Title of Invention	AN IMPROVED FAST ACTING ORAL PHARMACEUTICAL COMPOSITION AND A PROCESS FOR ITS PREPARATION
Abstract	The present invention relates to a novel freeze -dried pharmaceutical composition useful for the treatment of migraine and associated symptoms at a reduced total dose of active substance than required for oral administration in the form of a tablet comtaining a porous matrix net work of a water soluble or water dispersible carrier material, a pharmaceutically active substance(s); organoleptic additives such as sweetening agents, flavouring agents, coloring agents; pharmaceutically acceptable preservatives; solublising agents; surfaceactive agents and/or buffereing agents. The pharmaceutical composition optionally may contain other additives such as permeation enhancers, chelating salts and stabilising agents. The present invention , also relates to a process for preparation of the above said composition and its use.

Title of Invention

AN IMPROVED FAST ACTING ORAL PHARMACEUTICAL COMPOSITION AND A PROCESS FOR ITS PREPARATION

Abstract

The present invention relates to a novel freeze -dried pharmaceutical composition useful for the treatment of migraine and associated symptoms at a reduced total dose of active substance than required for oral administration in the form of a tablet comtaining a porous matrix net work of a water soluble or water dispersible carrier material, a pharmaceutically active substance(s); organoleptic additives such as sweetening agents, flavouring agents, coloring agents; pharmaceutically acceptable preservatives; solublising agents; surfaceactive agents and/or buffereing agents. The pharmaceutical composition optionally may contain other additives such as permeation enhancers, chelating salts and stabilising agents. The present invention , also relates to a process for preparation of the above said composition and its use.

Full Text	We claim: 1) An improved fast acting freeze dried oral pharmaceutical composition useful for the treatment of migraine and associated symptom which comprises one or more pharmaceutical active substances for the treatment of migraine and associated symptoms in an "open matrix network" of a water soluble or water dispersible carrier material, the composition being rapidly disintegrating in the mouth. 2) An improved pharmaceutical composition as claimed in claim 1 where in active substance for the treatment of migraine is selected from sumatriptan, zolmitriptan, rizatriptan, propranolol and the like. 3) An improved pharmaceutical composition as claimed in claims 1 & 2 wherein the active substance is present in the form of its base or pharmaceutically acceptable form of its salt or ester. 4) An improved pharmaceutical composition as claimed in claims 1 to 3 where in the dose of active substance(s) required to elicit desired therapeutic response is equivalent to or higher than the unit dose required for parenteral administration but 2 to 10 times less than the unit dose required for oral administration. 5) An improved pharmaceutical composition as claimed in claim 1 to 4 where in one or more active substances useful for the treatment of migraine and associated symptoms are co-administered. 6) An improved pharmaceutical composition as claimed in claims 1 to 5 where in the co-administered active substance useful for the treatment of migraine associated symptoms is selected from drugs such as antihistaminic and antiallergenic agents e.g. chlorpheniramine maleate, diphenhydramine, terphenidine, flunarizine, cetirizine, sympathomimetics e.g. phenylpropanolamine pseudoephedrine, anti emetics e.g. dimenhydrinate, domeperidone, ondansetron, granisetron, prochlorperazine metoclopropamide; analgesic and anti-inflammatory agents e.g.naproxen sodium, paracetamol and the like. 7) An improved pharmaceutial composition as claimed in claims 1 to 6 wherein the amount of co-administered active substance(s) useful for the treatment of migraine associated symptoms is equivalent one unit dose for oral administration to elicit desired therapeutic response. 8) An improved pharmaceutical composition as claimed in claims 1 to 7 wherein the carrier material is selected from polywinyl pyrrolidone, polyvinyl alcohol, partially hydrolysed gelatins, dextrins, alginates, carboxymethyl celluloses, pectins, hvdroxyproyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxy vinyl polymers such as carbomer 934P and carbomer 974P ; sugars such as dextrose, mannitol, lactose, galactose, cyclodextrins ; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicates, the preferred carrier materials include pharmaceutical grade gelatins, pectins (nonhydrolysed and partially hydrolysed); carboxy vinyl polymers ; polyvnvlpyrrolidone ; polyvinyl alcohol; mannitol and mixtures thereof 9) An improved pharmaceutical composition as claimed in claims 1 to 8 wherein the amount of carrier material employed ranges from 10.0 to 90.0 percent, preferably from 30.0 to 70.0 percent by weight of the composition on dry basis. 10) An improved pharmaceutical composition as claimed in claims 1 to 9 wherein the organoleptic additives such as flavouring agents, sweetening agents, colouring agents which are known in the art are incorporated in the composition. 11) An improved pharmaceutical composition as claimed in claims 1 to 10 where in anti-microbial preservatives known in the art are incorporated in the composition. 12) An improved pharmaceutical composition as claimed in claims 1 to 11 where in buffering agents such as citric acid / sodium citrate or citric acid / disodium hydrogen ortho phosphate and the like are incorporated in the composition. 13) An improved pharmaceutical composition as claimed in claims 1 to 12 where in solubilising agent, for dissolving the active substance, such as cyclodextrins, lecithin, surface-active agent such as sorbitan esters, polysorbates, sodium lauryl sulphate and the like is incorporated in the composition. 14) An improved pharmaceutical composition as claimed in claim 13 where in the amount of solublising agent ranges from 0.1 to 5.0 percent, preferably from 0.5 to 2.5 percent by weight on dry basis. 15) An improved pharmaceutical composition as claimed in claims 1 to 14 wherein penetration enhancer like bile salts such as sodium chelate, sodium glycocholate, sodium glycodeoxycholate, sodium deoxycholate ; surfactants such as sodium dodecyl sulphate, dimethyl sulphoxide, sodium lauryl sulphate; salts and other derivatives of saturated and unsaturated fatty acids; bile salt analogs; derivatives of bile salts, surfactants, or synthetic permeation enhancers is incorporated in the composition. 16) An improved pharmaceutical composition as claimed in claims 1 to 15 where in the stabilizing agent such as salts of citric acid and edetic acid and the like is incorporated in the composition. 17) An improved pharmaceutical composition as claimed in claim 16 where in the amount of stabilizing agent ranges from 0.01 to 0.1 percent on dry basis. 18) A process for the preparation of an improved pharmaceutical composition useful for the treatment of migraine and associated symptoms which comprises admixing one or more pharmaceutically active substances useful for the treatment of migraine or associated symptoms in solution or suspension of a water soluble or water dispersible carrier forming the " open matrix network" along with other pharmaceutical additives, transferring the resultant solution or suspension to a mold containing one or more depression or preformed blisters and freezing the product in a freeze dryer at a temperature in the range of -50 to 10 °C and subjected to drying at a temperature of-40 to 90°C under vacuum of in the range of 1.0 7.5 x torr. 19) A process as claimed in claim 18 where in the active substance for the treatment of migraine is selected from sumatriptan, Zolmitriptan, rizatriptan,, propranolol and the like. 20) A process as claimed in claims 18 & 19 where in the active substance is present in the form of its base or pharmaceutically acceptable form of its salt or esters. 21) A process as claimed in claims 18 to 20 where in the dose of active substance(s) required to elicit desired therapeutic response is equivalent to or higher than the unit dose required for parenteral administrations but 2 to 10 times less than the unit dose requirement for oral administration. 22) A process as claimed in claims 18 to 21 where in one or more active substances useful for the treatment of migraine and associated symptoms are co-administered. 23) A process as claimed in claims 18 to 22 where in the co-administered active substance useful for the treatment of migraine associated symptoms is selected from drugs such as antihistamine and antiallergenic agents e.g. chlorpheniramine maleate, diphenhydramine, terphenidine, flunarizine, cetirizine,; sympathomimetics e.g. phenylpropanolamine pseudoephedrine; anti emetics e.g. dimenhydrinate, domeperidone, ondansetron, granisetron, prochlorperazine metoclopropamide; analgesic and anti-inflammatory agents e.g. naproxen sodium, paracetamol and the like. 24) A process as claimed in claims 18 to 23 where in the carrier material used is selected from polyinyl pyrrolidone, polyvinyl alcohol, partially hydrolysed gelatins, dextrins, alginates, carboxymethyl celluloses, pectins, hvdroxyproyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxy vinyl polymers such as carbomer 934P and carbomer 974P ; sugars such as dextrose, mannitol, lactose, galactose, cyclodextrins ; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicates, the preferred carrier materials include pharmaceutical grade gelatins, pectins (non hydrolysed and partially hydrolysed); carboxy vinyl polymers ; polyvinylpyrrolidone ; polyvinyl alcohol; mannitol and mixtures thereof. 25) A process as claimed in claims 18 to 24 where in the solvent used in preparing the solution / dispersion of carrier material is water. 26) A process as claimed in claims 18 to 25 where in the active substance (s) is dissolved / dispersed in the solution / dispersion of carrier material(s) using co-solvents such as ethyl alcohol, tert-butyl alcohol and the like. 27) A process as claimed in claims 18 to 26 where in the amount of co-solvent used in dissolving the active substance(s) in the solution of carrier materials ranges from 2.0 to 25,0 percent more preferably 5.0 to 15.0 percent of total volume of the solvent used. 28) A process as claimed in claims 18 to 27 where in the active substance(s) is dissolved in the solution of carrier substance(s) using solublising agents such as cyclodextrins, lecithin, surface-active agent such as sorbitan esters, polysorbates, sodium lauryl sulphate and the like. 29) A process as claimed in claims 18 to 28 where in the amount of solublising agent used in the composition may ranges from 0.1 to 5.0 percent preferably from 0.5 to 2.5 percent by weight of the composition on dry basis. 30) A process as claimed in claims 18 to 29 where in the amount of carrier material ranges from 10.0 to 90.0 percent, preferably from 30.0 to 70.0 percent by weight of the composition on dry basis. 31) A process as claimed in claims 18 to 30 where in know organoleptic additives such as flavouring agents, sweetening agents, colouring agents are employed. 32) A process as claimed in claims 18 to 31 where in known anti-microbial preservatives are employed. 33) A process as claimed in claims 18 to 32 where in buffering agents selected from citric acid / sodium citrate or citric acid / disodium hydrogen ortho phosphate and the like are employed. 34) A process as claimed in claims 18 to 33 where in penetration enhancer selected from bile salts such as sodium cholate, sodium glycocholate, sodium glycodeoxycholate, taurodeoxycholate, sodium deoxycholate; surfactants such as sodium dodecyl sulphate, dimethylsulphoxide, sodium lauryl sulphate; salts and other derivatives of saturated and unsaturated fatty acids; bile salt analogues; derivatives of bile salts, surfactants, or synthetic permeation enhancers is employed. 35) A process as claimed in claims 18 to 34 where in the stabilizing agent selected from salts of citric acid and edetic acid and the like is employed. 36) A process as claimed in claims 32 where in the amount of stabilizing agent used ranges from 0.01 to 0.1 percent on dry basis. 37) A process as claimed in claims 18 to 37 where in the solution or suspension is transferred to a mold containing one are more depressions or to preformed blisters and freeze-dried in a manner known in the art. 38) An improved fast acting freeze dried oral pharmaceutical composition useful for the treatment of migraine and associated symptoms substantially as herein described with reference to the examples. 39) A process for the preparation of an improved pharmaceutical composition useful for the treatment of migraine and associated symptoms substantially as herein described with reference to the examples 1 to 8.

Full Text

We claim:
1) An improved fast acting freeze dried oral pharmaceutical composition useful for the treatment of migraine and associated symptom which comprises one or more pharmaceutical active substances for the treatment of migraine and associated symptoms in an "open matrix network" of a water soluble or water dispersible carrier material, the composition being rapidly disintegrating in the mouth.
2) An improved pharmaceutical composition as claimed in claim 1 where in active substance for the treatment of migraine is selected from sumatriptan, zolmitriptan, rizatriptan, propranolol and the like.
3) An improved pharmaceutical composition as claimed in claims 1 & 2 wherein the active substance is present in the form of its base or pharmaceutically acceptable form of its salt or ester.
4) An improved pharmaceutical composition as claimed in claims 1 to 3 where in the dose of active substance(s) required to elicit desired therapeutic response is equivalent to or higher than the unit dose required for parenteral administration but 2 to 10 times less than the unit dose required for oral administration.
5) An improved pharmaceutical composition as claimed in claim 1 to 4 where in one or more active substances useful for the treatment of migraine and associated symptoms are co-administered.
6) An improved pharmaceutical composition as claimed in claims 1 to 5 where in the co-administered active substance useful for the treatment of migraine associated symptoms is selected from drugs such as antihistaminic and antiallergenic agents e.g. chlorpheniramine maleate, diphenhydramine, terphenidine, flunarizine, cetirizine, sympathomimetics e.g. phenylpropanolamine pseudoephedrine, anti emetics e.g. dimenhydrinate, domeperidone, ondansetron, granisetron, prochlorperazine metoclopropamide; analgesic and anti-inflammatory agents e.g.naproxen sodium, paracetamol and the like.
7) An improved pharmaceutial composition as claimed in claims 1 to 6 wherein the amount of co-administered active substance(s) useful for the treatment of migraine associated symptoms is equivalent one unit dose for oral administration to elicit desired therapeutic response.

8) An improved pharmaceutical composition as claimed in claims 1 to 7 wherein the carrier material is selected from polywinyl pyrrolidone, polyvinyl alcohol, partially hydrolysed gelatins, dextrins, alginates, carboxymethyl celluloses, pectins, hvdroxyproyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxy vinyl polymers such as carbomer 934P and carbomer 974P ; sugars such as dextrose, mannitol, lactose, galactose, cyclodextrins ; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicates, the preferred carrier materials include pharmaceutical grade gelatins, pectins (nonhydrolysed and partially hydrolysed); carboxy vinyl polymers ; polyvnvlpyrrolidone ; polyvinyl alcohol; mannitol and mixtures thereof
9) An improved pharmaceutical composition as claimed in claims 1 to 8 wherein the amount of carrier material employed ranges from 10.0 to 90.0 percent, preferably from 30.0 to 70.0 percent by weight of the composition on dry basis.
10) An improved pharmaceutical composition as claimed in claims 1 to 9 wherein
the organoleptic additives such as flavouring agents, sweetening agents,
colouring agents which are known in the art are incorporated in the
composition.
11) An improved pharmaceutical composition as claimed in claims 1 to 10 where
in anti-microbial preservatives known in the art are incorporated in the
composition.
12) An improved pharmaceutical composition as claimed in claims 1 to 11 where in buffering agents such as citric acid / sodium citrate or citric acid / disodium hydrogen ortho phosphate and the like are incorporated in the composition.
13) An improved pharmaceutical composition as claimed in claims 1 to 12 where in solubilising agent, for dissolving the active substance, such as cyclodextrins, lecithin, surface-active agent such as sorbitan esters, polysorbates, sodium lauryl sulphate and the like is incorporated in the composition.
14) An improved pharmaceutical composition as claimed in claim 13 where in the
amount of solublising agent ranges from 0.1 to 5.0 percent, preferably from 0.5
to 2.5 percent by weight on dry basis.

15) An improved pharmaceutical composition as claimed in claims 1 to 14
wherein penetration enhancer like bile salts such as sodium chelate, sodium
glycocholate, sodium glycodeoxycholate, sodium deoxycholate ; surfactants
such as sodium dodecyl sulphate, dimethyl sulphoxide, sodium lauryl sulphate;
salts and other derivatives of saturated and unsaturated fatty acids; bile salt
analogs; derivatives of bile salts, surfactants, or synthetic permeation enhancers
is incorporated in the composition.
16) An improved pharmaceutical composition as claimed in claims 1 to 15 where in the stabilizing agent such as salts of citric acid and edetic acid and the like is incorporated in the composition.
17) An improved pharmaceutical composition as claimed in claim 16 where in the amount of stabilizing agent ranges from 0.01 to 0.1 percent on dry basis.
18) A process for the preparation of an improved pharmaceutical composition useful for the treatment of migraine and associated symptoms which comprises admixing one or more pharmaceutically active substances useful for the treatment of migraine or associated symptoms in solution or suspension of a water soluble or water dispersible carrier forming the " open matrix network" along with other pharmaceutical additives, transferring the resultant solution or suspension to a mold containing one or more depression or preformed blisters and freezing the product in a freeze dryer at a temperature in the range of -50 to 10 °C and subjected to drying at a temperature of-40 to 90°C under vacuum of in the range of 1.0 7.5 x torr.
19) A process as claimed in claim 18 where in the active substance for the treatment of migraine is selected from sumatriptan, Zolmitriptan, rizatriptan,, propranolol and the like.

20) A process as claimed in claims 18 & 19 where in the active substance is present in the form of its base or pharmaceutically acceptable form of its salt or esters.
21) A process as claimed in claims 18 to 20 where in the dose of active substance(s) required to elicit desired therapeutic response is equivalent to or higher than the unit dose required for parenteral administrations but 2 to 10 times less than the unit dose requirement for oral administration.

22) A process as claimed in claims 18 to 21 where in one or more active substances useful for the treatment of migraine and associated symptoms are co-administered.
23) A process as claimed in claims 18 to 22 where in the co-administered active substance useful for the treatment of migraine associated symptoms is selected from drugs such as antihistamine and antiallergenic agents e.g. chlorpheniramine maleate, diphenhydramine, terphenidine, flunarizine, cetirizine,; sympathomimetics e.g. phenylpropanolamine pseudoephedrine; anti emetics e.g. dimenhydrinate, domeperidone, ondansetron, granisetron, prochlorperazine metoclopropamide; analgesic and anti-inflammatory agents e.g. naproxen sodium, paracetamol and the like.
24) A process as claimed in claims 18 to 23 where in the carrier material used is selected from polyinyl pyrrolidone, polyvinyl alcohol, partially hydrolysed gelatins, dextrins, alginates, carboxymethyl celluloses, pectins, hvdroxyproyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxy vinyl polymers such as carbomer 934P and carbomer 974P ; sugars such as dextrose, mannitol, lactose, galactose, cyclodextrins ; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicates, the preferred carrier materials include pharmaceutical grade gelatins, pectins (non hydrolysed and partially hydrolysed); carboxy vinyl polymers ; polyvinylpyrrolidone ; polyvinyl alcohol; mannitol and mixtures thereof.
25) A process as claimed in claims 18 to 24 where in the solvent used in preparing the solution / dispersion of carrier material is water.
26) A process as claimed in claims 18 to 25 where in the active substance (s) is dissolved / dispersed in the solution / dispersion of carrier material(s) using co-solvents such as ethyl alcohol, tert-butyl alcohol and the like.
27) A process as claimed in claims 18 to 26 where in the amount of co-solvent used in dissolving the active substance(s) in the solution of carrier materials ranges from 2.0 to 25,0 percent more preferably 5.0 to 15.0 percent of total volume of the solvent used.
28) A process as claimed in claims 18 to 27 where in the active substance(s) is
dissolved in the solution of carrier substance(s) using solublising agents such as
cyclodextrins, lecithin, surface-active agent such as sorbitan esters,
polysorbates, sodium lauryl sulphate and the like.

29) A process as claimed in claims 18 to 28 where in the amount of solublising agent used in the composition may ranges from 0.1 to 5.0 percent preferably from 0.5 to 2.5 percent by weight of the composition on dry basis.
30) A process as claimed in claims 18 to 29 where in the amount of carrier material ranges from 10.0 to 90.0 percent, preferably from 30.0 to 70.0 percent by weight of the composition on dry basis.
31) A process as claimed in claims 18 to 30 where in know organoleptic additives such as flavouring agents, sweetening agents, colouring agents are employed.

32) A process as claimed in claims 18 to 31 where in known anti-microbial preservatives are employed.
33) A process as claimed in claims 18 to 32 where in buffering agents selected from citric acid / sodium citrate or citric acid / disodium hydrogen ortho phosphate and the like are employed.
34) A process as claimed in claims 18 to 33 where in penetration enhancer selected from bile salts such as sodium cholate, sodium glycocholate, sodium glycodeoxycholate, taurodeoxycholate, sodium deoxycholate; surfactants such as sodium dodecyl sulphate, dimethylsulphoxide, sodium lauryl sulphate; salts and other derivatives of saturated and unsaturated fatty acids; bile salt analogues; derivatives of bile salts, surfactants, or synthetic permeation enhancers is employed.
35) A process as claimed in claims 18 to 34 where in the stabilizing agent selected from salts of citric acid and edetic acid and the like is employed.
36) A process as claimed in claims 32 where in the amount of stabilizing agent used ranges from 0.01 to 0.1 percent on dry basis.
37) A process as claimed in claims 18 to 37 where in the solution or suspension is transferred to a mold containing one are more depressions or to preformed blisters and freeze-dried in a manner known in the art.
38) An improved fast acting freeze dried oral pharmaceutical composition useful for the treatment of migraine and associated symptoms substantially as herein described with reference to the examples.

39) A process for the preparation of an improved pharmaceutical composition useful for the treatment of migraine and associated symptoms substantially as herein described with reference to the examples 1 to 8.

Documents:

1160-mas-1999 abstract-duplicate.pdf

1160-mas-1999 abstract.pdf

1160-mas-1999 claims-duplicate.pdf

1160-mas-1999 claims.pdf

1160-mas-1999 correspondences-others.pdf

1160-mas-1999 correspondences-po.pdf

1160-mas-1999 form-1.pdf

1160-mas-1999 form-19.pdf

1160-mas-1999 form-3.pdf

1160-mas-1999 form-5.pdf

1160-mas-1999 petition.pdf

1160-mas-1999 description (complete)-duplicate.pdf

1160-mas-1999 description (complete).pdf

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Patent Number

217045

Indian Patent Application Number

1160/MAS/1999

PG Journal Number

21/2008

Publication Date

23-May-2008

Grant Date

24-Mar-2008

Date of Filing

01-Dec-1999

Name of Patentee

NATCO PHARMA LIMITED

Applicant Address

NATCO HOUSE, ROAD NO.2, BANJARA HILLS, HYDERABAD-500 033,

Inventors:

#	Inventor's Name	Inventor's Address
1	VENKTESWARA RAO PAVULURI	NATCO PHARMA LTD, NATCO HOUSE, ROAD NO.2, BANJARA HILLS, HYDERABAD-500 033,
2	KADGAPATHI PODILI	NATCO PHARMA LTD, NATCO HOUSE, ROAD NO.2, BANJARA HILLS, HYDERABAD-500 033,

PCT International Classification Number

A61P 25/06

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA