FIELD OF INVENTION

The invention relates to pharmaceutical compositions comprising frovatriptan or its pharmaceutically acceptable salts thereof and atleast one pharmaceutically acceptable excipient and a process for preparing the same.
Particularly, the invention relates to compositions comprising frovatriptan prepared by direct compression process.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ART

Frovatriptan is a 5-HTIB/ID receptor agonist that belongs to the triptan therapeutic class and is chemically known as (R)-(+)-6-carboxamido-3-N-methylamino-l,2,3,4-tetrahydrocarbazole. It is marketed in US under the name FROVA® and in Europe under the name MIGARD®. Frovatriptan is indicated for the acute treatment of migraine and has a relatively good safety and tolerability profile. Relative to other triptans, it has a long half-life (26 hours) and a low incidence of migraine recurrence (17%).

Several documents relating to compositions comprising frovatriptan are found in the prior art. Some of the prior arts are cited below.

US5962501 disclose frovatriptan succinate monohydrate, its process of preparation and compositions.

US 20040162333 disclose rapid absorption oral dosage pharmaceutical preparations comprising an effective amount of at least one selective 5-HT agonist for the treatment of migraine.

US 20070299123 disclose frovatriptan succinate substantially in an amorphous form. It also discloses compositions comprising frovatriptan succinate in a solid form, wherein at least about 80% by weight of the solid is frovatriptan succinate in an amorphous form.

WO2009043844 disclose an orally disintegrating tablet prepared by direct compression of a dry powdered mixture, said mixture comprising up to 15% by weight of calcium silicate, at least 50% of a diluent, a disintegrant agent and an active ingredient. It also discloses a process for preparing the tablets by homogeneous blending the specific excipients in powder form and subsequent direct compression of the mixture.

Though the above prior arts disclose many inventions relating to compositions comprising frovatriptan; till date no prior art was found which disclose process for preparing pharmaceutical compositions comprising frovatriptan.

The inventors hereby disclose pharmaceutical compositions comprising frovatriptan and at least one pharmaceutically acceptable excipient which is prepared by direct compression.

SUMMARY AND OBJECTIVES OF THE INVENTION

The invention relates to pharmaceutical compositions comprising frovatriptan or its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient and a process for preparing the same. More particularly the invention relates to compositions comprising frovatriptan prepared by direct compression.

In one aspect, the invention provides a direct compression process for preparing the compositions comprising frovatriptan or its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient.

In other aspect, the invention provides stable pharmaceutical compositions comprising frovatriptan or its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient which is prepared by direct compression.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

The invention relates to pharmaceutical compositions comprising frovatriptan or its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient and a process for preparing the same by direct compression.

Direct compression provides important advantages over other methods of preparing pharmaceutical compositions especially tablets. Unlike the wet granulation process, the direct compression has the advantage that the active ingredient is not subjected to humidity conditions (water or other solvents) or to high temperatures, which are known to be detrimental to the stability of the pharmaceutical composition. Further, unlike the dry granulation and wet granulation, due to its simplicity, it requires lesser procedural steps and few simple machinery leading to a reduction in economic and energetic manufacturing costs.

The term "pharmaceutical compositions" as used herein refers to dosage form for oral administration in the form of tablets, capsules, pills, powders, granules, particles, pellets, beads, or mini-tablets. Preferred dosage forms are tablets.

The term "stable" as used herein refers to the formulation that remains unchanged throughout its shelf life and does not suffer any changes in its chemical as well as physical characteristics.

The term "excipient" refers to any ingredient that may be added to the formulation besides the active ingredient and which are of pharmaceutical grade.

The term "total impurity" as used herein, refers to the sum of all degradation products.

The composition of the invention may comprise one or more pharmaceutically acceptable excipients which include, but are not limited to diluents, binders, disintegrants, lubricants, film former, plasticizers, coloring agent, flavoring agents, sweetening agent, preservatives and the like.

Diluents according to the invention may include, but are not limited to lactose, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, sugar alcohols such as mannitol and the likes, dextrates, dextrin, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, starch, pregelatinized starch, and the like.

Suitable disintegrants according to the invention may include, but are not limited to cross-linked polypyrollidone commercially available as Crospovidone™ & Polyplasdone™, sodium starch glycolate, maize starch, pregelatinized starch, salts of carboxy methyl cellulose, microcrystalline cellulose, alginic acid, sodium alginate, guar gum, low-substituted hydroxypropyl cellulose and the like.

Suitable glidants and lubricants according to the invention may include, but are not limited to silica, colloidal silica, magnesium trisilicate, talc, stearates, behenates, fumarates, hydrogenated castor oil, and the like.

Suitable surfactants according to the invention may include, but are not limited to sodium lauryl sulfate, quaternary ammonium salts, polysorbates, sorbitan esters, poloxamer, betaines, higher fatty alcohols such as cetyl alcohol and oleyl alcohol and the like.

In one embodiment, the invention relates to a composition comprising frovatriptan or its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient prepared by a direct compression process which includes the steps of:

1. sifting the drug together with anhydrous lactose followed by mixing;

2. sifting microcrystalline cellulose and mixing with the blend of step 1;

3. adding the remaining sifted lactose, sodium starch glycolate to the blend of step 2;

4. mixing the sifted colloidal silicon dioxide to the blend of step 3;

5. sifting magnesium stearate and lubricating the blend of step 4;

6. Compressing the blend of step 5 into a tablet which is further optionally film coated.

In another embodiment, the invention provides stable pharmaceutical compositions comprising frovatriptan or its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient which is prepared by direct compression.

There is provided a comparative stability study of pharmaceutical compositions comprising frovatriptan prepared by wet granulation process and pharmaceutical compositions comprising frovatriptan according to the invention which utilizes direct compression.

A three months comparative stability study for pharmaceutical compositions comprising frovatriptan was done by subjecting the compositions prepared by both wet granulation and direct compression to a temperature of 40°C and relative humidity of 75% in sealed HDPE bottles.

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.

Example 1

Unit composition:

S. Ingredient mg
No.
1 Frovatriptan succinate monohydrate 3.91
2 Lactose 108.09
3 Microcrystalline cellulose 21.00
4 Sodium starch glycolate 2.20
5 Colloidal silicon dioxide 1.40
6 Magnesium stearate 1.40
Core Tablet Weight 138.00
7 Opadry TM 4.00
Coated tablet weight 142.00

Brief Manufacturing Process:

1) Sift Frovatriptan Succinate along with Lactose anhydrous through ASTM #40 sieve and mix. Further add equal quantity of lactose and mix to obtain uniform blend.

2) Sift Microcrystalline cellulose through ASTM # 40 sieve and mix with the blend of step 1 and blend further.

3) Add remaining sifted Lactose, Sodium starch glycolate to the blend of step 2 and mix.

4) Sift Colloidal silicon dioxide and mix with the blend of step 3.

5) Sift Magnesium stearate and lubricate the blend of step 4.

6) Compress the blend into tablets using suitable tooling.

7) Coat the tablet with Opadry™.

Comparative Example 2

Unit Composition:

S. Ingredient mg
No.
Intra-granular
1 Frovatriptan succinate monohydrate 3.91
2 Lactose 125.09
3 Microcrystalline cellulose 60.00
4 Sodium starch glycolate 4.00
5 Water q.s.
Extra-granular
6 Sodium starch glycolate 4.00
7 Colloidal silicon dioxide 1.00
8 Magnesium stearate 2.00
Core tablet weight 200.00
9 Opadry TM 6.00
Coated tablet weight 206.00

Manufacturing Process:

1) Sift Frovatriptan Succinate along with Lactose and microcrystalline cellulose through ASTM #40 sieve and mix in Rapid mixer granulator. Further add equal quantity of lactose and mix to obtain uniform blend.

2) Sift Sodium starch glycolate through ASTM # 40 sieve and mix with the blend of step 1 and blend further.

3) Add water slowly to obtain good consistency granules.

4) Dry the granules to obtain suitable LOD.

5) Mill the dried granules using suitable size sieve.

6) Add extragranular sodium starch glycolate and colloidal silicon dioxide and mix in a blender.

7) Sift magnesium stearate and lubricate the blend of step 6.

8) Compress the blend into tablets using suitable tooling.

9) Coat the tablet with Opadry™.

Example 3

Unit Composition:

S. Ingredient mg
No.
1 Frovatriptan succinate monohydrate 3.91
2 Lactose 107.09
3 Microcrystalline cellulose 22.00
4 Sodium starch glycolate 2.80
5 Colloidal silicon dioxide 1.40
6 Magnesium stearate 2.80
Core Tablet Weight 140.00
7 Opadry'M 4.00
Coated tablet weight 144.00

Manufacturing Process:

1. Sift Frovatriptan succinate along with lactose anhydrous through ASTM #40 sieve and mix. Further add equal quantity of lactose and mix to obtain uniform blend.

2. Sift microcrystalline cellulose through ASTM # 40 sieve and mix with the blend of step 1 and blend further.

3. Add remaining sifted lactose, sodium starch glycolate to the blend of step 2 and mix.

4. Sift colloidal silicon dioxide and mix with the blend of step 3.

5. Sift magnesium stearate and lubricate the blend of step 4.

6. Compress the blend into tablets using suitable tooling.

7. Coat the tablet with Opadry™.

Comparative Stability Data:

A three months comparative stability study was carried out by subjecting the compositions prepared by both wet granulation and direct compression to a temperature of 40°C and relative humidity of 75% in sealed HDPE bottles and the results are given in the following table.

S. Parameters Example-1 Example-2 Example-3
No (Direct Compression) (Wet Granulation) (Direct Compression)
Initial 12week Initial 12week Initial 12week 40°C/75 % 40°C/75 40°C/75 RH %RH %RH
1. Total 0.22 0.32 1.14 3.12
0.092 0.145 Impurities

The increase in total impurity level is found to be more in compositions prepared by wet granulation than in case of compositions prepared by direct compression; thus suggesting the need for direct compression.

WE CLAIM:

1. A stable pharmaceutical composition comprising frovatriptan or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients wherein, said composition is prepared by direct compression.

2. The composition according to claim 1, wherein said pharmaceutically acceptable excipients include diluents, disintegrants, glidants, lubricants and optionally outer coating ingredients.

3. The composition according to claim 2, wherein said diluents are selected from a group comprising lactose, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, mannitol, dextrates, dextrin, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, starch, pregelatinized starch or combinations thereof.

4. The composition according to claim 2, wherein said disintegrants are selected from a group comprising cross-linked polypyrollidone, sodium starch glycolate, maize starch, pregelatinized starch, salts of carboxy methyl cellulose, alginic acid, sodium alginate, guar gum, low-substituted hydroxypropyl cellulose or combinations thereof.

5. The composition according to claim 2, wherein said lubricants and glidants are selected from a group comprising silica, colloidal silica, magnesium trisilicate, talc, stearates, behenates, fumarates, hydrogenated castor oil or combinations thereof.

6. The composition according to claim 1, wherein said composition is a tablet, a capsule, a pill, powders, granules, particles, pellets, beads or a minitablet.

7. A pharmaceutical composition comprising frovatriptan or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients wherein, said composition is prepared by direct compression.

8. A pharmaceutical composition comprising;

Ingredients % w/w
Frovatriptan succinate monohydrate 2.79
Lactose 76.49
Microcrystalline cellulose 15.71
Sodium starch glycolate 2
Colloidal silicon dioxide 1.34
Magnesium stearate 2

wherein, said composition is prepared by direct compression.