan or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof.

[00029] In accordance with the present invention, highly stable pharmaceutical
composition preferably is in the form of a solid oral dosage form. Preferably, the solid oral dosage form is a tablet, capsule, sachet of granules, film, wafer, powder. More preferably the solid oral dosage form is a tablet.
[00030] One form of the pharmaceutical composition in the present invention, in
the form of tablets have the hardness in the range of 30-120 N. More preferably the hardness is in the range of 40 - 100 N.
[00031] According to the present invention, a highly stable pharmaceutical
composition comprises zolmitriptan or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof and one or more of pharmaceutically acceptable excipients like, diluents, disintegrant, sweeteners, flavors and lubricants.
[00032] Diluents used in the present invention may be at least one or more of the
mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, starch 1500, calcium phosphate (dibasic/tribasic), calcium sulphate, calcium sulphate dihydrate, lactose, fructose, sucrose, sorbitol, xylitol, dextrose, compressible sugar, dextrates, dextrin, starch, powdered cellulose, cellulose acetate, polymethacrylates, sodium alginate and tragacanth.
[00033] Preferred diluents used in the present invention are one or more of
mannitol, silicified microcrystalline cellulose, lactose, and starch. More preferred diluents in the present invention are mannitol and silicified microcrystalline cellulose.
[00034] Disintegrants used in the present invention may be one or more of the
croscarmellose sodium, crospovidone, sodium starch glycollate, low-substituted hydroxypropyl cellulose, starch, pregelatinized starch, microcrystalline cellulose, emcosoy (Soya polysaccharide) and potassium polacrilin.
[00035] Preferred disintegrants used in the preparation are one or more of
croscarmellose sodium, crospovidone and sodium starch glycolate. More preferred disintegrant in the present invention is croscarmellose sodium.
[00036] Sweeteners used may be at least one or more of the aspartame, dextrose,
mannitol, neotame, sucrose, sucralose. More preferred sweetener in the present invention is sucralose.
[00037] Flavors used may be at least one or more of Ess apricot, Ess banana, Ess
orange sweet, Ess peppermint, Essence strawberry, chocolate flavor, flavor fruit cocktail, mango flavor, peppermint flavor, pineapple flavor, vanilla flavor, grape flavor,

mixed fruit flavor. More preferred flavor in the present invention is orange flavor
501071AP0551.
[00038] The lubricant used may be one or more of magnesium stearate, calcium
stearate, stearic acid, sodium stearyl fumerate, hydrogenated vegetable oils, magnesium
lauryl sulfate, talc, wax, polyethylene glycol, glyceryl behenate, glyceryl
palmitostearate, palmitic acid, poloxamer, sodium benzoate and sodium lauryl sulfate.
[00039] Preferred lubricants used in the preparation are one or more of magnesium
stearate and sodium stearyl fumarate. More preferred lubricant in present invention is
magnesium stearate.
[00040] The orodispersible pharmaceutical composition may contain from about
1% to 20% of the active ingredient. Preferably the pharmaceutical composition may
contain from about 1% to 10% of the active ingredient. More preferably, the
formulation may contain from about 1% to 2.5% of the active ingredient.
The 'active ingredient' may be zolmitriptan or its pharmaceutically acceptable salt,
solvate, enantiomers or mixtures thereof.
[00041] The orodispersible pharmaceutical composition may contain from about
1% to 97.5 % of one or more of diluents preferably from about 1% to about 90 %; and
from about 0.5 % to 20 % of one or more of disintegrants, preferably from about 1% to
about 8 % of one or more of disintegrants.
[00042] The orodispersible pharmaceutical composition may contain from about
0.25% to 5% of sweeteners. Preferably the formulation may contain from about 0.5% to
2% of sweeteners.
[00043] The orodispersible pharmaceutical composition may contain from about
0.1% to 2% of flavours. Preferably the formulation may contain from about 0.1% to 1%
of flavours.
[00044] The formulation may also contain from about 1% to 5 % of the lubricants.
Preferably formulation may contain from about 1% to 3 % of the lubricants.
[00045] An orodispersible pharmaceutical composition may contain croscarmellose
sodium in an amount from about 0.5% to about 20% by weight of said composition,
preferably, from about 1% to about 8%.
[00046] Zolmitriptan pharmaceutical composition containing croscarmellose
sodium as disintegrant was found to have improved impurity profile compared to
zolmitriptan pharmaceutical composition containing crospovidone XL 10 as a

disintegrant, which may be due to the stabilizing effect of croscarmellose sodium on zolimitriptan.
[00047] Based on the literature, it is evident that the zolmitriptan is prone to
oxidative degradation. Increased levels of N-oxide impurities were observed in the pharmaceutical compositions prepared by using crospovidone. This may be due to the trace levels of hydrogen peroxide which is likely to be present in the crospovidone itself. Low levels of N-oxide impurities were observed in the pharmaceutical compositions prepared by using croscarmellose sodium which in turn may be due to peroxide scavenging property of croscarmellose sodium.
[00048] Moreover stability studies at accelerated conditions revealed that the levels
of at least two impurities (refer Table 4) were increased for pharmaceutical composition containing crospovidone XL 10.
[00049] Stability studies of pharmaceutical composition containing croscarmellose
sodium as a disintegrant showed very less impurities even at accelerated conditions of storage (refer Table 9) when compared to pharmaceutical composition containing crospovidone XL 10.
[00050] The orodispersible pharmaceutical composition of zolmitriptan, releases
more than about 85% of the drug in about 5 minutes as measured in 0.1N HCl using TJSP Type II apparatus, at 37±2 °C.
[00051] The orodispersible pharmaceutical composition of zolmitriptan releases,
releases more than about 95%) of the drug in about 15 minutes as measured in 0.1N HCl using USP Type II apparatus, at 37±2 °C.
[00052] The compositions of the present invention may be administered to a
mammal. Preferably, the mammal is a human, and the composition is administered as said highly pharmaceutical composition. Preferably, the pharmaceutical composition is administered to treat migraine, cluster headache and headache associated with vascular disorders
[00053] The amount of the zolmitriptan in the present highly pharmaceutical
composition is preferably an amount that provides a therapeutically effective amount of zolmitriptan. The amount of zolmitriptan used differs according to the amount needed for effective therapeutic response.

[00054] According to the present invention, the method for preparation of
orodispersable pharmaceutical composition of zolmitriptan tablets comprise the steps of mixing of a dry blend of said zolmitriptan in a pharmaceutical effective amount with other pharmaceutically acceptable excipients, which essentially contains croscarmellose sodium & compressing into tablets.
[00055] In the present invention, active ingredient(s), directly compressible
excipients and other auxiliary substances, such as sweeteners, flavors, disintegrant and lubricant are blended in a double cone blender or similar low shear apparatus before being compressed into tablets. This type of mixing was believed to be essential in the preparation of "pharmaceutically acceptable" dosage forms. In addition, formulations prepared have good hardness and can be handled easily without the requirement of special peelable blister packing as marketed products.
EXAMPLES
The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims
10

Example 1
Table 1: Composition of Example 1

S.No. Ingredients mg/tablet
1. Zolmitriptan IH 5.00
2. Mannitol USP (Mannozem EZ) 137.00
3. Microcrystalline cellulose USP (Avicel PH 102) 30.00
4. Crospovidone XL 10 20.00
5. Sucralose 2.00
6. Orange flavor 501071AP0551 0.80
7. Colloidal silicone dioxide USP 1.20
8. Magnesium stearate USP 4.00
Tablet weight (mg) 200.0
Manufacturing process:
1. Co-sifted the zolmitriptan and half the quantity of microcrystalline cellulose through ASTM #. 60 mesh. Then, sifted the remaining quantity of microcrystalline cellulose and colloidal silicon dioxide through ASTM # 60 mesh. One portion of mannitol was also sifted through ASTM # 60 mesh. This powder mix was blended for 5 min.
2. Sifted crospovidone XL10, orange flavor, sucralose and half the portion of remaining mannitol through ASTM # 60 mesh and blended with step 1 blend for 7 minutes.
3. Sifted the remaining quantity of mannitol through ASTM # 60 mesh, blended with step 2 blend for 8 minutes.
4. Sifted magnesium stearte through ASTM # 60 mesh and blended with step 3 blend for 3 minutes.
5. Compressed lubricated blend using 8.00 mm round flat faced bevelled edged punches.
[00056] Dissolution studies of tablets of Example 1 and Zomig Rapimelt® were
carried out in USP Type-II apparatus using 500 ml of 0.1N HC1 as dissolution medium maintained 37±2° C with the paddle speed of 50 rpm, and the comparative dissolution profiles are given in Table 2 and Fig. 1

Table 2: Comparative dissolution profiles of the tablets of Example 1 and Zomig Rapimelt® in 0.1N HCl.

Time (minutes) Percent zolmitriptan released

Zomig Rapimelt® Example 1
0 0 0
5 91.0 91.4
10 95.1 96.9
15 94.9 97.7
30 94.3 98.2
45 95.1 97.8
[00057] Tablets of Example 1 were evaluated for assay and related substances.
Results of these studies are shown in Table: 3.
i
Table 3: Evaluation of the formulation of Example: 1

S.No. Parameters Result
1. Assay (%) 93.7
2. Related substances

Amine impurity (%) BQL

N-oxide impurity (%) 0.87

Stage IV impurity (%) BQL

Unknown impurities (%) 0.04, 0.08, 0.05, 0.02, 0.04, 0.02, 0.01

Total impurities (%) 1.00
BQL : Below quantification limit [00058] Stability studies were also conducted for the tablets of Example 1 after * |
packing in Alu-Alu blister for 3 months at accelerated conditions (40°C/75% RH) to [
evaluate the changes in related substances as well as changes in the dissolution profile in USP Type-II apparatus run at the paddle speed of 50 rpm by using 500 ml of 0.1N [
HC1 maintained at 37±2°C. The results of these studies are shown in Table 4 to 5 and f
Fig. 2. |
F; [■
E:
I
i f

Table 4: Accelerated stability study results of tablets of Example 1

s.
No. Parameters Accelerated conditions (40°C/75% RH)

1 month 2 month 3 month
1. Assay (%) 95.5 98.3 98.0
2. Related substances

Amine impurity (%) BQL BQL BQL

N-oxide impurity (%) 1.12 1.13 1.09

Stage IV impurity (%) BQL BQL BQL

Unknown impurities (%) 0.01,0.01,0.11, 0.05, 0.03, 0.04, 0.03,0.20,0.04 0.03, 0.09, 0.03, 0.01, 0.38, 0.01 0.01, 0.02, 0.01,
0.04, 0.09, 0.04,
0.02, 0.02, 0.64,
0.02

Total impurities (%) 1.48 1.60 1.82
BQL : Below quantification limit
Table 5: Dissolution profile of tablets of Example 1 stored at accelerated storage
condition (40°C/75%RH).

Time (minutes) Percent zolmitriptan released

1 month 2 month 3 month
0 0 0 0
5' 88.4 93.2 91.5
10 95.7 97.7 96.5
15 96.9 97.3 96.0
30 97.5 97.2 96.9
Example 2
Table 6: Composition of Example 2

S.No. Ingredients mg/tablet
1. Zolmitriptan IH 5.00
2. Mannitol USP (Mannozem EZ) 143.60
3. Silicified microcrystalline cellulose USP (Prosolv 90) 36.60
4. Croscarmellose sodium USP 8.00
5. Sucralose 2.00
6. Orange flavor 501071AP0551 0.80
7. Magnesium stearate USP 4.00
Tablet weight (mg) 200.00

[00059] Manufacturing process:
1. Zolmitriptan and one portion of mannitol were mixed in a polybag.
2. Sifted another portion of mannitol, stepl blend and silicified microcrystalline cellulose through ASTM # 60 mesh. This powder mixture was blended for 10 mins.
3. Sifted croscarmellose sodium, sucralose, orange flavor 501071AP0551 and half the portion of remaining mannitol through ASTM # 60 mesh and then blended with step 2 blend for 15 mins.
4. Sifted remaining quantity of mannitol through ASTM # 60 mesh and blended with step 3 blend for 10 mins.
5. Sifted magnesium stearate through ASTM # 60 mesh and blended with step 4 blend for 3 mins.
6. Compressed lubricated blend using 8.00 mm round flat faced bevelled edged punches.
[00060] Tablets of Example 2 and Zomig Rapimelt® were subjected to dissolution
studies in USP Type II apparatus using 500 ml of 0.1N HC1 as dissolution medium maintained at 37±2° C with the paddle speed of 50 rpm, and the comparative dissolution profiles are given in Table 7 and Fig. 3.
Table 7: Comparative dissolution profiles of the tablets of Example 2 and Zomig Rapimelt® in 0.1N HC1.

Time (minutes) Percent zolmitriptan released

Zomig Rapimelt® Example 2
0 0 0
' 5 91.0 93.4
10 95.1 100.0
15 94.9 100.6
30 94.3 101.1
45 95.1 101.4
30 SEP 2009

[00061] Tablets of Example 2 were evaluated for assay and related substances.
Results of these studies are shown in Table: 8. Table 8: Evaluation of the tablets of Example 2

S.No Parameters Result
1. Assay (%) 100.7
2. Related substances

Amine impurity (%) BDL

N-oxide impurity (%) 0.05

Stage IV impurity (%) BDL

Unknown impurities (%) 0.02, 0.01

Total impurities (%) 0.05
[00062] Stability studies were also conducted for the tablets of Example 2 after
packing in triplex blister for 3 months at accelerated conditions (40°C/75% RH) to evaluate the changes in related substances as well as changes in the dissolution in USP Type-II apparatus run at the paddle speed of 50 rpm by using 500 ml of 0.1N HCl maintained at 37±2°C. The results of these studies are shown in Table: 9 to 10 and Fig. 4.
Table 9: Accelerated stability study results of tablets of Example 2

S.No. Parameters Accelerated conditions (40°C/75% RH)

1 month 2 month 3 month
1. Assay (%) 102.7 101.7 101.2
2. Related substances

Amine impurity (%) BQL BQL BQL

N-oxide impurity (%) 0.07 0.11 0.10

Stage IV impurity (%) BQL BQL BQL

Unknown impurities (%) 0.02, 0.02, 0.01 0.05 0.05, 0.02,0.08

Total impurities (%) 0.07 0.16 0.23

i

Table 10: Dissolution profile of tablets of Example 2 stored at accelerated condition (40°C/75%RH).

Time (minutes) Percent zolmitriptan released

1 month 2 month 3 month
0 0 0 0
5 95.9 96.3 95.9
10 104.1 100.3 100.1
15 104.1 100.4 100.2
30 105.9 100.5 100.3

We Claim
1. An orodispersible pharmaceutical composition comprising zolmitriptan or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof, in a pharmaceutically effective amount, croscarmellose sodium in a stabilizing effective amount along with other pharmaceutically acceptable excipients.
2. An orodispersible pharmaceutical composition of claim 1, wherein the said croscarmellose sodium is present in an amount from about 0.5% to about 20% by weight of said composition, preferably, from about 1% to about 8%
3. An orodispersible pharmaceutical composition of claim 1, wherein said zolmitriptan or its pharmaceutically acceptable salt, solvate, enantiomers or mixture thereof, is present in an amount from about 1 mg to about 15 mg.
4. An orodispersible pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable excipients used are one or more of diluents, disintegrants, sweeteners, flavors and lubricants.
5. An orodispersible pharmaceutical composition according to claim 4, wherein diluents used may be at least one or more of mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, starch 1500, calcium phosphate (dibasic/tribasic), calcium sulphate, calcium sulphate dihydrate, lactose, fructose, sucrose, sorbitol, xylitol, dextrose, compressible sugar, dextrates, dextrin, starch, powdered cellulose, cellulose acetate, polymethacrylates, sodium alginate and tragacanth, preferrably mannitol and silicified microcrystalline cellulose.
6. An orodispersible pharmaceutical composition according to claim 4, wherein disintegrant used may be at least one or more of croscarmellose sodium, crospovidone, sodium starch glycollate, low-substituted hydroxypropyl cellulose, starch, pregelatinized starch, microcrystalline cellulose, emcosoy (Soya polysaccharide) and potassium polacrilin, preferably croscarmellose sodium.
7. An orodispersible pharmaceutical composition according to claim 4, wherein sweetener used may be at least one or more of the aspartame, dextrose, mannitol, neotame, sucrose, sucralose, preferrably sucralose.
8. An orodispersible pharmaceutical composition according to claim 4, wherein flavor used may be at least one or more of the Ess apricot, Ess banana, Ess orange sweet, Ess peppermint, Essence strawberry, chocolate flavor, flavor fruit cocktail, mango flavor,

peppermint flavor, pineapple flavor, vanilla flavor, grape flavor, mixed fruit flavor, preferably Orange flavor 501071AP0551.
9. An orodispersible pharmaceutical composition according to claim 4, wherein lubricant used may be one or more of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumerate, hydrogenated vegetable oils, magnesium lauryl sulfate, talc, wax, polyethylene glycol, glyceryl behenate, glyceryl palmitostearate, palmitic acid, poloxamer, sodium benzoate and sodium lauryl sulfate, preferably magnesium stearate.
10. An orodispersible composition according to claim 1, wherein active ingredient may contain about 1% to 20%, preferably about 1% to 10%, more preferably about 1% to 2.5%.
11. An orodispersible pharmaceutical composition according to claim 4, wherein diluents may contain about 1% to 97.5 %, preferably about 90 %; and disintegrants about 0.5 % to 20 %, preferably about 1 % to 8%.
12. An orodispersible pharmaceutical composition according to claim 4, wherein sweeteners may contain about 0.25% to 5%, preferably about 0.5% to 2%.
13. An orodispersible pharmaceutical composition according to claim 4, wherein flavors may contain about 0.1% to 2%, preferably about 0.1% to 1%.
14. An orodispersible pharmaceutical composition according to claim 4, wherein lubricants may contain about 1% to 5 %, preferably about 1% to 3%.
15. An orodispersible pharmaceutical composition according to claim 1, wherein the said pharmaceutical composition is a solid dosage form selected from the group comprising of tablet, capsule, sachet of granules, film, wafer, powder, which disintegrates with saliva in the mouth.
16. An orodispersible pharmaceutical composition according to claim 15, wherein the said dosage form is directly compressed orodispersible tablet.
17. An orodispersible pharmaceutical composition according to claim 16, wherein the directly compressed tablets have the hardness in the range of between 30-120 N, preferably, in the range of 40-100 N.
18. The pharmaceutical compositions of claim 1, wherein zolmitriptan releases more than 85% in about 5 minutes, preferably, it releases more than 95% in about 15 minutes as measured in 0.IN HC1 using USP Type II apparatus, at 37±2° C.

19. The method for preparation of orodispersable pharmaceutical composition of zolmitriptan tablets comprise the steps of mixing of a dry blend of said zolmitriptan in a pharmaceutical effective amount with other pharmaceutically acceptable excipients, which essentially contains croscarmellose sodium & compressing into tablets.
20. A method of stabilizing pharmaceutical compositions containing oxidation prone drugs by utilizing peroxide scavenging property of croscarmellose sodium
21. An orodispersable pharmaceutical compositions according to claim 1, wherein the dosage form is used in the treatment of migraine and cluster headache and headache associated with vascular disorders.
22. The oral pharmaceutical composition substantially as herein described and illustrated with reference to the accompanying examples