DESC:FIELD OF THE INVENTION
The present invention relates to a sublingual composition comprising nintedanib or salt thereof as an active agent, process of preparation thereof and method of using the same.

The present invention particularly relates to a sublingual composition comprising nintedanib or salt thereof and the use of said sublingual composition for the treatment of idiopathic pulmonary fibrosis, chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype, systemic sclerosis-associated interstitial lung disease and cancer.

BACKGROUND OF THE INVENTION
Cancers are a large family of diseases that involve abnormal cell growth with the potential to invade or spread to other parts of the body. They form a subset of neoplasms. A neoplasm or tumor is a group of cells that have undergone unregulated growth and will often form a mass or lump but may be distributed diffusely.

Idiopathic pulmonary fibrosis (IPF) is a type of chronic scarring lung disease characterized by a progressive and irreversible decline in lung function. Symptoms typically include gradual onset of shortness of breath and a dry cough.

Nintedanib is a synthetic indolinone compound developed by Boehringer Ingelheim (BIBF 1120) that inhibits vascular endotheliam growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR), a group of tyrosine kinase inhibitors, under study as an anti-cancer agent, and also for slowing progression of IPF.

Nintedanib is a kinase inhibitor. Nintedanib is presented as the ethanesulfonate salt (esylate), with the chemical name 1H-Indole-6-carboxylic acid, 2,3-dihydro-3-[[[4-[methyl[(4-methyl-1-piperazinyl)acetyl]amino]phenyl]amino]phenyl-methylene]-2-oxo-,methylester, (3Z)-, ethanesulfonate (1:1). The molecular formula of nintedanib is C31H33N5O4?C2H6O3S and a molecular weight of 649.76 g/mol. Nintedanib is represented by compound of structural formula I.

Formula I
Nintedanib esylate is a bright yellow powder.

Nintedanib esylate capsule oral was first approved by U. S. FDA on October 15, 2014 under the brand name OFEV for Boehringer Ingelheim Pharmaceuticals Inc. It is available in Eq 100mg base and Eq 150mg base strengths and mainly used for the treatment of idiopathic pulmonary fibrosis (IPF), chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype and systemic sclerosisassociated interstitial lung disease (SSc-ILD).

U.S. Patent No. 6,762,180 discloses nintedanib compound.

U.S. Patent No. 7,119,093 discloses nintedanib monoethanesulphonate salt, further discloses nintedanib monoethanesulphonate hemihydrate in crystalline form, having a melting point of Tm.p.=305±5° C. determined by DSC; evaluation using peak-maximum; heating rate: 10° C./min.

U.S. Patent Nos. 9,907,756 and 10,105,323 discloses pharmaceutical formulation comprising lipid suspension of nintedanib monoethanesulphonate in soft gelatin capsule. Said patents disclose composition approved under brand name OFEV.

U.S. Patents No. 1,0154,990 discloses use of nintedanib monoethanesulphonate for treating systemic scleroderma.

U.S. publication No. 20190070160 discloses various dosage forms of nintedanib generically like oral, parenteral, buccal, vaginal, rectal, inhalation, insufflation, sublingual, intramuscular, intradermal, subcutaneous, topical, intranasal, intraperitoneal, intrathoracic, intralesional, paralesional, intravenous, epidural, intrathecal, or intracerebroventricular routes, or by injection into the tissue and/or joints; however said patent publication does not discloses or teaches specifically sublingual composition of nintedanib.

The prior art compositions are available in the form of soft capsules in Eq 100mg base and Eq 150mg base strengths, said dosage form have several drawbacks such as low bioavailability, substantial first pass metabolism, pH sensitivity of nintedanib or salt thereof, formulations process associated problems, high dose, etc.

The absolute bioavailability of commercially available capsule of 100 mg dose was 4.7% in healthy volunteers. Absorption and bioavailability are decreased by transporter effects and substantial first-pass metabolism.

The prior art compositions do not disclose or claim low dose composition of comprising specific nintedanib or salt thereof intended for transmucosal, i.e., buccal / sublingual route administration which bypass first-pass metabolism.

The commercially available product is capsule, oral as well as products known in the prior art disclosed different dosage forms of nintedanib have drawbacks such as but not limited to less low bioavailability, processability issues, and substantial first pass metabolism.

Hence, there is still a need to design a pharmaceutical composition of nintedanib or salt thereof which will overcome the drawbacks associated with prior art pharmaceutical compositions.

The inventors of the present invention have developed a pharmaceutical composition comprising nintedanib or salt thereof intended for sublingual route administration and surprisingly found that the problems associated with commercial / prior art dosage forms can be overcome by composition of present invention such as:
i) Less bioavailability associated with prior art composition due to substantial first-pass metabolism can be overcome by newly developed sublingual composition, wherein said composition possess properties such as high therapeutic efficiency, storage stability and better patient compliance.

ii) Further as the drug nintedanib or salt thereof is pH sensitive, in present invention, pH of the composition is maintained in acidic range by acidic agent which avoids formulations process associated problems.

OBJECTS OF THE INVENTION:
The main object of the invention is to provide sublingual composition comprising:
a) Nintedanib or salt thereof; and
b) At least one pharmaceutically acceptable excipient.

The main object of the invention is to provide a sublingual composition comprising:
a) Nintedanib or salt thereof;
b) At least one diluent; and
c) At least one pharmaceutically acceptable excipient.

Another object of the invention is to provide a sublingual composition comprising:
a) 0.1-60% w/w of Nintedanib or salt thereof;
b) 30-90% w/w of diluent;
c) 1%-40% w/w of acidifying agents;
d) 5-35% w/w of solubility enhancer;
e) 0.1-5% w/w of lubricant; and
f) Optionally 1%-15% w/w of disintegrant.

Another object of the invention is to provide a sublingual tablet composition comprising:
a) 0.1-60% w/w of Nintedanib or salt thereof;
b) 30-90% w/w of diluent;
c) 1%-40% w/w of acidifying agents;
d) 5-35% w/w of solubility enhancer;
e) 0.1-5% w/w of lubricant; and
f) Optionally 1%-15% w/w of disintegrant; and
wherein the sublingual tablet composition is optionally coated.

A further object of the invention is to provide a process for the preparation of a sublingual composition comprising nintedanib or salt thereof which comprises steps of:
a) Co-sifting and mixing one or more diluents into suitable vessel;
b) Preparing binder solution;
c) Adding nintedanib or salt thereof to the binder solution obtained in step (b);
d) Granulating mixture of step (a) with binder solution obtained in step (c);
e) Drying granules obtained in step (d);
f) Optionally blending dried granules of step (e) with disintegrant;
g) Lubricating dried granules obtained in step (e) or (f);
h) Optionally compressing lubricated blend obtained in step (g) to get sublingual tablet dosage form; and
i) Optionally coating the sublingual tablet dosage form obtained in step (g).

A further object, there is provided a sublingual compositions of nintedanib or salt thereof for the treatment of idiopathic pulmonary fibrosis, chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype, systemic sclerosis-associated interstitial lung disease and cancer.

SUMMARY OF THE INVENTION
In one aspect, an invention provides sublingual composition comprising nintedanib or salt thereof and at least one pharmaceutically acceptable excipient.

In another aspect, an invention also relates to process of preparation of a sublingual composition comprising nintedanib or salt thereof.

In another aspect of the present invention is to provide sublingual film, sublingual tablet, sublingual spray, sublingual granule, sublingual powder or sublingual disc, buccal tablet of nintedanib or salt thereof comprising at least one pharmaceutically acceptable excipient.

In another aspect, an invention provides a sublingual composition comprising:
a) Nintedanib or salt thereof; and
b) Optionally other suitable pharmaceutically acceptable excipients.

In another aspect, an invention provides a sublingual composition comprising:
a) Nintedanib or salt thereof;
b) At least one diluent; and
c) Optionally other suitable pharmaceutically acceptable excipients.

In another aspect, an invention provides a sublingual composition comprising:
a) 0.1-60% w/w of Nintedanib or salt thereof;
b) 30-90% w/w of diluent;
c) 1%-40% w/w of acidifying agents;
d) 5-35% w/w of solubility enhancer;
e) 0.1-5% w/w of lubricant; and
f) Optionally 1%-15% w/w of disintegrant.

In another aspect, an invention provides a sublingual tablet composition comprising:
a) 0.1-60% w/w of Nintedanib or salt thereof;
b) 30-90% w/w of diluent;
c) 1%-40% w/w of acidifying agents;
d) 5-35% w/w of solubility enhancer;
e) 0.1-5% w/w of lubricant; and
f) Optionally 1%-15% w/w of disintegrant; and
Wherein the sublingual tablet composition is optionally coated.

In another aspect of an invention provides a process for the preparation of a sublingual composition comprising nintedanib or salt thereof which comprises steps of:
a) Co-sifting and mixing one or more diluents into suitable vessel;
b) Preparing binder solution;
c) Adding nintedanib or salt thereof to the binder solution obtained in step (b);
d) Granulating mixture of step (a) with binder solution obtained in step (c);
e) Drying granules obtained in step (d);
f) Optionally blending dried granules of step (e) with disintegrant;
g) Lubricating dried granules obtained in step (e) or (f);
h) Compressing lubricated blend obtained in step (g) to get sublingual tablet dosage form; and
i) Optionally coating the sublingual tablet dosage form obtained in step (g).

In another aspect of the present invention is to provide a sublingual compositions of nintedanib or salt thereof for the treatment of idiopathic pulmonary fibrosis, chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype, systemic sclerosis-associated interstitial lung disease and cancer.

DETAILED DESCRIPTION OF THE INVENTION
The term “nintedanib” is used in broad sense to include not only “nintedanib” per se but also its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, derivatives, isomers, polymorphs, prodrugs thereof. Preferably nintedanib ethanesulfonate salt (esylate).

The nintedanib or salt thereof according to present invention may be present in an amount from about 0.1% to about 60% by weight with respect to total weight of the pharmaceutical composition.

The nintedanib or salt thereof according to present invention may be present in an amount from about Eq 0.1 mg base to about Eq 150mg base with respect to total weight of the pharmaceutical composition.

The term “salt thereof” or "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counter ions.

The examples of nintedanib salt include but not limited as, examples of physiologically acceptable salts include particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid, ethanesulfonic acid (esylic acid) or methanesulphonic acid. Physiologically acceptable salts of a nitrogen atom or an amino group include (a) acid addition salts formed with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acids, phosphoric acid, nitric acid and the like; (b) salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, ethanesulfonic acid (esylic acid), methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine and the like; and (c) salts formed from elemental anions for example, chlorine, bromine, and iodine. Physiologically acceptable salts of a compound of a hydroxy group include the anion of said compound in combination with a suitable cation such as Na+, NR4+ or the like.

The term “composition”, as in sublingual composition, is intended to encompass a drug product comprising nintedanib or salts thereof, and other inert ingredient(s) (pharmaceutically acceptable excipients). The term “composition” is synonymous with "formulation" and "dosage form".

The term “sublingual composition” as used herein, refers to a composition selected from but not limited to sublingual tablet, sublingual spray, sublingual granule, sublingual powder, sublingual disc, sublingual film/ strip, buccal tablet, buccal film/strip, or mucoadhesive film/strip, or the like.

The term “sublingual administration” as used herein, according to present invention refers to a composition intended for placement of the drug under the tongue, within the oral mucosal environment and drug reaches directly in to the blood stream through the ventral surface of the tongue and floor of the mouth. The drug solutes are rapidly absorbed into the reticulated vein which lies underneath the oral mucosa, and transported through the facial veins, internal jugular vein.

The term "treating" or "treatment" refers to obtaining desired pharmacological and/or physiological effect. The effect can be therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially
or totally reducing the extent of the disease, disorder or syndrome; ameliorating or
improving a clinical symptom or indicator associated with the disorder or delaying, inhibiting or decreasing the likelihood of the progression of the disease,
disorder or syndrome.

In one embodiment, an invention provides a sublingual composition comprising nintedanib or salts thereof.

In another embodiment, a sublingual composition of the present invention may contain one or more pharmaceutically acceptable excipients.

The one or more pharmaceutically acceptable excipient according to present invention may be selected from the group consisting of diluents, disintegrants, binders, solubilizing agent, surfactant, absorption enhancer, bioadhesive agents or mucoadhesion promoting agent, polymers or release modifying agent, carriers, plasticiser, penetration enhancer, bases, lubricant, glidant, acidic agent, basic agent, chelators, sweeteners, flavoring agent, pH regulating agent, preservatives, antioxidants, coloring agents, solvents, taste masking agent, antifoaming agents, flow agents and opacifiers, antiadherent, stabilizing agent, antistatic agent, viscosity adjuster and coating agent.

The examples of diluent or filler according to present invention include but not limited to group comprising of citric acid, mannitol, microcrystalline cellulose, carboxymethyl cellulose (carmellose), sodium carboxymethyl cellulose (carmellose sodium), corn starch, potato stach, anhydrous lactose, lactose monohydrate and the mixtures thereof. Preferably the diluents are selected from citric acid and mannitol or combination thereof.

The diluents according to present invention may be present in an amount from about 10% to about 95% by weight with respect to total weight of the pharmaceutical composition, preferably 30% to 90% w/w.

The examples of disintegrants according to present invention include but not limited to group comprising of croscarmellose sodium, croscarmellose potassium, carboxymethyl cellulose, chitosan, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, starch, sodium starch glycolate, light anhydrous silicic acid, low substituted hydroxypropylcellulose, lactose, sucrose, starch, silicified microcrystalline cellulose, polarcilin potassium, crosslinked polyvinylpyrrolidone, ethyl hydroxyethyl cellulose, modified cellulose gum; moderately cross-linked starch, modified starch, hydroxylpropyl starch and pregelatinized starch; calcium alginate, sodium alginate, alginic acid, chitosan, colloidal silicon dioxide, docusate sodium, guar gum, agar, locust bean, karaya, pectin and tragacanth, magnesium aluminium silicate, polyvinylpyrrolidone or mixture thereof.

The disintegrants according to present invention may be present in an amount from about 1%-15% by weight with respect to total weight of the pharmaceutical composition.

The examples of binders according to present invention include but not limited to group comprising of microcrystalline cellulose, alginic acid, potato starch, corn starch, wheat starch, ethyl cellulose, gelatin, cellulose-based polymers like methylcellulose, ethylcellulose, hydroxylated derivatives, hydroxyethyl cellulose, carboxymethyl cellulose sodium, hydroxymethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, dihydroxy propylcellulose, hypromellose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetosuccinate, acrylic polymers and polyethylene glycols, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone, copovidone, sodium starch glycolate, starch, trehalose, flurane, sucrose, D-mannitol, sodium alginate, cellulose gum, pregelatinized starch, guar gum, pullulan, gum arabic, bentonites, sugars, invert sugars, polyvinyl pyrrolidone, polyacrylamides, polyvinyloxoazolidone, polyvinyl alcohols, or mixture thereof.

The examples of solubilizing agents or solubility enhancer according to present invention include but not limited to group comprising of cyclodextrin and/or its derivatives, 2-Hydroxypropyl-beta-cyclodextrin (Kleptose), polyethylene glycol, polyvinylpyrrolidone, dextran, sugars such as sucrose, lactose or dextrose, mannitol, sorbitol or lactitol, sodium chloride or mixture thereof.

The solubilizing agents or solubility enhancer according to present invention may be present in an amount from about 1% to about 40% by weight with respect to total weight of the pharmaceutical composition, preferably 5-35% w/w.

The examples of surfactants according to present invention include but not limited to group comprising of cationic, anionic, nonionic or amphoteric agents, polysorbate, sodium lauryl sulphate, polyoxyethylene, polyoxypropylene glycol, the monooleate, the monolaurate, the monopalmitate, the monostearate, the trioleate, the tristearate or any other ester of polyoxyethylenated sorbitan, glycerides of polyoxyethylenated fatty acids, poloxamers, ethylene oxide/propylene oxide block copolymers, lecithin, stearyl alcohol, cetearyl alcohol, cholesterol, polyoxyethylenated castor oil, fatty alcohol polyoxyethylenated ethers, and polyoxyethylenated stearates, cetyl alcohol, spans and tweens, ethoxylated oils, including ethoxylated castor oils, such as cremophor or mixture thereof.

The examples of absorption enhancer according to present invention include but not limited to group comprising of sodium lauryl sulphate, sodium caprate or chitosans, and also P-glycoprotein (P-gp) inhibitors, such as polysorbates, sorbitan esters, poloxamer block copolymers, PEG-35 castor oil, PEG-40 hydrogenated castor oil, caprylocaproyl macrogol-8 glycerides, PEG-8 caprylic/capric glycerides, dioctyl sulfosuccinate, polyethylene lauryl ether, ethoxydiglycol, propylene glycol mono-di-caprylate, glycerol monocaprylate, glyceryl fatty acids (C8-C18) ethoxylated, oleic acid, linoleic acid, glyceryl caprylate/caprate, glyceryl monooleate, glyceryl monolaurate, caprylic/capric triglycerides, ethoxylated nonylphenols, PEG-(8-50) stearates, olive oil PEG-6 esters, triolein PEG-6 esters, lecithin, d-alpha tocopheryl polyethylene glycol 1000 succinate, polycarbonate, sodium glycocholate, sodium taurocholate, cyclodextrins, citric acid, sodium citrate, triacetin, combinations thereof or the like.

The examples of bioadhesive agents or mucoadhesion promoting agents according to present invention include but not limited to group comprising of carbomers, sodium carboxymethylcellulose, sodium alginate, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, gelatine, guar gum, polyethylene oxide, and dextran, carbopol 934 P, methocel, polycarbophil, sodium hyaluronate and other natural or synthetic bioadhesives, cellulose derivatives such as modified cellulose gum and, more particularly, methyl cellulose, ethyl hydroxyethyl cellulose, carboxymethyl cellulose, starch derivatives such as modified starch, sodium starch glycolate and, more particularly, moderately cross-linked starch; acrylic polymers, polyvinylpyrrolidone; polyethylene oxide (PEO), chitosan (poly-(D-glucosamine); natural polymers such as gelatin, sodium alginate, pectin; scleroglucan; xanthan gum; poly co-(methylvinyl ether/maleic anhydride); and crosscarmellose (e.g. crosscarmellose sodium) or mixture thereof.

The examples of polymers or release modifying agent according to present invention include but not limited to water-soluble, water-insoluble and/or biodegradable polymers or combination thereof.

Water soluble polymers according to present invention include but are not limited to group comprising of polyethylene oxide (PEO), pullulan, water-soluble derivatives of cellulose: alkylcelluloses hydroxyalkylcelluloses and hydroxyalkylalkylcelluloses, such as methylcelulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, cellulose esters and hydroxyalkylcellulose esters such as cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose (HPMC), carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters such as carboxymethylcellulose and their alkali metal salts, polyethylene glycol, polydextrose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, poloxamers, sodium alginate, propylene glycol alginate, carrageenan, polyethylene glycol, polysaccharide and glycoprotein-based gums such as, pectin, locust bean gum, sodium alginate, xanthan gum, tragancanth gum, gellan gum, guar gum, acacia gum, arabic gum, polyacrylic acid, carbomer, dextran, poloxamer polymers, acrylic acid polymers and copolymers, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, ethyl methacrylate and alkyl acrylate, carboxyvinyl copolymers, starch, gelatin, polyacrylic acids and polyacrylic acid esters, polymethacrylic acids and polymethacrylic acid esters, polyvinylacetates, polyvinylalcohols, polyvinylacetatephthalates (PVAP), PVY/vinyl acetate copolymer, and polycrotonic acids; also suitable are phthalated gelatin, gelatin succinate, crosslinked gelatin, shellac, water-soluble chemical derivatives of starch, cationically modified acrylates and methacrylates or combinations thereof.

Water insoluble polymers according to present invention include, but are not limited to group comprising of ethyl cellulose, carboxymethylcellulose, cellulose acetate, nitrocellulose, hydroxypropyl ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, acrylic polymers, acrylic resin material, vinyl acetate, sodium sulphonated polyesters, carboxylated acrylics, trimethylpentanediol/adipic acid/glycerin cross polymer, polyglycerol-2-diisostearate/IPDI copolymer, carboxylated vinyl acetate copolymer, vinylpyrrolicone/vinyl acetate/alkylaminoacrylate terpolymers, vinylpyrrolidone/vinyl acetate copolymer, polyoxyethylene/polyoxypropylene polymers, copolymers or block copolymers, carbamer, Polyamines include homo and copolymers of dimethylaminoethyl-acrylate, dimethylaminoethyl-methacrylate, dimethylaminopropyl-acrylate, dimethylaminpropyl-methacrylate, or other similar amino-functionalized acrylate, chitosan or partially hydrolyzed chitin in a substantially basic form, homo and co polymers of polyethyleimine, polylysine, polyvinylimidazole, or polyvinylamine, waxes or combinations thereof.

Biodegradable polymers according to present invention include but not limited to group comprising of poly(glycolic acid) (PGA), poly(lactic acid) (PLA), polydioxanes, polyoxalates, poly(a-esters), polyanhydrides, polyacetates, polycaprolactones, poly(orthoesters), polyamino acids, polyaminocarbonates, polyurethanes, polycarbonates, polyamides, poly(alkyl cyanoacrylates), and mixtures and copolymers thereof. Additional useful polymers include, stereopolymers of L- and D-lactic acid, copolymers of bis(p-carboxyphenoxy) propane acid and sebacic acid, sebacic acid copolymers, copolymers of caprolactone, poly(lactic acid)/poly(glycolic acid)/polyethyleneglycol copolymers, copolymers of polyurethane and (poly(lactic acid), copolymers of polyurethane and poly(lactic acid), copolymers of a-amino acids, copolymers of a-amino acids and caproic acid, copolymers of a-benzyl glutamate and polyethylene glycol, copolymers of succinate and poly(glycols), polyphosphazene, polyhydroxy-alkanoates or mixtures thereof.

The examples of carriers according to present invention include but not limited to group comprising of mannitol, carbohydrates, e.g., sugars, such as lactose, and sugar alcohols, such as mannitol, sorbitol and xylitol; pharmaceutically-acceptable inorganic salts, such as sodium chloride. Water soluble carrier particles (poly)saccharides like hydrolysed dextran, dextrin, alginates and may also comprise the weakly acidic, and/or weakly acidic buffer forming materials such as citric acid and/or sodium citrate, insoluble or sparingly soluble in water, such as dicalcium phosphate anhydrate, dicalcium phosphate dihydrate, tricalcium phosphate, calcium carbonate, and barium sulphate; starch and pre-gelatinised starch; bioadhesive and mucoadhesive materials, such as polyvinylalcohol, polyvinylpyrrolidine, crosslinked polyvinylpyrrolidone and croscarmellose sodium and other polymers, such as microcrystalline cellulose, hydroxypropyl cellulose, water, buffer, saline, buffered saline, dextrose solution, propylene glycol, polyethylene glycols, miglyol or mixtures thereof.

The examples of plasticizers according to present invention include but not limited to group comprising of 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, fatty acid esters, such as glyceryl oleate, polyalcohols, sorbitan esters, citric acid esters, polyvinyl alcohol, polyvinyl methyl ether, triacetin; mannitol, xylitol, and sorbitol or mixtures thereof.

The examples of penetration enhancers according to present invention include but not limited to group comprising of bile salts, such as sodium cholate, sodium glycocholate, sodium glycodeoxycholate, taurodeoxycholate, sodium deoxycholate, sodium lithocholate chenocholate, chenodeoxycholate, ursocholate, ursodeoxy-cholate, hyodeoxycholate, dehydrocholate, glycochenocholate, taurochenocholate, and taurochenodeoxycholate; sodium dodecyl sulfate (SDS), dimethyl sulfoxide (DMSO), N-lauroyl sacrcosine, sorbitan monolaurate, stearyl methacrylate, N-dodecylazacycloheptan-2-one, N-dodecyl-2-pyrrolidinone, N-dodecyl-2-piperidinone, 2-(1-nonyl)-1,3-dioxolane, N-(2-methoxymethyl)dodecylamine, N-dodecylethanolamine, N-dodecyl-N-(2-methoxymethyl)acetamide, 1-N-dodecyl-2-pyrrolidone-5-carboxylic acid, 2-pentyl-2-oxo-pyrrolidineacetic acid, 2-dodecyl-2-oxo-1-pyrrolidineacetic acid, 2-dodecyl-2-oxo-1-pyrrolidineacetic acid, 1-azacylioheptan-2-one-dodecylacetic acid, menthol, propylene glycol, glycerol monostearate, sorbitol monolaurate, glycerol dilaurate, tocopherol acetate, phosphatidyl choline, glycerol, polyethyleneglycol, monoglycerides, diglycerides, triglycerides, lecithin, tween surfactants, sorbitan surfactants, sodium lauryl sulfate; salts and other derivatives of saturated and unsaturated fatty acids, surfactants, bile salt analogs, derivatives of bile salts, inclusion compounds, such as cyclodextrins and caged molecules; coloring agents; and flavors, cyclodextrin derivatives like hydroxypropyl, hydroxyethyl, glucosyl, maltosyl, ß-cyclodextrin maltotriosyl derivatives, ?-cyclodextrin maltotriosyl derivatives or mixtures thereof.

The examples of bases according to present invention include but not limited to group comprising of hydrophilic bases include, for example, polyethylene glycol, polyvinylpyrrolidone, D-mannitol, D-sorbitol, xylitol, lactose, white sugar, maltose anhydrous, D-fructose, dextran, glucose, polyoxyethylene curing It may be at least one selected from the group consisting of castor oil, polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitan higher fatty acid ester, citric acid, tartaric acid, glycine, ß-alanine, lysine hydrochloride and meglumine or mixture thereof.

The examples of lubricant according to present invention include but not limited to group comprising of calcium stearate, magnesium stearate, Sodium stearyl fumarate, fumaric acid, calcium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, colloidal silica, sucrose fatty acid esters, stearic acid, zinc stearate, hydrogenated vegetable oil, mineral oil, glyceryl behenate, polyoxyethylene glycols, sodium benzoate, dimethicone or liquid paraffin, or mixture thereof.

The lubricant according to present invention may be present in an amount from about 0.1% to about 10% by weight with respect to total weight of the pharmaceutical composition, preferably 0.1-5% w/w.

The examples of glidant according to present invention include but not limited to group comprising of colloidal silica, pyrogenic silica, hydrated sodium silicoaluminate, magnesium stearate, sodium stearyl fumarate, fumed silica (colloidal silicon dioxide), starch, talc, calcium phosphate tribasic, powdered cellulose, magnesium oxide; magnesium silicate, magnesium trisilicate, stearic acid, calcium stearate or mixture thereof.

The examples of acidic agents or acidifying agents according to present invention include but not limited to group comprising of citric acid maleic acid, tartaric acid, fumaric acid, adipic acid, succinic acid, lactic acid, glycolic acid, alpha-hydroxy acids, ascorbic acid and amino acids, anhydrides, salts and derivatives of these acids or mixture thereof.

The acidic agents or acidifying agents according to present invention may be present in an amount from about 1% to about 40% by weight with respect to total weight of the pharmaceutical composition.

The examples of basic agents according to present invention include but not limited to group comprising of potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, arginine carbonate, glycine carbonate or lithium carbonate, calcium carbonate, ammonium carbonate, L-lysine carbonate, sodium glycine carbonate, sodium carbonates of amino acids, anhydrous sodium perborate, effervescent perborate, sodium perborate monohydrate, sodium percarbonate, sodium dichloroisocyanurate, sodium hypochlorite, calcium hypochlorite, tris, tartrate, acetate, phosphate or mixture thereof.

The examples of chelators according to present invention include but not limited to group comprising of ethylene diamine tetra acetic acid (EDTA), proteins, polysaccharides, polynucleic acids, glutamic acid, histidine, organic diacids, polypeptides, phytochelatin, hemoglobin, chlorophyll, humic acid, phosphonates, transferrin, desferrioxamine, and combinations thereof.

The examples of sweeteners according to present invention include but not limited to group comprising of dipotassium glycyrrhizinate, aspartame, stevia, thaumatin, saccharose, glucose, maltose, galactose, and artificial sweeteners, such as acesulfame potassium, sodium saccharin, cyclamates, sucralose, sodium saccharinate, neohesperidine dihydrochalcone, monoammonium glycyrrhizinate, Thaumatic, dextrose, invert sugar, fructose, Stevia Rebaudiana (Stevioside); sugar alcohols such as sorbitol, mannitol, xylitol, and the like. Also contemplated are hydrogenated starch hydrolysates and the synthetic sweetener Acesulfame, particularly the potassium salt (acesulfame-K), and sodium and calcium salts thereof, and natural intensive sweeteners, or mixture thereof.

The examples of flavoring agent according to present invention include but not limited to group comprising of fruit flavor, peppermint flavor, lemon, lemon-lime, orange, sour cherry, flavor of mint, honey lemon, vanilla, citrus oil, grapefruit grape, menthol, cranberry, vanilla berry, bubble gum, cherry, alpha-citral, beta-citral, decanal, aldehyde C-8, aldehyde C-9, aldehyde C-12, and volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof. mint oils, cocoa, and citrus oils such as lemon, orange, grape, lime, cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leave oil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil, grapefruit and fruit essences including apple, pear, peach, strawberry, raspberry, plum, pineapple, apricot or other fruit flavors or mixture thereof.

The examples of pH regulating agent according to present invention include but not limited to group comprising of hydrochloric acid, fumarate, citrate, phosphate, carbonate, tartrate, acetate, amino acid, citric acid and sodium citrate or potassium citrate, sodium hydroxide, monoethanolamine, diethanolamine, sodium bicarbonate or potassium bicarbonate, sodium phosphate, tartaric acid, propionic acid, lactic acid, maleic acid, succinic acid, phosphoric acid, boric acid, succinic acid/monosodium succinate, glycine/sodium glycine, malic acid/sodium malate, phosphoric acid/sodium phosphate, fumaric acid/sodium fumarate, monosodium phosphate/disodium phosphate, and boric acid/sodium borate and monosodium glutamate or mixture thereof.

The examples of the preservatives according to present invention include but not limited to group comprising of phenethyl alcohol, benzyl alcohol, p-hydroxybenzoate esters, chlorobutanol, dehydroacetic acid, sorbic acid or mixtures thereof.

The examples of the antioxidants according to present invention include but not limited to group comprising of butylated hydroxytoluene (BHT), hydrogen sulfite, ascorbic acid, sodium ascorbate, erythorbic acid, sodium nitrite, propyl gallate (PG), butylhydroxyanisol (BHA), sodium bisulfite, sodium pyrosulfite, citric acid, and edetate sodium, Sodium bicarbonate, sodium citrate, sodium citrate, sodium metabisulfate, sodium tartrate, sodium sulphite, sodium metabisulphite, Sodium sulfate, potassium metabisulphite, potassium, bisulphite, potassium sulphite, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazole, thiols (e.g., aurothioglucose, dihydrolipoic acid, propylthiouracil, thioredoxin, glutathione, glutathione peroxidase or peroxidase catalase, cysteine, cystine, cystamine, thiodipropionic acid), sulphoximines (e.g., buthionine-sulphoximines, homo-cysteine-sulphoximine, buthionine-sulphones, and penta-, hexa- and heptathionine-sulphoximine), metal chelators (e.g, .alpha.-hydroxy-fatty acids, palmitic acid, phytic acid, lactoferrin, lactic acid, and malic acid, humic acid, bile acid, bile extracts, bilirubin, biliverdin, EDTA, EGTA, and DTPA), vitamins (e.g., vitamin E, vitamin C, ascorbyl palmitate, Mg ascorbyl phosphate, and ascorbyl acetate), phenols (e.g., butylhydroxytoluene, butylhydroxyanisole, ubiquinol, nordihydroguaiaretic acid, trihydroxybutyrophenone), benzoates (e.g. coniferyl benzoate), uric acid, mannose, selenium (e.g., selenium-methionine), stilbenes (e.g. stilbene oxide and trans-stilbene oxide), superoxide dismutase (SOD) or mixtures thereof.

The examples of the coloring agents according to present invention include but not limited to group comprising of carmine, caramel, ß-carotene, titanium oxide, talc, riboflavin sodium phosphate, hydrogenated starch hydrolysate, food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C). These colors are dyes, their corresponding lakes, and certain natural and derived colorants, yellow aluminum lake natural pigments (examples: beta-carotene, chlorophyll, and colcothar), water-insoluble lake pigments (examples: aluminum salts of the above water-soluble edible tar pigments), water-soluble edible tar pigments (examples: edible pigments such as food red No. 2, food red No. 3, food yellow No: 4, food yellow No. 5, food blue No. 1, and food blue No. 2), blue lake, titanium dioxide, natural coloring agents such as grape skin extract, beet red powder, annato, carmine, turmeric, paprika or mixtures thereof.

The examples of solvents according to present invention include but not limited to group comprising of aqueous or inert organic solvents or inorganic acids, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic solvents, aromatic solvents, heterocyclic solvents, and mixtures thereof. Typical solvents include acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl ethyl ketone, methylene chloride, methyl propyl ketone, n-hexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride, carbon tetrachloride, nitroethane, nitropropane, tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane, cyclooctane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diglyme, water, hydrochloric acid (HCl), aqueous solvents containing inorganic salts (such as sodium chloride, calcium chloride, and the like), and mixtures thereof (such as acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol, and ethylene dichloride and methanol) or mixture thereof.

The examples of taste masking agent according to present invention include but not limited to group comprising of ionic exchange resins including a water-insoluble organic or inorganic matrix material having covalently bound functional groups that are ionic or capable of being ionized under appropriate conditions. The organic matrix may be synthetic (e.g., polymers or copolymers or acrylic acid, methacrylic acid, sulfonated styrene or sulfonated divinylbenzene) or partially synthetic (e.g., modified cellulose or dextrans). The inorganic matrix may be, for example, silica gel modified by the addition of ionic groups. Most ion exchange resins are cross-linked by a crosslinking agent, such as divinylbenzene, sodium bicarbonate, cyclodextrin inclusion compounds, adsorbates or mixture thereof.

The examples of anti-foaming agents according to present invention include but not limited to group comprising of certain alcohols (cetostearyl alcohol), insoluble oils (castor oil), stearates, polydimethylsiloxanes and other silicones derivatives, ether and glycols or mixture thereof.

The examples of flow agents and opacifiers according to present invention include but not limited to group comprising of such as the oxides of magnesium, aluminum, silicon, titanium or mixture thereof

The examples of antiadherent according to present invention include but not limited to group comprising of talc, corn starch, colloidal silica, DL-leucine, sodium lauryl sulphate, stearates or mixture thereof.

The examples of stabilizing agent according to present invention include but not limited to group comprising of tocopherol, cyclodextrin tetrasodium edetate, nicotinamide, thermo-setting gels such as pectin, carageenan, and gelatin, yellow ferric oxide, red ferric oxide, black iron oxide or mixture thereof.

The examples of antistatic agents according to present invention include but not limited to group comprising of micronized or nonmicronized talc, colloidal silica, treated silica or precipitated silica or mixtures thereof.

The examples of viscosity adjusters according to present invention include but not limited to group comprising of alginate, carrageenan, hydroxypropyl methyl cellulose, locust bean gum, guar gum, xanthan gum, dextran, gum arabic, gellan gum or mixtures thereof.

The examples of coating agents according to present invention include but not limited to a film coating agent or the like. for example, an opadry film coating agents or film coating agent known in the prior art for sublingual dosage form.

In another aspect of the present invention is to provide process of manufacturing sublingual compositions of nintedanib or salt thereof along with one or more pharmaceutically acceptable excipient. The process like solvent casting, solvent evaporation, hot-melt extrusion, semisolid casting method, rolling method may be used in the preparation of sublingual film. The process like direct compression, dry granulation, wet granulation, spray granulation, extrusion-spheronization may be used in the preparation of sublingual tablet.

The concentration of nintedanib or salt thereof and process of manufacturing has been optimized in view of the need in the treatment of idiopathic pulmonary fibrosis, chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype, systemic sclerosis-associated interstitial lung disease and cancer.

The sublingual composition of nintedanib or salt thereof in the treatment of idiopathic pulmonary fibrosis, chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype, systemic sclerosis-associated interstitial lung disease and cancer according to present invention are placed under the tongue and nintedanib or salt thereof reaches directly into the blood stream through the ventral surface of the tongue and floor of the mouth. The nintedanib solutes are rapidly absorbed into the reticulated vein which lies underneath the oral mucosa, and transported through the facial veins, internal jugular vein, and braciocephalic vein and then drained into systemic circulation. Therefore, sublingual composition of nintedanib or salt thereof according to present invention prevents the degradation of Nintedanib in to the gastrointestinal tract (GIT), liver i.e. bypasses the first pass metabolism and desired therapeutic level of nintedanib is reached in the blood circulation which is required in the treatment of idiopathic pulmonary fibrosis, chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype, systemic sclerosis-associated interstitial lung disease and cancer.

The sublingual composition of nintedanib or salt thereof according to present invention provide immediate onset of action, better ease of self-administration without pain and without help of trained medical professional; therefore, provides better patient compliance in the treatment of idiopathic pulmonary fibrosis, chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype and cancer.

The sublingual or buccal composition of nintedanib or salt thereof according to present invention may be evaluated for the parameters like dissolution data, weight variation, rug content, hardness, friability, disintegration time, wetting time, thickness, tensile strength, folding endurance, surface pH, and swelling index.

The sublingual composition of nintedanib or salt thereof according to present invention can be packaged in suitable air-tight containers and moisture proof packs. Packaging may include but not limited to high density polyethylene bottle, aluminum blister package. The container material or packaging material of the present invention does not affect the quality of the preparation or does not allow diffusion of any kind into or across the material of the container into the preparation.

In another embodiment, an invention provides a sublingual composition comprising:
a) Nintedanib or salt thereof; and
b) optionally other suitable pharmaceutically acceptable excipients.

In another embodiment, an invention provides a sublingual composition comprising:
a) Nintedanib or salt thereof;
b) At least one diluent; and
c) Optionally other suitable pharmaceutically acceptable excipients.

In another embodiment, an invention provides a sublingual composition comprising:
a) 0.1-60% w/w of Nintedanib or salt thereof;
b) 30-90% w/w of diluent;
c) 1%-40% w/w of acidifying agents;
d) 5-35% w/w of solubility enhancer;
e) 0.1-5% w/w of lubricant; and
f) Optionally 1%-15% w/w of disintegrant.

In another embodiment, an invention provides a sublingual tablet composition comprising:
a) 0.1-60% w/w of Nintedanib or salt thereof;
b) 30-90% w/w of diluent;
c) 1%-40% w/w of acidifying agents;
d) 5-35% w/w of solubility enhancer;
e) 0.1-5% w/w of lubricant; and
f) Optionally 1%-15% w/w of disintegrant; and
Wherein the sublingual tablet composition is optionally coated.

In another embodiment, an invention provides process for the preparation of a sublingual composition comprising nintedanib or salt thereof which comprises steps of:
a) Co-sifting and mixing one or more diluents into suitable vessel;
b) Preparing binder solution;
c) Adding nintedanib or salt thereof to the binder solution obtained in step (b);
d) Granulating mixture of step (a) with binder solution obtained in step (c);
e) Drying granules obtained in step (d);
f) Optionally blending dried granules of step (e) with disintegrant;
g) Lubricating dried granules obtained in step (e) or (f);
h) Optionally Compressing lubricated blend obtained in step (g) to get sublingual tablet dosage form; and
i) Optionally coating the sublingual tablet dosage form obtained in step (g).

In another embodiment, an invention provides sublingual compositions of nintedanib or salt thereof for the treatment of idiopathic pulmonary fibrosis, chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype, systemic sclerosis-associated interstitial lung disease and cancer.

EXAMPLES:
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.

Example: 1: Wet granulation approach.
Sr. No Ingredient Weight (%)
Dry Mix
1 Citric acid 20-45
2 Mannitol (Pearlitol 200SD) 20-45
Binder Preparation
3 Nintedanib esylate 5-40
4 2-Hydroxypropyl-beta-cyclodextrin (Kleptose) 1-30
5 Tartaric acid 1-30
6 0.1N HCL solution q.s.
Lubrication
7 Magnesium stearate 0.5-5

Manufacturing Process:
1. All raw materials were dispensed accurately;
2. Citric acid and mannitol (Pearlitol) co-sifted through sieve no.20#;
3. Binder solution: 0.1N HCL solution was taken and 2-Hydroxypropyl-beta-cyclodextrin (Kleptose) was added to it and stirred well, tartaric acid was added to it and stirred until it dissolves completely. Solution was heated up to 50-60°C and API Nintedanib esylate was added to it and stirred well, it forms clear orange-yellow solution;
4. Co-sifted citric acid and mannitol (Pearlitol) loaded into Fluidized Bed processing (FBP) machine;
5. Spraying was done using sprays;
6. Drying was done in FBP, Loss on Drying (LOD) was checked;
7. Material from FBP unloaded and passed through sieve no.20#;
8. Magnesium stearate was sifted through sieve no.60# and lubricated with dried granules; and
9. Blend was compressed using 6.5mm round shape punch.

Dissolution data: 0.1N HCl solution, 900mL, Paddle, 100 rpm
Time (min) Drug release (%)
5 97
10 106
15 106
20 104
30 104
45 102
60 100

Example: 2: Wet granulation approach.
Sr. No Ingredient Weight (%)
Dry Mix
1 Citric acid 40-70
Binder Preparation
2 Nintedanib esylate 5-40
3 2-Hydroxypropyl-beta-cyclodextrin (Kleptose) 1-30
4 Tartaric acid 1-30
5 0.1N HCL solution q.s.
Lubrication
6 Magnesium stearate 0.5 - 5

Manufacturing Process:
1. All raw materials were dispensed accurately;
2. Citric acid sifted through sieve no.20#;
3. Binder solution: 0.1N HCL solution was taken and 2-Hydroxypropyl-beta-cyclodextrin (Kleptose) was added to it and stirred well, tartaric acid was added to it and stirred until it dissolves completely. Solution was heated up to 50-60°C and API Nintedanib esylate was added to it and stirred well, it forms clear orange-yellow solution;
4. Sifted citric acid loaded into Fluidized Bed processing (FBP) machine;
5. Spraying was done using sprays;
6. Drying was done in FBP, Loss on Drying (LOD) was checked;
7. Material from FBP unloaded and passed through sieve no.20#;
8. Magnesium stearate was sifted through sieve no.60# and lubricated with dried granules;
9. Blend was compressed using 6.5mm round shape punch.

Dissolution data: 0.1N HCl, 900mL, Paddle, 100rpm
Time (min) Drug Release (%)
5 86
10 97
15 96
20 96
30 94
45 94
60 92

Example: 3: Wet granulation approach.
Sr No. Ingredient Weight (%)
Dry Mix
1 Citric Acid 20-45
2 Mannitol (Pearlitol 200SD) 20-45
Binder Preparation
3 Nintedanib esylate 5-40
4 2-Hydroxypropyl-beta-cyclodextrin (Kleptose) 1-30
5 Tartaric acid 1-30
6 0.1N HCl solution q.s.
Pre-lubrication
7 Sodium starch glycolate 1-15
Lubrication
8 Magnesium stearate 0.5 - 7

Manufacturing Process:
1. All raw materials were dispensed accurately;
2. Citric acid and Mannitol (Peralitol) co- sifted through sieve no.20#;
3. Binder solution: 0.1N HCL solution was taken and 2-Hydroxypropyl-beta-cyclodextrin (Kleptose) was added to it and stirred well, tartaric acid was added to it and stirred until it dissolves completely. Solution was heated up to 50-60°C and API Nintedanib esylate was added to it and stirred well, it forms clear orange-yellow solution;
4. Co-Sifted citric acid and Mannitol (Peralitol) loaded into Fluidized Bed processing (FBP) machine;
5. Spraying was done using sprays;
6. Drying was done in FBP, Loss on Drying (LOD) was checked;
7. Material from FBP unloaded and passed through sieve no.20#; and
8. Sodium Starch glycolate was sifted through sieve no.40# and blended with dried granules;
9. Magnesium stearate was sifted through sieve no.60# and lubricated with above blend; and
10. Blend was compressed using 6.5mm round shape punch.
Dissolution data: 0.1N HCl, 900mL, Paddle, 100rpm

Example: 4: Wet granulation approach.
Sr. No Ingredient Weight (%)
Dry Mix
1 Citric Acid 30-70
Binder Preparation
2 Nintedanib esylate 5-40
3 2-Hydroxypropyl-beta-cyclodextrin (Kleptose) 1-30
4 Tartaric acid 1-30
5 0.1N HCL solution q.s.
Pre-lubrication
6 Sodium starch glycolate 1-15
Lubrication
7 Magnesium stearate 0.5-7

Manufacturing Process:
1. All raw materials were dispensed accurately;
2. Citric acid sifted through sieve no.20#;
3. Binder solution: 0.1N HCL solution was taken and 2-Hydroxypropyl-beta-cyclodextrin (Kleptose) was added to it and stirred well, tartaric acid was added to it and stirred until it dissolves completely. Solution was heated up to 50-60°C and API Nintedanib esylate was added to it and stirred well, it forms clear orange-yellow solution;
4. Sifted citric acid loaded into Fluidized Bed Processing (FBP) machine;
5. Spraying was done using sprays;
6. Drying was done in FBP, Loss on Drying (LOD) was checked;
7. Material from FBP unloaded and passed through sieve no.20#;
8. Sodium Starch glycolate was sifted through sieve no.40# and blended with above blend;
9. Magnesium stearate was sifted through sieve no.60# and lubricated with dried granules;
10. Blend was compressed using 6.5mm round shape punch.

Dissolution data: 0.1N HCl, 900mL, paddle, 100rpm.
Time (Min) Drug Release (%)
5 42
10 56
15 83
20 91
30 91
45 89
60 89

Example: 5: Wet granulation approach.
Sr. No Ingredient Weight (%)
Dry Mix
1 Mannitol (Pearlitol) 30-90
Binder Preparation
2 Nintedanib esylate 5-40
3 2-Hydroxypropyl-beta-cyclodextrin (Kleptose) 1-30
4 Tartaric acid 1-30
5 0.1N HCL solution q.s.
Lubrication
6 Magnesium stearate 0.5-7

Manufacturing Process:
1. All raw materials were dispensed accurately;
2. Pearlitol sifted through sieve no.20#;
3. Binder solution: 0.1N HCL solution was taken and 2-Hydroxypropyl-beta-cyclodextrin (Kleptose) was added to it and stirred well, tartaric acid was added to it and stirred until it dissolves completely. Solution was heated up to 50-60°C and API Nintedanib esylate was added to it and stirred well, it forms clear orange-yellow solution;
4. Sifted Mannitol (Pearlitol) loaded into Fluidized Bed Processing (FBP) machine;
5. Spraying was done using bottom spray;
6. Drying was done in FBP, Loss on Drying (LOD) was checked;
7. Material from FBP unloaded and passed through sieve no.20#;
8. Magnesium stearate was sifted through sieve no.60# and lubricated with dried granules; and
9. Blend was compressed using 6.5mm round shape punch.

Dissolution data: 0.1N HCl solution, 900mL, 100rpm, paddle

Time(min) Drug release (%)
5 102
10 106
15 105
20 104
30 103
45 101
60 100
,CLAIMS:1. A sublingual composition, comprising:
a) Nintedanib or salt thereof; and
b) optionally, at least one pharmaceutically acceptable excipient.

2. The sublingual composition as claimed in claim 1, wherein the salt is nintedanib esylate and is used as an active pharmaceutical ingredient.

3. The sublingual composition as claimed in claim 1, wherein the nintedanib or salt thereof is present in an amount of from about 0.1% to about 60% by weight with respect to total weight of the pharmaceutical composition.

4. The sublingual composition as claimed in claim 1, wherein the pharmaceutically acceptable excipient is selected from a group consisting of diluents, disintegrants, binders, solubilizing agent, solubility enhancer, surfactant, absorption enhancer, bioadhesive agents or mucoadhesion promoting agent, polymers or release modifying agent, carriers, plasticiser, penetration enhancer, bases, lubricant, glidant, acidic agent or acidifying agent, basic agent, chelators, sweeteners, flavoring agent, pH regulating agent, preservatives, antioxidants, coloring agents, solvents, taste masking agent, anti-foaming agents, flow agents and opacifiers, anti-adherent, stabilizing agent, antistatic agent, viscosity adjuster and coating agent.

5. The sublingual composition as claimed in claim 1, comprising:
a) 0.1-60% w/w of nintedanib esylate;
b) 30-90% w/w of at least one diluent;
c) 1%-40% w/w of an acidifying agent;
d) 5-35% w/w of a solubility enhancer;
e) 0.1-5% w/w of a lubricant;
f) optionally, 1%-15% w/w of a disintegrant; and
g) a pharmaceutically acceptable solvent or a mixture of pharmaceutically acceptable solvents;
wherein said composition is optionally coated.

6. The sublingual composition as claimed in claim 1, wherein the sublingual composition is formulated into a sublingual dosage form selected from a group comprising of sublingual tablet, sublingual film, sublingual spray, sublingual granule, sublingual powder, and sublingual disc.

7. The sublingual composition as claimed in claim 1, wherein the sublingual composition is useful in treatment of idiopathic pulmonary fibrosis, chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype, systemic sclerosis-associated interstitial lung disease and cancer.

8. A process for preparation of a sublingual composition comprising nintedanib or salt thereof, comprises steps of:
a) Co-sifting and mixing one or more diluents into a suitable vessel;
b) Preparing a binder solution by mixing a solubility enhancer into solvent followed by stirring and adding an acidifying agent to it;
c) Adding nintedanib or salt thereof to the binder solution obtained in step (b);
d) Granulating the mixture of step (a) with the binder solution obtained in step (c);
e) Drying the granules obtained in step (d);
f) Optionally, blending the dried granules of step (e) with a disintegrant;
g) Lubricating the dried granules obtained in step (e) or (f);
h) Optionally, Compressing the lubricated blend obtained in step (g) to get a sublingual tablet dosage form; and
i) Optionally, coating the sublingual tablet dosage form obtained in step (h).

9. The process as claimed in claim 8, wherein the sublingual composition is useful in treatment of idiopathic pulmonary fibrosis, chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype, systemic sclerosis-associated interstitial lung disease and cancer.