Claims:1. A sublingual pharmaceutical composition of Teriflunomide.
2. A method of treating multiple sclerosis, comprising steps of: administering a solid pharmaceutical composition comprising Teriflunomide or pharmaceutically acceptable salts thereof to a subject prone to multiple sclerosis.
3. A pharmaceutical composition of claim 1, wherein the composition is as effective as immediate release tablets and has fewer side effects when administered to suitable patient population.
4. A method of claim 2, wherein the solid pharmaceutical composition is a tablet.
5. A method of claim 2, wherein the solid pharmaceutical composition is a film.
6. A method of claim 2, wherein the solid pharmaceutical composition is a lozenge.
7. A method of claim 2, wherein the solid pharmaceutical composition is as effective as immediate release tablets and has fewer side effects when administered to suitable patient population.
8. A method of treating multiple sclerosis, comprising steps of: administering a solid pharmaceutical composition comprising teriflunomide or pharmaceutically acceptable salts thereof to a subject prone to multiple sclerosis, wherein the solid pharmaceutical composition releases at least about 70% of teriflunomide in 30 minutes in 0.05M phosphate buffer of pH 6.8 in USP dissolution apparatus using type II at about 50 RPM.
9. A method of claim 6, wherein said solid pharmaceutical is as effective as immediate release tablets and has fewer side effects when administered to suitable patient population.
10. A solid pharmaceutical composition for the treatment of multiple sclerosis, said composition comprising an effective amount of teriflunomide 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 sublingual pharmaceutical composition of drugs used for the treatment of multiple sclerosis.

Background of invention
Despite significant advances in diagnosis and therapy, neurologic diseases remain a major cause of morbidity and mortality throughout the world. Neurological diseases are common and costly. Treatment involves use of medicines for longer duration of time. Thus there is a strong incentive to identify new dosage forms that provide convenience of administration, compliance to adhere to treatment, and fewer incidences of side effects or adverse effects.

The chemical name of teriflunomide is 2-cyano-3-hydroxy-N-[4-(trifluoromethyl) phenyl]-2-butenamide and formula is C12H9F3N2O2 and molecular weight is 270.207.

Teriflunomide is a novel oral disease-modifying therapy (DMT) for the treatment of relapsing forms of multiple sclerosis (RMS). Teriflunomide blocks de novo pyrimidine synthesis, which inhibits the replication and function of activated lymphocytes.

Teriflunomide is used as immunosuppressant acts as tyrosine kinase inhibitor. It is used in the treatment of multiple sclerosis, rheumatoid arthritis, and auto immune diseases.

Teriflunomide was disclosed in US 5679709, US5494911, US6365626 and does not mention the use of teriflunomide by providing it in the form of sublingual pharmaceutical composition.

Detailed description
The present invention relates to the use of medicines for the treatment of multiple sclerosis for preparing pharmaceutical compositions in the form of sublingual formulations.

Accordingly the present invention provides a solid pharmaceutical composition suitable for sublingual administration, comprising teriflunomide and pharmaceutically acceptable excipients thereof.

It has been surprisingly been found that pharmaceutical compositions in the form of sublingual formulations of teriflunomide provide desired pharmacological actions and fewer side effects.

In one embodiment of the invention, teriflunomide is provided in the pharmaceutical compositions in the form of sublingual tablet.

In another embodiment of the invention, teriflunomide is provided in the pharmaceutical composition in the form of sublingual film.

In yet another embodiment of the invention, teriflunomide is provided in the pharmaceutical composition in the form of lozenge.

In another embodiment of the invention, teriflunomide is provided in the pharmaceutical composition in the form of granules.

In an embodiment of the invention, sublingual tablet, sublingual film, lozenge or granules comprise soluble excipients to provide better mouth feel.

In another embodiment of the invention, sublingual tablet, sublingual film, lozenge or granules comprise dispersible excipients to provide faster disintegration.
In yet another embodiment of the invention, sublingual tablet, sublingual film, lozenge or granules comprise combination of soluble and dispersible excipients to provide better mouth feel and faster disintegration.

In one of the embodiment of the invention, sublingual tablet, sublingual film, lozenge or granules comprise sweetening agents.

In an embodiment of the invention, sublingual tablet of present invention has as small and as thin tablet that suits pharmaceutical processing of said teriflunomide in the required dosage strength and provides ease of administration during the treatment.

Sublingual tablets of the invention include but not limited to dispersible tablets, dissolvable tablets, dispersible or dissolvable wafers, compressed or molded or lyophilized or made using sugar candy processes.

Sublingual films of the invention include but not limited to dispersible or dissolvable films made using casting, solvent casting, semisolid casting, solvent evaporation, hot melt extrusion, solid dispersion extrusion, rolling, and other processes known in the art of film making.

Usually tablets are designed so that the smallest tablet size which can be conveniently compressed is formed. Thus, if the dose is small more diluents are required and if the dose is high less diluents are required as not to increase the tablet size, which might make it difficult to keep under tongue.

Diluents selection should be made carefully as physical-chemical changes might render the product unstable and might cause problems in manufacturing. Binders are added to tablet formulations to add cohesiveness to powders thereby providing the necessary bonding to form granules which under compaction form a compact mass as tablet. In other words, binders are essential to achieve the “hardness” of the tablet.

Binders are usually selected on basis of previous experience, particular product needs, literature or vendor data or the preference of individual scientists or manufacturing unit. The primary criterion when choosing a binder is its compatibility with other tablet components.

It must add sufficient cohesion to the powders to allow for normal processing yet allow the tablet to disintegrate and the drug to dissolve upon ingestion, releasing the active ingredients for absorption. Disintegrants facilitate the breakup of a tablet after oral administration.

They can be added prior to granulation or during the lubrication step prior to compression or at both processing steps. The effectiveness of many disintegrants is affected by their position within the tablet. Since disintegration is the opposite operation to granulation (agglomeration) and the subsequent formation of strong compacts, one must carefully weigh these two phenomena when designing a tablet. Lubricants prevent sticking of the tablets to the tablet punches during the compression phase of the tablet manufacturing process.

When lubricants are added to a powder mass, they form a coat around individual particles which remains more or less intact during compression. Lubricants are mostly hydrophobic. The presence of lubricant coating may cause an increase in the disintegration time and a decrease in drug dissolution rate. The choice of a lubricant may depend upon the type of tablet being manufactured, dissolution, flow characteristics and requirements of the formulation in terms of hardness, friability and compatibility. Glidants are the materials that have good flow properties and poor lubrication properties.

Glidants improve the flow of powder into the tabletting machines for compaction. They act to minimize the tendency of a granulation to separate or segregate due to excessive vibration. High speed tablet machine require smooth even flow of material to die cavities (tablet mold). The uniformity of tablet weights directly depends on how uniformly the die cavity is filled. In general many materials commonly referred to as lubricants possess only a minimal lubricating activity and are better glidants or anti-adherents.

Thus a blend of two or more materials may be necessary to obtain these properties.
Exemplary list of excipients and its role in solid oral preparation is listed in Table 1.
Table 1
No: Excipient Number of times excipients used in tablets out of 200 Use
1 Acacia 2 Emulsifying agent; stabilizing agent; suspending agent; tablet binder; viscosity-increasing agent
2 Alginate 1 Binder
3 Alginic Acid 1 Stabilizing agent; suspending agent; tablet binder,
tablet disintegrant; viscosity-increasing agent.
4 Aluminum Acetate 1 Antiseptic
5 Benzyl Alcohol 2 Antimicrobial preservative; disinfectant; solvent
6 Butyl Paraben 1 Antimicrobial preservative
7 Butylated Hydroxy Toluene 1 Antioxidant.
8 Citric acid 1 Disintegrant
9 Calcium carbonate 1 Tablet and capsule diluent; therapeutic agent
10 Candelilla wax 4 Binder
11 Croscarmellose sodium 22 Tablet and capsule disintegrant
12 Confectioner sugar 1 Sugar coating adjunct; sweetening agent; tablet and capsule diluents
13 Colloidal silicone dioxide 22 Adsorbent; anticaking agent; emulsion stabilizer; glidant;
suspending agent; tablet disintegrant; thermal stabilizer;
viscosity-increasing agent.
14 Cellulose 19 Adsorbent; suspending agent; tablet and capsule diluent;
tablet disintegrant.(cellulose microcrystaline) Adsorbent; glidant; suspending agent;
tablet and capsule diluent; tablet disintegrant (cellulose powdered) Tablet and capsule diluent.(cellulose Silicified)
15 Plain or anhydrous calcium phosphate 3 Diluent
16 Carnuba wax 12 Binder
17 Corn starch 17 Binder
18 Carboxymethylcellulose calcium 3 Stabilizing agent; suspending agent;
tablet and capsule disintegrant;
viscosity-increasing agent; water-absorbing agent
19 Calcium stearate 5 Tablet and capsule lubricant
20 Calcium disodium EDTA 1 Chelation
21 Copolyvidone 1 Film-former; granulating agent; tablet binder
22 Castor oil hydrogenated 4 Extended release agent; stiffening agent; tablet and
capsule lubricant
23 Calcium hydrogen phosphate dihydrate 1 Diluent
24 Cetylpyridine chloride 1 Antimicrobial preservative; antiseptic;
cationic surfactant; disinfectant;
solubilizing agent; wetting agent
25 Cysteine HCL 1 Reducing Agent
26 Crosspovidone 20 Tablet disintegrant.
27 calcium phosphate di or tri basic 7 Tablet and capsule diluent Anticaking agent; buffer, nutrient; dietary supplement;
glidant; tablet and capsule diluent and
clouding agent (for calcium phosphate tribasic)
28 Dibasic Calcium Phosphate 9 Diluent
29 Disodium hydrogen phosphate 1 Buffering agent
30 Dimethicone 1 Antifoaming agent;
emollient
31 Erythrosine Sodium 2 Color
32 Ethyl Cellulose 3 Coating agent; flavoring fixative; tablet binder; tablet filler; viscosity-increasing agent.
33 Gelatin 14 Coating agent; film-former; gelling agent; suspending agent; tablet binder; viscosity-increasing agent
34 Glyceryl monooleate 2 Nonionic surfactant
35 Glycerin 3 Antimicrobial preservative; emollient; humectant;
plasticizer; solvent; sweetening agent; tonicity agent
36 Glycine 1 Tonicity
37 Glyceryl monostearate 1 Emollient; emulsifying agent; solubilizing agent;
stabilizing agent; sustained-release ingredient;
tablet and capsule lubricant
38 Glyceryl behenate 1 Coating agent; tablet binder; tablet and capsule lubricant
39 Hydroxy propyl cellulose 25 Coating agent; emulsifying agent; stabilizing agent; suspending agent; tablet binder; thickening agent;
viscosity-increasing agent.
40 Hydroxyl propyl methyl cellulose 45 Coating agent; film-former; rate-controlling polymer for sustained release; stabilizing agent; suspending agent; tablet binder; viscosity-increasing agent.
41 Hypromellose 7 Coating agent; film-former; rate-controlling polymer for sustained release; stabilizing agent; suspending agent; tablet binder; viscosity-increasing agent.
42 HPMC Pthalate 1 Coating agent.
43
Iron oxides or ferric oxide 15 Color
44 Iron oxide yellow 5 Color
45 Iron oxide red or ferric oxide 6 Color
46 Lactose hydrous or anhydrous or monohydrate or spray dried 77 Binding agent; diluent for dry-powder inhalers; lyophilization aid; tablet binder; tablet and capsule diluent.( lactose anhydrous) Binding agent; diluent for dry-powder inhalers; tablet binder; tablet and capsule diluent(lactose monohydrate) Binding agent; diluent for dry-powder inhalations; tablet and capsule diluent;
tablet and capsule filler.(lactose spray dried)
47 Magnesium stearate 108 Tablet and capsule lubricant
48 Microcrystalline cellulose 61 Adsorbent; suspending agent; tablet and capsule diluent; tablet disintegrant
49 Mannitol 4 Sweetening agent; tablet and capsule diluent; tonicity agent; vehicle (bulking agent) for lyophilized preparations
50 Methyl cellulose 3 Coating agent; emulsifying agent; suspending agent;
tablet and capsule disintegrant; tablet binder; viscosity-increasing agent
51 Magnesium carbonate 2 Tablet and capsule diluent
52 Mineral oil 3 Emollient; lubricant; oleaginous vehicle; solvent
53 Methacrylic acid copolymer 5 Coating
54 Magnesium oxide 2 Tablet and capsule diluent
55 Methyl paraben 5 Antimicrobial preservative
56 Povidone or PVP 36 Disintegrant; dissolution aid; suspending agent; tablet binder.
57 PEG 40 Ointment base; plasticizer; solvent; suppository base;
tablet and capsule lubricant
58 Polysorbate 80 19 Solubilizer
59 Propylene glycol 10 Antimicrobial preservative; disinfectant; humectant; plasticizer; solvent; stabilizer for vitamins; water-miscible cosolvent.
60 Polyethylene oxide 3 Mucoadhesive; tablet binder; thickening agent.
61 Propylene paraben 4 Antimicrobial preservative
62 Polaxamer 407 or 188 or plain 3 Dispersing agent; emulsifying and co-emulsifying agent;
solubilizing agent; tablet lubricant; wetting agent.
63 Potassium bicarbonate 1 Alkalizing agent; therapeutic agent
64 Potassium sorbate 1 Antimicrobial preservative
65 Potato starch 1 Binder
66 Phosphoric acid 1 Acidifying agent
67 Polyoxy140 stearate 1 Emulsifying agent; solubilizing agent; wetting agent
68 Sodium starch glycolate 20 Tablet and capsule disintegrant
69 Starch pregelatinized 21 Tablet and capsule diluent; tablet and capsule disintegrant; tablet binder (starch pregelatinized Glidant; tablet and capsule diluent; tablet and capsule disintegrant; tablet binder.( starch , potato, corn , wheat, rice) so check the above and make the changes
70 Sodium crossmellose 1 Disintegrant
71 Sodium lauryl sulfate 13 Anionic surfactant; detergent; emulsifying agent;
skin penetrant; tablet and capsule lubricant; wetting agent
72 Starch 19 Glidant; tablet and capsule diluent; tablet and capsule disintegrant; tablet binder.( starch , potato, corn , wheat, rice) combine all the starches
73 Silicon dioxide 14 Same as colloidal silicon dioxide
74 Sodium benzoate 2 Antimicrobial preservative; tablet and capsule lubricant
75 Stearic acid 12 Emulsifying agent; solubilizing agent; tablet and capsule lubricant.
76 Sucrose 9 Base for medicated confectionery; granulating agent;
sugar coating adjunct; suspending agent; sweetening agent; tablet and capsule diluent; viscosity-increasing agent.
77 Sorbic acid 3 Antimicrobial preservative
78 Sodium carbonate 1 Carbonating agent
79 Saccharin sodium 1 Sweetening agent
80 Sodium alginate 1 Stabilizing agent; suspending agent; tablet and capsule disintegrant; tablet binder; viscosity-increasing agent.
81 Silica gel 1 Adsorbant
82 Sorbiton monooleate 1 Solubilizer
83 Sodium stearyl fumarate 4 Tablet and capsule lubricant.
84 Sodium chloride 3 Tablet and capsule diluent; tonicity agent
85
Sodium metabisulfite 1 Antioxidant.
86 Sodium citrate dihydrate 1 Alkalizing agent; buffering agent; emulsifier; sequestering agent.
87 Sodium starch 1 Binder
88 Sodium carboxy methyl cellulose 1 Coating agent; tablet and capsule disintegrant;
tablet binder; stabilizing agent; suspending agent;
viscosity-increasing agent; water-absorbing agent.
89 Succinic acid 1 Acidity
90 Sodium propionate 1 Antimicrobial preservative
91 Titanium dioxide 49 Coating agent; opacifier; pigment
92 Talc 20 Anticaking agent; glidant; tablet and capsule diluent; tablet and capsule lubricant.
93 Triacetin 6 Humectant; plasticizer; solvent
94 Triethyl citrate 3 Plasticizer

Examples:
Example 1
S.No. Material mg per unit g per batch
1. Teriflunomide 7 14
2. Mannitol 40 80
3. Microcrystalline Cellulose 15 30
4. Polyplasdone 10 20
5. Cheery Flavour 0.5 1
6. Aspartame 2 4
7. Magnesium Stearate 0.5 1
Total 75 150

Manufacturing process
Step-1: Sifted the Teriflunomide, Mannitol, Microcrystalline Cellulose, Polyplasdone, Cheery flavour and Aspartame through the #40 mesh.
Step-2: The above sifted materials were mixed for 100 rotations.
Step-3: Sifted Magnesium Stearate through #60 mesh.
Step-4: The above sifted material of step-3 added into step-2 and mixed for 25 rotations.
Step-5: The tablets were compressed by using rotary compression machine by using 6 mm flat round shaped punches.

Example 2
S.No. Material mg per unit g per batch
1. Teriflunomide 7 14
2. Mannitol 40 80
3. Microcrystalline Cellulose 15 30
4. Polyplasdone 10 20
5. Cheery Flavour 0.5 1
6. Aspartame 2 4
7. Magnesium Stearate 0.5 1
Total 75 150

Manufacturing process
Step-1: Sifted the Teriflunomide, Mannitol, Microcrystalline Cellulose, Polyplasdone, Cheery flavour and Aspartame through the #40 mesh.
Step-2: Loaded the Step-1 material in blender and mixed it for 200 rotations.
Step-3: Sifted Magnesium Stearate through #60 mesh.
Step-4: Loaded the step-3 material to step-2 in blender and further mixed it for 100 rotations.
Step-5: The tablets were compressed by using rotary compression machine by using 6 mm flat round shaped punches.

Example 3
S.No. Material mg per unit g per batch
1. Teriflunomide 7 14
2. Mannitol 65 130
3. Microcrystalline Cellulose 15 30
4. Polyplasdone 10 20
5. Cheery Flavour 0.5 1
6. Aspartame 2 4
7. Magnesium Stearate 0.5 1
Total 100 200

Manufacturing process
Step-1: Sifted the Teriflunomide, Mannitol, Microcrystalline Cellulose, Polyplasdone, Cheery flavour and Aspartame through the #40 mesh.
Step-2: Loaded the Step-1 material in blender and mixed it for 200 rotations.
Step-3: Sifted Magnesium Stearate through #60 mesh.
Step-4: Loaded the step-3 material to step-2 in blender and further mixed it for 100 rotations.
Step-5: The tablets were compressed by using rotary compression machine by using 6 mm flat round shaped punches.

Example 4
S.No. Material mg per unit g per batch
1. Teriflunomide 7 7
2. Pharmaburst 75 75
3. Microcrystalline Cellulose 10 10
4. Polyplasdone 5 5
5. Cheery Flavour 0.5 0.5
6. Aspartame 2 2
7. Magnesium Stearate 0.5 0.5
Total 100 100

Manufacturing process
Step-1: Sifted the Teriflunomide, Pharmaburst, Microcrystalline Cellulose, Polyplasdone, Cheery flavour and Aspartame through the #40 mesh.
Step-2: Loaded the Step-1 material in blender and mixed it for 200 rotations.
Step-3: Sifted Magnesium Stearate through #60 mesh.
Step-4: Loaded the step-3 material to step-2 in blender and further mixed it for 100 rotations.
Step-5: The tablets were compressed by using rotary compression machine by using 6 mm flat round shaped punches.

Example 5-8
S.No. Material Example 5 Example 6 Example 7 Example 8
1. Teriflunomide 7 7 7 7
2. Mannitol 50 - - -
3. Lactose - 50 - -
4. Povidone k30 - - 50 -
5. Sorbitol - - - 50
6. Xantham gum - 5 - 5
7. Gelatin 5 - 5 -
8. L-Arginine 2 2 2 2
9. Sucralose 0.2 - 0.1 -
10. Aspartame - 0.2 0.1 0.2
11. Peppermint oil 0.2 0.1 0.1 0.1
Total

Manufacturing process
Step-1: Dissolve mannitol, lactose, povidone, sorbitol, xanthan gum, l-arginine, sucralose, aspartame in about 40% batch quantity water.
Step-2: Dissolve gelatin in 10% of batch quantity water by heating.
Step-3: Add step 2 solution to step 1 solution under stirring.
Step-4: Disperse peppermint oil in the step 3 solution under stirring.
Step-5: Dissolve teriflunomide in 50% batch quantity water under stirring and use heating if required and transfer this solution to step 4 solution and stir.
Step-6: Measured quantity of solution is filled into cavities of blisters.
Step-7: Freeze above solution in blisters at -55 oC for about 4 hours.
Step-8: Allow above freezed solution for primary drying as per Tg of solution determined by DSC.
Step-9: Above primary dried material is subjected to secondary drying at 25 oC for about 10 hours.
Step-10: Remove the dried material and quickly seal the blisters using sealing machine.