Patent Application
20170049774
The present invention relates to sustained release oral pharmaceutical compositions of tofacitinib comprising tofacitinib, a release controlling polymer, and pharmaceutically acceptable excipients, wherein the sustained release oral pharmaceutical compositions further comprise an outer modified release coating that includes a modified release polymer. The invention also relates to a process for the preparation of the compositions.
Tofacitinib citrate is a Janus kinase inhibitor, which is chemically designated as (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-β-oxo-1-piperidinepropanenitrile, 2-hydroxy-1,2,3-propanetricarboxylate (1:1).
Processes for the preparation of tofacitinib are disclosed in U.S. Pat. Nos. RE41,783 and 7,301,023. A process for the preparation of tofacitinib citrate is disclosed in U.S. Pat. No. 6,965,027.
U.S. Publication No. 2013/0344149 discloses oral dosage forms comprising tofacitinib suitable for modified release.
Oral sustained release formulations of tofacitinib are also disclosed in U.S. Publication No. 2014/0271842. This application discloses once-daily oral formulations of tofacitinib with a shorter duration of release. The claimed pharmaceutical dosage forms of tofacitinib disclosed therein release more than 75% of the drug in 5 hours.
The present invention discloses alternate sustained release pharmaceutical compositions of tofacitinib.
The present invention relates to sustained release oral pharmaceutical compositions of tofacitinib comprising tofacitinib, a release controlling polymer, and pharmaceutically acceptable excipients, wherein the sustained release oral pharmaceutical compositions further comprise an outer modified release coating that includes a modified release polymer. The invention also relates to a process for the preparation of the compositions.
A first aspect of the present invention provides a sustained release oral pharmaceutical composition of tofacitinib comprising tofacitinib, a release controlling polymer, and pharmaceutically acceptable excipients, wherein the sustained release oral pharmaceutical composition further comprises an outer modified release coating.
According to a first embodiment of the above aspect, the composition comprises a core comprising tofacitinib, optionally a first coating over the core, and an outer modified release coating either over the core or over the first coating.
According to a first embodiment of the above aspect, the first coating comprises from about 5% by weight to about 20% by weight of the core weight, and the outer coating comprises from about 1% by weight to about 15% by weight either of the core weight or weight of the coated core coated with the first coating.
According to a second embodiment of the above aspect, the composition further comprises an acidifying agent or a surfactant or combinations thereof.
According to a third embodiment of the above aspect, the composition has an in-vitro release profile such that the pharmaceutical composition releases not more than 30% of the tofacitinib in 1 hour, not less than 35% and not more than 75% of tofacitinib in 2.5 hours and not less than 75% of tofacitinib in 5 hours.
According to a fourth embodiment of the above aspect, the composition has a release profile such that it releases less than 35% of the tofacitinib in 2.5 hours.
According to a fifth embodiment of the above aspect, the composition has a release profile such that it releases less than 75% of the tofacitinib in 5 hours.
According to a sixth embodiment of the above aspect, the composition comprises tofacitinib having a particle size distribution D90 value of about 30 μm or less, D50 value of about 20 μm or less, and D10 value of about 5 μm or less.
According to a seventh embodiment of the above aspect, the composition comprises tofacitinib having a particle size distribution D90 value of about 25 μm or less, D50 value of about 15 μm or less, and D10 value between about 0.1 μm and 5 μm.
According to an eighth embodiment of above aspect, the sustained release oral pharmaceutical composition is an osmotic tablet, wherein the osmotic tablet is in the form of a single core osmotic tablet or a bilayer osmotic tablet.
According to a first embodiment of the eighth embodiment above, the single core osmotic tablet comprises:
According to a second embodiment of the eighth embodiment, the bilayer osmotic tablet comprises:
According to a ninth embodiment of above aspect, the sustained release oral pharmaceutical composition is a sustained release matrix tablet.
According to a first embodiment of the ninth embodiment, the sustained release matrix tablet comprises:
According to a second embodiment of the ninth embodiment, the sustained release matrix tablet comprises:
According to a tenth embodiment of the above aspect, the sustained release oral pharmaceutical composition is a sustained release reservoir tablet.
According to a first embodiment of the tenth embodiment, the sustained release reservoir tablet comprises:
The term “pharmaceutical composition,” as used herein, may include tablets, capsules, granules, and the like.
The term “tofacitinib,” as used herein, refers to tofacitinib free base or pharmaceutically acceptable salts, in particular pharmaceutically acceptable acid addition salts, e.g., citrate, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, tartarate, succinate, malate, maleate, oxalate, fumarate, gluconate, saccharate, benzoate, methansulfonate, ethanesulfonate, benzenesulfonate, and the like. The preferred pharmaceutically acceptable salt is citrate salt.
The compositions of the present invention comprise an outer modified release coating. The modified release coating may comprise a modified release polymer. The modified release polymer may be a pH dependent polymer, such as those marketed under the brand name Eudragit®, or a copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate, such as those marketed under the brand names Eudragit® E PO, Eudragit® E 100, and Eudragit® E 12.5; a copolymer of methacrylic acid or methacrylic acid esters e.g., copolymer based on methacrylic acid and ethyl acrylate (Eudragit® L 100-55), copolymers based on methacrylic acid and methyl methacrylate (Eudragit® S 100). Preferably, Eudragit® E PO and Eudragit® L 100-55 are used.
The term “release controlling polymer,” as used herein, refers to polymers which control the release of a drug. Such polymers may be present in the core of a tablet which helps in releasing the drug by matrix erosion or in the coating over a core which helps in releasing the drug by osmotic pressure, or by diffusion of the drug through coating.
These polymers may be:
(i) water swellable or water soluble or erodible polymers; or
(ii) water insoluble or non-erodible polymers.
In a matrix core, water swellable or water soluble or erodible polymers are either swellable or dissolvable or erodible in pure water or requiring the presence of an acid or base to ionize the polymeric matrix sufficiently to cause erosion or dissolution. When contacted with an aqueous environment, the polymer imbibes water and forms an aqueous-swollen gel or matrix that entraps tofacitinib. The aqueous swollen matrix gradually erodes, swells, disintegrates, disperses, or dissolves in the environment of use, thereby controlling the release of tofacitinib.
The water swellable or water soluble or erodible polymers include polyethylene oxide, in particular polyethylene oxide water soluble resins (Polyox® WSR Coagulant and Polyox® WSR-303); glyceryl fatty acid esters, e.g., glyceryl behenate, glyceryl monostearate, glycerol distearate, glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, and glyceryl behenate; hydrogenated castor oil; cellulose derivatives, e.g., hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethylhydroxy ethylcellulose, methylethyl cellulose, carboxymethyl cellulose, and carboxymethyl ethylcellulose; pullulan; polyvinyl pyrrolidone; polyvinyl alcohol; and polyvinyl acetate. Preferably, the water swellable or water soluble or erodible polymers include polyethylene oxide water soluble resins, glyceryl behenate, hydroxyethyl cellulose, hydroxypropyl methylcellulose, and polyvinyl pyrrolidone.
Water insoluble or non-erodible polymers control the drug release by osmotic pressure or by diffusion. Suitable water insoluble or non-erodible polymers include copolymers of methacrylic acid or methacrylic acid esters; polyvinyl chloride; polyethylene; cellulose and cellulose derivatives, e.g., ethylcellulose, cellulose acetate, cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), and cellulose acetate succinate (CAS); polyvinyl polymers, e.g., polyvinyl alcohol phthalate, polyvinyl acetate phthalate, and polyvinyl butyl phthalate; polyvinyl acetate or polyvinyl acetate copolymers; crosslinked polyvinylpyrrolidone (also known as crospovidone); and fatty compounds, e.g., carnauba wax, microcrystalline wax, and triglycerides; and mixtures of one or more of these polymers.
The term “particle size distribution” as used herein is defined by one or more of D90 value, D50 value, or D10 value.
D90 value is defined as the particle diameter at which 90% of the particles have a diameter less than the diameter which corresponds to that D90 value. The D90 value of tofacitinib particles in the present invention is about 30 μm or less, in particular about 25 μm or less, in particular between about 15 μm and 25 μm.
D50 value, also known as median particle size, is defined as the particle diameter at which 50% of the particles have a diameter less than the diameter which corresponds to that D50 value. The D50 value of tofacitinib particles in the present invention is about 20 μm or less, in particular about 10 μm or less, in particular between about 1 μm and 10 μm.
D10 value is defined as the particle diameter at which 10% of the particles have a diameter less than the diameter which corresponds to that D10 value. The D10 value of tofacitinib particles in the present invention is about 5 μm or less, in particular between about 0.1 μm and 5 μm.
The term “pharmaceutically acceptable excipients,” as used herein, includes any physiologically inert additives that are routinely used in pharmaceutical dosage forms. Pharmaceutically acceptable excipients are selected from the group comprising diluents, binders, osmogens, acidifying agents, surfactants, disintegrants, lubricants, and glidants.
Suitable diluents are selected from the group comprising lactose, e.g., directly compressible lactose (Pharmatose® DCL11), lactose monohydrate, lactose anhydrous, and spray dried lactose; microcrystalline cellulose, e.g., microcrystalline PH 112, microcrystalline PH 101, and microcrystalline PH 102; sugar alcohols, e.g., sorbitol, erythritol, xylitol, and mannitol; sugars, e.g., sucrose, DiPac® (a directly compressible, co-crystallized sugar consisting of 97% sucrose and 3% maltodextrin), and starch, e.g., pregelatinized starch. Preferably, the diluents are directly compressible lactose (preferably Pharmatose® DCL11), microcrystalline cellulose, sorbitol, pregelatinized starch, and combinations thereof.
Water soluble diluents, e.g., directly compressible lactose and sorbitol, may also act as an osmotic agent.
Suitable binders are selected from the group comprising povidone, in particular PVP K30; copovidone; celluloses, e.g., hydroxypropyl methylcellulose, in particular, HPMC E-5; hydroxy ethylcellulose, hydroxypropyl cellulose, methylcellulose, and ethylcellulose; starch, e.g., pregelatinized starch and low density starch; microcrystalline cellulose; lactose; xanthan gum; gum acacia; sodium alginate; propylene glycol; polyvinyl alcohol; corn syrup; methacrylates; carboxyvinyl polymers, e.g., carbomers; and combinations thereof.
The term “osmogens” as used herein, are water-soluble compounds capable of imbibing water and thereby establishing an osmotic pressure gradient across the barrier of the surrounding coating. Suitable osmogens are selected from the group comprising salts, e.g., sodium chloride, magnesium chloride, calcium chloride, potassium chloride, magnesium sulfate, potassium sulfate, sodium carbonate, and sodium sulfate; organic acids, e.g., ascorbic acid, benzoic acid, fumaric acid, and citric acid; and sugars, e.g., mannitol, sucrose, sorbitol, xylitol, lactose, dextrose, and trehalose.
The term “acidifying agents,” as used herein, are acidic substances which help in solubilizing the drug by creating an acidic microenvironment. Suitable acidifying agents are organic acids selected from the group comprising citric acid, fumaric acid, tartaric acid, succinic acid, malic acid, glutamic acid, and aspartic acid hydrates and acid salts thereof. Preferably, suitable acids are citric acid, fumaric acid, tartaric acid, and succinic acid. The acids may be used alone or in combinations thereof.
Suitable surfactants are selected from the group comprising polyoxyethylene sorbitan monooleate (Tween® 80), sodium lauryl sulphate, sorbitan monolaurate, sorbitan trioleate, polyoxyethylene sorbital, sorbitan tristearate, polyoxyethylene sorbital hexastearate, ethylene glycol fatty acid esters, propylene glycol fatty acid esters, propylene glycol monostearate, glycerol monostearate, and sorbitan monooleate. Preferably, suitable surfactants are polyoxyethylene sorbitan monooleate (Tween® 80) and sodium lauryl sulphate.
Suitable disintegrants are selected from the group comprising croscarmellose sodium, hydroxypropyl cellulose (L-HPC), crospovidone, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, sodium starch glycolate, gums, alginic acid or alginates, pregelatinized starch, corn starch, modified starch, carboxymethyl starch, polyacrylates, and combinations thereof.
Suitable glidants are selected from the group comprising magnesium stearate, stearic acid, calcium stearate, colloidal silicon dioxide, starch, talc, and combinations thereof.
Suitable lubricants are selected from the group comprising magnesium stearate, talc, and silica.
The term “osmotic tablet,” as used herein, includes an osmotic release oral system in the form of a tablet as known in the art. The osmotic tablet comprises a semipermeable membrane which may optionally comprise one or more laser drilled openings. The tablets can also be drilled manually. The term “semipermeable,” as used herein, includes a membrane through which water readily diffuses through the means of a membrane, but solutes dissolved in water typically cannot readily diffuse through the membrane. As the tablet passes through the body, the osmotic pressure of water entering the tablet pushes the drug through the opening(s) in the semipermeable membrane.
The term “single core osmotic tablet,” as used herein, includes an osmotic delivery system as known in the art. The single core osmotic tablets comprise a compressed core containing an osmotically effective composition surrounded by a semipermeable membrane.
The term “bilayer osmotic tablet,” as used herein, includes an osmotic delivery system in the form of a tablet comprising two adjacent layers, (i) a drug layer comprising the drug and a water soluble polymer, and (ii) a push layer or water swelling layer which comprises water swellable polymers and/or osmogens. The push layer does not contain the drug. The bilayer tablet is surrounded by a semipermeable membrane which comprises one or more laser drilled openings.
The term “sustained release matrix tablet,” as used herein, refers to a sustained release tablet which has a matrix system comprising of a release controlling polymer which sustains tofacitinib release.
The term “sustained release reservoir tablet,” as used herein, refers to a sustained release tablet comprising a coating of release controlling polymer imposed between a tofacitinib core and the elution medium. Drug release results from diffusion of the drug through the release controlling layer, permeation of the release controlling layer by water and/or erosion of the coating.
Suitable coating additives are selected from the group comprising pore formers, surfactants, plasticizers, anti-foaming agents, opacifiers, anti-tacking agents, coloring agents, coating solvents, and combinations thereof.
The term “pore former,” as used herein, may include the materials incorporated in a pharmaceutical composition, particularly in the coating or in the matrix, for forming a micro-porous membrane or micro-porous matrix. The micro-porous membrane or micro-porous matrix may be formed in situ by a pore former by its leaching during the operation of the system. Suitable pore formers are selected from the group comprising water soluble polymers, e.g., hydroxypropyl methylcellulose (HPMC); hydroxyethyl cellulose (HEC); hydroxypropyl cellulose (HPC); polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; surfactant, e.g., sorbitan monolaurate, sorbitan trioleate, polyoxyethylene sorbital, sorbitan tristearate, polyoxyethylene sorbital hexastearate, ethylene glycol fatty acid ester, propylene glycol fatty acid ester, propylene glycol monostearate, glycerol monostearate, and sorbitan monooleate; alkaline metal salts, e.g., sodium chloride, sodium bromide, and potassium chloride; alkaline earth metals, e.g., calcium chloride and calcium nitrate; carbohydrates, e.g., sucrose, glucose, fructose, mannose, lactose, sorbitol, and mannitol; and diols and polyols.
Suitable surfactants are selected from the group comprising sorbitan monolaurate, sorbitan trioleate, polyoxyethylene sorbital, sorbitan tristearate, polyoxyethylene sorbital hexastearate, ethylene glycol fatty acid ester, propylene glycol fatty acid ester, propylene glycol monostearate, glycerol monostearate, sorbitan monooleate, and combinations thereof.
Suitable plasticizers are selected from the group comprising triethyl citrate, dibutyl sebacate, acetylated triacetin, tributyl citrate, glyceryl tributyrate, monoglyceride, rapeseed oil, olive oil, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, glycerin, sorbitol, diethyloxalate, diethyl phthalate, diethyl malate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, and combinations thereof.
A suitable anti-foaming agent is simethicone. Simethicone imparts smoothness to the coating.
Suitable opacifiers are selected from the group comprising titanium dioxide, manganese dioxide, iron oxide, silicon dioxide, and combinations thereof.
Suitable anti-tacking agents are selected from the group comprising talc, magnesium stearate, calcium stearate, stearic acid, silica, glyceryl monostearate, and combinations thereof.
Suitable coloring agents are selected from the group consisting of FD&C (Federal Food, Drug and Cosmetic Act) approved coloring agents; natural coloring agents; pigments, e.g. iron oxide, titanium dioxide, and zinc oxide; and combinations thereof.
Suitable coating solvents used for forming a solution or suspension for coating are selected from the group comprising water, ethanol, methylene chloride, isopropyl alcohol, acetone, methanol, and combinations thereof.
The “in-vitro release profile” of the pharmaceutical compositions of the present invention is the release profile obtained when dissolution testing was performed for tablets in USP type 2 apparatus at 50 r.p.m. in (i) pH 6.8 phosphate buffer/900 mL or (ii) 0.1N HCl/900 mL at 37° C.
The invention is further illustrated by the following examples, which are for illustrative purposes only and should not be construed as limiting the scope of the invention in anyway.
10. Tofacitinib citrate and talc and were added into water and homogenized. Eudragit® E PO was successively added to the dispersion under stirring, and then stirred for 1 hour.
11. The tablets of step 8 or step 9 were coated using the dispersion of step 10.
12. The tablets of step 11 were dried in a coating pan at 40° C. for 2 hours.
Drug Layer
Push Layer
Compression
Coating
Drug Layer
Push Layer
Compression
Coating
Drug Layer
Push Layer
Compression
Coating
Drug Layer
Push Layer
Compression
Coating
In-vitro dissolution testing was performed for tablets prepared according to Examples 1 to 2 in USP type 2 apparatus at 50 r.p.m. in pH 6.8 phosphate buffer/900 mL (Example 1(a), Example 1(f), Example 1(i), and Example 2(a)) and 0.1N HCl/900 mL (Example 2(a)) at 37° C. The results are presented in Table 1 below.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2560/DEL/2015 | Aug 2015 | IN | national |
| 4146/DEL/2015 | Dec 2015 | IN | national |
