FIELD OF INVENTION

The invention particularly relates to stable pharmaceutical compositions comprising triptans and processes for preparing them, wherein said compositions are preferably in the form of orally disintegrating tablet (ODT).

BACKGROUND OF THE INVENTION AND RELATED PRIOR ART

The invention is related to stable pharmaceutical compositions comprising 5- HTIB/ID receptor agonist which are also known as triptans.

Many triptans are approved and commercially available in the market and they can be mentioned here chronologically with respect to clinical development for e.g., sumatriptan, zolmitriptan, naratriptan, rizatriptan, almotriptan, eletriptan and frovatriptan.

US Patent No. 4,816,470 discloses sumatriptan; US Patent No. 5,466,699 discloses zolmitriptan; US Patent No. 4,997,841 discloses naratriptan; US Patent No. 5,298,520 discloses rizatriptan, US Patent No. 5,565,447 discloses almotriptan, US Patent No. 5,545,644 discloses eletriptan; & US Patent No. 5,616,603 discloses frovatriptan.

The above marketed triptans are available in various dosage forms like oral tablets, ODT, nasal sprays and subcutaneous injections. Zolmitriptan ODT is available in the US and other countries as Zomig-ZMT® and that of Rizatriptan ODT as Maxalt-MLT®.

ODT according to European Pharmacopoeia is defined as an uncoated tablet, with the intent to deliver drug in the mouth, and generally disintegrating in the mouth within 3 minutes.

The objective to formulate an ODT is primarily to improve patient's compliance and thus being more preferable dosage form for children and elderly patients, who might have problem swallowing a conventional tablet or capsule dosage form.

Preparation of an ODT is known very well in the art and literatures are replete with such preparatory methods. Typical approaches for formulating such dosage forms include direct compression, molding, lyophilization, fast dissolving film etc. to name a few.

US Patent No. 6,024,981 discusses method of making rapidly disintegrating compositions by direct compression of active substance and non-direct compression sugar alcohols.

PCT Application No. WO 2007/074472 discusses preparation of mouth dissolving compositions using larger particle size fillers and high percentage of silicon dioxide.

US Patent Application No. 2008/0254120 discusses orally disintegrating tablet, which comprises active agent, sugar alcohol powder and granulated sugar alcohol. It further exemplifies that when ODT is prepared only with sugar alcohol granules, the buccal disintegration time increases, and on the other hand when only sugar alcohol powder is used, tableting is impossible and tablets could not be formed. Thus there was a need to incorporate both sugar alcohol powder and granulated sugar alcohol in order to get the desired properties of the ODT.

US Patent No. 5,576,014 discusses method of preparing intra-buccally dissolving compressed molding compositions, by granulating a mixture of low moldability sugars and high moldability sugars. Combining these two types of saccharides results in a composition, having fast dissolution rate and sufficient hardness.

PCT Application No. WO 2008/007151 discusses compositions for triptans in the form of nano-dispersion as an improvement in pharmaceutical formulations and suitable for water insoluble triptans.

PCT Application No. WO 2005/044222 discusses compositions which contain water resistant coating over the core to prevent possible degradations of triptans from moisture exposure.

PCT Application No. WO 2005/018565 discusses composition to deliver 5-HT agonist across oral mucosa. Said composition is prepared with buffer system that facilitates release and absorption of 5-HT agonist across oral mucosa.

The ODT compositions are suitable for different therapeutic class of drugs including triptans which are anti-migraine agents.

Thus, there is need to develop improved pharmaceutical compositions and processes for the preparation of ODTs comprising triptans and other pharmaceutically acceptable salts which prevents degradation of triptans during manufacturing and/or any stage due to factors like moisture and/or heat.

SUMMARY AND OBJECTIVE OF THE INVENTION

The invention relates to stable pharmaceutical compositions comprising triptans and processes for preparing them, wherein said compositions are preferably in the form of ODT.

More particularly, the invention relates to stable ODT compositions comprising triptans which is prepared by a process which involves adding the triptans and pharmaceutically acceptable salts thereof extra-granularly to a blend comprising inert-granular saccharides, and optionally other pharmaceutically acceptable excipients, in order to reduce the level of impurities in the final composition.

DETAILED DESCRIPTION OF INVENTION

The invention particularly relates to stable pharmaceutical compositions comprising triptans and processes for preparing them, wherein said compositions are preferably in the form of ODT.

The term ODT can be used synonymously with orally disintegrating tablets, oro-dispersible tablets, mouth dissolving tablets, fast dissolving tablets, quick disintegrating tablets. The said ODT compositions dissolve/disintegrate in the mouth or saliva within 3 minutes, preferably within 2 minutes, more preferably within 1 minute.

The stable ODT compositions as disclosed in the invention, comprises:

1) at least one triptan and pharmaceutically acceptable salts thereof;

2) inert-granular saccharide(s); and

3) optionally other pharmaceutically acceptable excipients.

An aspect of the invention relates to process for preparing stable ODT compositions which comprises preparing inert-granular saccharide, preferably by wet granulation and separately preparing a blend of triptans and pharmaceutically acceptable salts thereof along with other pharmaceutically acceptable excipients and adding this blend extra-granularly to the inert-granular saccharide; blending the same, lubricating and compressing to form final composition.

When said triptan is added extra-granularly in the extra-granular excipients, it is not exposed to moisture and excessive heat during wet granulation and subsequent drying step, which may possibly cause triptans to degrade.

It is surprisingly found that formation of impurities in said composition is very less when compared to compositions containing the drug intra-granularly. The stability of said composition is comparatively improved when triptans are blended with extra-granular excipients.

In context of the present invention, "stability" may be defined as capability of a particular composition, in a specific container/closure system to remain within its physical, chemical, microbiological, toxicological and therapeutic specifications.

The term "triptan" generically discloses all 5-HTIB/ID receptor agonists selected from group consisting of sumitriptan, zolmitriptan, naratriptan, rizatriptan, almotriptan, eletriptan and frovatriptan and pharmaceutically acceptable salts thereof. In context of the invention, among all the triptans preferably zolmitriptan and rizatriptan are used.

The term "saccharide" as used herein represents all type of sugar-based excipients. These saccharides are classified as Type I saccharides (low moldability; high dissolution rate) and Type II saccharides (high moldability; low dissolution rate). Type I saccharides according to the invention include lactose, mannitol, glucose, sucrose, xylitol and the like. Mannitol and lactose are widely used and are preferred saccharides in ODT compositions because of its high aqueous solubility and sweetness and hence, imparts taste masking and a pleasing mouth feel. Type II saccharides according to the invention include maltose, maltitol, sorbitol, oligosaccharides and the like.

Mannitol exhibits low moldability but high dissolution rate. There were many attempts made to improve compressibility/rnoldability of type I saccharides in order to get good uniformity in compositions and improved flow properties. In the present context to improve flowability and moldability of saccharides, the inert-granular saccharides are prepared.

The term "inert-granular saccharide" represents saccharide(s) wet-granulated with pharmaceutically acceptable excipients and the said granulation process is carried out by any conventional methods. This inert-granular saccharide is devoid of triptans and contains at least one super-disintegrant.

The super-disintegrant may be present as an extra-granular and/or as an intra-granular material. Said super-disintegrant may be a single super-disintegrant or a combination of super-disintegrants with one or more common disintegrants. Super-disintegrants according to the invention include without any limitation, crospovidone, pregelatinized starch, starch 1500, low-substituted, hydroxypropylcellulose, sodium starch glycolate, croscarmellose, bentonite and the like.

Pharmaceutically acceptable excipients as used herein is a collective term representing all tableting excipients such as disintegrants, binders, glidants, lubricants, sweetening agent, flavoring agents and like.

Binders, according to the invention include without any limitation, methylcellulose, sodium carboxymethycellulose, calcium carboxymethycellulose, ethyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, gelatin, polyvinyl alcohol, acacia, tragacanth, guar, pectin, starch paste, pre-gelatinized starch, and sodium alginate.

Sweeteners, according to the invention include without any limitation, sucrose, dextrose, fructose, invert sugar, mannitol, sorbitol, and the like, as well as synthetic sweeteners such as saccharin, sucralose, aspartame, acesulfame potassium, cyclamates, and other commercial artificial sweeteners well-known to those of skill in the art.

Flavors, according to the invention include without any limitation, any of the conventional flavors such as natural flavoring agents or synthetic flavoring agents, but preferably peppermint flavor is selected.

Lubricants, according to the invention include without any limitation, alkaline stearates, stearic acid, mineral and vegetable oils, glyceryl behenate and sodium stearyl fumarate, magnesium stearate, talc and the like.

The inventors have devised a process which is suitable to prevent the exposure of triptans to moisture and/or heat during process of preparing such compositions. The process involves addition of the triptans extra-granularly to a blend comprising inert-granular saccharide and optionally other pharmaceutically acceptable ingredients; thereby avoiding the exposure of triptans to moisture and heat which is commonly encountered when said triptans are added intra-granularly and granulation process is further involved.

The inert-granular saccharide is usually prepared by wet-granulation technique which is generally known in the art. It involves granulation of a blend comprising saccharide and other pharmaceutically acceptable excipients with the help of solvents to get the granules which are further dried and reduced in size if required. Granulating the saccharides also help in improving flowability and moldability of low-moldable saccharides. To avoid degradations due to moisture and/or heat, triptans are added directly to the granulated inert saccharides, optionally in combination with other pharmaceutically acceptable excipients.

The following examples illustrate specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof.

It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.

Comparative Example 1

Unit Composition:
S. No. Ingredients % w/w
Intra-granular
1 Rizatriptan benzoate 7.24
2 Mannitol 59.26
3 Colloidal silicon dioxide 2.00
4 Crospovidone 4.00
5 Purified water q.s
Extra-granular
6 Microcrystalline cellulose with guar 15.00 gum
7 Aspartame 5.00
8 Peppermint flavor 1.00
9 Crospovidone 6.00
10 Magnesium stearate 0.5
Total 100.00

Brief manufacturing process:

1. Sift rizatriptan benzoate, mannitol, and crospovidone separately through suitable sieve/screen.

2. Disperse colloidal silicon dioxide in purified water.

3. Granulate step 1 material using dispersion of step 2.

4. Sift microcrystalline cellulose with guar gum, aspartame, crospovidone, and peppermint flavor through suitable sieve/screen.

5. Blend the granules obtained from step 3 with step 4 material for suitable time.

6. Sift magnesium stearate through suitable sieve/ screen and add to the blend of step 5 and blend for suitable period of time.

7. Compress the blend to obtain final tablet.

Comparative Example 2

Unit Composition:
S. No. Ingredients % w/w
Intra-granular
1 Rizatriptan benzoate 7.13
2 Mannitol 57.15
3 Colloidal silicon dioxide 0.99
4 Crospovidone 4.93
5 Purified water q.s
Extra-granular
6 Microcrystalline cellulose with guar 14.78 gum
7 Colloidal silicon dioxide 2.96

7 Sucralose 4.93
8 Peppermint flavor 0.25
9 Crospovidone 4.93
10 Magnesium stearate 1.97
Total 100.00

Brief manufacturing process:

1. Sift Rizatriptan benzoate, mannitol, and crospovidone separately through suitable sieve/screen.

2. Disperse colloidal silicon dioxide in purified water

3. Granulate step 1 material using dispersion of step 2.

4. Sift microcrystalline cellulose with guar gum, sucralose, crospovidone, colloidal silicon dioxide and peppermint flavor through suitable sieve/screen.

5. Blend the granules obtained from step 3 with step 4 material for suitable time

6. Sift Magnesium stearate through suitable sieve/ screen and add to the blend of step 5 and blend for suitable period of time.

7. Compress the blend to obtain final composition.

Example 3

Unit Composition:
S. No. Ingredients %w/w
Intra-granular
1 Mannitol 54.22
2 Colloidal silicon dioxide 1.00
3 Crospovidone 5.00
4 Aspartame/Sucralose 5.00
5 Purified water q.s
Extra-granular
6 Rizatriptan benzoate 7.29
7 Microcrystalline Cellulose with guar 15.00 gum
8 Peppermint Flavor 0.5
9 Crospovidone 7.00
10 Colloidal silicon dioxide 2.00
11 Magnesium stearate 3.00
Total 100.00

Brief Manufacturing Procedure:

1. Sift mannitol, crospovidone (intra-granular) and aspartame separately through suitable sieve / screen.

2. Disperse silica, colloidal anhydrous (intra-granular) in purified water.

3. Granulate the step 1 material using dispersion of step 2.

4. Sift rizatriptan benzoate, microcrystalline cellulose and guar gum (Avicel CE 15), Peppermint Flavor, crospovidone (extra-granular) and colloidal silicon dioxide (extra-granular) through suitable sieve/ screen.

5. Blend together the materials of step no. 3 and 4 for suitable period of time.

6. Sift Magnesium stearate through suitable sieve/ screen and add to the blend of step 5 and blend for suitable period of time.

7. Compress the blend using approved tooling.

Comparative Example 4

Unit Composition:
S. No. Ingredients % w/w
Intra-granular
1 1 Zolmitriptan 5.00
2 Mannitol 61.50
3 Colloidal silicon dioxide 2.00
4 Crospovidone 5.00
5 Purified water .q.s.
Extra-granular
6 Microcrystalline cellulose with guar 15.00 gum
7 Aspartame 5.00
8 Orange Flavor 1.00
9 Crospovidone 5.00
10 Magnesium stearate 0.50
Total 100.00.

Brief manufacturing process:

1. Sift Zolmitriptan, mannitol, and crospovidone separately through suitable sieve/screen.

2. Disperse colloidal silicon dioxide in purified water.

3. Granulate step 1 material using dispersion of step 2.

4. Sift microcrystalline cellulose with guar gum, aspartame, crospovidone, and orange flavor through suitable sieve/ screen.

5. Blend the granules obtained from step 3 with step 4 material for suitable time.

6. Sift magnesium stearate through suitable sieve/ screen and add to the blend of step 5 and blend for suitable period of time.

7. Compress the blend to obtain final tablet.

Example 5

Unit Composition:
S. No. Ingredients %w/w
Intra-granular
1 Mannitol 56.50
2 Colloidal Silicon dioxide 1.00
3 Crospovidone 5.00
4 Aspartame 5.00
5 Purified water q.s.
Extra-granular
6 Zolmitriptan 5.00
7 Microcrystalline cellulose with guar 15.00 gum
8 Orange Flavor 0.50
9 Crospovidone 7.00
10 Colloidal Silicon dioxide 2.00
11 Magnesium stearate 3.00
Total 100.00

Brief Manufacturing Procedure:

1. Sift saccharide, crospovidone (intra-granular) and aspartame separately through suitable sieve / screen.

2. Disperse silica, colloidal anhydrous (intra-granular) in purified water.

3. Granulate the step 1 material using dispersion of step 2.

4. Sift Zolmitriptan, microcrystalline cellulose and guar gum, orange flavor, crospovidone (extra-granular) and colloidal silicon dioxide (extra-granular) through suitable sieve / screen.

5. Blend together the materials of step no. 3 and 4 for suitable period of time.

6. Sift Magnesium stearate through suitable sieve / screen and add to the blend of step 5 and blend for suitable period of time.

7. Compress the blend using approved tooling.

Stability Study

The compositions disclosed above in the examples (1-5) were subjected to accelerated stability testing at 40°C ± 2°C and 75% RH ± 5% RH for 6 months packed in HDPE bottles and Alu/Alu Blister separately and were monitored for individual impurity as well as the total impurities generated in the final tablet dosage form. Results obtained are summarized below in Table 1.

Table 1
Compositions Initial 1 month 2 months 3 months 6 Months
HDPE Bottle
Example 1 * 0.75 0.82 1.62 1.95
Example 2 0.75 1.09 1.20 1.25 *
Example 3 0.12 0.18 0.23 0.22 0.597
Example 4 *
Example 5 0.15 * * 0.87 1.04
Alu-Alu Blister
Example 1 * 0.70 1.18 1.34 1.34
Example 2 0.75 * 1.13 1.14 1.01
Example 3 0.12 0.35 0.59 0.93 1.09
Example 4 0.93 1.08 * 133 1.25
Example 5 0.15 * * 0-69 [ 1.66
* Not Monitored

WE CLAIM

1. A stable orally disintegrating tablet comprising a triptan or its pharmaceutically acceptable salts thereof, prepared by a process which involves adding said triptan or its pharmaceutically acceptable salts thereof extra-granularly to an intra-granular blend comprising inert-granular saccharide and optionally other pharmaceutically acceptable excipient.

2. The stable orally disintegrating tablet according to claim 1, wherein said triptan is selected from a group consisting of sumatriptan, eletriptan, rizatriptan, frovatriptan, almotriptan, zolmitriptan, naratriptan, or their pharmaceutically acceptable salts and mixtures thereof.

3. The stable orally disintegrating tablet according to claim 4, wherein said saccharide is selected from a group consisting of lactose, mannitol, glucose, sucrose, xylitol, maltose, maltitol, sorbitol and their combinations thereof.

4. The stable orally disintegrating tablet according to claim 1, wherein said inert-granular saccharide comprises at least one super-disintegrant.

5. The stable orally disintegrating tablet according to claim 4, wherein said at least one super-disintegrant is selected from a group consisting of crospovidone, pregelatinized starch, starch 1500, low-substituted, hydroxypropylcellulose, sodium starch glycolate, croscarmellose and their combinations thereof.

6. The stable orally disintegrating tablet according to claim 1, wherein said intra-granular blend further comprises at least one disintegrant, binder, glidant, and sweetener.

7. The stable orally disintegrating tablet according to claim 1, wherein diluents, flavors, disintegrants, lubricant, glidants are optionally added extra-granularly along with said triptan.

8. A process for preparing stable orally disintegrating tablet comprising a triptan or its pharmaceutically acceptable salts thereof; wherein said process involves the steps of:

a. wet-granulating an inert saccharide with optionally other pharmaceutically acceptable excipient to get inert-granular saccharide;

b. mixing said inert-granular saccharide with other pharmaceutically excipient to form an intra-granular blend;

c. adding triptan and optionally other pharmaceutically acceptable excipient extra-granularly to said intra-granular blend;

d. blending and lubricating the product of step c.

e. compressing the product of step d. to form an orally disintegrating tablet.

9. The process according to claim 8, wherein said wet granulation is carried
out by water.

10. A stable orally disintegrating tablet comprising a triptan or its pharmaceutically acceptable salts thereof, as herein disclosed and
exemplified.