ORALLY ADMINISTRABLE FILM DOSAGE FORM CONTAINING FINGOLIMOD

FIELD OF INVENTION

The invention relates to orally administrable, disintegrating film dosage forms comprising fingolimod or pharmaceutically acceptable salts or solvates thereof and methods of orally administering the film dosage forms. BACKGROUND OF THE INVENTION

Fingolimod (FTY 720) is a sphingosine 1 -phosphate receptor modulator indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS) to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability. Fingolimod itself is a prodrug and gets phosphorylated to the active metabolite (S) - fingolimod phosphate ester by sphingosine kinases in liver cells. Fingolimod may form stable acid addition salts, of which fingolimod hydrochloride is the most common one.

Chemically fingolimod hydrochloride is 2-amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-diol hydrochloride and chemically represented as

The approved product of fingolimod hydrochloride is sold with the brand name Gilenya, by Novartis in US market. Fingolimod hydrochloride dosage form marketed in US is a hard-shell capsule filled with a powder comprising 0.56 mg of Fingolimod hydrochloride (corresponding to 0.5 mg of Fingolimod) per capsule. In further the powder comprises mannitol as a filler and small amount of magnesium stearate as lubricant.

Fingolimod has been first disclosed in the US Patent No. 5,604,229. US Publication No. 20100040678A1 provides the fast disintegrating solid compositions comprising fingolimod hydrochloride, an alkaline earth metal silicate and a disintegrating agent, which can be easily swallowed e.g. by children or elderly patients. The invention provides dosage forms, which disintegrate rapidly in the mouth and do not depend on the presence of taste masking agent or on presence of water for washing down the dosage forms. It also provides compositions comprising fingolimod, wherein the composition is coated by a mixture comprising one or more polymer resins and one or more metal oxides.

US Patent No. 8,324,283 discloses a solid pharmaceutical composition suitable for oral administration comprising fingolimod and a sugar alcohol. The sugar alcohol may act as a diluent, carrier, filler or bulking agent and may suitably be mannitol, maltitol, inositol, xylitol and/or lactitol. US '283 patent teaches that these compositions provide a convenient means of systemic administration of fingolimod, do not suffer from the disadvantages of liquid formulations for injection or oral use, and have good physicochemical and storage properties and in particular, the composition of the invention. Further, the US '283 patent discloses in particular, that the compositions of the invention may have high level of uniformity in the distribution of fingolimod hydrochloride throughout the composition, as well as high stability. The composition disclosed may be in a form of a powder, granule, pellet or a tablet. In examples of preferred embodiment, fingolimod hydrochloride is mixed with mannitol and lubricant and, optionally with a binder such as hydroxypropylcellulose or hydroxypropylmethylcellulose, milled and/or granulated. The oral solid dosage forms disclosed in this invention are tablets and capsules.

US Publication No. 20130095177 discloses a method of preparing an oral dosage form resulting from the combination of fingolimod and excipients with a particle size of less than 250μηι and greater than 0.6 μηι. PCT Publication No. WO2013019872A1 discloses a process for preparing pharmaceutical composition comprising fingolimod in a solid dosage form such as capsules. PCT Publication No. WO2013091704A1 covers a pharmaceutical composition comprising fmgolimod or pharmaceutically acceptable salt or ester thereof, calcium lactate and optionally a lubricant. The oral solid dosage forms disclosed in this invention are tablets and capsules.

PCT Publication No. WO20141 11955A1 discloses a pharmaceutical composition comprising fingolimod and weak acid cation exchange resin in the form of ion-exchange complex and pharmaceutically acceptable excipients. The oral dosage forms disclosed in this invention are tablets and capsules.

US Patent No. 8,673,918 teaches that fingolimod is not easy to formulate in solid oral formulation and only limited excipients are potentially feasible. In particular reducing sugars are not considered due to danger of Maillard reaction with the amino group of fingolimod. Thus US '918 patent discloses the stable pharmaceutical compositions of fingolimod in free form and one or more excipients:; fillers selected from the group consisting of lactose monohydrate, lactose anhydrous, maize starch, sucrose, microcrystalline cellulose, citric acid and sodium hydrogen carbonate; one or more binders selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose; one or more disintegrants selected from the group consisting of maize starch, eroscarmellose sodium, sodium carboxymethyl starch, and starch pregelatinized; one or more lubricants selected from the group consisting of hydrogenated castor oil and magnesium stearate; a flow regulator that is colloidal silicone dioxide; and one or more matrix formers selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, starch and povidone. The oral solid dosage forms disclosed in this invention are soluble tablets, capsules and sachets.

The stability and uniformity of pharmaceutical composition containing fingolimod is heavily dependent on the choice of excipients used in the formulation and the process by which the formulation is prepared. In summary the prior art teachings indicate that fingolimod is available in the oral conventional dosage forms of tablets, disintegrating tablets, capsules and sachets. Preparing the conventional dosage forms as disclosed in the prior art has many disadvantages including that a large proportion of adjuvants must be added to obtain the dosage form and a larger medication form requires additional storage space. In addition, many people, estimated to be as much as 28% of the population, have difficulty in swallowing conventional dosage forms. As an alternative to conventional dosage forms disclosed in the prior art there exists a need to develop orally administrable, disintegrating film dosage forms comprising fingolimod.

Further the prior art teaching indicates that fingolimod due to its reactive amino propane- 1,3-diol group is not amenable to prepare a stable oral formulation. Only a limited amount of suitable pharmaceutical excipients, particularly fillers have been accordingly found. Thus, administration of fingolimod in an alternate and/or improved orally disintegrating film dosage form will be beneficial with its stable and good handling properties.

SUMMARY OF INVENTION

The present invention relates to an orally administrable disintegrating film dosage form comprising fingolimod, which exhibits improved stability upon long term storage and has advantages in handling. In the first aspect, the present invention relates to an orally administrable disintegrating film dosage form comprising fingolimod and one or more excipients.

In the second aspect, the present invention provides an orally administrable, disintegrating film dosage form comprising fingolimod and one or more film forming polymers

In one embodiment of the second aspect, the present invention provides an orally administrable, disintegrating film dosage form comprising fingolimod, one or more film forming polymers, surfactants and plasticizers. In preferred embodiments of the second aspect the term "fingolimod" means the hydrochloride salt form of fingolimod. In the third aspect, the present invention provides an orally administrable disintegrating film dosage form comprising

a) Fingolimod hydrochloride and

b) Film forming polymer comprising at least one water soluble polysaccharide, at least one cellulosic polymer or cellulosic derivative polymer, at least one synthetic polymer, and/or combinations thereof.

In the fourth aspect, the present invention provides an orally administrable, disintegrating film dosage form comprising

a) Fingolimod hydrochloride

b) Film forming polymer comprising at least one water soluble polysaccharide, at least one cellulosic polymer or cellulosic derivative polymer, at least one synthetic polymer, and/or combinations thereof.

c) a surfactant and

d) a plasticizer.

In the fifth aspect, the invention relates to an orally administrable, disintegrating film dosage form comprising fingolimod or pharmaceutically acceptable salts thereof and one or more film forming polymers, for use in treatment of patients with relapsing forms of multiple sclerosis (MS).

DETAILED DESCRIPTION OF THE INVENTION The present invention provides an orally administrable, disintegrating film dosage form comprising fingolimod or pharmaceutically acceptable salts or solvates thereof. The term "fingolimod" refers to fingolimod, pharmaceutically acceptable salts, hydrates, solvates, polymorphs, complexes, and pro-drugs thereof. The term "fingolimod" further includes a moiety which yields the fingolimod active component. In preferred embodiments "fingolimod" is the hydrochloride salt form of fingolimod. As used herein, the term "complex" is intended to include any construct including fingolimod and a ligand to which it may be associated by any association, including by ionic bond, by covalent bond, by inclusion, or by any other methods of forming a complex desired.

In one embodiment according to the present invention, it provides the method of treating multiple sclerosis in a human patient by administering to the tongue of said patient, preferably one time daily, a fingolimod film/strip dosage form of the present invention that contains about 0.5mg of fingolimod.

As used herein the terms "disintegrate", "disintegrating", and "disintegrated" includes dissolving, dispersing or otherwise breaking apart for release of the drug particles and other components contained therein, such that they may be swallowed and/or absorbed into the body, including absorption into the oral cavity and/or the gastro intestinal tract.

It will be understood that the term "film" includes delivery systems of any thickness, including films, sheets, strips, discs, wafers and the like, in any shape including rectangular, square, or other desired shape. The film may be in the form of a continuous roll of film or may be sized to a desired length and width. The films described herein may be any desired thickness and size suitable for the intended use. For example, a film of the present invention may be sized such that it may be placed into the oral cavity of the user. For example some films may have relative thickness of about ΙΟΟμηι to 600μηπ, while the others may have a somewhat higher thickness of about 600μηι to ΙΟΟΟμηι. In addition, the term "film" includes single-layer composition as well as multi-layer compositions, such as laminated films, coatings on the films and the like. The composition in its dried film form maintains a uniform distribution of components. The term "disintegrating film dosage form" refers to a dosage form in the form of a sheet or film that can be administered orally to a subject, preferably a human subject. The disintegrating film dosage form contains fingolimod hydrochloride and one or more pharmaceutically acceptable excipients. The fingolimod hydrochloride in the film dosage form may be dissolved in solution or suspended in the film. Upon placement of the film dosage form in the mouth of a subject, the film dosage form disintegrates, releasing the fingolimod hydrochloride, and making it available for absorption in the oral cavity or gastrointestinal tract. In preferred embodiments, the disintegrating film dosage form rapidly disintegrates, meaning that substantially all of the film dosage form disintegrates in the oral cavity in less than 5 minutes, more preferably in less than 3 minutes, and most preferably in less than 1 minute, after placement in the oral cavity. The fmgolimod hydrochloride used in the present invention may be-of any desirable particle size. The fmgolimod hydrochloride in the film may include smaller sized particles, intermediate sized particles, larger sized particles, and combinations thereof.

For smaller sized particles, the fmgolimod hydrochloride may have a particle size of about 0.5 to about 10.0 microns in diameter.

For intermediate sized particles, the fmgolimod hydrochloride may have a particle size of about 1.0 to about 50.0 microns in diameter. For larger sized particles, the fmgolimod hydrochloride may have a particle size of about 3.0 to about 200.0 microns in diameter.

The present invention provides an orally administrable, disintegrating film dosage form comprising

a) Fingolimod hydrochloride

b) Film forming polymer comprising at least one water soluble polysaccharide, at least one cellulosic polymer or cellulosic derivative polymer, at least one synthetic polymer, and a combination thereof. The disintegrating film dosage form includes one or more film-forming polymers. The film- forming polymer may be a water soluble polymer, a water insoluble polymer, or a combination of one or more water soluble polymers and/or water insoluble polymers.

As used herein the phrase "water soluble polymer" and variants thereof refer to a polymer that is at least partially soluble in water, and desirably fully or predominantly soluble in water, or absorbs water. Polymers that absorb water are often also referred to as being water swellable polymers, and this term is synonymous for the purposes of the present invention. The materials useful with the present invention may be water soluble at room temperature and other temperatures, such as temperatures exceeding room temperature. Moreover, the materials may be water soluble at pressures less than atmospheric pressure. Desirably, the water soluble polymers have at least 20 percent by weight water uptake. Water soluble polymers having a 25 or greater percent by weight water uptake are also useful. Films or dosage forms of the present invention formed from such water soluble polymers are desirably sufficiently water soluble to be disintegratable upon contact with oral fluids. Examples of water soluble polymers include, but are not limited to water-soluble polysaccharides, cellulose polymers or cellulosic derivative polymers, and water-soluble synthetic polymers.

Water soluble polysaccharides include, maltodextrin, sodium alginate, carrageenans, guar gum, acacia gum, agar, xanthan gum, gellan gum, arable gum and related gums (gum ghatti, gum karaya, gum tragacanth), and pectin. The most preferred water soluble polysaccharide is maltodextrin. In preferred embodiments, the disintegrating film dosage form includes one or more water soluble polysaccharides. Examples of cellulosic polymers and cellulosic derivative polymers include, but are not limited to alkyl celluloses, hydroxyalkylcelluloses and hydroxyalkylcelluloses such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethyl- methylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, cellulose esters and hydroxyalkylcellulose esters such as cellulose acetate phthalate; carboxyalkylcelluloses, carboxyalkylcellulose esters such as carboxymethylcellulose and their alkali metal salts. In some preferred embodiments, the cellulose polymer and cellulosic derivative polymers include, but are not limited to, methylcellulose, ethylcellulose, hydroxypropyl ethylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, and combinations thereof. The most preferred cellulose polymer is hydroxypropyl methylcellulose. In the preferred embodiments, the disintegrating film dosage form includes one or more cellulose polymers or cellulosic derivative polymers Synthetic polymers include, but are not limited to polyacrylic acids and polyacrylic acid esters, polymethacrylic acids and polymethacrylic acid esters, polyalkylene oxides, such as polyethylene oxide, polyvinylacetates, polyvinylalcohols, polyvinylacetatephthalates (PVAP), polyvinylpyrrolidone (PVP), polyvinyl acetate copolymers, and poly(crotonic acid derivatives; also suitable are phthalated gelatin, gelatin succinate, crosslinked gelatin, shellac, water soluble chemical derivatives of starch, cationic modified acrylates and methacrylates possessing, for example, a tertiary or quaternary amino group, such as the diethylaminoethyl group, which may be quarternized if desired. The most preferred synthetic polymer is polyethylene oxide. In preferred embodiments, the disintegrating film dosage form comprises one or more water-soluble synthetic polymers.

In preferred embodiments, the disintegrating film dosage form includes one or more film- forming polymers, preferably one or more cellulose polymers or cellulosic derivative polymers. In preferred embodiments, the total amount of the one or more film-forming polymers ranges from about 5% to about 95%, preferably about 10% to about 85%, and more preferably about 20% to about 75%, by weight of the dosage form. In some preferred embodiments, the dosage form includes two or more film-forming polymers, preferably at least one water soluble polysaccharides, at least one cellulose polymer or cellulosic derivative polymer and at least one synthetic polymer.

In some embodiments of the present invention water soluble polysaccharide desirably ranges from about 0% to 50% w/w of the total weight of the water soluble polymer component of the film dosage form, preferably from about 10% to 45% w/w of the total weight of the water soluble polymer component and more preferably from about 20% to 40% w/w of the total weight of water soluble polymer component of the film dosage form.

In some embodiments of the present invention cellulosic polymers or cellulosic derivative polymer desirably ranges from about 0% to 80% w/w of the total weight of the water soluble polymer component of the film dosage form, preferably from about 10% to 70% w/w of the total weight of the water soluble polymer component and more preferably from about 15% to 60% w/w of the total weight of water soluble polymer component of the film dosage form.

In some embodiments of the present invention synthetic polymer desirably ranges from about 0% to 20% w/w of the total weight of the water soluble polymer component of the film dosage form, preferably from about 2% to 15% w/w of the total weight of the water soluble polymer component and more preferably from about 5% to 10% w/w of the total weight of water soluble polymer component of the film dosage form. In the fourth aspect, the present invention provides an orally administrable, disintegrating film dosage form comprising

a) Fingolimod hydrochloride

b) Film forming polymer comprising at least one water soluble polysaccharide, at least one cellulosic polymer or cellulosic derivative polymer, at least one synthetic polymer, and a combination thereof.

c) a surfactant and

d) a plasticizer.

The disintegrating film dosage form of the invention also may include a variety of other pharmaceutically acceptable excipients. These may include, without limitation, surfactants; plasticizers which assist in compatibilizing the components within the mixture; polyalcohols; anti-foaming agents, such as silicone-containing compounds, which promote a smoother film surface by releasing gases, such as oxygen, from the film; and thermo-setting gels such as pectin, carrageenan, and gelatin, which help in maintaining the dispersion of components.

The surface active agents, i.e. surfactants, present in this invention include, but are not limited to, cetyl alcohol, sodium lauryl sulfate, and the commercially available polysorbates for example the Span™ and Tween™ (polysorbate-80). Ethoxylated oils, including ethoxylated castor oils, and commercially available ones such as Cremophor® are also useful. Tween™ or combinations of surface active agents may be used to achieve the desired hydrophilic-lipophilic balance ("HLB"). In accordance with the present invention "surface active agents" desirably range from about 0% to 10% w/w of the total weight of the film dosage form.

Usually plasticizer significantly improves the strip properties by reducing the glass transition temperature of the polymer. Further examples of pharmaceutically acceptable excipients are plasticizers which include polyalkylene oxides, such as polyethylene glycols, polypropylene glycols, polyethylene-propylene glycols, organic plasticizers with low molecular weights, such as glycerol, glycerol monoacetate, diacetate or triacetate, triacetin, polysorbate, cetyl alcohol, propylene glycol, sorbitol, sodium diethylsulfosuccinate, triethyl citrate, tributyl citrate, and the like, which may be added in concentrations ranging from about 0 % to about 30% w/w of the total weight of the film dosage form.

Other components include co-polymers which contribute to the ease of formation and general quality of the films. Non-limiting examples of co-polymers include starches, pregelatinized starches, gelatin, polyvinylpyrrolidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, and polyvinylalcohols.

The present invention further includes incorporation of a taste masking agent wherein the taste masking agent is carboxylic acid ion exchange resin comprising methacrylic acid cross-linked with divinyl benzene or polymers or cellulosics such as ethyl cellulose. Specifically the taste masking agent as per the present invention is Methacrylic acid polymer with divinylbenzene, potassium salt (Polacrilin Potassium).

The present invention optionally further comprises pharmaceutical additives such as fillers and/or disintegrants. The amount of filler may range from about 1 to 20% w/w of the total dosage form. As for the exemplary embodiment, the filler may include at least one selected from group consisting of mannitoi, microcrystaiiine ceiiufose, lactose. The amount of the disintegrant may range from about 1 to 10% w/w of the total dosage form. Examples of disintegrants include crospovidone, crosscarmellose sodium, sodium starch glycolate and pre-gelatinized starch.

Buffering agents or pH adjusting agents may also be used, such as calcium carbonate, sodium bicarbonate, citric acid, tartaric acid, succinic acid, maleic acid, and fumaric acid. Antioxidants and preservatives may also be added to the film. Examples of antioxidants and preservatives include, but are not limited to parabens, such as methyl paraben, ethyl paraben, propyl paraben, and butyl paraben, benzoic acid, sodium benzoate, sorbic acid, sodium sorbate, cetrimide, benzalkonium chlorise, cetylpyridium chloride, benzaethonium chloride, phenylmercuric nitrate, benzyl alcohol, phenylethyl alcohol, bronabol, chlorbutanol, chlorhexidine, butylated hydroxyanisole, butylated hydroxytoluene, tert-butyl hydroquinone, and 4-hydroxymethyl-2,6,-di-ter-butylphenol. The present investigation may include incorporation of color additives of food, drug and cosmetic usage colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors. These colors are dyes, their corresponding lakes, and certain natural and derived colorants. Lakes are dyes absorbed on aluminum hydroxide. Other examples of coloring agents include known azo dyes, organic or inorganic pigments, or coloring agents of natural origin. FD&C colors are preferred and most preferred is FD&C Blue No.l .

Flavors may be chosen from natural and synthetic flavoring liquids. An illustrative list of such agents includes volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof. A non- limiting representative list of examples includes mint oils (peppermint flavor), cocoa, and citrus oils such as lemon, orange, grape, lime and grapefruit and fruit essences including apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot or other fruit flavors. Other useful flavorings include aldehydes and esters such as benzaldehyde (cherry, almond), citral i.e., alphacitral (lemon, lime), neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon), aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehyde C-12 (citrus fruits), tolyl aldehyde (cherry, almond), 2,6-dimethyloctanol (green fruit), and 2-dodecenal (citrus, mandarin), combinations thereof and the like.

The sweeteners may be chosen from the following non-limiting list: glucose (corn syrup), dextrose, invert sugar, fructose, and combinations thereof; saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds. glycyrrhizin; Stevia Rebaudiana (Stevioside); chloro derivatives of sucrose such as sucralose; sugar alcohols such as sorbitol, mannitol, xylitol, and erythritol. Also contemplated are hydrogenated starch hydrolysates and the synthetic sweetener 3,6-dihydro-6-rnethyl-l-l-l,2,3-o- xathiazin-4-one-2,2-dioxide, particularly the potassium salt (acesulfame-K), ammoniated glycyrrhizin and monoammonium glycyrrhizinate, and sodium and calcium salts thereof, and natural intensive sweeteners. Other sweeteners may also be used.

In another embodiment of the present invention it provides a process for preparing an orally administrable, disintegrating film dosage form comprising fingolimod hydrochloride

a) Dispersion of fingolimod hydrochloride in purified water,

b) Adding at least one surfactant into step (a) solution.

c) Adding at least one coloring additives into step (b) solution.

d) Adding at least one sweetener to into step (c) solution.

e) Adding at least water soluble polysaccharide into step (d).

f) Adding at least one synthetic polymer into step (e)

g) Adding at least one cellulosic polymers or cellulosic derivative polymer into step (f) h) Adding at least one plasticizer into step (g)

i) Adding at least one flavor into step (h)

j) Homogenizing the solution in step (i) and

k) Obtaining the film composition on a polyester film

In the preferred embodiment of obtaining the film composition on a polyester film includes the steps of

a) Feeding the polyester film roll on the lab scale layering machine.

b) Adjusting the layering thickness using Doctor's knife.

c) Pouring the slurry of the fingolimod hydrochloride film suspension through the hopper on to the support polyester film.

d) Cutting the layered polyester film and separate it from the layering machine.

e) Drying the layered polyester film in an oven at 60-80°C for 18 minutes.

f) Taking out the dried polyester film and cutting into desired size (32 x 25mm strips). g) Packing the Fingolimod hydrochloride strips into tri-laminated aluminum pouches/sachets.

The present invention also provides for methods of using the disintegrating film dosage forms. In preferred embodiments, the disintegrating film dosage form is placed in the oral cavity of the subject, such as on the tongue, and allowed to disintegrate completely. The disintegrating film dosage form may be administered to a subject in a fed state or a fasted state. The disintegrating film dosage form may also be administered with or without the administration of water. In some embodiments, more than one disintegrating film may be administered sequentially. When more than one disintegrating film dosage form is administered sequentially, preferably the subject places the disintegrating film dosage form in the oral cavity and allows the dosage form to completely disintegrate before administration of the next dosage form.

In some embodiments of the present invention the disintegrating film dosage form of fingolimod hydrochloride is used for treatment of patients with relapsing forms of multiple sclerosis (MS).

An example given below serves to illustrate the embodiments of the present invention. However, they do not intend to limit the scope of present invention. Example: An oral film formulation containing fingolimod equivalent to 0.5mg was prepared with the following components.

Table-l: Composition of the Fingolimod film

S.No Ingredients Wt. in Composition Function

mg/strip % (unit)

1. Fingolimod HC1 0.56 1.19 API

2. Tween-80 1 2.1 Surfactant

3. Sucralose 2 4.2 Sweetener

4. Maltodextrin 10 21.3 Polysaccharide

polymer

5. Polyethylene Oxide 2.5 5.3 Synthetic polymer

6. Hydroxypropylmethylcellulose 19.92 42.4 Cellulosic polymer

7. Glycerol 7 14.9 plasticizer

8. Peppermint flavor 4 8.5 flavor

9. FD&C Blue No.l. 0.02 0.04 Color additive. 10. Purified Water Q.S - Vehicle

Strip weight 47 -

Process for preparation:-

1. Prepare 10% HPMC base in a SS container and allow the contents to swell for about 12 to 15 hours.

2. Take Purified Water in a SS container and add weighed amount of fmgolimod slowly under stirring for 5 minutes.

3. Add Tween-80 slowly to step No. 2 under stirring for 5 minutes.

4. Add coloring agent (Brilliant Blue) slowly to step No.3 under stirring for 3 minutes.

5. Add Sucralose slowly to step No. 4 under stirring for 3 minutes.

6. Add Maltodextrin slowly to step No. 5 under stirring for 5 minutes.

7. Add Polyethylene oxide slowly to step No. 6 under stirring for 10 minutes.

8. Transfer 10% HPMC base to step no. 7 under stirring for 12 minutes.

9. Add Glycerol slowly to step No. 8 under stirring for 2 minutes.

10. Add Pepper Mint flavor slowly to step No.9 under stirring for 12 minutes.

1 1. Continue the stirring for additional 10 minutes to attain uniform slurry.

12. Allow the slurry to be stored overnight under closed condition to get rid of air bubbles.

Layering, Drying, Slitting & Packing:- a) Feed the polyester film roll on the lab scale layering machine.

b) Adjust the layering thickness using Doctor's knife (640μπΐ).

c) Pour the slurry through the hopper on to the support polyester film.

d) Cut the layered polyester film and separate it from the layering machine.

e) Dry the layered polyester film in an oven at 60°C - 80°C for 18 minutes.

f) Take out the dried polyester film and cut into desired size (32 x 25mm strips).

g) Pack the fingolimod strips into tri-laminated aluminum pouches/sachets.