Claims:1. A mouth dissolving pharmaceutical composition of apixaban.
2. A method of treating cardio vascular disorder, comprising steps of: administering a solid pharmaceutical composition comprising apixaban or pharmaceutically acceptable salts thereof to a subject prone to cardio vascular disorders.
3. A method of claim 2, wherein the solid pharmaceutical composition is a tablet.
4. A method of claim 2, wherein the solid pharmaceutical composition is a film.
5. A method of claim 2, wherein the solid pharmaceutical composition is a lozenge.
6. A method of claim 2, wherein the solid pharmaceutical composition is as effective as immediate release tablets when administered to suitable patient population.
7. A method of treating cardio vascular disorder, comprising steps of: administering a solid pharmaceutical composition comprising apixaban or pharmaceutically acceptable salts thereof to a subject prone to cardio vascular disorder, wherein the solid pharmaceutical composition releases at least about 70% of apixaban in 30 minutes in 0.05M phosphate buffer with 0.05% of sodium lauryl sulphate of pH 6.8 in USP dissolution apparatus using type II at about 75 RPM.
8. A solid pharmaceutical composition for the treatment of cardio vascular disorder, said composition comprising an effective amount of apixaban or pharmaceutically acceptable salts thereof, a diluent, a disintegrant, a binder, a lubricant and/or any other pharmaceutically acceptable excipient thereof. , Description:Field of invention:
The present invention provides oral pharmaceutical dosage forms used for the treating of thrombolic events.

Background of invention:
ELIQUIS (apixaban), a factor Xa (FXa) inhibitor, is chemically described as 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c] pyridine-3-carboxamide. Its molecular formula is C25H25N5O4 which corresponds to a molecular weight of 459.5. Apixaban has the following structural formula:

Apixaban is a white to pale-yellow powder. At physiological pH (1.2–6.8), Apixaban does not ionize; its aqueous solubility across the physiological pH range is ~0.04 mg/ml. Apixaban is an anticoagulant used for the treatment of venous thromboembolic events. It is taken by mouth. It is a direct factor Xa inhibitor.

Apixaban is a selective inhibitor of Factor Xa. Apixaban inhibits free and clot-bound Factor Xa, and prothrombinase activity. Apixaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting Factor Xa, Apixaban decreases thrombin generation and thrombus development.

US6413980, US6967208 patents describe apixaban and its related compounds and there is no specific mention about apixaban formulations or apixaban mouth dissolving formulations.

In treating patients with thrombolytic disorders one has to take medicines for long period of time and most of the times due to cumbersome administration processes or difficulty in swallowing patients may skip or miss a dose and then treatment becomes ineffective hence, there is strong un met need in the treatment of thrombolytic disorders and through the current invention we have formulated existing medicines in patient friendly dosage form and this will improve treatment outcomes.

Currently various country regulatory agencies have approved apixaban, dabigatran, rivaroxaban, for the treatment of events related to thrombolytic disorders. All these products exist as oral tablets or capsules and there are no mouth dissolving tablet formulations.

Detailed description:
The present invention relates to the use of medicines for the treatment of thrombolic events and reducing the risk of stroke and serious blood clots in certain patients with atrial fibrillation.

In another embodiment, the present invention provides a novel method of treating a patient in need of thromboembolic disorder treatment, comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat thromboembolic events.

In another preferred embodiment, the present invention provides a novel method, wherein the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) haemodialysis, or (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis.

In one of the embodiment of the invention apixaban is presented in the form of mouth dissolving tablets.

In another embodiment of the invention apixaban is presented in the form of mouth dissolving films.

In another embodiment of the invention apixaban is presented in the form of mouth dissolving granules.

In another embodiment of the invention apixaban is presented in the form of mouth dissolving lozenges.

In an embodiment of the invention apixaban is provided in the form of mouth dissolving formulations where in formulation less dis integration time which is less than 30seconds or less than 20 seconds or 10seconds.

In yet another embodiment of the invention apixaban is provided in the form of mouth dissolving formulations where in the formulation has weight less than 500mg or 300mg or preferably 150mg.

In an embodiment of the invention apixaban is provided in the form of mouth dissolving formulations comprises apixaban and sweeteners.

In another embodiment of the invention, apixaban is provide in the form of mouth dissolving formulations where in tablet is manufactured using direct compression, dry granulation, wet granulation, moulding and lyophilisation.

In another embodiment of the invention apixaban is presented as mouth dissolving formulation where in formulation comprises of pharmaceutically acceptable excipients where in excipients are preferably dissolving type.

In another embodiment of the invention apixaban is presented as mouth dissolving formulations where in the formulation comprises of pharmaceutically acceptable excipients where in excipients are preferably disintegration types.

In another embodiment of the invention apixaban is presented as mouth dissolving formulations where in the formulation comprises of pharmaceutically acceptable excipients where in the excipients are preferably combination of both disintegration and dissolving type.

In one embodiment of the invention apixaban is presented as mouth dissolving formulations where in formulation provides better mouth feel.

Various processes used for making mouth dissolving tablets includes but not limited to freeze drying, tablet moulding, spray drying, sublimation, direct compression, mass extrusion, nanonization, cotton candy process.

Various processes used for making mouth dissolving films includes but not limited to solvent casting method, hot melt extrusion process, semi solid casting, solid dispersion extrusion, rolling.

Various processes used for making mouth dissolving granules includes but not limited to dry fusion method, wet granulation method, hot melt extrusion or direct blending or pellets.

Diluents: lactose, lactose anhydrous, lactose spray dried, directly compressible starch, hydrolyzed starch, MCC, other cellulose derivatives, dibasic calcium phosphate dihydrate, mannitol, sorbitol, sucrose, calcium sulfate dehydrate, dextrose, micro crystalline cellulose, starch, confectioner sugar, cellulose, magnesium oxide, sodium chloride.

Binders: Starch paste, pregelatinized starch, alginic acid, cellulose, hydroxyl propyl methyl cellulose, poly vinyl pyrrolidine, poly ethylene glycol, povidone, acacia, carboxymethyl cellulose sodium, methyl cellulose, ethyl cellulose, liquid glucose, sodium alginate, candelilla wax, carnauba wax, corn starch, copolyvidone, poly ethylene oxide, sodium starch.

Disintegrants: Alginic acid, citric acid, crosscarmellose sodium, colloidal silicone dioxide, cellulose, carboxy methyl cellulose calcium, micro crystalline cellulose, methyl cellulose, povidone, sodium starch glycolate, sodium carmellose, starch, sodium alginate.

Lubricants: Stearic acid, stearic acid salts, stearic acid derivatives, talc, polyethylene glycols, surfactants, magnesium stearate, mineral oil, polaxamer, sodium benzoate, sodium stearyl fumarate.

Glidants: Fumed silica, magnesium carbonate, talc, colloidal silicone dioxide, tri calcium phosphate.

Sweeteners: Confectioner sugar, mannitol, saccharin and its pharmaceutically acceptable salts, aspartame, cyclamate, sucralose, acesulfame and its pharmaceutically acceptable salts, glycerol, glycin.

Coating agents: Ethyl cellulose, gelatine, glyceryl behenate, cellulose derivatives such as but not limited to hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose (HPMC), HPMC phthalate, methyl cellulose, methacrylic acid, titanium dioxide, sodium carboxy methyl cellulose, plasticizers.

Example 1:
S.No Material mg per unit
1 Apixaban 5
2 Mannitol 53
3 Microcrystalline cellulose 21
4 Crospovidone 17
5 Saccharin sodium 2
6 Colloidal silicon dioxide 1
7 Magnesium stearate 1

Manufacturing process:-
1. In the first step active pharmaceutical ingredient and crosspovidone were weighed and dispensed.
2. Active pharmaceutical ingredient was sifted along with crosspovidone in the form of geometrical mixing (10+10g) and passed through mesh #40 and sifting is continued (20+24g) and passed through mesh#30.
3. Because of the fluffy nature of the active pharmaceutical ingredient, it is not possible to pass through mesh#40, hence it is sifted through mesh#30
4. Required amount of sweetening agent was weighed and added to micro crystalline cellulose.
5. Step 4 materials were co sifted with mannitol and passed through mesh#40
6. Step 2 materials were added to step 5 and passed through mesh#30
7. Colloidal silicon dioxide was weighed and passed through mesh#40
8. Step 6 and 7 materials were blended for 10 min
9. Required quantity of lubricant was weighed and passed through mesh# 40and added to step 8 and blended for 5 min

Example 2:
S.No Material mg per unit
1 Apixaban 5
2 Pharmaburst 91
3 Saccharin sodium 2

Manufacturing process:-
1. Active pharmaceutical ingredient and pharmaburst were weighed and co sifted geometrically and passed through mesh#40 followed by mesh#30.
2. Required quantity of sodium saccharin was weighed and added to step 1
3. Required amount of lubricant was weighed and passed through mesh#40 and added to step 3 and blended for five min.
4. Finally, the blend was directly compressed into tablets.

Example 3:
S.No. Materials mg per unit
1 Apixaban 5
2 Mannitol 40
3 L- arginine 30
4 Peppermint oil 4
5 Xanthan gum 0.1
6 PVP K 30 10
7 Sucralose 2

Manufacturing process:
1. All the excipients are dissolved in 50 % batch quantity water by stirring using magnetic stirrer
2. In another beaker dissolve or disperse API in 20 % batch quantity water. The solution/dispersion is stirred using magnetic stirrer.
3. Add step 2 solution/dispersion to step 1 solution with continuous stirring.
4. To the above step 3 solution/dispersion, add peppermint oil with stirring.
5. Make up the volume to the batch quantity and stir for 15 min.
6. Measured quantity of liquid which is equivalent to the dosage quantity is filled into the cavities of blister. The blisters are loaded in lyophilizer for lyophilisation.
7. Lyophilisation cycle (Freezing, primary and secondary drying) is set based on the Tg of the solution determined using DSC.
8. Once the process is complete, remove the blisters from the lyophilizer and seal them immediately.
9. The sealed blisters are stored at controlled room temperature.

Example 4:
S.No. Materials Mg per unit
1 Apixaban 5
2 Lactose 40
3 Leucine 20
4 Strawberry flavour 2
5 Xanthan gum 0.1mg
6 PVPk30 20mg
7 Sucralose 2 mg

1. All the excipients are dissolved in in 50 % batch quantity water by stirring using magnetic stirrer.
2. In another beaker dissolve or disperse API in 20 % batch quantity water. The solution/dispersion is stirred using magnetic stirrer.
3. Add step 2 solution/dispersion to step 1 solution with continuous stirring.
4. To the above step 3 solution/dispersion, add strawberry flavour with stirring.
5. Make up the volume to the batch quantity and stir for 15 min.
6. Measured quantity of liquid which is equivalent to the dosage quantity is filled into the cavities of blister. The blisters are loaded in lyophilizer for lyophilisation.
7. Lyophilisation cycle (Freezing, primary and secondary drying) was set based on the Tg of the solution determined using DSC.
8. Once the process is complete, remove the blisters from the lyophilizer and seal them immediately.

Example 5:
S.No. Material mg per unit
1 Apixaban 5
2 Mannitol 50
3 Strawberry flavour 2
4 Xanthan gum 0.1
5 PVP K30 20
6 Sucralose 2

Manufacturing process:
1. All the excipients are dissolved in 50 % batch quantity water by stirring using magnetic stirrer.
2. In another beaker dissolve or disperse API in 20 % batch quantity water. The solution/dispersion is stirred using magnetic stirrer.
3. Add step 2 solution/dispersion to step 1 solution with continuous stirring.
4. To the above step 3 solution/dispersion, add peppermint oil with stirring.
5. Make up the volume to the batch quantity and stir for 15 min.
6. Measured quantity of liquid which is equivalent to the dosage quantity is filled into the cavities of blister. The blisters are loaded in lyophiliser for lyophilization.
7. Lyophilization cycle (Freezing, primary and secondary drying) was set based on the Tg of the solution determined using DSC.
8. Once the process is complete, remove the blisters from the lyophilisers and seal them immediately.
9. The sealed blisters are stored at controlled room temperature.

Example 6:
S.No. Materials mg per unit
1 Apixaban 5
2 Lactose 40
3 Peppermint oil 4
4 L- arginine 30
5 Xanthan gum 0.1
6 PVP K 30 10
7 Sucralose 2

Manufacturing process:
1. All the excipients are dissolved in 50% batch quantity water by stirring using magnetic stirrer.
2. In another beaker dissolve or disperse API in 20 % batch quantity water. The solution/dispersion is stirred using magnetic stirrer.
3. Add step 2 solution/dispersion to step 1 solution with continuous stirring.
4. To the above step 3 solution/dispersion, add peppermint oil with stirring.
5. Make up the volume to the batch quantity and stir for 15 min.
6. Measured quantity of liquid which is equivalent to the dosage quantity is filled into the cavities of blister. The blisters are loaded in lyophiliser for lyophilisation.
7. Lyophilization cycle (Freezing, primary and secondary drying) was set based on the Tg of the solution determined using DSC.
8. Once the process is complete, remove the blisters from the lyophilisers and seal them immediately.
9. The sealed blisters are stored at controlled room temperature.

Example 7:
S.No. Materials mg per unit
1 Apixaban 5
2 Mannitol 35
3 L- arginine 25
4 Peppermint oil 3
5 Xanthan gum 0.1
6 PVP K30 10
7 sucralose 2

Manufacturing process:
1. All the excipients are dissolved in 50 % batch quantity water by stirring using magnetic stirrer.
2. In another beaker dissolve or disperse API in 20 % batch quantity water. The solution/dispersion is stirred using magnetic stirrer.
3. Add step 2 solution/dispersion to step 1 solution with continuous stirring.
4. To the above step 3 solution/dispersion, add peppermint oil with stirring.
5. Make up the volume to the batch quantity and stir for 15 minutes.
6. Measured quantity of liquid which is equivalent to the dosage quantity is filled into the cavities of blister. The blisters are loaded in lyophilizer for lyophilisation.
7. Lyophilisation cycle (Freezing, primary and secondary drying) was set based on the Tg of the solution determined using DSC.
8. Once the process is complete, remove the blisters from thelyophillizers and seal them immediately.
9. The sealed blisters are stored at controlled room temperature.